Published using Google Docs
Hydrogen Cancer Control
Updated automatically every 5 minutes

Content Introduction

This is a groundbreaking, almost revolutionary, exploratory work. Using hydrogen to control cancer and prolong patients' lives represents a completely new concept and technology. As the oldest and most abundant natural energy in the celestial bodies, using hydrogen to benefit humanity is a manifestation of "harmony between heaven and man." As a physiological energy constantly generated within the human body, hydrogen maintains health, a manifestation of "following the laws of nature."

This book perfectly integrates theory and practice, each enhancing the other. Starting with the development of hydrogen molecular biology and hydrogen medicine, it discusses how hydrogen can maintain health, then introduces the scientific basis for hydrogen cancer control. It then presents experimental evidence, "real-world" case studies, typical cases, and vivid and moving stories of hydrogen cancer control. Finally, it presents the objective observations and descriptions of a journalist with a "third eye." This book is ingeniously crafted, with each layer tightly linked and seamlessly written, making it a captivating read, offering endless benefits for both health and well-being.

In particular, the "real world" stories in this book, real people and real events, real feelings and real emotions, are permeated with scientific elements, demonstrating the use of art to benefit the world and witnessing the power of life.

This book has been highly praised by leading figures in my country. Academician Wu Mengchao, the "Father of Hepatobiliary Surgery," Academician Wang Zhenyi, the pioneer of "tumor-induced differentiation," Academician Tang Zhaoyou, the founder of small liver cancer research, and Academician Zhong Nanshan, the renowned respiratory disease expert known for his "more of a warrior" approach, have all reviewed the theoretical basis, practicality, and feasibility of hydrogen cancer control from diverse perspectives, offering heartfelt and valuable support for this emerging technology.

This book is a labor of love. Chief Editor Professor Xu Kecheng is a renowned oncologist in my country. His life-saving deeds have been widely publicized both domestically and internationally, touching countless patients. He now devotes his heart and soul to the research and practice of hydrogen cancer control, reflecting his sentiment of "old swaying new green, and secluded flowers flourishing in late spring." The three co-editors, Professors Lü Youyong, Wu Hong, and Shi Jianguo, as well as Professors Wang Xiaoning and Yin Zhinan, who wrote the book's preface with sincerity and candor, are all renowned scholars and clinical practitioners in my country's medical field. Breaking away from tradition, they bravely embrace and research emerging disciplines, demonstrating a spirit of continuously expanding their thinking and keeping pace with the times. Chief Editor Professor Sun Xuejun is a pioneering expert in hydrogen molecular biology and hydrogen medicine in my country. His enthusiastic praise and support for the "later" development of hydrogen cancer control is a major highlight of this book.

We thank the author for his trust. We are honored to have the privilege of publishing this book. We sincerely recommend it to our readers.

Yangcheng Evening News Publishing House

May 2019

Editor's Note

Why did you edit "Hydrogen Cancer Control: Theory and Practice"?

Why do people live? Perhaps only those who are facing death are most concerned about this question.

Exactly 13 years ago, I had one-third of my liver removed due to cancer. After waking from anesthesia, I insisted on seeing the removed left lobe. Within the reddish-brown liver tissue was a round, yellowish-white mass. Drawing on decades of experience studying the liver, I concluded it was a malignant tumor. Could I survive? Literature suggests the five-year survival rate for such patients is less than 5%.

At that time, I was over 60 years old, but the "happy" life I wanted to live seemed to have just begun! Moreover, I had not had time to fulfill the promise I made to my mother when I was a child.

Nobel Prize winner Kapitsa said, "The starting point for developing one's outlook on life is kindergarten." My "kindergarten" was the smoke-filled battlefields of the 1940s. I will always remember that it was a "good man" at the time who shielded me from enemy bullets. Ever since I can remember, my mother often told me, "It was the villagers who saved you and our family. When you grow up, you must do good things for the people." As I was just beginning to understand things, I promised her this in her arms. Forty-seven years ago, my mother passed away from liver cancer. In her final moments, she held my hand tightly and told me intermittently, "You are a doctor. You must take good care of your patients..."

For decades, whenever I encountered a critically ill patient, especially one in dire straits, I could vaguely hear my mother's instructions, and the image of the "good man" who shielded and saved me would come to mind...

When I became a fellow cancer sufferer, I suddenly realized that as a doctor and a patient, doing good deeds meant sharing the same fate with my fellow cancer patients. I wanted to enjoy life myself while also helping them live beautiful lives together.

Nobel laureate Bertrand Russell said: “The trouble with the world is that smart people are full of doubts, and stupid people are full of"I firmly believe in it." The WHO declares: "Let cancer become a controllable chronic disease." To achieve this goal, we need to question the existing and explore the unknown "real world." "Treatments" aimed at eliminating cancer are only the first step to success; long-term survival is the ultimate goal. Recovery after "treatment" is a lifelong task for me and my fellow cancer patients. In short: it requires lifelong "care"!

I proposed the "ABC" principles of cancer rehabilitation, namely effectiveness (A, Applicable), simplicity (B, Brief) and affordability (C, Cheap).

Following this principle, I have been searching and exploring for several years and finally found "hydrogen medicine".

Studying a vast amount of basic and experimental research literature convinced me; experiencing hydrogen myself filled me with gratitude; and visiting nearly every cancer patient who inhaled hydrogen at home thrilled me...

So, I teamed up with relevant experts to edit the book "Hydrogen Cancer Control - Theory and Practice"!

Nobel Prize winner Erwin Schrödinger said: "Our task is not to discover something that no one else has discovered, but to think about things that everyone sees that have never been thought of before." The purpose of editing this book is to make hydrogen or hydrogen molecules, this natural gas, also a physiological gas,

Through our observation, experience, investigation, and description, and through further reflection and research, we have transformed “ordinary” things “seen by everyone” into “non-drug medicines” for maintaining health and controlling cancer!

For cancer patients, including me, we look forward to enjoying health and happiness from "hydrogen", "living like the splendor of summer flowers and dying like the tranquility and beauty of autumn leaves".

This book positions "hydrogen cancer control" as a "recovery" approach, not a "treatment." Whether it can be used as a "treatment" requires following established procedures, testing, and assessment. Currently, in the entire process of "treating" cancer, hydrogen is not the "main force," but rather a "supporting force." It doesn't "occupy the stage," but rather "protects it." It doesn't "disrupt it," but rather "adds to it." Within the concept of "comprehensive health," hydrogen plays a role in comprehensively protecting the entire life process.

After this book was published, it was inevitable that there would be doubts. In fact, I have been questioning myself. One of the fundamental attitudes of science is questioning, and one of its most basic spirits is criticism.

Sincerely welcome more questions and criticisms!

Back to the original question: Why do people live? I was inspired by a short poem on the Internet -

Pick up the pen of hope

Write a eulogy for yesterday

Put an end to today

Color tomorrow

This is also my original intention in editing "Hydrogen Cancer Control - Theory and Practice".

Xu Bing Line

March 2019

Commentary

Hydrogen controls cancer: I'm convinced

Tang Zhaoyou: Academician of the Chinese Academy of Engineering, professor, renowned oncologist, and founder of small hepatocellular carcinoma research. He received the Ho Leung Ho Lee Foundation Science and Technology Progress Award in 1995, the Wu Jieping Medical Award in 2008, and was awarded the "Lifetime Honorary Professor" certificate by Zhongshan Hospital, Fudan University, in 2018.

I am approaching 90 years old and would like to have some quiet time. Unexpectedly, Professor Xu Kecheng asked me to write a preface for his upcoming book "Hydrogen Control of Cancer - Theory and Practice". I gladly took up the task because I firmly believe that "practice is the only criterion for testing truth."

When Professor Xu showed me the first case study of hydrogen cancer control, I was skeptical. But after seeing nearly 50 cases, I was convinced. The cancer was clearly diagnosed, and all treatments had been exhausted, yet it remained difficult to control. Yet, after months of hydrogen inhalation, the tumor remained, yet the patient returned to a normal life, like a completely different person. This is why I'm convinced that hydrogen has a certain cancer-control effect.

At the 2018 National Cancer Conference, I gave a speech titled "The Battle Against Cancer Focuses on Six Integrations." It now appears that these six integrations correspond to "hydrogen cancer control." The first is the integration of "elimination and transformation strategies." Hydrogen inhalation may not directly kill cancer cells, but rather "transforms" them. The second is the integration of "individual combat and comprehensive treatment." While hydrogen inhalation alone may not cure cancer, just as exercise helps control cancer, exercise alone is not enough; treatment to eliminate the tumor is also necessary. The third is the integration of "rapid victory" and "long-term strategy." While tumor elimination therapies (surgery, radiotherapy, chemotherapy, and most molecular targeted therapies) often have immediate effects, hydrogen inhalation often requires several hours daily and often takes months to show results. The fourth is the integration of "passive treatment and active participation." Cancer treatment is often "administered" by doctors, while hydrogen inhalation involves active patient participation, requiring confidence and perseverance. The fifth is the integration of "high-tech, precision, and innovation" with "fast, good, and economical." According to foreign reports, some molecular targeted therapies cost approximately $150,000 (approximately 1 million RMB) per year. Hydrogen inhalation clearly represents a fast, good, and economical approach. Given China's national conditions, fast, good, and economical approaches are indispensable. The sixth is the integration of "using foreign ideas for Chinese benefit" and "integrating Chinese thinking." We should learn from Western methods of combating cancer and adapt them to our national conditions. However, to surpass them, we need to incorporate Chinese thinking. Lao Tzu famously said, "The highest good is like water," and "Water benefits all things without contending." Coincidentally, hydrogen is generated through the electrolysis of water. Perhaps the underlying Chinese thinking behind this is "using softness to overcome hardness."

Admittedly, any new thing raises a lot of questions. Initially, I wondered whether it was hydrogen or oxygen that was responsible (water electrolysis produces two parts hydrogen and one part oxygen); whether hydrogen inhalation would be effective for all cancers; what was its effectiveness rate; what was the mechanism of hydrogen inhalation's effectiveness; whether there were any side effects; and what were the long-term effects of hydrogen inhalation? After reading this book, I realized that some of these answers already exist, but many are still under research. Let's wait and see.

In fact, hydrogen treatment for cancer was reported in the leading journal Science in 1975, and its antioxidant effects were reported in Nature Medicine in 2007. However, these discoveries have not garnered widespread attention. It's not uncommon for major discoveries to slip by due to neglect of fortuitous events. This may be related to the belief that the only correct approach to combating cancer is to eliminate it. The strategy for combating cancer requires a conceptual refresh. Cancer is an internal disturbance within the body, unlike infectious diseases, which are "foreign invasions." Simply eliminating it isn't enough; it requires transformation. Isn't the key to the publication of "Hydrogen Cancer Control: Theory and Practice" precisely because it shifts the focus from "killing cancer" to "controlling cancer"?

For this reason, I solemnly recommend the publication of this book. I believe it will benefit cancer patients and provide some inspiration to doctors.

Tang Zhaoyou

March 2019

Academician Comments 1

Hydrogen cancer control: a disruptive exploration of tumor rehabilitation

Wu Mengchao: Academician of the Chinese Academy of Sciences, professor, renowned liver surgeon, and one of the founders of hepatobiliary surgery in China. Recipient of the 2005 National Highest Science and Technology Award, he was awarded the Asteroid Naming Certificate and the Asteroid Orbit Bronze Medal in 2011.

On the eve of the 2019 Spring Festival, Professor Xu Kecheng handed me a stack of drafts for his book, "Hydrogen Control of Cancer: Theory and Practice." I immediately noticed it was "control cancer," not "fight cancer." The difference in meaning is profound! "Control" is a brilliant choice! Having spent a lifetime in surgery, my biggest lesson is that simply killing or fighting cancer isn't enough; you must control it, keeping cancer cells "behaved," "behaved," and "reformed." As Professor Xu Kecheng wrote in his book, "Coexisting with Cancer," "Keeping patients alive and happy is the bottom line." Hydrogen may indeed help achieve this goal.

As early as 1975, the American journal Science published an article reporting that high-pressure hydrogen could inhibit cutaneous squamous cell carcinoma. In 2007, Nature Medicine published a study showing that low-concentration hydrogen inhalation could improve cerebral ischemia-reperfusion injury and exhibit selective antioxidant effects. Our Naval Medical University (Second Military Medical University) was the first in China to conduct research on hydrogen molecular biology. Professor Sun Xuejun of our Naval Medical Department, who specializes in diving illness and hyperbaric medicine, was the first to publish an internationally recognized academic paper on hydrogen medicine in 2008. In 2013, he edited and published the first Chinese monograph on hydrogen molecular biology in China. In 2015, he published the English edition of hydrogen molecular biomedicine, which systematically outlined the main mechanisms and research progress of hydrogen treatment for diseases. Many other scholars at our university have also participated in hydrogen medical research, contributing to the establishment and development of Chinese medicine.

Professor Xu Kecheng is the first expert in my country to clinically study hydrogen cancer control. He and his team have followed a large number of cancer patients who have recovered at home through hydrogen inhalation. These patients were primarily those who had lost surgery, had relapsed after surgery, or had failed chemotherapy or radiotherapy (including molecular targeted therapy). However, after prolonged hydrogen inhalation (primarily a hydrogen-oxygen mixture), not only did their symptoms (sleep, appetite, and fatigue) improve significantly, but many also experienced a decrease or stabilization of their tumor markers. In some cases, their tumors shrank or stabilized. This is a remarkable and innovative exploration. The results of some of these cases are truly encouraging.

The mechanism by which hydrogen inhibits cancer is still unclear, but it primarily involves modifying the microenvironment, inhibiting the growth, proliferation, motility, and invasion of cancer cells. I was particularly interested in an article in this book titled "Transforming Cancer Cells: The Intimate Contact Between Hydrogen and Cancer Cells," which suggests that hydrogen may transform cancer cells, turning them from bad to good. Another article, written by Japanese researchers, suggests that hydrogen can restore exhausted cytotoxic T cells by improving mitochondrial function. These are innovative findings worthy of further research.

The authors of this book, many of them renowned experts from prestigious universities and hospitals, demonstrate the widespread attention being paid to the topic of "hydrogen cancer control." my country's research in hydrogen molecular biology and hydrogen medicine has made a strong start and is already at the forefront of the world in many areas. We must firmly maintain confidence in our theories, our path, and our institutions, as well as our culture. We must seize opportunities, diligently research, and implement them. I believe that as science, and especially hydrogen energy, become strategic projects for national development, hydrogen medicine will undoubtedly enjoy a promising future.

Professor Xu Kecheng and I have been friends for over 40 years. I am now in my twilight years, and he is in his 80s. We share a common philosophy: not to be the best, but to be among the best. As doctors, we seek not financial rewards, but the happiness and gratitude of our patients. To explore the use of hydrogen in cancer control, Professor Xu has traveled thousands of miles, spending his own money, visiting patients' homes, providing warmth and providing real data. This spirit is truly invaluable and worthy of emulation by future generations. It has also moved me, and I must carefully read and study this new book written by "truth." Cancer is a systemic, chronic disease that can be controlled. Surgery and radiotherapy are the mainstays of local tumor elimination. Chemotherapy, a systemic treatment, is not designed for rehabilitation, but rather for its toxicity and eventual drug resistance. Hydrogen's high safety, its effects on cancer cells and various body systems, and its ease of use make it suitable for long-term, even lifelong, use. This is a revolutionary exploration in cancer rehabilitation.

This book is the first monograph on hydrogen and cancer. As with anything that's "first," there are bound to be flaws. I sincerely hope that our academic community will adopt a supportive and tolerant attitude, offering assistance, corrections, and improvements. This is also the wish that the editor-in-chief of this book hopes I can convey.

I congratulate the publication of this book and hope that its publication will promote the research and development of hydrogen medicine.

February 20, 2017

Academician Commentary 2

Hydrogen cancer control: an innovative topic in tumor rehabilitation

Wang Zhenyi: Academician of the Chinese Academy of Engineering, professor, foreign member of the French Academy of Sciences, internal medicine hematologist, one of the pioneers of thrombosis and hemostasis in China, known as the "Father of Cancer-Induced Differentiation." He received the 2010 National Highest Science and Technology Award, and the International Astronomical Union designated asteroid 43259 "Wang Zhenyi Star" permanently.

I often say that cancer treatment shouldn't be so complicated, let alone so painful. After reading the draft of Professor Xu Kecheng's new book, "Hydrogen Cancer Control: Theory and Practice," I'm delighted. Perhaps my hope could become a reality, at least for certain tumors, or at certain stages of cancer treatment.

Hydrogen, a naturally occurring gas, was reported by American researchers over 40 years ago to have an inhibitory effect on cancer cells. Although published in the prestigious journal Science, this report received little attention. This may be because "hydrogen" is too simple and commonplace, as if something so ordinary could hardly be considered high-brow. In the 1990s, a middle school teacher in Shandong, my country, proposed that hydrogen could have antioxidant and anti-inflammatory properties and predicted its ability to inhibit cancer. His ideas and research were published in a university journal in 1999. Perhaps because the author wasn't a prominent figure, his work was quickly forgotten and received no significant support. This is undoubtedly a historical regret.

Professor Xu Kecheng, the editor-in-chief of the book "Hydrogen Control of Cancer: Theory and Practice," documents the visits he and his team have made to cancer patients undergoing home hydrogen inhalation. Cancer by Cancer has successfully treated many of the most challenging cancer patients. Most patients, despite being unable to respond to conventional treatment, have experienced significant improvement and survival with this seemingly simple treatment. Some may argue that this isn't evidence-based medical research, but the patients have survived, some enjoying a high quality of life, "coexisting with cancer." We cannot ignore the "real-world" facts documented in this book.

I once wrote the preface for Professor Xu Kecheng's book "Living with Cancer." At the time, I said I felt I could and should write about it, because Professor Xu always approached the most challenging issues from the perspective of morality and the universe. I remember meeting him again over 20 years ago after an absence of over 20 years. When I learned that he had undergone surgery for liver cancer a few years prior, I told him that cancer treatment shouldn't just focus on the local tumor; it must be based on systemic control and the courage to innovate. He was incredibly insightful, focusing on strategies and methods, diligently researching cancer recovery, and proposing that "the ultimate truth in cancer treatment is patient survival." He said this was for both his patients and himself. He achieved success, both in himself and in treating many of the most challenging cancer patients.

"The truth is simple, but knowing is easy, practicing is difficult." I admire Professor Xu Kecheng's "ABC principle" for cancer treatment: Applicable (A), Brief (B), and Cheap (C). Hydrogen cancer control aligns with this ABC principle.

Although this is a new topic, it is an innovative topic that is particularly worth exploring.

I am pleased to recommend "Hydrogen Cancer Control - Theory and Practice" to readers, and I hope that our professionals will be inspired by this book to further study this very young field of hydrogen medicine.

Wang Zhenyi

2019.2.1

Academician Commentary 3

Commendable "real world" exploration

Zhong Nanshan: Academician of the Chinese Academy of Engineering, professor, renowned respiratory disease expert, honorary doctorate from the University of Edinburgh, UK, and director of the State Key Laboratory of Respiratory Diseases. In 2003, he received the Ho Leung Ho Lee Science and Technology Award. In 2009, he was named one of the "100 People Who Moved China Since the Founding of the People's Republic of China." In 2018, he was awarded the title of "Comrade Zhong Nanshan Reform Pioneer" and the Reform Pioneer Medal by the CPC Central Committee and the State Council.

Hydrogen molecular medicine, also known as hydrogen medicine, is an emerging discipline. Molecular hydrogen has attracted widespread attention due to its strong antioxidant properties, particularly its high selectivity (neutralizing only toxic reactive oxygen free radicals), high diffusivity, and high safety.

For many years, antioxidants have been a hot topic, resulting in the development of numerous "antioxidant" drugs and health supplements, but generally speaking, they have not been very successful. This is because there are two types of free radicals in the body: physiological ones that play a role in metabolism; and toxic ones that cause oxidative stress, tissue damage, and numerous diseases.

Common chest, lung, and heart diseases are often associated with oxidative stress. We conducted hydrogen inhalation experiments using a smoking-induced COPD mouse model and found that hydrogen molecules can reduce lung function decline, emphysema, inflammatory cell infiltration, small airway remodeling, and goblet cell proliferation in the tracheal epithelium, and downregulate the activation of inflammatory factors ERK1/2 and NK-KB. Based on this, we conducted clinical observations on chronic airway diseases and found that hydrogen inhalation improves acute exacerbations of chronic airway diseases and can quickly reduce shortness of breath. Currently, a randomized, double-blind, controlled, multicenter study of hydrogen inhalation is underway in China for three conditions: chronic obstructive pulmonary disease (COPD), including acute exacerbations, bronchial asthma, and bronchiectasis.

In fact, the use of gases to treat respiratory diseases has a history of decades. Initially, nitrogen and oxygen mixtures were used. Because nitrogen has a relatively small molecular weight and is inert, it can easily carry oxygen deep into the airways. Hydrogen, with its even smaller molecules, can reduce airway resistance more effectively than helium. More importantly, hydrogen's antioxidant properties make it a promising treatment for cancer. Could hydrogen delay resistance to targeted drugs and mitigate disease progression?

The development and progression of tumors are linked to chronic oxidative stress and inflammation. Oxidative stress triggers inflammation, and chronic inflammation in turn promotes the production of reactive oxygen species (ROS), exacerbating the oxidative stress response. Both oxidative stress and inflammation can cause nuclear DNA damage and gene mutations, or damage mitochondria, leading to abnormal energy metabolism. The accumulation of these abnormalities can promote tumor development and progression. Therefore, the use of hydrogen to control cancer has theoretical basis. Numerous experiments have demonstrated that hydrogen has an inhibitory effect on the growth, motility, and invasiveness of cancer cells.

Professor Xu Kecheng's book, "Hydrogen Cancer Control: Theory and Practice," reports on the follow-up results of nearly 100 cancer patients who inhaled hydrogen (66% hydrogen, 34% oxygen) at home. The book also presents numerous case studies demonstrating the beneficial effects of inhaling this hydrogen-oxygen mixture. Most of these patients were those who had been denied conventional treatment. After a period of inhalation, some experienced significant symptom improvement, while others remained stable. This is the first real-world exploration of this field and a commendable endeavor.

Cancer treatment is a global challenge. Regarding "hydrogen gas cancer control," I look forward to conducting more experimental research and translating it into clinical studies as soon as possible. Hydrogen gas inhalation can be used in at least the following areas:

First, as an adjuvant treatment for cancer. As this book explains, it's about "protecting" mainstream treatment, not "occupying" it; it's about "supporting," not "undermining." For example, in lung cancer, can hydrogen delay the development of resistance to targeted drugs and reduce the adverse effects of chemotherapy? Studies have shown that hydrogen can reduce chemotherapy side effects without compromising its therapeutic effectiveness.

Second, as an alternative cancer treatment, it is primarily used for patients who have failed various treatments or are unable to respond to conventional treatments. Some of the patients described in this book who have successfully undergone hydrogen inhalation therapy fall into this category. Research should focus on several cancer types, conducting "real-world evidence" (RWE) or randomized controlled trials examining hydrogen dosage, administration method, and optimal duration or duration of treatment.

Third, it can be used for symptomatic treatment. While not unique to cancer, sleep, appetite, fatigue, and pain are major issues for cancer patients. Given that hydrogen has positive effects on all body systems, using it to improve overall well-being is a good strategy.

Fourth, it's used to "treat before illness occurs." This includes cancer prevention, moving cancer treatment forward, particularly for those in "high-risk groups," such as those with a family history of the disease, long-term smokers, or those working in polluted environments. It also includes those who have received effective treatment to prevent recurrence (third-level prevention). The "home rehabilitation" approach proposed in this book aligns with the concept of "comprehensive health."

While congratulating the publication of "Hydrogen Cancer Control - Theory and Practice", the above opinions are put forward as a starting point for reference by colleagues.

Zhong Nanshan

Guangzhou, February 2019

The judge's words

People cannot live without oxygen, and people cannot live well without hydrogen.

Sun Xuejun: Professor and doctoral supervisor at the Naval Medical University, he is one of the pioneers of hydrogen medicine research in my country. He has published over 260 academic papers, including 148 indexed by the SCI. He has edited the Chinese and English editions of Hydrogen Molecular Biology. He serves as chairman of the Hydrogen Molecular Biomedicine Branch of the Chinese Medical Association, adjunct professor at Shanghai Jiao Tong University and Xi'an Jiaotong University, and associate editor of the journal Medical Gas Research. He pioneered international research using hydrogen saline solution to treat various diseases.

I am very happy and excited that the book "Hydrogen Cancer Control - Theory and Practice" edited by Professor Xu Kecheng is about to be published, because this is a milestone event in the field of hydrogen biomedicine.

In 2007, at the Second Military Medical University, I initiated the first systematic research on hydrogen medicine in China. From studying the cellular biological effects of hydrogen, studying animal disease models, and conducting case studies to human clinical trials, I continuously challenged conventional medical concepts. Despite my persistent efforts in researching and promoting hydrogen medicine, I have achieved limited success. Professor Xu, a widely respected expert in frontline clinical medicine, is excited to hear that his new book will herald the clinical application of hydrogen medicine and open up a new landscape for clinical medicine. Professor Xu has invited me to serve as the lead editor for his new book, and I am grateful and glad to accept. This will be a new impetus for me to further pursue hydrogen medicine research and popularization.

Extensive research in diving medicine has long confirmed the extreme safety of hydrogen for the human body, but its potential therapeutic effects have been overlooked. A 2007 study by Japanese scholar Shigeo Ohta suggested that trace amounts of hydrogen could have therapeutic effects. As a well-established, potentially therapeutic, and most commonly studied form of hydrogen, its potential for application and research is enormous. This quickly became a consensus, as evidenced by the rapid international attention paid to hydrogen biomedicine. Hydrogen has been found to not only possess selective antioxidant properties but also to alleviate inflammation and influence cell apoptosis. Numerous researchers have conducted bold experiments and studies across a wide range of diseases and conditions, finding that hydrogen possesses unique benefits in preventing and controlling chronic metabolic diseases such as arteriosclerosis and intractable skin conditions such as psoriasis. While relatively limited compared to other fields, research on hydrogen applications in cancer prevention and treatment is highly groundbreaking. Evidence suggests that hydrogen can prevent the toxic side effects of radiation and chemotherapy without compromising efficacy, and can significantly improve the quality of life of cancer patients.

Cancer treatment presents a challenging and challenging issue in contemporary medicine. While classic therapies such as surgery, radiotherapy, and chemotherapy exist, these are virtually ineffective for most advanced cancers. Professor Xu's long-standing advocacy and personal practice of "Chinese-style cancer control" have contributed Chinese wisdom to this international medical dilemma, yielding fruitful results. Recently, Professor Xu compiled clinical data from numerous patients who have successfully used hydrogen therapy for cancer. Significantly, he personally visited and verified each patient's success. Combining his years of clinical experience with evidence-based medicine's rationale, he objectively analyzed the data and concluded that hydrogen inhalation is effective for advanced cancer, highly safe, and valuable in improving patient survival and quality of life. Particularly valuable, renowned oncologist Academician Tang Zhaoyou provided commentary on each case that Professor Xu followed. Academician Tang and Professor Xu clearly proposed hydrogen therapy as a viable approach to Chinese-style cancer control, significantly advancing basic and clinical research on hydrogen therapy for the treatment and adjuvant treatment of cancer patients. The forthcoming book will primarily present these research findings. Professor Xu's pioneering work has not only brought new hope to many cancer patients but also served as a gentle springboard for the development of hydrogen medicine.

While there are over 1,000 international medical academic papers, there are only a little over 50 clinical research papers. This demonstrates the numerous bottlenecks and challenges facing the clinical application of hydrogen medicine. Professor Xu's new book adds further clinical evidence and provides numerous insights into basic research in hydrogen medicine, which will undoubtedly boost enthusiasm for medical research. The book will also provide first-hand, objective material for a precise understanding of the medical value of hydrogen, and is both highly scholarly and readable. As a humble scholar in hydrogen medicine research, I sincerely thank and admire Professor Xu for his significant academic contributions to hydrogen medicine.

"Without oxygen, people can't live; without hydrogen, people can't live well." This casual remark I made during a 2016 CCTV interview embodies the hallmarks of hydrogen medicine. Hydrogen has biomedical applications, but its status is far inferior to that of oxygen. I'm using this quote again as a title, hoping to convey this message to the hydrogen health industry and the general public: Hydrogen medicine is amazing, but it's definitely not a panacea. To fully realize the safe and effective value of hydrogen, we must be realistic and avoid exaggeration or misleading claims. Only truth can withstand scrutiny and possess vitality.

Sun Xuejun

Shanghai, March 1, 2019

Prologue

Hydrogen cancer control: a new health civilization

Wang Xiaoning: Professor, Director of the PLA General Hospital and the PLA Institute of Geriatrics, Vice President of the Chinese Society of Immunology, Chairman of the China Alliance of Geriatrics Institutions, Secretary-General of the China Association for Science and Technology Life Science Societies Federation, and a senior expert in the Ministry of Science and Technology's 863 and 973 Programs. He is the founder of the Department of Biotechnology and Immunology at the former First Military Medical University. He pioneered the field of cell-in-cell research and has become a leading international scholar in this field.

In 2018, the China Association for Science and Technology's Life Sciences Societies Consortium commissioned me as Executive Secretary-General to coordinate the organization of the Second World Life Sciences Congress and to identify collaborative projects for the consortium's development. During this time, Professor You Yong of the Peking University Cancer Institute suggested collaborating with an institution working on hydrogen medicine. Since You Yong and I are both senior consultants in the field of population health under the "973 Program," and he is known for his rigor and meticulousness, when he began to explain hydrogen medicine, the thought of "another health supplement" flashed through my mind, and I listened intently to his brief overview of the progress of hydrogen medicine.

Ten days later, I met Mr. Lin Xinyong and Professor Xu Kecheng, the inventors of the medical hydrogen machine, in Beijing. I felt a sense of déjà vu the moment I met Professor Xu. He first took out his laptop and gave a clear overview of the development of hydrogen medicine, including its current mechanisms, safety, and scope of application. He also highlighted recent cases of advanced cancer patients he had followed up on through home hydrogen inhalation in Taipei, Shanghai, and Beijing, as well as at the Xu Kecheng Care Health Studio in Guangdong Province. I was deeply impressed. After inquiring about the development of Mr. Lin's medical hydrogen machine, I quickly came to the conclusion that hydrogen has been used as a diving pressurizer for over a century and is very safe. Although researchers had reported hydrogen's anti-cancer effects in the 1970s, it wasn't until 2007, when Japanese researchers published a paper in Nature Medicine demonstrating the effectiveness of hydrogen intervention in stroke treatment, that it attracted widespread attention from both the academic and medical communities. Previously commonly used hydrogen-rich water may have a dosage ceiling due to solubility limitations. However, Mr. Lin's "Mei Medical" company's hydrogen-oxygen atomizer solves this problem. This device has been initially validated in a double-blind clinical trial for chronic obstructive pulmonary disease (COPD) intervention. It has also received "National Innovation" designation and is currently applying for CFDA Class III medical device approval. It has the potential to become the world's first medical hydrogen machine, laying the foundation for further exploration of hydrogen's clinical applications. Currently, over a thousand published papers, both domestically and internationally, explore the medical and health benefits of hydrogen and its potential mechanisms, demonstrating its multiple biological effects.

After returning to Guangzhou, Professor Xu personally accompanied me on a tour of his studio. The studio was packed with cancer patients of all stages who had come for free hydrogen inhalation. Professor Xu enthusiastically took me through each patient's basic information. During this time, I was deeply impressed by the fact that several patients had come for hydrogen inhalation after reading Professor Tang Zhaoyou's evaluation of hydrogen medicine, with the common Chinese patient mentality of "just accepting it"—a determination to persevere until their tumors were completely eliminated. Professor Xu explained that hydrogen inhalation is only for supplemental use, and that he generally does not accept patients who have abandoned regular medical treatment. There was not a trace of marketing or promotional activity in the studio!

Professor Xu told me that he and Professor Lv Youyong are currently adopting a "real world evidence" (RWE) design plan to widely collect data on the effects of hydrogen inhalation on cancer patients, especially those in the advanced stage, to provide clues for further exploring the role of hydrogen in adjuvant tumor treatment.

On the plane back to Beijing, I finished reading Professor Xu's book, Living with Cancer. I learned that Professor Xu is a 13-year cholangiocarcinoma survivor, nearly 80 years old, a figure you wouldn't be able to tell from his appearance. Professor Xu's dedication to his work, his profound knowledge, and his deep love for his patients are evident throughout the book. Furthermore, the book includes numerous health and disease management concepts that were implemented in his early years and have only recently become popular, demonstrating its foresight. It's no wonder he still maintains a whirlwind of energy that even young people can't match! I later recommended this book to cancer patients close to me.

Professor Xu also gave me the manuscript of his new book, "Hydrogen Cancer Control: Theory and Practice," and asked me to write a preface. Seeing that the commentaries were all from the nation's top medical professionals, I felt a bit embarrassed. But I couldn't resist my curiosity and wanted to offer a preview.

What exactly is the mechanism underlying the health and medical benefits of hydrogen? Answering this question requires sophisticated in vitro and in vivo devices to confirm its biological effects, as well as methods to label hydrogen and determine where it goes and what it becomes. Fortunately, Professor Wei Youzhen of the Shanghai Oriental Hospital Experimental Center, a partner of "Mei Medical," has already done substantial work to answer this question. He has developed hydrogen chambers for in vitro and in vivo experiments with cells and animals, and has isolated pure tritium for tracing. Professor Gu Ning, a nanotechnology expert at Central South University, is willing to create a hydrogen nanobubble to explore the effects of its targeted release in vivo. Academician Cheng Heping of Peking University is also willing to build a more rigorous device to investigate the effects of hydrogen on mitochondrial function. I believe that more Chinese biologists will join the research on the physiological and medical effects of hydrogen. As time goes by, the mechanisms behind the vivid cases in Professor Xu's book will be gradually deciphered. Perhaps in the near future, China will usher in a true era of hydrogen medicine, ushering in a vast emerging health industry that will benefit both patients and humanity.

Civilization is born from water. Water is dissociated into oxygen and hydrogen, and hydrogen and oxygen are then reduced to water in the body. Hydrogen health is water health. In this sense, hydrogen cancer control is a new healthy civilization.

Wang Xiaoning

Beijing, February 2019

First two

Research on "Hydrogen Control of Cancer": A Demonstration of Noble Beliefs

Yin Zhinan graduated from Hubei Medical University in 1984 and received a master's degree in immunology from Shanghai Second Medical University in 1988. At the end of 1992, he went to the Italian National Cancer Center for advanced studies. Two years later, he transferred to the German Center for Rheumatology, led by immunologist Av. Mitchson, and three years later, he received his doctorate. In 1997, he began postdoctoral research in the Department of Rheumatology at Yale University School of Medicine. He was promoted to associate professor in 2006 and received the Yale Department of Medicine Research Achievement Award that same year. In March 2007, he was appointed Dean of the School of Life Sciences at Nankai University. He is a "Changjiang Scholar" Distinguished Professor, a national "High-level Returned Overseas Entrepreneurial Talent," and a "Young and Middle-aged Expert with Outstanding Contributions" in the National "Hundred, Thousand, and Ten Thousand" Talent Program. In July 2013, he was recruited to Jinan University to establish the Institute of Biomedical Translational Research and served as its Director. He has published 118 academic papers, including in top international journals such as Nature, Hepatology, and JEM.

Professor Xu Kecheng is a mentor I deeply respect. I had heard of his character and academic achievements back in the United States. After returning to Guangzhou, we hit it off immediately. My research is in immunology, and I desperately need clinical support and collaboration. Professor Xu, as a clinical doctoral supervisor at Jinan University, and we quickly became the best of partners. Recently, one of our papers on gdT cell therapy for liver cancer was published in a high-impact journal internationally. This is something I had longed for while at Yale University, a project I'd been working on for nearly a decade after returning to China. It's also the first report of its kind in the world. This groundbreaking research was accomplished with Professor Xu's support and collaboration. Whenever I present this research at academic conferences both domestically and internationally, I can't help but express my gratitude to Professor Xu.

In recent years, Professor Xu has been researching cancer rehabilitation, focusing on "hydrogen cancer control." I initially thought my expertise wasn't relevant to hydrogen molecules, and that this was a topic rarely explored by predecessors or others, so I didn't pay much attention. However, out of trust in Professor Xu, I remained a firm believer in his work. Then, by chance, I visited Professor Xu's studio and met some people who had experienced hydrogen inhalation. They all beamed, describing how they felt "refreshed," with increased appetites, increased energy, and improved sleep. Upon further investigation, I learned that most of them were cancer patients, many of whom were incurable with other treatments. After weeks or months of hydrogen inhalation, some had seen their tumor markers drop, even their tumors shrink. In one case, the brain metastases disappeared. Professor Xu's work is rigorous, and he keeps comprehensive records of all hydrogen inhalation experiences, which are made available to visitors.

While the results of these hydrogen experiences require further research, the patients' genuine experiences prompted me to consider deeper mechanisms. I hypothesize that the improvements experienced by patients after hydrogen inhalation are related to energy, and energy is linked to mitochondria. Hydrogen, as a selective antioxidant, can improve mitochondrial function. Evidence suggests that healthy mitochondrial function is associated with maintaining a healthy immune system, and that mitochondrial failure can lead to immune failure.

Recent research suggests that many cancers are closely linked to a weakened immune system, while others are more likely to be linked to a combination of immune system decline and multiple genetic mutations. This suggests that the key to cancer prevention may lie in the immune system, rather than genetic mutations. Chinese-American scientist Chen Lieping notes that cancer immunotherapy has undergone a paradigm shift, from immune enhancement (systemically boosting immune response activity) to immune normalization (selectively correcting immune deficiencies within the tumor microenvironment).

A study by Japanese researchers confirmed my hypothesis. The study found that cancer patients' PD-1-positive anti-CD8 T cells were in a state of exhaustion. After three months of hydrogen inhalation, these T cells turned PD-1-negative. The hydrogen "saved" the T cells, meaning it "normalized" the immune system.

This excited me immensely. Hydrogen seemed to open a new window into my lifelong research in immunology.

Science, especially natural science, is constantly seeking to understand the objective world, exploring new phenomena and new laws, and relentlessly pursuing truth. Hydrogen science is a very young discipline. Professor Xu Kecheng, at his octogenarian age, still remains vigorous and dedicated, starting from scratch to research the "real world" of hydrogen cancer control. This is an expression of his spirit and a manifestation of his lofty beliefs, worthy of admiration and emulation by future generations.

What I blame myself for is that Professors You Yong and Wang Xiaoning, renowned experts in my country's bio-immunology field, have long been fans of Professor Xu. Notable figures like Wu Mengchao, Wang Zhenyi, Tang Zhaoyou, and Academician Zhong Nanshan have also strongly supported Professor Xu's research on hydrogen cancer control, yet I hesitated for a long time. But "there will always be a time to ride the wind and waves, and set sail to cross the vast ocean." The past is not to be trifled with, but the future can be pursued. Not long ago, Professor Xu was appointed Lifetime Honorary Dean of the Institute of Biomedical Translational Research at Jinan University. I believe this marks the beginning of a new and higher-level collaboration between us.

I've reviewed the first draft of "Hydrogen Cancer Control: Theory and Practice" and am deeply impressed by the contributions of Professor Xu Kecheng and other experts at home and abroad. I've also learned a great deal from it. As a person of insight, I sincerely congratulate the publication of this book and hope that readers who carefully read and understand it will benefit from it.

Yin Zhinan

Guangzhou, March 2019

Preface

"Truth" is the soul of this book

Can hydrogen cure diseases? To quote Zhong Nanshan, an academician of the Chinese Academy of Engineering: "It's true!"

It is said that there are over 1,000 papers on hydrogen biology and hydrogen medicine, and we have read hundreds of them.

A Japanese scholar said that hydrogen is effective for 67 diseases or pathological conditions, while an American scholar said it is 170. Another American expert believes that hydrogen has a certain effect on the top ten causes of death in the United States, except for suicide and accidents. Their main basis is

Animal experiments and a small number of clinical observations.

But as to whether hydrogen can control cancer, only an article by Dole published in the American journal Science in 1975 clearly showed that hydrogen

Can cure cancer!

We were shocked: Is this true?

As clinicians and oncology researchers, it's crucial to see patients in person, understand their entire medical history and experiences, and gather a wide range of clinical evidence. We organized an investigative team and embarked on a "hydrogen tour," visiting over 20 cities domestically and internationally. We conducted retrospective interviews with cancer patients who had inhaled hydrogen at home over the past few years, and also conducted prospective observations in the studio with hundreds of patients who had volunteered to experience hydrogen inhalation. Particularly encouraging was the discovery that some patients with progressive cancers who had failed or were struggling with conventional treatment had experienced significant recovery after hydrogen inhalation, with some even experiencing "miraculous" results.

We found that hydrogen can control cancer, it's true!

Moved by the patients' joy, grateful for their courage to practice, and thankful for their selfless sharing, we, along with media professionals known as "third-eyes," have written down these "real-world" stories. This is the basic content of this book.

We sincerely thank the patients who accepted our interviews; they are our best teachers. With unwavering sincerity and unreservedness, they shared their experiences of various treatments and hydrogen inhalation, down to the smallest details, with a sense of gratitude and appreciation. They also provided a wide range of information, sharing experiences that inspired and filled the doctors with confidence.

We thank "everyone" for their guidance and encouragement——

We thank Academician Tang Zhaoyou, who advocated for the "Chinese-style cancer control" approach of combining "elimination" with "transformation." He identified "transformation" as a key strategy for long-term survival and proposed hydrogen as a means of "transformation." He emphasized that practice is the only criterion for testing truth. He stated, "In today's world of high-tech, seemingly accidental events like hydrogen inhalation shouldn't be overlooked." He excitedly stated, "When I saw my first case, I was skeptical. After seeing nearly 50 cases, I was convinced."

We would like to thank Academician Wu Mengchao, a renowned liver surgeon and recipient of the National Highest Science and Technology Award. He believes that "we must change the view that surgery is a panacea. For patients' long-term survival, simple and effective rehabilitation methods are necessary," and that "hydrogen may truly help patients achieve this goal." He calls hydrogen cancer control a "disruptive exploration of tumor rehabilitation."

We also want to thank Academician Wang Zhenyi, another recipient of the National Highest Science and Technology Award and a pioneer of "induced differentiation therapy" for cancer treatment. He has consistently advocated for less complex and less painful cancer treatment. He said, "After reading the first draft of 'Hydrogen Cancer Control: Theory and Practice,' I'm delighted. Perhaps my hopes will become a reality, at least for certain tumors or at certain stages of cancer treatment." He called hydrogen cancer control a "revolutionary topic in cancer rehabilitation."

We would like to thank Academician Zhong Nanshan, a famous respiratory disease expert. He was one of the first experts in my country to conduct clinical research on hydrogen medicine. It was he who "enlightened" us to study hydrogen cancer control and believed that this was "the first real-world exploration in this field and a commendable attempt."

We are grateful to the experts who first introduced hydrogen medicine to China and conducted remarkable basic research. Professor Sun Xuejun served as the lead editor of this book, and Professors Qin Shucun and Ma Xuemei contributed to the book. They described the publication of this book as a "milestone event," which is admittedly an exaggeration, but it is a great encouragement to us in our clinical research on hydrogen.

We would also like to thank the experts engaged in related research. Professor Wang Xiaoning, a renowned geriatric rehabilitation and immunology expert, and Professor Yin Zhinan, an immunology expert, generously wrote the preface for this book, demonstrating their strong interest in furthering research in hydrogen biology and hydrogen medicine.

This book does not refer to hydrogen inhalation (or other methods of hydrogen ingestion) as a "therapy." We envision that if conventional therapies such as surgery, chemotherapy (including molecularly targeted therapy), and radiotherapy are the "mainstays" of cancer treatment, then hydrogen inhalation can serve as a "backstop." Currently, hydrogen cannot "take over" these roles, but it can "supplement." For patients to survive, initial treatment is crucial, and proper rehabilitation is paramount. We do not want patients reading this book to abandon their "mainstay" treatments. Given hydrogen's high safety and ease of use, currently, classifying hydrogen as "post-treatment rehabilitation," "home rehabilitation," or "hydrogen health care" would be a more appropriate evaluation of this "natural" and "physiological energy" within the broader concept of health.

Research on hydrogen cancer control is just beginning, and there are many unknowns. Science itself is a process of constant questioning, constant rethinking, and gradual exploration of its true meaning. We welcome skepticism. However, medicine is a fusion of science, technology, and art. We prioritize "real-world research" to generate "real-world data," and ultimately, "real-world evidence."

Regardless, hydrogen can control cancer; this is a real fact. "Truth" is the soul of this book!

This book is merely a starting point, and its content and perspectives certainly have many flaws. I simply hope that its publication will serve as a starting point to inspire more researchers to enter the emerging field of oncology. I also hope that readers, especially researchers in hydrogen molecular biology and hydrogen medicine, will criticize and correct me.

Editor-in-Chief: Xu Kecheng

Co-Editors: Lü Youyong, Wu Peihong, Shi Jianguo

May 2019

Table of contents

Chapter 1 History and Overview of Hydrogen Medicine
002 Research History of the Biological Effects of Hydrogen and Its Medical Significance

009 Hydrogen: A new approach to preventing illness before it occurs and treating different diseases with the same method

033 Chinese cancer control and hydrogen cancer control

Chapter 2 Scientific Basis of Hydrogen Cancer Control
042 Hydrogen molecules are antioxidant and anti-inflammatory

051 Hydrogen molecules maintain mitochondrial function and stability

058 Hydrogen molecules "save" T cells and regulate immunity

063 Transforming cancer cells: "Intimate contact" between hydrogen and cancer cells

065 Hydrogen molecules’ effects on scavenging reactive oxygen species and preventing and treating tumors

071 Thinking about “Qi Circulating Blood” and Hydrogen Ion Transfer

Chapter 3 Experimental Research
080 Experimental Study on Hydrogen Cancer Control

085 Experimental study on the inhibition of lung cancer by hydrogen in cellular and animal models

090 Experimental study on the inhibition of ovarian cancer by hydrogen

Chapter 4 Case Studies

096 A "real world" investigation of hydrogen cancer control: a follow-up report of 82 patients with progressive cancer who received hydrogen inhalation

112 The “Real World” of Hydrogen Cancer Control: Case Studies and Comments

Chapter 5: The “Real World” Story of Hydrogen Controlling Cancer
130 Hydrogen and “Cancer Suffering”: Relieving Bitterness and Condensing Joy

136 Hydrogen and Lung Cancer: A Wasted Surgery

141 Hydrogen and Lung Cancer: Survive

144 Hydrogen and Lung Cancer Bone Metastasis: Surviving the Cold

148 Hydrogen and Lung Cancer Brain Metastasis: "Ten Times Better"

153 Hydrogen and Lung Cancer with Brain Metastasis: Farewell to Suffering

159 Hydrogen and Liver Cancer: Unexpected

163 Hydrogen and Cholangiocarcinoma: "From the Death of a Clam to a Pearl"

168 Hydrogen and Colorectal Cancer: Infinite Relief

173 Hydrogen and Ovarian Cancer: Initial Elimination of “Pre-disease”

178 Hydrogen and Esophageal Cancer: Testing Hydrogen on Yourself

181 Hydrogen and Gastric Cancer: Live Freely

185 Hydrogen and Thymic Cancer: Conquered by Hydrogen

189 Hydrogen and Pancreatic Cancer: Daren Miracle (I)

194 Hydrogen and Pancreatic Cancer: Daren Miracle (Part 2)

199 Hydrogen and Pancreatic Cancer: Daren Miracle (Part 3)

204 Hydrogen "protects" the lungs: escort

Chapter 6: "Third Eye" View of Hydrogen Cancer Control

212 Surprise! Her cancer relapsed with multiple metastases, and after inhaling hydrogen for a month, all indicators were normal.

216 "Hydrogen Inhaler Sister" Controls Cancer Easily, Walking 20,000 Steps a Day Without Feeling Tired

218 Luck or Qi? Another ovarian cancer patient's indicators returned to normal after hydrogen inhalation

221 How to improve the sequelae of radiotherapy? A nasopharyngeal cancer patient tells you - hydrogen inhalation!

223 His metastatic tumor actually shrank. He said it was thanks to hydrogen.

225 23-year cancer warriors found a new magic weapon to control cancer

227 Hydrogen's Power? Brain Metastasis Miraculously Disappeared...

229 Because of hydrogen, she entered the rehabilitation sports meeting for the first time

231 Almost a revolutionary discovery! A patient with advanced gallbladder cancer was “revived” due to a tiny amount of “hydrogen”

235 Hydrogen inhalation brings many surprises. She said this "treasure" is priceless.

237 When she got the medical report, she couldn't believe her eyes.

239 Because of hydrogen, he excitedly walked onto the stage and bowed deeply to Xu Kecheng

242 She was ecstatic because she smelled a bad smell

244 Is hydrogen magical? After an accidental experience, she went from being weak and frail to feeling refreshed.

246 A Beijing professor who suffers from allergic rhinitis shares his experience

249 A sub-healthy person excitedly wrote these words after inhaling hydrogen for 30 days

Chapter 7 Selected Media Reports

252 Can hydrogen cure diseases? Yes! Guangzhou oncologists also use "hydrogen" to control cancer

259 Can Inhaling Hydrogen Really Cure All Diseases?

263 Appendix From Water to Hydrogen: Principles, Technologies, and Innovations in Hydrogen Production by Water Electrolysis

267 Postscript

Chapter 1 History and Overview of Hydrogen Medicine

Research history of hydrogen's biological effects and medical significance

Reading Key Points

The Big Bang 4.6 billion years ago gave rise to the vast, diverse, and constantly evolving galaxies. Hydrogen is the most abundant element in the universe, by atomic percentage. Its number is approximately 100 times greater than that of all other elements combined.

Although hydrogen accounts for only 9.5% of all elements in the human body, it provides vital chemical energy for life and is essential for maintaining health. Since the discovery of nitrogen, hydrogen, and oxygen between 1766 and 1800, and the beginnings of our understanding of life and its mechanisms, humans have created countless miracles in numerous fields, including life sciences and medicine. However, human society is still very young in the universe, and we face many unknowns, including our understanding of the relationship between hydrogen and life and health.

 

1. The Discovery and Existence of Hydrogen

Hydrogen was first discovered by Swiss chemist Philippus Aureolus Paracelsus in 1520 and described as a flammable gas. In 1671, Robert Boyle, a famous Irish philosopher, chemist, physicist, and inventor, described the properties of hydrogen. He was the first in the world to use the mercury trough method to collect hydrogen and conducted relatively systematic experimental observations. In 1766, Boyle presented a research report entitled "On Artificial Air" to the Royal Society of London, focusing on the characteristics of hydrogen. He called this gas "flammable air" and found that it was 11 times lighter than ordinary air and insoluble in water or alkaline solutions. More importantly, he discovered that when this gas is mixed with oxygen and an electric current is applied, water is generated (2).

Later, in 1787, the renowned French chemist Lawrence Lavoisier confirmed that hydrogen is an element and named the gas "hydrogen," meaning "water-forming element." He also pointed out that water is not an element, but a compound of hydrogen and oxygen. To this day, hydrogen is still called "water-based" in Japanese.

On Earth, there is only a very small amount of free hydrogen in the atmosphere. At the Earth's surface, hydrogen accounts for approximately 0.5 parts per million (ppm) of the total air volume. In the atmosphere 20 to 25 kilometers above the ground, there are only helium and hydrogen. Soil contains approximately 1.5% hydrogen, and oil, natural gas, and plants and animals also contain hydrogen. Therefore, hydrogen plays a significant role in life and health (2, 3).

2. Proposal and Evaluation of the Concept of Hydrogen Molecular Medicine 

Due to its properties, hydrogen was initially used as a carrier for airbags and later became widely used in spacecraft. Hydrogen is now being developed and utilized as a low-pollution renewable energy source. In addition to its applications in the energy sector, hydrogen is currently attracting increasing attention as a new medical gas. It is recognized as a selective scavenger of reactive oxygen species (ROS), particularly hydroxyl radicals (・OH), which are implicated in the development and progression of many pathological conditions, including cancer.

As early as 1937, hydrogen was first tested as a diving gas, proving that it is the best breathing medium for moderate and deep diving, and is extremely safe to the body, with no toxic side effects found (1).

In 1969, Levittl (4) of the United States published a paper in the New England Journal of Medicine, reporting the results of a study on hydrogen production by intestinal flora, which showed that the colon of a normal person produces 0.06 to 29 mL of hydrogen per minute (average 0.24 mL) in a fasting state.

It can be calculated that the human body can produce a maximum of about 345mL of hydrogen per day when fasting, and hydrogen production increases 7 to 30 times after eating.

In 1975, Dole et al. (5) from Baylor College of Medicine and A&M Corporation in the United States reported on the effect of hydrogen on cancer in Science. In a nude mouse model of ultraviolet-induced skin squamous cell carcinoma, tumors significantly shrank and regressed when placed in a chamber containing 2.5% oxygen and 97.5% hydrogen at 8 atmospheres.

In 1978, Roberts et al. (6) in the United States reported that high-pressure hydrogen has an inhibitory effect on leukemia cells. In 1988, Rostain et al. (7) in the United States reported that the use of Hydreliox, a product containing 49% hydrogen, 50% helium, and 1% oxygen, can effectively prevent divers from experiencing decompression sickness and nitrogen narcosis when working below 500 meters above sea level. In 2001, Gharib et al. (8) in France reported that high-pressure hydrogen has an anti-inflammatory effect on a mouse model of chronic hepatitis associated with schistosomiasis, suggesting that high-pressure hydrogen may have therapeutic effects on certain diseases.

Following a small number of studies on high-pressure hydrogen, people are now studying the effects of alkaline water. Shirahata et al. (9) in the United States proposed that a type of hydrogen atom called active hydrogen can be produced during electrolysis, and this active hydrogen can scavenge ROS. Although hydrogen atoms cannot exist in our bodies for a long time, hydrogen gas does exist in electrolyzed water. Li and his colleagues reported that electrolyzed water scavenged ROS and protected hamster pancreatic cell lines from alloxan-induced cell damage. A hemodialysis fluid produced by Nihon Trim can reduce oxidative stress in hemodialysis patients. Researchers from the Graduate School of Medicine at Tohoku University in Japan and Nihon Trim began collaborating on clinical research in 2008 and established the Electrolyzed Water-Hemodialysis Research Group Association. They believe that the effects of electrolyzed water may be due to the action of dissolved hydrogen molecules (1, 2).

In 2005, Yanagihara et al. (10) of Miz Corporation reported that hydrogen-rich neutral water produced by their unique electrolysis device could reduce oxidative stress in rats. This was groundbreaking work because they clearly demonstrated that it was the hydrogen in the alkaline water, rather than the alkaline substances, that exerted the therapeutic effect.

In 2007, Shigeo Ohta et al. (11) from Japan Medical University published a paper in Nature Medicine, reporting that hydrogen has a significant therapeutic effect on a rat cerebral infarction model. Experimental data showed that inhaling 1% to 4% hydrogen can reduce the area of ​​cerebral infarction in rats. They further pointed out that hydrogen has a specific effect of removing •OH and peroxynitrite, but does not affect hydrogen peroxide or superoxide. This result has aroused interest in the medical field in the biological effects of hydrogen and its clinical significance for various human diseases, which in turn has led to increasing attention to the value of hydrogen to life and health in the medical, scientific, industrial and capital fields.

In recent years, researchers primarily from Japan, China, and the United States have conducted extensive research on hydrogen and its relationship to the human internal environment, cytology, genetics, signal transduction, disease models, human diseases, and treatment-related pathologies and pathophysiology. They have discovered that hydrogen molecules can exert powerful antioxidant and anti-inflammatory effects, and have also analyzed their effects on cell signaling, gene expression regulation, and cytoprotection. Based on these studies, it has been further clarified that hydrogen can intervene in and improve many diseases related to peroxidation and inflammation in the body (12, 14).

Throughout the history of medical development, new scientific discoveries and technological inventions require solid scientific research to underpin them. In particular, methods or products with medical benefits must clearly define their impact on normal physiological functions. This is a fundamental scientific question, requiring a long and arduous process. The concept of "hydrogen medicine" was gradually established through this process (12, 14).

Based on these research advances, the U.S. Food Safety Office of Additive Safety issued a statement in 2014 stating that hydrogen is safe when dissolved in water. In 2015, China promulgated national standards designating hydrogen as a food additive.

3. The relationship between hydrogen and traditional medicine 

Zhang Xichun, a famous doctor in the Qing Dynasty, wrote in his book "Medical Records of Chinese and Western Medicine": "There is hydrogen in the heart of the furnace and in the human abdomen. The yellow one can lead the hydrogen up to the lungs, where it combines with the inhaled oxygen to transform into water. It can also encourage the upward movement of body fluids in the stomach and regulate the transformation of qi in the lower part of the body, thus preventing frequent urination. Therefore, it can cure diabetes."

Zhang Xichun's idea of ​​"hydrogen in the abdomen" coincides with the current understanding that colon bacteria produce hydrogen; "the yellow ones (probably referring to raw Rehmannia root and Astragalus root) can lead hydrogen up to the lungs...it does not cause frequent urination, so it can cure thirst", which seems to coincide with the current proof that hydrogen can improve the symptoms of diabetes.

In 1996, Du Yuanwei (15), a teacher in Shandong Province, my country, first proposed exploring the significance of hydrogen for life. In the abstract of a paper presented at an international conference, he proposed the “important role of hydrogen in living organisms” and believed that the hydrogen produced by water electrolysis has a significant promoting effect on the life activities of plants (lilac branches), animals (mice), and humans. He also pointed out that the occurrence of cancer, regardless of the theory, is essentially the oxidation and peroxidation of substrates in the biological metabolism process, and hydrogen may play the role of a “scavenger” in the body. Between 2002 and 2013, he published a number of papers, elaborating on the view that “an appropriate amount of hydrogen in the human body may have an immeasurable effect on various diseases and delay the aging process of life” (16-18), including its effect on the germination and growth of wheat seeds. He placed wheat seeds at the anode (producing oxygen) and cathode (producing hydrogen) of water electrolysis, and the results showed that the germination rate of the cathode wheat was higher than that of the anode wheat on the 8th and 15th days. He injected hydrogen into the central pith of lilac and peach branches, and the results showed that compared with the control group, the buds opened earlier and withered later. Subcutaneous injections of hydrogen into mice showed a shorter recovery time after anesthesia, improved starvation tolerance, and accelerated growth compared with the control group. He further injected hydrogen into his own skin and muscles and reported a "strengthened vitality" with no adverse reactions.

In 1999, Du Yuanwei et al. (19) published an article in the Journal of Shandong Normal University, pointing out that hydrogen has reducing and antioxidant effects in the body. He proposed that "people accumulate too much peroxides during metabolism, and many diseases and aging are caused by these peroxides. The human body must have certain life mechanisms to fight these peroxides. Hydrogen is a strong reducing agent, which naturally eliminates peroxides without side effects and achieves a balance in the sense of redox." The viewpoint put forward by Du Yuanwei coincides with people's current understanding of hydrogen molecular biology. If this paper is regarded as the beginning of his research on biological effects, his discovery was 3 years earlier than the French diving medical scientist in 2001 who proved that breathing 8 atmospheres of high pressure hydrogen has anti-inflammatory effects (8), and 8 years earlier than Ota Shigeo's discovery in 2007 that hydrogen molecules have the specific effect of scavenging hydroxyl free radicals. Unfortunately, the influence of the publications in which these studies were published is limited. If they were published in domestic English journals such as Sci Rep and Chin Med, their impact might be different, and they might obtain the first publication rights for "hydrogen biomedicine" research.

It is worth noting that Du Yuanwei proposed the relationship between "qi" and hydrogen in traditional Chinese medicine [15-17]. The "Inner Canon of Medicine" says that "ying is the essence of water and grain" and "ying qi is the body fluid, which is injected into the veins and transformed into blood." Du Yuanwei believes that the traditional Chinese medicine saying that "people are born with the qi of heaven and earth" and "qi is the root of people" refers to hydrogen. He also proposed the concept of "biohydrogen energy". He believes that as an ideal clean energy, hydrogen has high energy in organisms. Under normal circumstances, hydrogen can be used as a "supplementary energy" in addition to organic energy (16). He boldly speculated that the energy used by "biguo" people to maintain their life activities for a long time without taking food and only drinking a small amount of water is biohydrogen energy.

In 2013, to further verify whether hydrogen can diffuse rapidly throughout the body, Du Yuanwei et al. (19) produced tritium gas by electrolyzing tritium water (a hydrogen isotope that can be distinguished from other hydrogen elements after special labeling). They then introduced tritium gas into the living environment of mice instead of hydrogen. Finally, they detected the presence of tritium in various tissues and organs of the mice, thus proving that tritium gas participates in the life activities of organisms, is converted into ions, and is ubiquitous in organisms. This also indirectly proves that hydrogen produced in the air and in the intestines is both a component and an energy source for life.

In 2017, based on previous research results, Du Yuanwei et al. (20) proposed the hypothesis that tissue fluid circulates in the human body. Combining the feeling of inflation and flow of qi produced by “internal martial arts practitioners” during practice, he believed that the “true qi and primordial qi” and “positive qi and central qi” mentioned in traditional Chinese medicine are “neither entities nor pipelines, but merely channels, marrow channels, and gaps of qi”, and that what circulates in the meridians is hydrogen. He believed that tissue fluid might be what traditional Chinese medicine calls “qi”, and that the gaps and channels through which tissue fluid circulate are meridians. Tendons, ligaments, and fascia are also transport networks. Du Yuanwei’s hypothesis that hydrogen mainly travels along tissue fluid is the first of its kind in human history.

On March 27, 2018, Sci Rep magazine reported that two doctors at Yobe Israel Medical Center in the United States discovered a network of tissue located beneath the skin, around blood vessels, and in the lining of the lungs, digestive organs, and urinary system, with fluid flowing through it. They called it a new organ (21). Does this coincide with Du Yuanwei's hypothesis? Is it equivalent to the "meridians" in traditional Chinese medicine? And could the "fluid" contain "hydrogen"? It is worth studying.

Du Yuanwei's ideas hold theoretical value at the academic level, but their verification through scientific experimentation requires systematic observation and analysis. If confirmed, they could open a new avenue for studying the biological effects of hydrogen and imbue the long-standing, unsolved concept of "meridians" in Traditional Chinese Medicine with modern scientific meaning.

IV. Clinical Observation and Evaluation of Hydrogen Therapeutic Effects 

Based on observations and reports on hydrogen biology and medicine, numerous medical institutions and technology companies in my country have conducted research on the clinical value of hydrogen. Six multicenter, randomized, double-blind, controlled trials of hydrogen therapy have been conducted or are about to begin. These include: 1. Hydrogen-assisted treatment for allergic rhinitis; 2. Hydrogen-assisted treatment for acute exacerbations of chronic obstructive pulmonary disease (COPD); 3. Hydrogen-assisted treatment for severe stable COPD; 4. Hydrogen-assisted treatment for severe asthma; 5. Hydrogen-assisted treatment for bronchiectasis; and 6. Hydrogen-assisted treatment for non-small cell lung cancer. These studies are being conducted by 16 hospitals in Shanghai, Tianjin, Guangzhou, Hebei, and other regions, enrolling hundreds of patients.

There are also many single-center studies on hydrogen therapy across the country, covering the therapeutic effects of hydrogen on airway stenosis, Alzheimer's disease, Parkinson's disease, spinal cord injury rehabilitation, PM2.5 haze damage, respiratory sleep disorders and metabolic disorders, respiratory sleep disorder respiratory rhythm regulation, postoperative cognitive impairment in elderly patients, herpes zoster neuralgia, non-alcoholic fatty liver disease, diabetes, hyperlipidemia, pulmonary fibrosis, depression, etc.

5. Problems and Prospects of Hydrogen Medicine Research

This issue needs to be considered from three aspects: clinical problems and scientific hypotheses, research methods and tools, market potential and funding.

Throughout the history of scientific research, proposing creative scientific questions and choosing the right, important ones is an extremely difficult task. In particular, employing appropriate research methods is a crucial step in scientific discovery. In today's society, support from funds and capital also plays a crucial role.

1. Considerations from the perspective of clinical problems and scientific hypotheses

Over the past decade or so, Chinese academia and industry have begun to focus on the scientific significance and application value of hydrogen. In particular, the biological and physiological significance and clinical applications of hydrogen molecules have garnered significant attention from the medical industry. Experimental observations have initially confirmed that hydrogen has the potential to regulate physiological functions, maintain health, and treat conditions including radiation injury, brain trauma, burn shock, sepsis, pancreatitis, decompression sickness, oxygen poisoning, cirrhosis, and Alzheimer's disease.

The Naval Medical University (formerly the Second Military Medical University) is the first academic institution in China to conduct hydrogen medical research. In 2011, Academician Wu Mengchao and his team discovered that hydrogen can protect against liver damage and inhibit the processes that lead to cirrhosis and compensatory liver cell proliferation (22). Academician Xia Zhaofan was the first internationally to propose the concept of hydrogen resuscitation (23). Professor Sun Xuejun edited Hydrogen Molecular Biology and co-authored Hydrogen Molecular Biology and Midicine with Professor Shigeo Ota of Japan, focusing on the mechanism of hydrogen treatment of diseases, provide important references for the research of hydrogen biology and its applications.

In 2014, a research team from Guangzhou Medical University, led by Academician Zhong Nanshan, joined the field of hydrogen medicine research and organized and carried out a number of clinical multicenter trials related to COPD. They also proposed that hydrogen therapy "belongs to etiological treatment", "preventive treatment", and "mainly targets chronic diseases", pointing out the direction for the healthy development of hydrogen biomedicine.

Xu Kecheng and his team were the first to link hydrogen with cancer. Their retrospective and prospective investigation of hydrogen inhalation to control progressive cancer is a groundbreaking study that has attracted great attention.

2. Considerations from the perspective of research methods and tools

Technological innovation is a key driver of scientific discovery. Shanghai Mei Medical Technology Co., Ltd., utilizing novel water electrolysis technology, has developed the world's first medical-grade oxygen-hydrogen atomizer. In 2018, the device was designated a Class III medical device (Classification No. 6826) by the China Food and Drug Administration and has been granted 118 invention and utility model patents both domestically and internationally. The device utilizes a "zero-gas chamber" design to prevent hydrogen and oxygen gas accumulation. Its integrated atomization system prevents static electricity from drying out and potentially causing spontaneous combustion, ensuring safety.

3. Considerations from the perspective of market potential and capital

Due to its biological significance and potential clinical value, hydrogen has garnered significant attention from funding bodies, industry, and investment and financing sectors. From 2008 to 2017, the number of projects and funding supported by the National Natural Science Foundation for hydrogen biomedical research increased annually, reaching a total of 69 approved projects by 2018. These projects covered topics such as the mechanisms of action of hydrogen molecules and the protective effects of hydrogen inhalation on various diseases (particularly neurological, respiratory, cardiovascular, and metabolic disorders) and pathological conditions (radiation damage, wounds, and inflammation). In addition to the National Natural Science Foundation, hydrogen medical research has received over 100 grants from provincial and municipal governments, as well as universities, hospitals, and research institutions. Shanghai Jiao Tong University established a Hydrogen Science Research Center in early 2019, covering hydrogen energy, agriculture, and medicine, which has garnered significant attention from relevant national authorities and the public.

Even more encouraging is that this research has been centered on enterprises from the outset, leveraging the resources, technology, and talent of universities and research institutes to promote innovation and development. The aforementioned Shanghai-made hydrogen-oxygen nebulizer possesses unique advantages, providing a reliable means for conducting randomized, controlled, multicenter studies in both natural and diseased populations, garnering attention both domestically and internationally.

Conclusion

Although hydrogen is the earliest, oldest and most basic element in the universe, and the original universe is almost entirely composed of hydrogen, and although bacteria in the human intestine produce hydrogen all the time, people's understanding of hydrogen in life activities and health maintenance is still preliminary.

of.

In the early stages of any scientific discipline, various hypotheses and theories often question or even exclude each other, making communication and understanding difficult between different schools of thought. History reminds us that good things are often met with opposition at the outset. We believe that over time, through observation and experimentation, people will ultimately gain true knowledge. Fortunately, scientists from diverse fields are now joining the field of hydrogen medicine, gradually forming a comprehensive research community through exploration. They are not only conducting basic scientific experiments but are also gradually translating them into clinical research. "Real-world evidence" research, which has already garnered widespread attention, is expected to play a role in clinical translation.

I believe that as long as we uphold appropriate academic viewpoints, adopt correct research ideas, methods and techniques, conduct serious exploration, and incorporate elements of traditional Chinese culture into our research, China's hydrogen medicine research will surely make great progress.

Lü Youyong Xu Kecheng Wu Peihong Li Jiaping

References

[1] Sun Xuejun, Hydrogen Molecular Medicine. Shanghai Second Military Medical University Press, 2013.

[2] Ohta S. Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical

applications. Elservier Inc, 2015.

[3] Ohta S. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and

therapeutic applications. Curr Pharm Des, 2011, 17(22): 2241-2252.

[4] Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med, 1969, 281(3):122-127.

[5] Dole M, Wilson FR,Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science, 1975,

190(4210): 152-154.

[6] Roberts BJ, Fife WP, Corbett TH,Schabel FM, Jr. Response of five established solid transplantable mouse

tumors and one mouse leukemia to hyperbaric hydrogen. Cancer Treat Rep, 1978, 62(7):1077-1079.

[7] Rostain JC, Gardette-Chauffour MC, Lemaire C,Naquet R. Effects of a H2-He-O2 mixture on the HPNS up to 450 msw. Undersea Biomed Res, 1988, 15(4): 257-270.

[8] Gharib B, Hanna S, Abdallahi OM, et al. Anti-inflammatory properties of molecular hydrogen: investigation

on parasite-induced liver inflammation. CR Acad Sci III, 2001, 324(8): 719-724.

[9] Shirahata S, Hamasaki T,Teruya K. Advanced research on the health benefit of reduced water. Trends Food Sci Tech, 2012, 23: 124-131.

[10] Yanagihara T, Arai K, Miyamae K, et al. Electrolyzed hydrogen-saturated water for drinking use elicits an antioxidative effect: a feeding test with rats. Biosci Biotechnol Biochem, 2005, 69(10): 1985-1987.

[11] Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13(6): 688-694.

[12] Ichihara M, Sobue S, Ito M, et al. Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles. Med Gas Res, 2015, 5: 12.

[13] Ostojic SM. Targeting molecular hydrogen to mitochondria: barriers and gateways. Pharmacol Res, 2015, 94:51-53.

[14] Dixon BJ, Tang J, Zhang JH. The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance. Med Gas Res, 2013, 3(1): 10.

[15] Du Yuanwei. Thinking about the Materiality of Qi. Qigong and Science, 1996, 11:34.

[16] Du Yuanwei. Hydrogen energy and life hydrogen. Solar Energy, 2002, 5:15.

[17] Du Yuanwei. Hydrogen energy and life hydrogen energy. Secondary School Biology Teaching, 2002, 1-2: 42.

[18] Du Yuanwei, Li Peng, Zhao Xianfeng. Experimental confirmation of the role of hydrogen in the meaning of life, Journal of Zibo Teachers College, 2013, 1: 81-82.

[19] Du Yuanwei, Wei Cuigui. A new scientific topic: A preliminary study on the significance and role of hydrogen in life activities. Journal of Shandong Normal University, 1999, 2: 196-197.

[20] Wang Yusheng, Jiang Jinxu, Zhang Guangfu, Du Yuanwei. Tissue fluid circulation, a human body system that is more comprehensive than blood circulation. Chinese Journal of Health Care and Nutrition, 2017, 27(10): 97.

[21] Benias PC, Wells RG, Sackey-Aboagye B, et al. Structure and Distribution of an Unrecognized Interstitium in Human Tissues. Sci Rep, 2018, 8(1): 4947.

[22] Sun H, Chen L, Zhou W, et al. The protective role of hydrogen-rich saline in experimental liver injury in mice. J Hepatol, 2011, 54(3): 471-480.

[23] Zheng XF, Sun XJ, Xia ZF. Hydrogen resuscitation, a new cytoprotective approach. Clin Exp Pharmacol Physiol, 2011, 38(3): 155-163.

Hydrogen: A new approach to prevent disease before it occurs and treat different diseases with the same method

Reading Key Points

Hydrogen diffuses easily in the body and can enter the cytoplasm, nucleus and mitochondria. This is the basis for hydrogen to be used to maintain health and assist in the treatment of various diseases throughout the body.

Molecular hydrogen can be obtained through inhalation, oral administration, or injection of hydrogen-rich (salt) water. It has antioxidant (eliminating toxic reactive oxygen free radicals) and anti-inflammatory effects, maintains metabolic balance, and participates in gene expression regulation. This is the main mechanism by which it has a certain therapeutic effect on diseases associated with peroxidation and chronic uncontrollable inflammation.

Molecular hydrogen has a certain auxiliary therapeutic effect on diseases of most systems and organs of the human body, and has the effect of treating different diseases with the same effect.

In terms of health management, molecular hydrogen can eliminate unexplained "discomfort" in the body, improve sleep, fight fatigue, and has the effects of beautifying the body and anti-aging. It may be a new means of achieving "prevention before illness occurs."

The human colon can produce up to 12 liters of hydrogen per day, indicating that hydrogen is necessary for maintaining normal physiological functions. Hydrogen absorption is merely a compensation for insufficient hydrogen production in the body.

Human cells are constantly in a state of oxidative stress, stemming from the abnormal oxidative potential of excessive reactive oxygen species (ROS). While the vast majority of inhaled oxygen is converted into non-toxic ROS to perform physiological functions, a smaller fraction becomes toxic ROS. If not promptly cleared, these ROS can cause damage within cells (particularly within mitochondria). Toxic ROS can arise from various conditions, such as intense exercise, inflammation, ischemia-reperfusion (I/R) injury, bleeding, and tissue and organ transplantation. Chronic, persistent oxidative stress is closely linked to many lifestyle-related diseases, aging, and cancer. While many antioxidant supplements are available clinically, these are ineffective at low doses and highly toxic at high doses, making them difficult to tailor to individual needs. Therefore, the search for non-toxic or less toxic antioxidants for maintaining health or treating certain conditions has long been a research and pursuit.

In recent decades, through unremitting efforts, people have finally discovered that hydrogen (Hz) is a non-toxic, natural, simple, and effective selective antioxidant molecule. As early as 1975, Dole et al. in the United States reported that hydrogen inhalation inhibits squamous cell carcinoma in mice. In 2001, Gharib et al. in France reported that hydrogen inhalation can treat hepatitis caused by parasitic infection of the human liver. In 2007, Ota Shigeo et al. (3) in Japan reported that hydrogen inhalation can selectively neutralize hydroxyl (·OH) and peroxynitrite (ONO), protecting the brains of mice modeled after radiation and stroke from damage.

The idea that gases can have therapeutic effects on diseases is not new. Oxygen is essential for human survival, and its medical applications are well known. In the 1980s, the molecular mechanism behind nitroglycerin's effectiveness in treating angina pectoris was discovered to be nitric oxide (NO). NO originates in coronary artery endothelial cells and can induce vasodilation. Its researchers were awarded the Nobel Prize in Physiology or Medicine in 1998. Since then, research on medical gases has made rapid progress. Carbon monoxide (CO) and hydrogen sulfide (HS) both have strong antioxidant properties and are considered important neurotransmitters. These three gas molecules are known as gaseous signaling molecules in the body (see table below).

NO is already clinically used to treat heart and lung diseases. Clinical studies have begun using CO2 therapy in patients with renal transplantation and severe respiratory failure, as well as H2S therapy in patients with renal insufficiency and those undergoing coronary artery bypass surgery. However, it has long been difficult to believe that H2S could exert any biological effects. This is because, compared to other gases, H2S is a non-radical, non-reactive, non-polar, and highly diffusible neutral gas, making it unlikely to have specific binding sites or interact specifically with specific receptors.

1. Characteristics of Molecular Hydrogen

Molecular hydrogen has a variety of biological effects because it has properties that general drugs and biological molecules do not have:

1. High penetrability and rapid diffusion ability

Hydrogen molecules have high biomembrane penetration and intracellular diffusion capabilities, and can enter various cells in the cell nucleus and cytoplasm.

It can penetrate both normal tissues and ischemic areas, and can even cross the blood-brain barrier, something that conventional antioxidants and chemical drugs cannot achieve. Testing of exhaled hydrogen shows that inhaled hydrogen is distributed throughout the body through the bloodstream within 10 minutes.

In 2019, Yamamoto et al. (6) in Japan studied the distribution of hydrogen in rats after continuous inhalation of 3% hydrogen (see Figure 1). The time it took for hydrogen to reach saturation in muscle was 20.2 minutes, significantly longer than the 6.3–9.4 minutes in other organs, and the hydrogen concentration in muscle gradually increased over time. By organ, the highest hydrogen concentration was in the liver (29.0 ± 2.6 μmol/L) and the lowest in the kidney (18.0 ± 2.2 μmol/L).

2. High selectivity and protective effect on functional ROS

Hydrogen has a weak reducing property and selectively neutralizes only highly active and toxic reactive oxygen species (such as ·OH), while having no adverse effects on other free radicals involved in normal signal regulation, such as ·O2 and H2O2. Low concentrations of ·O2 and H2O2 can act as signal molecules.

Regulate cell proliferation, differentiation, and apoptosis (7). Although antioxidants such as vitamin C or E have strong reducing properties, they can destroy normal ROS and may interfere with normal cell signaling (8). Some studies have reported that at higher concentrations, H2O2 is converted into hypochlorous acid under the action of myeloperoxidase, which can prevent bacterial invasion. NO acts as a neurotransmitter and is crucial for vasodilation. Excessive antioxidants can destroy the above-mentioned important defense mechanisms, thereby increasing the morbidity and mortality of patients with diseases including cancer. Molecular hydrogen does not have these toxic side effects (12).

3. High safety, even at high concentrations

Over the past few decades, the biological effects of several gaseous molecules, including NO, CO, and H2S, have gained attention. Inhalation of exogenous CO or H2S can have beneficial effects on most vital organs (13, 14). However, these gases can be highly toxic at high concentrations. NO reacts with O2- to produce highly oxidizing peroxynitrite (NO+·O2- →ONOO-), which enhances oxidative stress. Even the most widely used in clinical practice can cause oxygen toxicity at high concentrations (4). H2 is different and is not cytotoxic even at high concentrations. The product of H2's reaction with free radicals is water, and excess H2 can be exhaled without any residue. High-pressure H2 is used in deep diving gas mixtures to prevent decompression sickness and arterial gas thrombosis. Hydreliox, used for deep diving, is an exogenous breathing gas mixture containing 49% Hz, 50% He, and 1% NH3.

H₂ is quite inert and behaves as an inert gas in the absence of a catalyst or at body temperature. It does not react with most compounds, including oxygen at room temperature. Hydrogen is flammable only at temperatures above 527°C and explodes only when H₂ concentrations are within the explosive range (4% to 75%), through a rapid chain reaction with oxygen (4.17).

2. Biological Roles of Molecular Hydrogen

1. Antioxidant effect

The Yellow Emperor's Classic of Internal Medicine describes cancer as a vast accumulation of "toxins," including heat and dampness. The most commonly used treatment in Traditional Chinese Medicine is "detoxification." What is "toxin"? Modern biomedicine believes that the most powerful "toxin" in the body is toxic ROS. Numerous pathogenic factors, whether physical (such as ionizing radiation and ultraviolet light), chemical (such as chemical toxins), biological (such as bacterial and viral infections and the biological toxins they release), or abnormal immunity (such as rheumatoid arthritis), can trigger the production of toxic ROS. The mechanism by which hydrogen molecules eliminate toxic ROS may involve several different pathways:

(1) Activate the Nrf2-Keap1 system, induce the activation of antioxidant response elements (ARE), and secrete various cytoprotective proteins, such as glutathione, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase, and heme-1 oxygenase.

(2) Activate the transcription factor FoxO1, upregulate the expression of manganese superoxide dismutase (MnSOD) and CAT, and reduce OH-induced mitochondrial damage and the massive generation of ROS.

(3) Activate the cellular adenosine monophosphate-activated protein kinase (AMPK) pathway, regulate cell growth, reshape energy metabolism, and play an anti-apoptotic role.

2. Anti-inflammatory effect

Inflammation is one of the important causes of many diseases and sub-health conditions. Cancer is also considered to be a chronic, uncontrollable inflammation. Some people also believe that cancer is actually a long-lasting inflammatory wound (18).

In 2001, Gharib et al. (2) in France reported that inhaling high concentrations of hydrogen cured parasite-induced liver inflammation, suggesting that hydrogen has anti-inflammatory properties. In 2013, Ishibashi et al. (19) in Japan reported that hydrogen inhalation had a residual effect in the treatment of rheumatoid arthritis, with the disease continuing to improve four weeks after hydrogen inhalation stopped. Many cytological experiments have shown that cells remain resistant to attacks (such as toxins, radiation, and damage) long after hydrogen disappears from the culture system, indicating that the anti-inflammatory effect of hydrogen is persistent.

The anti-inflammatory effect of H2 is mainly achieved by downregulating various pro-inflammatory and inflammatory cytokines (20), including interleukin (IL)-1B, IL-6, tumor necrosis factor (TNF)-a, intracellular cell adhesion molecule (ICAM)-1, high mobility group box (HMGB)-1, nuclear factor (NF)-kB, and prostaglandin (PG) E2.

3. Anti-apoptosis effect, protecting cells

Apoptosis is programmed cell death, a slow, natural way for cells to die (21). Apoptosis and regeneration are in balance. If there is too little apoptosis, the number of cells will continue to increase, forming a tumor. However, if there is too much apoptosis, the structure and function of organs will be damaged, diseases may develop, and vital functions cannot be maintained. In 2017, Ge et al. (12) in China reviewed the basic and clinical data on H2, which can significantly reduce apoptosis caused by ischemia, infarction, poisoning, and inflammation, and implement cell protection.

The mechanism by which H2 inhibits apoptosis is primarily through the inhibition of Caspase-3 (22) and -12 (23) activity. Furthermore, H2 can inhibit the expression of pro-apoptotic factors and Bax (24) and upregulate the expression of anti-apoptotic factors and Bcl-2 (25). In 2012, Hou et al. (26) from China reported that H2 can activate anti-apoptotic protein kinase B in neurons, exerting a neuroprotective effect. In 2011, Nakai et al. (27) from Japan summarized and reported that drinking hydrogen-rich water can alter the functions of over 200 biomolecules, thereby affecting the expression of over 1,000 genes.

4. Regulating signaling pathways

Life is composed of matter (physical matter), energy, and signals. Without the transmission, connection, and communication of information, life processes would be impossible. H2 can influence multiple signaling pathways (12, 28, 29). As a gaseous signaling regulator, H2's effects involve a network of signaling molecules, such as:

(1) Regulate NF-kB. This factor controls hundreds of genes involved in cell growth, differentiation, development, inflammation and apoptosis. H2 can activate NF-KB, thereby activating a series of cell behaviors.

(2) Promotes the expression of Nrf2 in the body, especially in organs such as the lungs, liver, and kidneys. Nrf2 is a novel regulator of the innate immune response. H2 upregulates Nrf2 and maintains the body's immune function.

(3) Induction of heme oxygenase-1 (HO-1) and its enzymatic reaction. HO-1 and its product CO not only have significant anti-inflammatory properties, but also eliminate infection by increasing phagocytosis and endogenous antibacterial responses, but also reduce inflammation caused by hyperoxia and improve blood oxygenation.

3. Treating Different Diseases with the Same Method and Preventive Treatment

Traditional Chinese medicine believes that maintaining human health depends on "keeping the head cool, the feet warm, and bowel movements smooth," and that "stagnation of qi and blood stasis leads to pain." Current human health problems are closely related to "the lack of qi and blood." Ge et al. (12) summarized the literature published as of March 2017 and found that H2 has potential therapeutic effects on over 100 diseases in biology and medicine. Some believe that H2 has therapeutic effects on all of the top 10 causes of death in the United States, except for suicide and accidents (see Figure 2). The following lists these by type.

1. Central nervous system diseases

Oxidative stress and nervous system inflammation can cause nervous system diseases, such as brain damage, neurodegenerative diseases, and other secondary nervous system diseases. In 2009, Japanese researchers Nagata et al. (30) found through mouse experiments that H2 can diffuse through the blood-brain barrier and has therapeutic effects on some central nervous system diseases.

(1) Ischemia-reperfusion (I/R) injury: also known as tissue damage caused by vascular occlusion (stroke, i.e., cerebral thrombosis or cerebral embolism) - recanalization (thrombolysis) - blood reperfusion. The occurrence of this condition is often more harmful than the stroke itself. Reports on hydrogen treatment of I/R injury are the most numerous among all H studies. In 2007, Ota Shigeo et al. (3) in Japan first reported that hydrogen inhalation significantly inhibited focal I/R brain injury in rats and proved that this therapeutic effect was due to hydrogen eliminating the excessive toxic ROS caused by I/R injury.

(2) Cerebral hemorrhage: It is an emergency with a very high mortality rate and is often a complication of hypertension. In 2013, Manaenko et al. (31) in the United States used collagenase intracerebral injection to induce cerebral hemorrhage in animals. After the animals inhaled hydrogen, the brain barrier and neurological function were significantly improved compared with the group without hydrogen inhalation. They also found that mast cell activation is related to the pathogenesis of cerebral hemorrhage, and H can block mast cell activation. In 2013, Shao et al. (32) in China confirmed through rabbit experiments that hydrogen-rich water injection can reduce brain edema and blood-brain barrier damage, reduce neuronal apoptosis, and improve neurological function. The improvement of oxidative damage is related to the activation of the NF-kB pathway. In 2016, Shao et al. (33) repeated similar results in a rat model and found that in addition to the activation of the NF-kB pathway, the formation of NLRP3 inflammasome was also involved.

(3) Parkinson's disease: The main pathological changes are abnormalities of dopaminergic neurons in the substantia nigra and nigrostriatal pathways, and this abnormality is related to excessive oxidation in the substantia nigra and reduced endogenous antioxidant function. The incidence of this disease increases sharply with age, and about 1.5% of the human population is at risk of developing this disease. Currently, the antioxidants used in clinical practice have failed to show significant therapeutic effects. In 2009, Fu et al. (3) and Fujita et al. (35) in Japan, respectively, confirmed that hydrogen-rich water can alleviate nigrostriatal degeneration and inhibit the loss of dopaminergic neurons using rat and mouse models. In 2013, Yoritaka et al. (36) in Japan conducted a randomized double-blind placebo-controlled trial in which participants drank 1 liter of hydrogen-rich water or ordinary water daily for 48 weeks. The results showed that the Parkinson's Disease Rating Scale scores in the hydrogen-rich water group improved, while the scores in the placebo group worsened.

(4) Alzheimer's disease: commonly known as senile dementia, there is no effective treatment to date. In 2010, Li et al. (37) in China injected hydrogen-rich saline into an Alzheimer's rat model and found that cognitive and memory functions improved. In 2011, Wang et al. (38) from the same research group reported that the mechanism may be that hydrogen-rich saline improves abnormal signal transduction related to the disease.

(5) In 2009, Nagata et al. (30) from Japan found through mouse experiments that the injection of hydrogen-rich water can improve neuronal damage in the hippocampus of fetal mice caused by uterine I/R, block endotoxin-induced microglial activation in the fetal mouse brain, and thus reduce neuronal damage and brain damage caused by such cell activation.

2. Cardiovascular diseases

(1) Myocardial infarction is an emergency caused by persistent coronary ischemia, with a high mortality rate. In 2008, Hayashida et al. (5) from Japan used coronary artery clamping to create a rat model of myocardial infarction and found that hydrogen inhalation could reduce the severity of myocardial infarction. In 2015, Jing et al. (39) from China used isoproterenol to induce myocardial infarction in rats, and in 2016, Gao et al. (40) from China used doxorubicin to induce myocardial injury in rats, both of which obtained similar experimental results.

(2) The mortality rate of cardiac arrest/resuscitation is extremely high. In 2014, Huo et al. (41) in China confirmed through a rat model that hydrogen-rich saline can significantly improve the survival rate of cardiac arrest and reduce the sequelae of neurological damage. Currently, Japan has listed cardiac arrest/resuscitation as a legal indication for hydrogen inhalation therapy.

(3) Heart transplantation has been increasingly used to treat heart failure and myocardial diseases. In 1997, Knight et al. (42) in the United States conducted a rat heart transplantation experiment and confirmed that preservation fluid containing hydrogen-rich saline was more effective than ordinary preservation fluid, and the survival time of the heart after transplantation was longer. In 2009, Sun et al. in China used a rat model to confirm that adding hydrogen-rich saline during extracorporeal circulation during cardiac surgery could improve myocardial damage caused by extracorporeal circulation and block myocardial cell apoptosis. In 2011, the same research group (44) found that this effect was achieved by activating the JAK2/STAT3 signaling pathway.

(4) Myocardial hypertrophy can lead to primary or secondary cardiomyopathy. In 2018, Fan et al. (China) confirmed through a rat model that hydrogen-rich saline can protect the myocardium and reduce hypertrophy and damage.

(5) Atherosclerosis is a common chronic disease that often causes hypertension. Apolipoprotein E plays an important role in preventing atherosclerosis. In 2008, Ohsawa et al. (46) in Japan created mice with knockout apolipoprotein E gene and created an atherosclerosis model. The researchers found that after multiple injections of hydrogen-rich water, inflammation in the arterial lining was reduced, the stability of atherosclerotic plaques was enhanced, and the formation of macrophage-derived foam cells was reduced, thereby preventing various complications of atherosclerosis. In 2018, Matsuoka et al. (47) in Japan created an atherosclerosis model in rats by using a high-salt diet and obtained similar research results after hydrogen inhalation.

(6) Hypertension is the most common disease in modern society, with an incidence rate exceeding 40%. In 2019, Guan et al. (48) in China used a spontaneous hypertension model in rats to demonstrate that hydrogen inhalation could prevent the disease.

3. Hepatobiliary and pancreatic diseases

(1) Viral hepatitis: In 2001, Gharib et al. (2) from France reported a study on professional deep-sea divers and found that inhaling a high-pressure hydrogen-oxygen mixture (oxygen cylinder) had a therapeutic effect on hepatitis and various liver injuries, increasing the content of antioxidant enzymes in the blood, reducing the level of lipid peroxides, and reducing the degree of liver fibrosis. In 2009, Kajiya et al. (4) from the United States confirmed that hydrogen inhalation can improve the liver function of mice with concanavalin A-induced hepatitis. In 2013, Xia et al. from China reported that drinking hydrogen-rich water can reduce oxidative stress in patients with chronic hepatitis B, improve liver function, and reduce viral load.

(2) Liver damage: It can be caused by many reasons. In 2007, Fukuda et al. (5) from Japan reported that hydrogen inhalation can treat I/R-induced liver damage in mice, and the mechanism is to reduce the oxidative stress of liver cells. In 2011, Kang et al. (2) from the United States reported that patients undergoing radiotherapy for liver tumors drank hydrogen-rich water, and their quality of life was significantly improved. In 2012, Kawai et al. (53) from Japan reported that injection of hydrogen-rich water can delay the progression of non-alcoholic fatty liver disease and prevent liver cancer. In 2014, Tan et al. (54) from China reported that liver failure after major hepatectomy can be prevented by injecting hydrogen-rich saline into mouse models. In 2014, Liu et al. (55) from China reported that hydrogen-rich saline can treat I/R-induced liver damage in rats, and the mechanism is to reduce the oxidative stress of liver cells and reduce the release of HMGB1. In 2015, Lee et al. (56) from China reported that the injection of hydrogen-rich saline into rats with acetaminophen-induced cirrhosis could improve the blood supply to the whole body, spleen, and liver. In 2016, Liu et al. (57) from China reported that the injection of hydrogen-rich saline could improve the mitochondrial function of hepatocytes and reduce hepatocyte apoptosis in mice with obstructive jaundice. In 2016, Shi et al. (58) from China reported that the injection of hydrogen-rich saline could improve acute liver injury caused by acute necrotizing pancreatitis. The mechanism was to inhibit inflammation and apoptosis of hepatocytes and reduce the production of ROS by inhibiting the JNK and p38-MAPK signaling pathways. In 2017, Zhai et al. (59) from China reported that the injection of hydrogen-rich saline could treat rats with non-alcoholic fatty liver disease. The mechanism was to alleviate oxidative stress and activate liver PPARx and y.

(3) Liver fibrosis: This is an important pathological process of liver cirrhosis. In 2014, Koyama et al. (60) confirmed through mouse experiments that oral administration of hydrogen-rich water can improve liver fibrosis caused by chronic hepatitis B.

(4) Pancreatitis: In 2013, Zhang et al. (61) reported that acute pancreatitis induced by taurocholate in rats could be alleviated by injection of hydrogen-rich saline. In 2015, Luo et al. (62) reported that injection of hydrogen-rich saline could reduce the severity of acute pancreatitis after pancreatic transplantation in rats and improve pancreatic I/R injury.

4. Gastrointestinal diseases

The gastrointestinal tract is home to a complex and diverse microbial community, which forms a symbiotic relationship with the human host and maintains human health. Most gastrointestinal microbes have the genetic ability to encode H2 metabolism, which means that H2 may affect the composition of the intestinal microbiome. In 1980, Levittl (63) reported that the intestinal bacteria of normal adults produce up to 3000 mL of H2 per day. Therefore, it is not surprising that H2 can improve intestinal diseases.

Gastric ulcer: In 2012, Liu et al. (64) from China reported that injection of hydrogen-rich saline could treat stress-related gastric ulcers in mice. In 2014, Zhang et al. (65) from China reported that injection of hydrogen-rich water could treat aspirin-induced gastric damage. In 2015, McCarty et al. (66) from the United States reported that giving mice hydrogen-rich water increased the expression and secretion of ghrelin, significantly enhancing gastric digestion. In the same year, Ichihara et al. (67) from Japan summarized 321 papers, which also confirmed the conclusion that hydrogen can improve gastric damage.

Intestinal injury: In 2008, Buchholz et al. (68) from the United States reported that hydrogen inhalation can alleviate oxidative stress in a rat intestinal transplant model, improve mucosal erosion and mucosal barrier damage, and reduce the incidence of postoperative intestinal obstruction. In 2009, Zheng et al. (69) from China reported that injection of hydrogen-rich saline can alleviate intestinal I/R injury in rats. In 2011, Chen et al. (70) from the same group reported that this method can enhance intestinal contractility and prevent intestinal structural changes after I/R injury. In 2015, Shigeta et al. (71) from Japan also reported similar findings.

5. Respiratory diseases

Since inhaled hydrogen enters the lungs directly, H2 may be more effective in treating bronchopulmonary diseases.

(1) Acute lung injury is a very common disease. In 2013, Zhou et al. (72) from China reported that hydrogen inhalation could improve I/R-induced injury in rat lung transplant models. In 2015, Zhai et al. (73) from China reported that injection of hydrogen-rich saline could inhibit acute lung injury caused by sepsis in rats, eliminate extravascular pulmonary edema, and alleviate sepsis-related lung failure. In animal experiments on lung injury caused by many other factors, such as hyperoxia (74), lipopolysaccharide (LP) (75), smoking, paraquat (76), monocrotaline, and extensive burns (77), injection of hydrogen-rich water/saline had the effects of protecting the airway mucosa and promoting mucus production.

(2) Asthma is a common chronic airway disease worldwide, and oxidative stress is considered to be an important pathogenesis of asthma. In 2013, Xiao et al. (29) reported that injection of hydrogen-rich saline into mice with allergic asthma could reverse severe inflammatory infiltration and goblet cell hyperplasia, significantly reduce the number of eosinophils and lymphocytes, and the levels of inflammatory factors such as IL-4, IL-13, and TNF-a, while also upregulating the activity of SOD.

(3) Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease caused by harmful gases or particles, which is mainly manifested by progressive airway remodeling and airflow obstruction. It has a high incidence rate and is difficult to treat. In 2017, Liu et al. from China reported that a mouse COPD model was prepared by exposing mice to cigarette smoke and then injecting hydrogen-rich saline, which could inhibit airway inflammation and excessive secretion of the bronchial mucosa through anti-apoptotic effects. In the same year, Liu et al. from China [80] prepared the same model and treated it with hydrogen inhalation. They found that it had an improvement effect on emphysema, chronic bronchitis, small airway remodeling and decreased lung function. In the same year, Suzuki et al. from Japan (81) reported that this protective effect was the result of the anti-inflammatory and antioxidant effects of H2.

6. Urinary system diseases

(1) I/R injury is often difficult to avoid during kidney transplantation, especially for kidneys from donors who have died of cardiac death. Cold ischemia time is often too long, which poses a potential risk of reduced kidney survival after transplantation. The main factor causing kidney injury due to I/R is the production of ROS (82). In 2015, Liu et al. (8) from China reported that pre-preserving rat kidneys with hydrogen-rich saline can reduce renal cell death during storage and transportation and alleviate I/R injury after transplantation. The mechanism is to inhibit DNA oxidative stress and PPM-1 overexpression. In 2015, Wang et al. (8) from China reported that using the same pre-treatment method, they found that the activity of renal ganglion cells was significantly improved, which directly led to an improvement in transplantation efficiency.

(2) Kidney damage: In 2009, Nakashima-Kamimura et al. (85) from Japan reported that both hydrogen inhalation and oral administration of hydrogen water could alleviate cisplatin-induced nephrotoxicity without affecting the anti-tumor activity in tumor-bearing mice. Recent studies have shown that hydrogen inhalation and oral administration of hydrogen water can alleviate kidney damage caused by ferric nitrotriacetate (86), dicarbonyl compounds (87), unilateral ureteral obstruction (88), spontaneous hypertension (89), glycerol (90), septic shock (91), acute pancreatitis (92), and burns.

(3) Bladder pain: In 2013, Matsumoto et al. (94) from Japan reported that drinking hydrogen water can relieve the symptoms of interstitial cystitis and treat bladder pain syndrome.

7. Metabolic syndrome

(1) Obesity: It has become the most common modern lifestyle disease. In 2011, Kamimura et al. (95) from Japan reported that drinking hydrogen-rich water reduced liver oxidative stress in spontaneously obese db/db mice, significantly alleviated high-fat diet-induced fatty liver, and reduced plasma glucose, insulin, and triglyceride levels. The mechanism is to improve obesity and metabolic parameters at the molecular level, including enhancing the expression of fibroblast growth factor (FGF21), which functions to enhance fatty acid and glucose consumption.

(2) Hyperlipidemia: It is a common metabolic syndrome that often leads to secondary atherosclerosis. In 2008, Kajiyama et al. (96) of Japan reported that after oral administration of hydrogen water for 8 weeks, patients with type II diabetes had significantly reduced LDL and urinary 8-isoprostane, and significantly reduced insulin dosage. In 2012, Zong et al. (7) of China reported that after a high-fat diet was used to induce the disease in hamsters, injection of hydrogen-rich saline could reduce plasma LDL levels and enhance HDL function. In 2013, Nishimura et al. (98) of Japan reported that oral administration of fructan promoted increased hydrogen production in rat colon and reduced oxidative stress induced by inflammation. In 2013, Song et al. (99) of China reported that after oral administration of hydrogen water for 8 weeks, patients with metabolic syndrome had an increase of 39% in urinary SOD, a decrease of 43% in urinary thiobarbituric acid reactive substances, an increase of 8% in HDL, and a decrease of 13% in the total cholesterol/HDL ratio.

(3) Diabetes: In 2009, Suzuki et al. (100) from Japan reported that oral administration of acarbose can induce endogenous hydrogen production, improve glucose tolerance, and reduce the risk of cardiovascular disease in patients with type II diabetes. In 2013, Amitani et al. (0) from Japan reported the effects of hydrogen on two tumor cell lines (hydrogen participated in cell culture) and three diabetic mouse models (oral administration or injection of hydrogen-rich water). They believed that hydrogen can exert a metabolic effect similar to that of insulin and may even become a new alternative therapy for the treatment of type I diabetes.

8. Reproductive system diseases

(1) Testicular damage: It can be caused by radiotherapy and induce azoospermia or infertility (102). In the rat testicular damage model induced by gamma ray, hydrogen-rich saline has a protective effect, reducing the loss of male germ cells and protecting spermatogenesis (103-105). Studies on rat models have shown that hydrogen-rich saline can prevent testicular damage caused by I/R and spinal cord hemisection (106,107). In 2014, Li et al. (108) from China reported that long-term injection of hydrogen-rich saline can reduce nicotine-induced testicular oxidative stress damage in mice.

(2) Erectile dysfunction: In 2013, Fan et al. [109] from China reported that this symptom often occurs in diabetic rat models induced by streptozotocin (STZ), and injection of hydrogen-rich saline has a preventive effect.

(3) Ovarian damage: In 2015, Meng et al. (110) from China reported that injection of hydrogen-rich saline could alleviate ovarian damage in female rats induced by chemotherapy.

(4) Eclampsia: This is the most severe stage of gestational hypertension, and refers to convulsions that cannot be explained by other reasons based on gestational hypertension. It can occur at different times, such as before, during, and after delivery. In 2011, Yang et al. (111) reported that injection of hydrogen-rich saline had a preventive effect on epilepsy in hypertensive pregnant rats, but had no effect on normotensive pregnant rats.

9. Sensory system

(1) Vision: Retinal ischemia is a common cause of visual impairment and blindness. At the cellular level, ischemic retinal damage consists of a self-reinforcing destructive cascade, including neuronal depolarization, calcium influx, oxidative stress caused by energy failure, and glutamatergic stimulation. In 2010, Oharazawa et al. [112] from Japan reported that hydrogen-containing eye drops can improve retinal I/R damage caused by elevated intraocular pressure in rats, inhibit the increase of ·OH, reduce the number of retinal apoptotic cells, and prevent glial cell activation associated with retinal thinning. In 2012, Wei et al. (113) from China reported that glutamate-induced excitotoxic retinal damage prepared in guinea pigs can be alleviated by hydrogen-rich saline eye drops. In 2014, Sun et al. (114) from China reported that hydrogen-rich saline eye drops can promote the survival of retinal ganglion cells in a rat optic nerve injury model. In 2016, Chen et al. (5) from China reported that hydrogen-rich saline eye drops had a good therapeutic effect on retinal receptor degeneration induced by N-methyl-N-nitrosourea in rats. In 2011, Kubota et al. [116] from Japan reported that hydrogen-rich saline eye drops dissolved in N-acetyl-L-cysteine ​​could relieve oxidative stress on the corneal surface and inhibit angiogenesis in a mouse corneal alkali burn model.

(2) Hearing: In 2014, Kikkawa et al. (117) from Japan reported that when the ear is exposed to loud sounds for a long time, hair cells are overstimulated, leading to the production of ROS, which in turn causes cell death. Hydrogen has the effect of protecting hair cells. In the explant culture of auditory tissue, H can reduce the oxidative stress induced by epimycin and cisplatin, thereby protecting hair cells and preventing inner ear damage. A series of studies have shown that inhaling hydrogen, drinking hydrogen water, and injecting hydrogen-rich saline can protect inner ear hair cells and prevent noise-induced hearing loss in mice [118-121].

(3) Olfaction: In 2017, Yu et al. (122) reported that in a guinea pig allergic rhinitis model, injection of hydrogen-rich saline could attenuate eosinophil activation, reduce oxidative stress on the nasal mucosal surface, and improve allergic rhinitis.

(4) Touch: In 2012, Guo et al. (123) from China reported that intraperitoneal injection of hydrogen-rich saline could alleviate symptoms in a rat model of ultraviolet-induced dermatitis and skin damage. In 2014, Watanabe et al. (124) from Japan reported that hydrogen inhalation could alleviate symptoms after using a gamma-ray-induced model. In 2014, Mei et al. (125) from China reported that similar results were obtained by subcutaneous injection of hydrogen-rich water after using X-ray-induced models. In 2012, Ono et al. (126) from the United States reported that intravenous infusion of hydrogen-rich water was used for 4 patients with acute erythematous skin disease accompanied by fever and/or pain. After treatment, erythema and related symptoms were significantly improved and there was no recurrence. In 2013, Zhao et al. (127) from China reported that intraperitoneal injection of hydrogen-rich saline 10 minutes before skin flap transplantation in rats significantly increased the flap survival rate and flap blood perfusion compared with the group injected with normal saline. In 2015, Liu et al. (128) from China reported that when rats were rinsed with hydrogen-rich saline before flap transplantation, the flap survival rate and blood perfusion were significantly higher than those in the saline group. In 2015, Ishibashi et al. (129) from Japan reported that psoriasis patients were treated with three methods: dripping hydrogen-rich saline, inhaling hydrogen, and drinking hydrogen water. After treatment, the psoriasis disappeared in all three groups, and there was no difference in the efficacy.

(5) Taste: The development of oral bacterial biofilm is a major factor in causing oral diseases. In 2011, Kasuyama et al. (130) from Japan reported that rinsing the oral cavity with hydrogen-rich water in a rat periodontitis model could inhibit the formation of dental plaque by Streptococci and improve periodontitis symptoms. In 2017, Yoneda et al. (131) from Japan reported that long-term drinking of hydrogen-rich water could alleviate gingival oxidative stress and inhibit alveolar bone dissolution in rats fed a high-fat diet.

10. Musculoskeletal system

(1) Joint diseases: In 2011, Hanaoka et al. [132] from Japan reported that hydrogen can prevent NO from being converted to ONOO, protect cartilage cells from oxidative stress, indirectly change gene expression, and prevent or treat joint diseases. In 2014, Ishibashi et al. (133) from Japan reported that for patients with rheumatoid arthritis, infusion of hydrogen-rich saline for 4 weeks can significantly reduce the level of rheumatic factor in the blood, while the level of rheumatic factor in the saline control group increased. Jaw osteoporosis is a serious complication after radiotherapy for head and neck cancer. Most radiation-induced symptoms are caused by ROS produced by water radiolysis. In 2013, Sun et al. (134) from China reported that rats developed osteoporosis under simulated microgravity conditions. Injection of hydrogen-rich water can alleviate bone oxidative stress and reduce bone loss. In 2016, Huang et al. (135) from China reported that intraperitoneal injection of hydrogen-rich saline can play a preventive role in the steroid-induced osteonecrosis model. In 2017, Li et al. (136) from China reported that their experiments replicated the results of Huang et al. and found that hydrogen prevented hormone-induced rabbit osteonecrosis by inhibiting immune oxidative damage, vascular damage and cell apoptosis.

(2) Muscle diseases: In 2011, Ito et al. (137) from Japan reported that 5 patients with progressive muscular dystrophy (PMD), 4 patients with polymyositis/dermatomyositis (PM/DM), and 5 patients with mitochondrial myopathy (MM) were treated for 12 weeks by drinking 1 liter of hydrogen-rich water daily. They found that hydrogen-rich water could improve mitochondrial dysfunction in MM and reduce the intensity of PM/DM inflammation. In 2012, Aoki et al. [138] from Japan reported that drinking hydrogen-rich water could accelerate the relief of muscle fatigue in athletes with acute sports injuries. In 2014, Gu et al. (90) from China reported that glycerol could induce rhabdomyolysis and acute kidney injury models in rats, but if hydrogen-rich saline was injected intraperitoneally for 7 consecutive days before the model was established, it would not be successful. In 2017, Hasegawa et al. (139) from Japan reported that long-term drinking of hydrogen-rich water could inhibit the onset of mdx mice with congenital muscular dystrophy.

11. Blood system

(1) Acute graft-versus-host disease (GVHD): This is a fatal complication of hematopoietic stem cell transplantation, which usually occurs within a few months after transplantation. In 2013, Qian et al. (140) from China reported that intraperitoneal injection of hydrogen-rich saline before or after transplantation could prevent the occurrence of GVHD in a major histocompatibility complex (MHC)-incompatible mouse bone marrow transplantation model, and improve the survival rate and clinical scores of mice. In 2015, Yuan et al. (141) from China reported that they had repeated the same results, confirming that hydrogen-rich saline could improve the survival rate of mice after bone marrow transplantation, promote the recovery of white blood cells, reduce serum cytokine levels, and reverse tissue damage.

(2) Chronic graft-versus-host disease (GVHD): This disease usually occurs months or years after transplantation and is the most difficult complication of bone marrow transplantation to treat. Inflammation and fibrosis play a major role in the pathogenesis of chronic GVHD. In 2017, Qian et al. (142) reported that a chronic bone marrow transplant model was established in mice. Long-term intraperitoneal injection of hydrogen-rich saline into the recipient mice significantly alleviated the symptoms of scleroderma caused by rejection and prolonged the time it took for the graft to be rejected.

(3) Aplastic anemia (AA): In 2013, Zhao et al. (43) from China reported that they established an AA model in mice. After intraperitoneal injection of hydrogen-rich saline, the body weight and peripheral blood cell count of the mice were significantly improved, the bone marrow microenvironment was significantly improved, and tissue repair was accelerated. The number of CD4+ and CD8+ cells and the CD4/CD8 ratio in the peripheral blood of the treatment group gradually returned to normal, and the levels of serum TNF, IFN, and IL-6 decreased. In addition, the use of hydrogen water has been found to increase blood alkalinity in healthy men (144, 1457), inhibit collagen-induced platelet aggregation in healthy humans and rats (146), and increase the serum antioxidant level of thoroughbred horses (147).

12. Infection

(1) Sepsis: Sepsis is characterized by a severe inflammatory response to infection and is the main cause of death in critically ill patients. In 2014, Xie et al. (48) from China reported that zymosan is a substance derived from the cell wall of Saccharomyces cerevisiae that can induce multiple inflammatory mediators and lead to systemic inflammation. Inhalation of H2 starting 1 hour and 6 hours after zymosan injection significantly improved the 14-day survival rate of mice, from 10% to 70%, and the damage to liver and kidney function was also significantly reduced. In 2016, Zheng et al. (149) from China summarized the literature on the protective effect of molecular hydrogen therapy on patients with sepsis and believed that the protective effect was manifested in basic vital signs, organ function (brain, lung, liver, kidney, small intestine, etc.), survival rate, etc. Molecular hydrogen therapy can significantly reduce the release of inflammatory factors and oxidative stress damage, thereby reducing the damage of sepsis to the function of various organs and improving survival rate.

(2) Sepsis complications: In 2018, Dong et al. (150) from China reported that a mouse sepsis model was established using the cecal ligation method. They found that hydrogen inhalation could increase the 14-day survival rate of mice with moderate sepsis to 100%, and the 7-day survival rate of mice with severe sepsis from 0% to 70%. It also reduced lung, liver, and kidney damage in patients with severe sepsis. The authors believed that the therapeutic mechanism was related to regulating mitochondrial function.

13. Neonatal diseases

(1) Neonatal encephalopathy is a major cause of neonatal and infant mortality, often leading to autism, cerebral palsy, mental retardation, and other neurological and cognitive disorders. Perinatal asphyxia is an important cause of brain damage, and inflammation and oxidative stress are the main mechanisms leading to hypoxic-ischemic damage and neuronal apoptosis. In 2009, Cai et al. (151) from China reported that a hypoxic-ischemic model was prepared in neonatal rats by ligating the left common carotid artery. Intraperitoneal injection of hydrogen-rich saline inhibited neuronal apoptosis and improved long-term neurological and neurobehavioral functions. In 2014, Dohi et al. from the United States reported that giving pregnant women hydrogen-rich water could improve brain damage caused by intrauterine ischemia in newborns (152).

(2) Anesthetic damage: The use of anesthetics in the immature brain can lead to pathological changes and long-term behavioral abnormalities (153). A basic study showed that exposure to sevoflurane (SEV) can induce abnormal behaviors similar to autism (154). In 2017, Shi et al. (155) from China reported that combined hydrogen inhalation in neonatal mice could inhibit the increase in oxidative stress, neuronal apoptosis, and subsequent neurobehavioral deficits caused by SEV exposure, and reduce the adverse reactions caused by anesthetic exposure.

14. Cancer recovery

More and more studies have found that ROS are related to the generation, proliferation, angiogenesis, invasion and distant metastasis of human tumor cells (156). Molecular hydrogen is being increasingly studied for the treatment, prevention and rehabilitation of cancer. In 2009, Nakashima-Kamimura et al. (Japan) reported that cisplatin is an anticancer drug widely used in tumor treatment and has obvious nephrotoxicity. Mice given cisplatin inhaled hydrogen and found that the complications caused by cisplatin were significantly reduced. Mice given cisplatin and drinking water also had an effect similar to hydrogen inhalation. In 2010, Kitamura et al. (157) of Japan reported that drinking hydrogen-rich water 7 days before cisplatin injection showed significant improvement in the renal CT imaging and serum creatinine clearance compared with drinking ordinary water. In 2011, Kang et al. (52) of China reported that cancer patients receiving radiotherapy often feel fatigue and have a decreased quality of life. Drinking hydrogen-rich water has antioxidant properties and significantly improves the quality of life score during radiotherapy without affecting the effect of tumor treatment.

4. Maintaining Health and Treating Disease Before It Happens

Modern lifestyles significantly increase oxidative stress in our bodies, disrupting our internal balance and leading to a growing number of sub-health conditions. Molecular hydrogen not only provides safe and effective treatments for diseases but also helps restore homeostasis in cells and organs, preventing severe disruptions from adverse environments and playing a unique role in maintaining overall human health. Molecular hydrogen can overcome sub-health conditions and enhance and improve quality of life in the following ways.

1. Eliminate fatigue

Chronic fatigue syndrome is a major disease that plagues modern urbanites. It is often accompanied by elevated levels of inflammatory cytokines (including TNF-a, IL-1B, and IL-6) and Th-17 cell-mediated pro-inflammatory cytokines (such as IL-23 and IL-17), which disrupt energy homeostasis. Continuous or repetitive exercise can over-consume glycogen and ATP. In 2018, Ara et al. (159) from South Korea reported that drinking hydrogen-rich water blocked blood lactate production in mice, reduced urea nitrogen, ROS, and inflammatory factor levels, increased lactate degrading enzyme and glutathione peroxidase activity, improved the tolerance of the test animals, and promoted liver glycogen synthesis, thereby exerting an anti-fatigue effect.

2. Improve the quality of life

Everyone seeks a healthy and vibrant life, that is, a high quality of life. Aging, poverty, and work-related stress can all lead to increased oxidative stress in healthy individuals. Molecular hydrogen can improve quality of life by eliminating various "discomforts" through its antioxidant activity and inflammation prevention. In 2017, Mizuno et al. (160) in Japan reported that regular consumption of hydrogen-rich water can improve mood, anxiety, and autonomic dysfunction in adults, thereby enhancing quality of life.

3. Beauty effect

In 2018, Zhou et al. [161] reported that they used electron beam irradiation to prepare a skin wound model in rats (simulating ultraviolet damage such as sunlight). The rats were treated with spraying ordinary water, hydrogen-rich water, and drinking hydrogen-rich water, respectively, and the wound healing time and the healing speed of the wound surface were observed. It was found that the effects of the spraying and drinking hydrogen-rich water groups were similar. The levels of various inflammatory factors secreted by the animals were significantly reduced, and the wound healing was significantly better than that of the ordinary water group. The therapeutic effect was positively correlated with the hydrogen concentration.

4. Anti-aging

Although aging is an irresistible process, everyone hopes that aging will proceed as slowly as possible. The arrest of the cell cycle is a prerequisite for cell aging. Studies have shown that p53 and 16 genes play an important role in the aging process (162,163). p53 is a stress protein that is rapidly upregulated when cells are stimulated, preventing the cell cycle and promoting cell aging (163). p16 protein can competitively bind to cell cycle-dependent kinases, preventing the cell cycle and inducing aging (164). In 2016, Zhu et al. (165) from China reported that with age, p53 and 16 showed an upregulation trend, and H2 can inhibit their expression and promote the cell cycle. In 2017, Ghoshal et al. (166) from India reported a meaningful survey: the concentration of H2 in the exhaled breath of centenarians was measured to reflect the H2 produced by the intestine. The results showed that the H2 concentration of centenarians was significantly higher than that of healthy controls and elderly diabetic patients. The survey suggests that increasing the production of H2 in the intestine may help prolong the life of the elderly, which may also be related to diet and intestinal microbiota.

5. Safety of Hydrogen

According to the British newspaper The Guardian, from its DNA to its atoms, the human body itself is a scientific marvel. Strangely behaving quantum particles, such as atoms and their constituents, make up the solid body we live in. Every atom in our bodies is billions of years old. Hydrogen, the most common element in the universe and the primary component of our bodies, formed during the Big Bang 13.7 billion years ago. Atoms heavier than hydrogen, such as carbon and oxygen, formed in stars between 7 and 12 billion years ago and spread throughout the universe as those stars exploded. This means that the human body is made of incredibly ancient materials: humans are essentially stardust.

In the Chinese Taoist view, heaven is nature, and man is part of nature. Zhuangzi said, "Man is heaven; heaven is also heaven; heaven and man are one." Laozi said, "Man follows the earth, the earth follows heaven, heaven follows the Tao, and the Tao follows nature."

Perhaps hydrogen is a part of our body, and it is probably a very important component. As early as 1969, the New England Journal of Medicine (N EnglJ Med) published an article by Levitt entitled "Hydrogen Production and Excretion in the Human Body" [167] (see Figure 3, left). The author measured the production of hydrogen in the intestine in 10 normal people. The results showed that 0.06 to 29 ml of hydrogen was produced per minute in the fasting state, with an average of 0.24 ml; after lactulose was infused into the intestine, hydrogen production increased rapidly, reaching an average of 1.6 ml/minute; after eating, hydrogen production increased by 7 to 30 times. Under normal circumstances, 99% of hydrogen is produced in the colon. In a patient with excessive small intestinal flora, the production of hydrogen in the small intestine increased significantly. 14% of hydrogen produced in the body is excreted through the lungs.

The amount excreted is positively correlated with the amount produced.

Figure 3 Levitt's articles published in N Engl J Med in 1969 and 1980

In 1980, Levitt published another article in the New England Journal of Medicine (see Figure 3, right), criticizing some reports for deliberately introducing H2 research into the field of hot air (163), pointing out that H2 production in the intestine is an integral part of human physiology. If calculated based on Levitt's H2 production rate, the average daily production of a normal person is 345.6 ml, with a maximum of 41,740 ml; after eating, the maximum H2 production is 292.18 liters if multiplied by 7, and 1252.8 liters if multiplied by 30. The hydrogen-oxygen atomizer currently used for hydrogen inhalation produces a maximum gas flow of 3 liters per minute, containing 66% hydrogen and 34% oxygen. It is estimated that 20% is actually inhaled into the lungs. If calculated based on 2 hours of hydrogen inhalation per day, the amount of hydrogen inhaled per day is 47.52 liters, and if calculated based on 4 hours, the amount is 95.4 liters, both of which are far lower than the amount of hydrogen produced in the body after eating.

From an evolutionary perspective, it's not surprising that molecules can produce biological effects. Beyond its role in the origin of the universe, hydrogen also played a role in the origin of life and has played a significant role in the evolution of eukaryotes. Over millions of years of evolution, plants and animals have developed a mutualistic relationship with hydrogen-producing bacteria, maintaining a certain base level of molecular hydrogen in eukaryotic systems. It's reasonable to infer that eukaryotic organisms may have retained their sensitivity and dependence on molecular hydrogen over these millions of years of evolution.

Therefore, inhaling hydrogen or taking other methods (oral intake of hydrogen water, hydrogen water baths, hydrogen salt water infusion) to introduce molecules into the body is just an adaptation to the biological process of living organisms and a form of compensation for the body.

Conclusion

Is there a "magic bullet" that can cure all diseases? In recent years, people have favored two drugs - metformin and aspirin. The former is believed to be able to treat diabetes and prevent and treat cancer, while the latter is considered to be an "evergreen tree" that has withstood 120 years of wind and frost, and has preventive and therapeutic effects on both cardiovascular disease and cancer.

However, at the European Society of Cardiology (ESC) Annual Meeting held in 2018, research teams from Harvard University and Oxford University respectively reported the results of two large clinical trials: for middle-aged and elderly people at moderate risk of cardiovascular disease and diabetic patients, there is basically no benefit in using aspirin to prevent cardiovascular disease and stroke! The papers were published in Lancel (168) FIIN Engl J Med (169) respectively.

While metformin hasn't suffered the same fate, the saying "beauties age with age, heroes are not allowed to see old age" seems to have faded the glory days of aspirin. However, history is ultimately a long, unending river, sweeping away the frivolous dregs and leaving behind the shining essence. Perhaps chemical drugs, not meant for the human body, will always be its companions.

Molecular hydrogen is different. It is not a medicine, but a natural and physiological thing. It benefits people and seems to be a good medical prescription for "treating illness before it occurs", "treating different diseases with the same method" and "treating without medicine".

References

[1] Dole M, Wilson FR,Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science, 1975, 190(4210): 152-154.

[2] Gharib B, Hanna S, Abdallahi OM, et al. Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation. CR Acad Sci III, 2001, 324(8): 719-724.

[3] Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13(6): 688-694.

[4] Ohta S. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des, 2011, 17(22): 2241-2252.

[5] Hayashida K, Sano M, Ohsawa I, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun, 2008, 373(1): 30-35.

[6] Yamamoto R, Homma K,Suzuki K. Hydrogen gas distribution in organs after inhalation: real-time monitoring of tissue hydrogen concertration in rat. Sci Rep, 2019, 9(1): 1255.

[7] Liu H, Colavitti R, Rovira, II, et al. Redox-dependent transcriptional regulation. Circ Res, 2005, 97(10): 967-974. [8] Salganik RI. The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J Am Coll Nutr, 2001, 20(5 Suppl): 464S-472S; discussion 473S-475S.

[9] Winterbourn CC. Biological reactivity and biomarkers of the neutrophil oxidant, hypochlorous acid. Toxicology, 2002, 181-182: 223-227.

[10] Murad F. Discovery of some of the biological effects of nitric oxide and its role in cell signaling. Biosci Rep, 2004, 24(4-5): 452-474.

[11] Bjelakovic G and Gluud C. Surviving antioxidant supplements. Journal of the National Cancer Institute, 2007, 99(10): 742-743.

[12] Ge L, Yang M, Yang NN, et al. Molecular hydrogen: a preventive and therapeutic medical gas for various diseases. Oncotarget, 2017, 8(60): 102653-102673.

[13] Kajimura M, Fukuda R, Bateman RM, et al. Interactions of multiple gas-transducing systems: hallmarks and uncertainties of CO, NO, and H2S gas biology. Antioxid Redox Signal, 2010, 13(2): 157-192. [14] Szabo C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov, 2007, 6(11): 917-935. [15] Abraini JH, Gardette-Chauffour MC, Martinez E, et al. Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture. J Appl Physiol (1985), 1994, 76(3): 1113-1118.

[16] Fontanari P, Badier M, Guillot C, et al. Changes in maximal performance of inspiratory and skeletal muscles during and after the 7.1-MPa Hydra 10 record human dive. Eur J Appl Physiol, 2000, 81(4): 325- 328.

[17] Sano M, Suzuki M, Homma K, et al. Promising novel therapy with hydrogen gas for emergency and critical care medicine. Acute Med Surg, 2018, 5(2): 113-118.

[18] Diakos CI, Charles KA, McMillan DC, et al. Cancer-related inflammation and treatment effectiveness. Lancet Oncol, 2014, 15(11): e493-503.

[19] Ishibashi T. Molecular hydrogen: new antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Curr Pharm Des, 2013, 19(35): 6375-6381.

[20] Zhang JY, Liu C, Zhou L, et al. A review of hydrogen as a new medical therapy. Hepatogastroenterology, 2012, 59(116): 1026-1032.

[21] Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol, 2007, 35(4): 495-516.

[22] Du H, Sheng M, Wu L, et al. Hydrogen-Rich Saline Attenuates Acute Kidney Injury After Liver Transplantation via Activating p53-Mediated Autophagy. Transplantation, 2016, 100(3): 563-570.

[23] Cai J, Kang Z, Liu WW, et al. Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci Lett, 2008, 441(2): 167-172.

[24] Kawamura T, Huang CS, Tochigi N, et al. Inhaled hydrogen gas therapy for prevention of lung transplant- induced ischemia/reperfusion injury in rats. Transplantation, 2010, 90(12): 1344-1351.

[25] Hong Y, Shao A, Wang J, et al. Neuroprotective effect of hydrogen-rich saline against neurologic damage and apoptosis in early brain injury following subarachnoid hemorrhage: possible role of the Akt/GSK3beta signaling pathway. PLoS One, 2014, 9(4): e96212.

[26] Hou Z, Luo W, Sun X, et al. Hydrogen-rich saline protects against oxidative damage and cognitive deficits after mild traumatic brain injury. Brain Res Bull, 2012, 88(6): 560-565.

[27] Nakai Y, Sato B, Ushiama S, et al. Hepatic oxidoreduction-related genes are upregulated by administration of hydrogen-saturated drinking water. Biosci Biotechnol Biochem, 2011, 75(4): 774-776.

[28] Liu Q, Shen WF, Sun HY, et al. Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice. Liver Int, 2010, 30(7): 958-968.

[29] Xiao M, Zhu T, Wang T, et al. Hydrogen-rich saline reduces airway remodeling via inactivation of NF- kappaB in a murine model of asthma. Eur Rev Med Pharmacol Sci, 2013, 17(8): 1033-1043.

[30] Nagata K, Nakashima-Kamimura N, Mikami T, et al. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology, 2009, 34(2): 501-508.

[31] Manaenko A, Lekic T, Ma Q, et al. Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice. Crit Care Med, 2013, 41(5): 1266-1275.

[32] Zhuang Z, Sun XJ, Zhang X, et al. Nuclear factor-kappaB/Bcl-XL pathway is involved in the protective effect of hydrogen-rich saline on the brain following experimental subarachnoid hemorrhage in rabbits. J Neurosci Res, 2013, 91(12): 1599-1608.

[33] Shao A, Wu H, Hong Y, et al. Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-kappaB Pathway and NLRP3 Inflammasome. Mol Neurobiol, 2016, 53(5): 3462-3476.

[34] Fu Y, Ito M, Fujita Y, et al. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease. Neurosci Lett, 2009, 453(2): 81-85. [35] Fujita K, Seike T, Yutsudo N, et al. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. PLoS One, 2009, 4(9): e7247.

[36] Yoritaka A, Takanashi M, Hirayama M, et al. Pilot study of H(2) therapy in Parkinson's disease: a randomized double-blind placebo-controlled trial. Mov Disord, 2013, 28(6): 836-839.

[37] Li J, Wang C, Zhang JH, et al. Hydrogen-rich saline improves memory function in a rat model of amyloid- beta-induced Alzheimer's disease by reduction of oxidative stress. Brain Res, 2010, 1328: 152-161.

[38] Wang C, Li J, Liu Q, et al. Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-kappaB activation in a rat model of amyloid-beta-induced Alzheimer's disease. Neurosci Lett, 2011, 491(2): 127-132.

[39] Jing L, Wang Y, Zhao XM, et al. Cardioprotective Effect of Hydrogen-rich Saline on Isoproterenol-induced Myocardial Infarction in Rats. Heart Lung Circ, 2015, 24(6): 602-610.

[40] Gao Y, Yang H, Fan Y, et al. Hydrogen-Rich Saline Attenuates Cardiac and Hepatic Injury in Doxorubicin Rat Model by Inhibiting Inflammation and Apoptosis. Mediators Inflamm, 2016, 2016: 1320365. [41] Huo TT, Zeng Y, Liu XN, et al. Hydrogen-rich saline improves survival and neurological outcome after cardiac arrest and cardiopulmonary resuscitation in rats. Anesth Analg, 2014, 119(2): 368-380.

[42] Knight RJ, Dikman S, Liu H, et al. Cold ischemic injury accelerates the progression to chronic rejection in a rat cardiac allograft model. Transplantation, 1997, 64(8): 1102-1107.

[43] Sun Q, Kang Z, Cai J, et al. Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp Biol Med (Maywood), 2009, 234(10): 1212-1219.

[44] Zhang Y, Sun Q, He B, et al. Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion. Int J Cardiol, 2011, 148(1): 91-95.

[45] Fan Z, Gao Y, Huang Z, et al. Protective effect of hydrogen-rich saline on pressure overload-induced cardiac hypertrophyin rats: possible role of JAK-STAT signaling. BMC Cardiovasc Disord, 2018, 18(1): 32. [46] Ohsawa I, Nishimaki K, Yamagata K, et al.Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochem Biophys Res Commun, 2008, 377(4): 1195-1198.

[47] Matsuoka H, Miyata S, Okumura N, et al. Hydrogen gas improves left ventricular hypertrophy in Dahl rat of salt-sensitive hypertension. Clin Exp Hypertens, 2018, 1-5.

[48] Guan P, Lin XM, Yang SC, et al. Hydrogen gas reduces chronic intermittent hypoxia-induced hypertension by inhibiting sympathetic nerve activity and increasing vasodilator responses via the antioxidation. J Cell Biochem, 2019, 120(3): 3998-4008.

[49] Kajiya M, Sato K, Silva MJ, et al. Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis. Biochem Biophys Res Commun, 2009, 386(2): 316-321.

[50] Xia C, Liu W, Zeng D, et al. Effect of hydrogen-rich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis B. Clin Transl Sci, 2013, 6(5): 372-375.

[51] Fukuda K, Asoh S, Ishikawa M, et al. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem Biophys Res Commun, 2007, 361(3): 670- 674.

[52] Kang KM, Kang YN, Choi IB, et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Med Gas Res, 2011, 1(1): 11.

[53] Kawai D, Takaki A, Nakatsuka A, et al. Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. Hepatology, 2012, 56(3): 912-921.

[54] Tan YC, Xie F, Zhang HL, et al. Hydrogen-rich saline attenuates postoperative liver failure after major hepatectomy in rats. Clin Res Hepatol Gastroenterol, 2014, 38(3): 337-345.

[55] Liu Y, Yang L, Tao K, et al. Protective effects of hydrogen enriched saline on liver ischemia reperfusion injury by reducing oxidative stress and HMGB1 release. BMC Gastroenterol, 2014, 14: 12.

[56] Lee PC, Yang YY, Huang CS, et al. Concomitant inhibition of oxidative stress and angiogenesis by chronic hydrogen-rich saline and N-acetylcysteine treatments improves systemic, splanchnic and hepatic hemodynamics of cirrhotic rats. Hepatol Res, 2015, 45(5): 578-588.

[57] Liu Q, Li BS, Song YJ, et al. Hydrogen-rich saline protects against mitochondrial dysfunction and apoptosis in mice with obstructive jaundice. Mol Med Rep, 2016, 13(4): 3588-3596.

[58] Shi Q, Chen C, Deng WH, et al. Hydrogen-Rich Saline Attenuates Acute Hepatic Injury in Acute Necrotizing Pancreatitis by Inhibiting Inflammation and Apoptosis, Involving JNK and p38 Mitogen- Activated Protein Kinase-dependent Reactive Oxygen Species. Pancreas, 2016, 45(10): 1424-1431. [59] Zhai X, Chen X, Lu J, et al. Hydrogen-rich saline improves nonalcoholic fatty liver disease by alleviating oxidative stress and activating hepatic PPARalpha and PPARgamma. Mol Med Rep, 2017, 15(3): 1305-

1312.

[60] Koyama Y, Taura K, Hatano E, et al. Effects of oral intake of hydrogen water on liver fibrogenesis in mice. Hepatol Res, 2014, 44(6): 663-677.

[61] Zhang DQ, Feng H,Chen WC. Effects of hydrogen-rich saline on taurocholate-induced acute pancreatitis in rat. Evid Based Complement Alternat Med, 2013, 2013: 731932.

[62] Luo ZL, Cheng L, Ren JD, et al. Hydrogen-rich saline protects against ischemia/reperfusion injury in grafts after pancreas transplantations by reducing oxidative stress in rats. Mediators Inflamm, 2015, 2015: 281985.

[63] Levitt MD. Intestinal gas production--recent advances in flatology. N Engl J Med, 1980, 302(26): 1474-1475.

[64] Liu X, Chen Z, Mao N, et al. The protective of hydrogen on stress-induced gastric ulceration. Int Immunopharmacol, 2012, 13(2): 197-203.

[65] Zhang JY, Wu QF, Wan Y, et al. Protective role of hydrogen-rich water on aspirin-induced gastric mucosal damage in rats. World journal of gastroenterology: WJG, 2014, 20(6): 1614-1622.

[66] McCarty MF. Potential ghrelin-mediated benefits and risks of hydrogen water. Med Hypotheses, 2015, 84(4): 350-355.

[67] Ichihara M, Sobue S, Ito M, et al. Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles. Med Gas Res, 2015, 5: 12.

[68] Buchholz BM, Kaczorowski DJ, Sugimoto R, et al. Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am J Transplant, 2008, 8(10): 2015-2024.

[69] Zheng X, Mao Y, Cai J, et al. Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res, 2009, 43(5): 478-484.

[70] Chen H, Sun YP, Hu PF, et al. The effects of hydrogen-rich saline on the contractile and structural changes of intestine induced by ischemia-reperfusion in rats. J Surg Res, 2011, 167(2): 316-322.

[71] Shigeta T, Sakamoto S, Li XK, et al. Luminal injection of hydrogen-rich solution attenuates intestinal ischemia-reperfusion injury in rats. Transplantation, 2015, 99(3): 500-507.

[72] Zhou H, Fu Z, Wei Y, et al. Hydrogen inhalation decreases lung graft injury in brain-dead donor rats. J Heart Lung Transplant, 2013, 32(2): 251-258.

[73] Zhai Y, Zhou X, Dai Q, et al. Hydrogen-rich saline ameliorates lung injury associated with cecal ligation and puncture-induced sepsis in rats. Exp Mol Pathol, 2015, 98(2): 268-276.

[74] Sun Q, Cai J, Liu S, et al. Hydrogen-rich saline provides protection against hyperoxic lung injury. J Surg Res, 2011, 165(1): e43-49.

[75] Muramatsu Y, Ito M, Oshima T, et al. Hydrogen-rich water ameliorates bronchopulmonary dysplasia (BPD) in newborn rats. Pediatr Pulmonol, 2016, 51(9): 928-935. E40288 2105

[76] Liu S, Liu K, Sun Q, et al. Consumption of hydrogen water reduces paraquat-induced acute lung injury in rats. J Biomed Biotechnol, 2011, 2011: 305086.

qque vd zim bend

[77] Wang Y, Jing L, Zhao XM, et al. Protective effects of hydrogen-rich saline on monocrotaline-induced diy pulmonary hypertension in a rat model. Respir Res, 2011, 12:26. Hapi aboU,2 olemusta [4] [78] Fang Y, Fu XJ, Gu C, et al. Hydrogen-rich saline protects against acute lung injury induced by extensive no burn in rat model. J Burn Care Res, 2011, 32(3): e82-91.

[79] Liu Z, Geng W, Jiang C, et al. Hydrogen-rich saline inhibits tobacco smoke-induced chronic obstructive

[113 pulmonary disease by alleviating airway inflammation and mucus hypersecretion in rats. Exp Biol Med ban (Maywood), 2017, 242(15): 1534-1541.0 MonseA,Dnwego2sH2 invite pe

[80] Liu X, Ma C, Wang X, et al. Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model. Int J Chron Obstruct Pulmon Dis, 2017, 12: 1309-1324. AT

[81] Suzuki Y, Sato T, Sugimoto M, et al. Hydrogen-rich pure water prevents cigarette smoke-induced eriz pulmonary emphysema in SMP30 knockout mice. Biochem Biophys Res Commun, 2017, 492(1): 74-81.

[82] Sun L, Dutta RK, Xie P, et al. Myo-Inositol oxygenase overexpression accentuates generation of reactive si oxygen species and exacerbates cellular injury following high glucose ambience: a new mechanism relevant -E to the pathogenesis of diabetic nephropathy. J Biol Chem, 2016, 291(11): 5688-5707.diven Innimobde

[83] Liu H, Hua N, Xie K, et al. Hydrogen-rich saline reduces cell death through inhibition of DNA oxidative Svo stress and overactivation of poly (ADP-ribose) polymerase-1 in retinal ischemia-reperfusion injury. Mol [118 Med Rep, 2015, 12(2): 2495-2502.

I

[84] Wang R, Wu J, Chen Z, et al. Postconditioning with inhaled hydrogen promotes survival of retinal ganglion cells in a rat model of retinal ischemia/reperfusion injury. Brain Res, 2016, 1632: 82-90.

[85] Nakashima-Kamimura N, Mori T, Ohsawa I, et al. Molecular hydrogen alleviates nephrotoxicity induced In by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol, 2009, 64(4): 753-761.

Iso bomb

[86] Li FY, Zhu SX, Wang ZP, et al. Consumption of hydrogen-rich water protects against ferric nitrilotriacetate- induced nephrotoxicity and early tumor promotional events in rats. Food Chem Toxicol, 2013, 61: 248-254. [87] Katakura M, Hashimoto M, Tanabe Y, et al. Hydrogen-rich water inhibits glucose and alpha,beta -dicarbonyl compound-induced reactive oxygen species production in the SHR.Cg-Leprcp/NDmcr rat kidney. Med Gas Res, 2012, 2(1): 18.

[88] Xu B, Zhang YB, Li ZZ, et al. Hydrogen-rich saline ameliorates renal injury induced by unilateral ureteral obstruction in rats. Int Immunopharmacol, 2013, 17(2): 447-452.

[89] Xin HG, Zhang BB, Wu ZQ, et al. Consumption of hydrogen-rich water alleviates renal injury in To spontaneous hypertensive rats. Mol Cell Biochem, 2014, 392(1-2): 117-124.

[90] Gu H, Yang M, Zhao X, et al. Pretreatment with hydrogen-rich saline reduces the damage caused by glycerol-induced rhabdomyolysis and acute kidney injury in rats. J Surg Res, 2014, 188(1): 243-249.

[91] Liu W, Dong XS, Sun YQ, et al. A novel fluid resuscitation protocol: provide more protection on acute kidney injury during septic shock in rats. Int J Clin Exp Med, 2014, 7(4): 919-926.J 2 J [807]

[92] Shi Q, Liao KS, Zhao KL, et al. Hydrogen-rich saline attenuates acute renal injury in sodium taurocholate- induced severe acute pancreatitis by inhibiting ROS and NF-kappaB pathway. Mediators Inflamm, 2015, 2015: 685043.

[93] Guo SX, Fang Q, You CG, et al. Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation. J Transl Med, 2015, 13: 183.

[94] Matsumoto S, Ueda T,Kakizaki H. Effect of supplementation with hydrogen-rich  water in patients with interstitial cystitis/painful bladder syndrome. Urology, 2013, 81(2): 226-230.

[95] Kamimura N, Nishimaki K, Ohsawa I, et al. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity (Silver Spring), 2011, 19(7): 1396- 1403.

[96] Kajiyama S, Hasegawa G, Asano M, et al. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res, 2008, 28(3): 137- 143.

[97] Zong C, Song G, Yao S, et al. Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet-fed hamsters. Metabolism, 2012, 61(6): 794-800.

[98] Nishimura N, Tanabe H, Adachi M, et al. Colonic hydrogen generated from fructan diffuses into the abdominal cavity and reduces adipose mRNA abundance of cytokines in rats. J Nutr, 2013, 143(12): 1943- 1949.

[99] Song G, Li M, Sang H, et al. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome. J Lipid Res, 2013, 54(7): 1884-1893. [100] Suzuki Y, Sano M, Hayashida K, et al. Are the effects of alpha-glucosidase inhibitors on cardiovascular events related to elevated levels of hydrogen gas in the gastrointestinal tract? FEBS Lett, 2009, 583(13): 2157-2159.

[101] Amitani H, Asakawa A, Cheng K, et al. Hydrogen improves glycemic control in typel diabetic animal model by promoting glucose uptake into skeletal muscle. PLoS One, 2013, 8(1): e53913.

[102] Colpi GM, Contalbi GF, Nerva F, et al. Testicular function following chemo-radiotherapy. Eur J Obstet Gynecol Reprod Biol, 2004, 113 Suppl 1: S2-6.

[103] Chuai Y, Shen J, Qian L, et al. Hydrogen-rich saline protects spermatogenesis and hematopoiesis in irradiated BALB/c mice. Med Sci Monit, 2012, 18(3): BR89-94.

[104] Chuai Y, Gao F, Li B, et al. Hydrogen-rich saline attenuates radiation-induced male germ cell loss in mice through reducing hydroxyl radicals. Biochem J, 2012, 442(1): 49-56.

[105] Jiang Z, Xu B, Yang M, et al. Protection by hydrogen against gamma ray-induced testicular damage in rats. Basic Clin Pharmacol Toxicol, 2013, 112(3): 186-191.

[106] Jiang D, Wu D, Zhang Y, et al. Protective effects of hydrogen rich saline solution on experimental testicular ischemia-reperfusion injury in rats. J Urol, 2012, 187(6): 2249-2253.

[107] Ge L, Wei LH, Du CQ, et al. Hydrogen-rich saline attenuates spinal cord hemisection-induced testicular injury in rats. Oncotarget, 2017, 8(26): 42314-42331.

[108] Li S, Lu D,Zhang Y. Long-term treatment of hydrogen-rich saline abates testicular oxidative stress induced by nicotine in mice. J Assist Reprod Genet, 2014, 31(1): 109-114.

[109] Fan M, Xu X, He X, et al. Protective effects of hydrogen-rich saline against erectile dysfunction in a streptozotocin induced diabetic rat model. J Urol, 2013, 190(1): 350-356.

[110] Meng X, Chen H, Wang G, et al. Hydrogen-rich saline attenuates chemotherapy-induced ovarian injury via regulation of oxidative stress. Exp Ther Med, 2015, 10(6): 2277-2282.

[111] Yang X, Guo L, Sun X, et al. Protective effects of hydrogen-rich saline in preeclampsia rat model. Placenta, 2011, 32(9): 681-686.

[112] Oharazawa H, Igarashi T, Yokota T, et al. Protection of the retina by rapid diffusion of hydrogen: administration of hydrogen-loaded eye drops in retinal ischemia-reperfusion injury. Invest Ophthalmol Vis Sci, 2010, 51(1): 487-492.

[113] Wei L, Ge L, Qin S, et al. Hydrogen-rich saline protects retina against glutamate-induced excitotoxic injury in guinea pig. Exp Eye Res, 2012, 94(1): 117-127.

[114] Sun JC, Xu T, Zuo Q, et al. Hydrogen-rich saline promotes survival of retinal ganglion cells in a rat model of optic nerve crush. PLoS One, 2014, 9(6): e99299.

[115] Chen T, Tao Y, Yan W, et al. Protective effects of hydrogen-rich saline against N-methyl-N-nitrosourea- induced photoreceptor degeneration. Exp Eye Res, 2016, 148: 65-73.

[116] Kubota M, Shimmura S, Kubota S, et al. Hydrogen and N-acetyl-L-cysteine rescue oxidative stress- induced angiogenesis in a mouse corneal alkali-burn model. Invest Ophthalmol Vis Sci, 2011, 52(1): 427- 433.

[117] Kikkawa YS, Nakagawa T, Taniguchi M, et al. Hydrogen protects auditory hair cells from cisplatin- induced free radicals. Neurosci Lett, 2014, 579: 125-129.

[118] Taura A, Kikkawa YS, Nakagawa T, et al. Hydrogen protects vestibular hair cells from free radicals. Acta Otolaryngol Suppl, 2010, 563): 95-100.

[119] Lin Y, Kashio A, Sakamoto T, et al. Hydrogen in drinking water attenuates noise-induced hearing loss in guinea pigs. Neurosci Lett, 2011, 487(1): 12-16.

[120] Chen L, Yu N, Lu Y, et al. Hydrogen-saturated saline protects intensive narrow band noise-induced hearing loss in guinea pigs through an antioxidant effect. PLoS One, 2014, 9(6): e100774.

[121] Kurioka T, Matsunobu T, Satoh Y, et al. Inhaled hydrogen gas therapy for prevention of noise-induced hearing loss through reducing reactive oxygen species. Neurosci Res, 2014, 89: 69-74.

[122] Yu S, Zhao C, Che N, et al. Hydrogen-rich saline attenuates eosinophil activation in a guinea pig model of

allergic rhinitis via reducing oxidative stress. J Inflamm (Lond), 2017, 14: 1.

[123] Guo Z, Zhou B, Li W, et al. Hydrogen-rich saline protects against ultraviolet B radiation injury in rats. J

Biomed Res, 2012, 26(5): 365-371.

[124] Watanabe S, Fujita M, Ishihara M, et al. Protective effect of inhalation of hydrogen gas on radiation- induced dermatitis and skin injury in rats. J Radiat Res, 2014, 55(6): 1107-1113.

[125] Mei K, Zhao S, Qian L, et al. Hydrogen protects rats from dermatitis caused by local radiation. J Dermatolog Treat, 2014, 25(2): 182-188.

[126] Ono H, Nishijima Y, Adachi N, et al. Hydrogen (H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers. Med Gas Res, 2012, 2(1): 14.

[127] Zhao L, Wang YB, Qin SR, et al. Protective effect of hydrogen-rich saline on ischemia/reperfusion injury in rat skin flap. J Zhejiang Univ Sci B, 2013, 14(5): 382-391.

[128] Liu YQ, Liu YF, Ma XM, et al. Hydrogen-rich saline attenuates skin ischemia/reperfusion induced apoptosis via regulating Bax/Bcl-2 ratio and ASK-1/JNK pathway. J Plast Reconstr Aesthet Surg, 2015, 68(7): e147- 156.

[129] Ishibashi T, Ichikawa M, Sato B, et al. Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. Mol Med Rep, 2015, 12(2): 2757-2764. [130] Kasuyama K, Tomofuji T, Ekuni D, et al. Hydrogen-rich  water attenuates experimental periodontitis in a rat model. J Clin Periodontol, 2011, 38(12): 1085-1090.

[131] Yoneda T, Tomofuji T, Kunitomo M, et al. Preventive Effects of Drinking Hydrogen-Rich Water on Gingival Oxidative Stress and Alveolar Bone Resorption in Rats Fed a High-Fat Diet. Nutrients, 2017, 9(1).

[132] Hanaoka T, Kamimura N, Yokota T, et al. Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide. Med Gas Res, 2011, 1(1): 18.

[133] Ishibashi T, Sato B, Shibata S, et al. Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: a randomized, double-blind, placebo-controlled pilot study. Int Immunopharmacol, 2014, 21(2): 468-473.

[134] Sun Y, Shuang F, Chen DM, et al. Treatment of hydrogen molecule abates oxidative stress and alleviates bone loss induced by modeled microgravity in rats. Osteoporos Int, 2013, 24(3): 969-978.

[135] Huang SL, Jiao J, Yan HW. Hydrogen-rich saline attenuates steroid-associated femoral head necrosis through inhibition of oxidative stress in a rabbit model. Exp Ther Med, 2016, 11(1): 177-182.

[136] Li J, Ge Z, Fan L, et al. Protective effects of molecular hydrogen on steroid-induced osteonecrosis in rabbits via reducing oxidative stress and apoptosis. BMC Musculoskelet Disord, 2017, 18(1): 58. [137] Ito M, Ibi T, Sahashi K, et al. Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Med Gas Res, 2011, 1(1): 24.

[138] Aoki K, Nakao A, Adachi T, et al. Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes. Med Gas Res, 2012, 2: 12.

[139] Hasegawa S, Ito M, Fukami M, et al. Molecular hydrogen alleviates motor deficits and muscle degeneration in mdx mice. Redox Rep, 2017, 22(1): 26-34.

[140] Qian L, Mei K, Shen J, et al. Administration of hydrogen-rich saline protects mice from lethal acute graft- versus-host disease (aGVHD). Transplantation, 2013, 95(5): 658-662.

[141] Yuan L, Chen X, Qian L, et al. Administration of hydrogen-rich saline in mice with allogeneic hematopoietic stem-cell transplantation. Med Sci Monit, 2015, 21: 749-754.

[142] Qian L, Liu X, Shen J, et al. Therapeutic effects of hydrogen on chronic graft-versus-host disease. J Cell Mol Med, 2017, 21(10): 2627-2630.

[143] Zhao S, Mei K, Qian L, et al. Therapeutic effects of hydrogen-rich solution on aplastic anemia in vivo. Cell Physiol Biochem, 2013, 32(3): 549-560.

[144] Ostojic SM. Serum alkalinization and hydrogen-rich water in healthy men. Mayo Clin Proc, 2012, 87(5): 501-502.

[145] Ostojic SM and Stojanovic MD. Hydrogen-rich water affected blood alkalinity in physically active men. Res Sports Med, 2014, 22(1): 49-60.

[146] Takeuchi S, Wada K, Nagatani K, et al. Hydrogen may inhibit collagen-induced platelet aggregation: an ex vivo and in vivo study. Intern Med, 2012, 51(11): 1309-1313.

[147] Tsubone H, Hanafusa M, Endo M, et al. Effect of Treadmill Exercise and Hydrogen-rich Water Intake on Serum Oxidative and Anti-oxidative Metabolites in Serum of Thoroughbred Horses. J Equine Sci, 2013, 24(1): 1-8.

[148] Xie K, Liu L, Yu Y, et al. Hydrogen gas presents a promising therapeutic strategy for sepsis. Biomed Res Int, 2014, 2014: 807635.

[149] Zheng Y and Zhu D. Molecular Hydrogen Therapy Ameliorates Organ Damage Induced by Sepsis. Oxid Med Cell Longev, 2016, 2016: 5806057.

[150] Dong A, Yu Y, Wang Y, et al. Protective effects of hydrogen gas against sepsis-induced acute lung injury via regulation of mitochondrial function and dynamics. Int Immunopharmacol, 2018, 65: 366-372.

[151] Cai J, Kang Z, Liu K, et al. Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res, 2009, 1256: 129-137.

[152] Dohi K, Kraemer BC, Erickson MA, et al. Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS One, 2014, 9(9): e108034.

[153] Houck CS and Vinson AE. Anaesthetic considerations for surgery in newborns. Arch Dis Child Fetal Neonatal Ed, 2017, 102(4): F359-F363.

[154] Chung W, Park S, Hong J, et al. Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors. Paediatr Anaesth, 2015, 25(10): 1033-1045.

[155] Shi Y, Wang G, Li J, et al. Hydrogen gas attenuates sevoflurane neurotoxicity through inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells signaling and proinflammatory cytokine release in neonatal rats. Neuroreport, 2017, 28(17): 1170-1175.

[156] Gunther S, Ruhe C, Derikito MG, et al. Polyphenols prevent cell shedding from mouse mammary cancer spheroids and inhibit cancer cell invasion in confrontation cultures derived from embryonic stem cells.Cancer Lett, 2007, 250(1): 25-35.

[157] Kitamura A, Kobayashi S, Matsushita T, et al. Experimental verification of protective effect of hydrogen- rich water against cisplatin-induced nephrotoxicity in rats using dynamic contrast-enhanced CT. Br J Radiol, 2010, 83(990): 509-514.

[158] Roerink ME, Buckland M, Lloyd AR, et al. Cytokine signature in chronic fatigue syndrome. Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(45): E9435.

[159] Ara J, Fadriquela A, Ahmed MF, et al. Hydrogen Water Drinking Exerts Antifatigue Effects in Chronic Forced Swimming Mice via Antioxidative and Anti-Inflammatory Activities. Biomed Res Int, 2018, 2018: 2571269.

[160] Mizuno K, Sasaki AT, Ebisu K, et al. Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life. Med Gas Res, 2017, 7(4): 247-255.

[161] Zhou P, Lin B, Wang P, et al. The healing effect of hydrogen-rich water on acute radiation-induced skin injury in rats. J Radiat Res, 2019, 60(1): 17-22.

[162] Al-Khalaf HH, Nallar SC, Kalvakolanu DV, et al. p16(INK4A) enhances the transcriptional and the apoptotic functions of p53 through DNA-dependent interaction. Mol Carcinog, 2017, 56(7): 1687-1702.

[163] Carrasco-Garcia E, Moreno M, Moreno-Cugnon L, et al. Increased Arf/p53 activity in stem cells, aging and cancer. Aging Cell, 2017, 16(2): 219-225.

[164] Lapak KM and Burd CE. The molecular balancing act of p16(INK4a) in cancer and aging. Molecular cancer research: MCR, 2014, 12(2): 167-183.

[165] Zhu Y, Liao W, Niu L, et al. Nitric oxide is involved in hydrogen gas-induced cell cycle activation during adventitious root formation in cucumber. BMC Plant Biol, 2016, 16(1): 146.

[166] Ghoshal UC, Shukla R,Ghoshal U. Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome: A Bridge between Functional Organic Dichotomy. Gut Liver, 2017, 11(2): 196-208.

[167] Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med, 1969, 281(3): 122-127. [168] Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo- controlled trial. Lancet, 2018, 392(10152): 1036-1046.

[169] Bowman L, Mafham M, Wallendszus K, et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus. N Engl J Med, 2018, 379(16): 1529-1539.

Chinese cancer control and hydrogen cancer control

Reading Key Points

I. Severe Challenges 

Cancer has become the most serious disease threatening humanity, and combating it has become a global challenge. The current anti-cancer situation, as the British writer Charles Dickens put it, is "the best of times, it is the worst of times," a situation characterized by both joy and sorrow.

In 2005, Chabner and Roberts (1) of the United States discussed cancer treatment in an article entitled “Timeline: Chemotherapy and the War on Cancer”: “60% of lung cancer patients die within one year, and only 15% survive for five years”; “The mortality rate of breast cancer has decreased since 1975, but if metastasis occurs, only 27% of patients can survive for five years”; “Pancreatic cancer is a catastrophic cancer. Since 1975, the mortality rate has remained almost unchanged, and the five-year survival rate is less than 5%”.

Although the concept of precision medicine is very attractive to patients and institutions supporting cancer research, as the American Prasad's article published in Nature in 2016 (2) stated: "Precision strategies have not benefited most cancer patients." The Canadian Tannock and Hickman's article published in the New England Journal of Medicine in 2016 (3) pointed out: "Only 3% to 13% of patients can find precision medicine" and "Even if paired drugs are used, they are only effective for a small number (30%) of patients" and "Patients should be given a clear message: personalized treatment of tumors has not yet shown substantial efficacy."

The 2017 Annals of Oncology published a report on the UK Cancer Drugs Fund, stating: "The UK Cancer Drugs Fund has failed to provide meaningful value to patients and society. From 2010 to 2016, a total of £1.3 billion was spent on cancer chemotherapy drugs, including 29 commonly used chemotherapy drugs for 47 types of cancer. These drugs have no clear effect on the majority (62%) of cancer patients. For only 18 of the 47 cancer types (38%) did they extend the lifespan of cancer patients by three months? However, these three months of life were fraught with toxic side effects."

In the face of the challenges of cancer treatment, improving the severe situation of cancer treatment requires breakthroughs in concepts and new ideas and strategies.

2. Chinese-style cancer control

The goal of cancer treatment is patient survival. Keeping patients alive isn't about a few extra months, but years, even multi-year lives. It's not about living a miserable life, but about living a quality, happy life. This is the fundamental principle of cancer treatment.

Nisbet, a famous American cultural psychologist, believes that the development of Eastern and Western cultures has their own trajectories: Western civilization is built on the traditions of ancient Greece, and its thinking style is characterized by Aristotle's logic and analytical thinking, while Eastern culture represented by China is built on the Eastern cultural tradition deeply influenced by Confucianism and Taoism, and its thinking style is mainly characterized by dialectical and holistic thinking.

Academician Tang Zhaoyou, a famous Chinese oncologist, proposed a cancer control strategy with Chinese characteristics that combines traditional Chinese and Western medicine in his book "Elimination and Transformation - New Perspectives on Cancer Control by Academicians" (Shanghai Science and Technology Press, 2011), based on the characteristics of Eastern and Western thinking.

Tang Zhaoyou proposed: it is about controlling cancer, not fighting cancer. Fighting mainly refers to elimination; controlling means both elimination and transformation. Only by eliminating the tumor to the greatest extent possible can the body be effectively preserved. Surgery, ablation (cryotherapy, radiofrequency, irreversible electroporation), radiation, and chemotherapy are the means of “elimination.” For early-stage tumors that have not metastasized, surgery is the most important way to cure them. However, for advanced tumors, especially those that have metastasized, the “elimination” strategy is a double-edged sword (5), with the following problems.

(1) Cancer metastasis can occur in the "early stage", and almost all "elimination" methods promote the metastasis and development of residual cancer.

(2) Cancer cells are derived from cancer stem cells, which are insensitive to standard treatments. Even if chemotherapy achieves clinical remission, recurrence is inevitable due to the presence of latent cancer stem cells, and they are often drug-resistant.

(3) Cancer is in a continuous evolutionary process. After chemotherapy or radiotherapy eliminates “sensitive” cancer cells, the previously “insensitive” cancer cells gain room for development and can grow against the trend, thus accelerating the progression of cancer.

(4) Chemotherapy or radiotherapy can cause the genes of cancer cells to mutate again, forming "outliers" that are not only drug-resistant but also more malignant.

(5) Chemotherapy and radiotherapy simultaneously suppress the body's immune function and weaken immune surveillance. For more than a century, cancer treatment has been mainly based on pathology, focusing on eliminating tumors while neglecting "treating the patient" and the body's anti-cancer ability. As a result, there has been limited progress in prolonging life and improving survival rates. Professor Audrew Weil of Harvard University said it well: "The ultimate goal of any treatment method is to restore the body's self-healing ability."

The "Chinese-style" approach to cancer control advocates both the elimination of cancer and its transformation. While "elimination" refers to removing the local manifestations of cancer—the tumor mass visible on CT scans, ultrasound, and MRI scans—the "transformation" following "elimination" eliminates the foundation upon which the tumor mass depends and the root cause of recurrence. This "transformation" strategy encompasses both modifying the cancer cells themselves and their microenvironment, as well as improving the body's overall anti-cancer capacity (see "Coexisting with Cancer," by Xu Kecheng, Guangzhou Publishing House, 2016).

1. "Transforming" cancer cells

(1) Allowing cancer cells to “reform” and return to the path of differentiation is called “induced differentiation therapy”.

(2) Allow cancer cells to control each other, "fighting evil with evil." Cancer cells compete with each other. Harsh treatment interventions with high-dose chemotherapy drugs eliminate sensitive cells and also eliminate "competitors." Short-term adaptive therapy is designed with this concept in mind.

(3) Reduce the malignancy of cancer cells. Usually, cancer cells are less malignant in the early stages, but become more malignant as time goes on, especially after being “tested” by chemotherapy and radiotherapy.

2. "Transforming" the microenvironment

Inflammatory cells and toxic ROS in the microenvironment are important factors that promote tumor gene instability, including:

(1) The “tumor suppressor” T lymphocytes in tumor tissue are inhibited by regulatory T cells and lose their function.

(2) The incomplete or missing endothelial cells of tumor blood vessels and the increase of extracellular interstitial fluid cause high pressure in the tumor interstitial space.

(3) Tumor cells have an increased demand for substances such as oxygen and glucose, which leads to hypoxia in the tumor tissue and anaerobic glycolysis, which releases a large amount of lactic acid, making the tumor tissue acidic.

These factors can promote the growth of cancer cells. By eliminating inflammation, toxic ROS and improving hypoxia, the tumor microenvironment can be improved.

3. "Renovation" of the whole

Cancer is a systemic disease. "Remodeling" the body involves maintaining and improving the functions of the nervous system, immune system, endocrine system, and metabolic system. Improving the body's immune function is key to "remodeling" the body's ability to fight cancer.

3. Hydrogen Cancer Control Practices "Chinese-Style Cancer Control"

In his new book, "The War on Cancer Control, Not the War Against Cancer: On the Protracted War and Cancer Prevention and Control Strategies" (Shanghai Science and Technology Press, 2018), Tang Zhaoyou argues that the war on cancer control is a systematic project with the following main contents:

(1) Regarding “internal environment stability”: multi-system intervention is needed.

(2) Targeting “external environmental imbalance”: Eliminate carcinogenic environmental factors.

(3) Targeting “internal disturbances in the body”: It is necessary to “eliminate” cancer cells and “transform” cancer cells, the microenvironment and the body.

(4) Regarding “multi-factorial causes”: eliminate carcinogenic factors from multiple aspects.

(5) Regarding “multiple gene involvement”: Target multiple genes and adopt comprehensive treatment.

(6) Regarding “multi-stage formation”: take appropriate measures from the precancerous stage to the advanced stage.

(7) For “systemic diseases”: focus on the whole body and maintain the healthy functions of each organ system.

(8) For “chronic diseases”: fight a protracted war, provide treatment throughout life, and pay attention to lifestyle.

(9) Regarding “dynamic changes”: Dynamic intervention according to the development of the disease.

Among the aforementioned “targeting” measures, molecular hydrogen can undoubtedly play a crucial role in “cancer control”67, as shown in:

(1) Tumor cells themselves produce a large amount of ROS. Molecular hydrogen can eliminate ROS, transform cancer cells, inhibit cancer cell proliferation, invasion and movement, and reduce their "cancerous nature".

(2) Molecular hydrogen selectively eliminates toxic ROS, downregulates pro-inflammatory and inflammatory factors, eliminates chronic inflammation, and transforms the microenvironment.

(3) Molecular hydrogen protects mitochondria, maintains energy production, and helps correct hypoxia; it has a protective effect on the cardiovascular, endocrine, and nervous systems, thereby "transforming" the entire body.

(4) Molecular hydrogen can regulate immune function, selectively downregulate the expression of pro-inflammatory cytokine genes, and upregulate the expression of anti-inflammatory cytokine genes; restore the function of exhausted CD8+T cells and enhance the body's own anti-cancer effect.

Molecular hydrogen possesses highly selective antioxidant properties, high diffusivity, and high safety, ensuring the feasibility and effectiveness of clinical translation. Based on current research, molecular hydrogen can serve as an important tool for implementing Chinese-style cancer control. Within the cancer control strategy of combining "elimination" with "transformation," molecular hydrogen can play a role in many areas, primarily in "transformation," as summarized in the table below.

 

4. Tang Zhaoyou’s Discussion on Hydrogen Cancer Control

Academician Tang Zhaoyou briefly commented on each story of "hydrogen controlling cancer" in this book, and the selected excerpts are compiled as follows:

In combating cancer, the West advocates a "hard-hitting" approach, while the East often employs a "soft-overcoming-hard" approach. The West advocates "annihilation," while the East often advocates "leaving the enemy in despair" (from "Chinese-Style Cancer Fighting: Wisdom from the Art of War," Shanghai Science and Technology Press, 2014). Chemotherapy and hydrogen inhalation are clearly two different types of treatments. The former can be likened to an "elimination" approach, while the latter might be classified as a "transformation" approach. The former can be described as "positional warfare," while the latter might be "guerrilla warfare." The appropriate application of these two different treatments (hardware) (software) depends on the individual and the specific situation. Hardware and software complement each other and are indispensable. However, the current trend emphasizes the use of powerful weapons over strategic tactics. This is a flaw in the fight against cancer and deserves deep consideration.

Hydrogen inhalation is clearly not a therapy for mass tumor elimination, but on the basis of tumor elimination therapy, it may achieve the same "accumulation of small victories into a big one" as in guerrilla warfare. This may once again highlight the importance of "elimination and transformation at the same time."

Nowadays, people place too much emphasis on expensive "miracle drugs" and dismiss simple, easy-to-use methods like hydrogen inhalation. This is worth reflecting on. Practice is the sole criterion for testing truth. In today's world of "high-tech," seemingly "chance" events like hydrogen inhalation cannot be ignored. A cancer patient is like a drowning person desperately fighting for survival. If they were just a foot from shore and drowning, a gentle pull could save them. Don't underestimate the impact of this gentle pull. Hydrogen inhalation is that "pull."

Cancer is a chronic disease, so the battle to control cancer is a protracted war of elimination and transformation. Hydrogen inhalation can certainly play a vital role in this protracted war.

Conclusion

Research on hydrogen molecular biology is still in its infancy, and investigation into its value in cancer prevention and treatment has only just begun. Further basic and preclinical studies should be conducted to elucidate the biological effects induced by the driving molecules and their upstream and downstream regulatory mechanisms. Furthermore, carefully designed multicenter clinical trials should be conducted to clarify the optimal administration method and hydrogen dosage regimen.

Indeed, allowing patients to leisurely inhale hydrogen and enjoy the physical and mental well-being benefits of this simplest, most relaxing, most natural, and safest small molecule is undoubtedly highly rational and practical, both ethically and practically, whether in hospitals, health centers, or at home, as a neoadjuvant therapy before "eliminating" cancer treatment, as a supplemental therapy after treatment, or as a rehabilitation tool. Even for patients with advanced cancer who have lost the possibility of conventional treatment or refuse conventional treatment, it is worth a try.

“I will climb to the top of the mountain and look down on all the other mountains.” I believe that with the deepening of research and further practice of hydrogen molecular medicine, in the “Chinese-style cancer control” with Chinese characteristics advocated by Tang Zhaoyou, hydrogen cancer control will surely show its unique charm, both in concept and strategy.

Xu Kecheng Lu Tianyu Chen Jinfei

References

[1] Chabner BA and Roberts TG, Jr. Timeline: Chemotherapy and the war on cancer. Nature reviews. Cancer, 2005, 5(1): 65-72.

[2] Prasad V. Perspective: The precision-oncology illusion. Nature, 2016, 537(7619): S63.

[3] Tannock IF and Hickman JA. Limits to Personalized Cancer Medicine. N Engl J Med, 2016, 375(13): 1289-1294.

[4] Cutbacks at England's Cancer Drugs Fund. Cancer Discov, 2015, 5(4): 338-339.

[5] Haines I. The war on cancer: time for a new terminology. Lancet, 2014, 383(9932): 1883.

[6] Jiang Y, Liu G, Zhang L, et al. Therapeutic efficacy of hydrogenrich saline alone and in combination with PI3K inhibitor in nonsmall cell lung cancer. Mol Med Rep, 2018, 18(2): 2182-2190.

[7] Yang Y, Zhu Y,Xi X. Anti-inflammatory and antitumor action of hydrogen via reactive oxygen species. Oncol Lett, 2018, 16(3): 2771-2776.

[8] Wang D, Wang L, Zhang Y, et al. Hydrogen gas inhibits lung cancer progression through targeting SMC3. Biomed Pharmacother, 2018, 104: 788-797.

[9] Huang L. Molecular hydrogen: a therapeutic antioxidant and beyond. Med Gas Res, 2016, 6(4): 219-222. [10] Hu Z, Wu B, Meng F, et al. Impact of molecular hydrogen treatments on the innate immune activity and survival of zebrafish (Danio rerio) challenged with Aeromonas hydrophila. Fish Shellfish Immunol, 2017, 67: 554-560.

[11] Grazioli S and Pugin J. Mitochondrial Damage Associated Molecular Patterns: From Inflammatory Signaling to Human Diseases. Front Immunol, 2018, 9: 832.

[12] Li HM, Shen L, Ge JW, et al. The transfer of hydrogen from inert gas to therapeutic gas. Med Gas Res, 2017, 7(4): 265-272.

Reading Extension

Holy Water

Nordenau, Germany

Nordenau, a small village east of Düsseldorf in northwestern Germany, boasts a cave where sweet spring water gushes endlessly from the rock face. Locals who drink the water experience a surge of vitality, and various health symptoms, including insomnia, anxiety, back and leg pain, and gastrointestinal discomfort, disappear. Their skin becomes smooth and delicate, and many chronic illnesses experience significant improvement, with some even experiencing miraculous recovery.

On June 13, 1998, TV Asahi's "Seeking the Truth" aired an episode titled "Cure for All Diseases: The Truth Behind the Miraculous Water," which reported that the water in the Nordenau Cave in Germany had miraculous effects in curing many diseases. It suggested that the miraculous water contained a very rich amount of hydrogen, meaning that hydrogen was the main mechanism by which the magical water could cure diseases.

On September 22, 2006, at the 15th Academic Conference of the Japanese Society of Animal Cell Technology, Japanese scholars reported on the therapeutic effect of the magical water from the German Magic Cave on patients with type 2 diabetes.

Lourdes in southern France

This spring never dries up, attracting over five million people from over 150 countries each year seeking its holy waters. Legend has it that on February 11, 1858, a 14-year-old shepherdess named Bernadette was collecting firewood near a cave on the banks of the Po River when the Virgin Mary suddenly appeared before her, calling her to drink some water and wash her face. When she dug in the ground near the cave, spring water gushed out. Since then, many people have been cured of their illnesses by drinking from this spring's waters.

Over the past 100 years, at least 67 people have been confirmed to have recovered from years of illness after drinking the holy water. Ms. Ana Santaniello is one of them.

In 1952, at the age of 40, she suffered a severe heart attack. Anna's brother and sister had also suffered the same condition and had both died. Holding onto a glimmer of hope, Anna traveled to Lourdes and insisted on bathing in holy water. Miraculously, soon after soaking in the spring, she felt a warmth in her chest, her breathing became smoother, and she regained feeling in her legs.

It has long been a mystery that this "holy water" only has a "healing" effect in the local area and loses its effect if taken outside. Now it is known that the active ingredient in the "holy water" is actually hydrogen molecules.

Bama in Guangxi, China

Bama Yao Autonomous County, located in the northwestern mountainous area of ​​Guangxi, China, is a magical and beautiful place. Since ancient times, there have been people living to be over 100 years old, and it is known as the hometown of longevity.

The secret to Bama's longevity lies in its springs. Formed in karst strata hundreds of millions of years ago, the springs possess a natural wonder, traveling underground four times and then flowing to the surface four times. Seven years of research by the International Society of Natural Medicine has shown that Bama spring water can penetrate cell nuclei and DNA, activate cellular enzymes, and stimulate vitality.

Studies suggest that Bama water can disperse clumped red blood cells, reduce blood viscosity, and promote microcirculation, alleviating or eliminating symptoms such as heart tightness, heartache, leg weakness, shortness of breath, fatigue, headaches, dizziness, insomnia, cold limbs, numbness, tinnitus, and blurred vision. It can also lower blood lipids and blood pressure, alleviating or eliminating cardiovascular and cerebral atherosclerosis. Young women use Bama water as a toner for more radiant skin. Drinking four liters of Bama water daily for three months can restore blood sugar levels in diabetic patients. Long-term consumption of Bama Shouzhen Spring significantly enhances physical fitness and delays aging.

Bama water is so similar to the "holy water" of Germany and France mentioned above in its magical aspects! It is not an exaggeration to call it "Bama holy water"! There are many different opinions on the nature of Bama water. Does hydrogen also play a role in it? It is worth studying.

"Holy Water"
Zhongzimei

In France, Germany or China
The good news of the cases released by Sanshengquan
The invisible hand that brings back the dead
Stretching out from the clear spring
Heal the pain and grant longevity and health

Ethereal aura
The secret has long been unknown
Now

Medical pioneers discern
The inventor of the device generates
Hydrogen mask breathes in the sacred blessing
Holy springs enter thousands of households

People in despair due to cancer

Defeat death and feel the miracle of rebirth

A new era has begun
Nature's most common ingredient
Lift the heavy lid of human chronic disease
Gently, gently lift up
Holy water from the spring in the garden of health
Whirling, rejoicing, jumping...

Chapter 2

The scientific basis of hydrogen cancer control

Hydrogen molecules are antioxidant and anti-inflammatory

Reading Key Points

1. Discovery of Hydrogen’s Cancer Control Effect

In recent years, the biological effects of molecular hydrogen have garnered significant attention, with its clinical application beginning with cancer treatment. In 1975, Dole et al. (USA) first proposed that hydrogen (H) could directly inhibit cancer. They exposed hairless mice with cutaneous squamous cell carcinoma to a mixture of 97.5% hydrogen and 2.5% oxygen at 8 atmospheres for two weeks. This resulted in significant tumor regression, manifested by darkening and detachment of the tumors. Subcutaneous tumor biopsies revealed no signs of squamous cell carcinoma. These changes were absent in the control group and in mice receiving hyperbaric oxygen-helium (H2H) (see Figure 1).

Figure 1. Dole et al. published an article in Science in 1975 titled "High-Pressure Hydrogen Therapy: A Possible Treatment for Cancer." The figure shows the initial and 10-day tumor sizes (cm) of three groups of animals: (i) the control group, (ii) the high-pressure helium-oxygen inhalation group, and (iii) the high-pressure hydrogen-oxygen inhalation group. The numbers in parentheses refer to the tumor size at the end of 10 days (9 days for the helium-oxygen group).

In 1978, Roberts et al. (2) in the United States studied the effect of applying high-pressure H2 on five transplanted tumor mice and one leukemia mouse, and also found that hydrogen inhalation could inhibit the growth of tumor cells and leukemia cells.

In 2008, Saitoh et al. (3) of Japan studied the effect of neutral pH hydrogen-rich electrolyzed water on tumor cells and found that this water inhibited

Hydrogen-rich water also inhibited the colony formation rate and size of the human tongue cancer cell line HSC-4, but had no significant inhibitory effect on normal human tongue epithelial cells. Hydrogen-rich water also caused growth inhibition and cell degeneration in the human fibrosarcoma cell line HT-1080, reducing its invasiveness. In 2009, Saitoh et al. (4) reported that platinum-enhanced colloid hydrogen-containing water also had a similar inhibitory effect on the colony formation and size increase of human HSC-4 tongue cancer cells.

In 2010, Chinese scholars published three reports on the use of molecular hydrogen to treat radiation damage. Liu C et al. (5) reviewed that hydrogen inhalation has antioxidant and anti-apoptotic activities, and protects the brain from ischemia-reperfusion injury and stroke by selectively reducing hydroxyl radicals (OH) and peroxynitrite (ONOO ̄). Reducing hydroxyl radicals can significantly improve the protective effect of cells against radiation damage. The authors believe that hydrogen therapy may be an effective, specific, and unique treatment for acute radiation syndrome. Qian et al. (6) reported that treating cells with H before irradiation can significantly inhibit radiation-induced apoptosis of human lymphocyte ah-1 cells and improve cell viability in vitro. Hydrogen inhalation can protect the gastrointestinal endoderm of mice from radiation damage, reduce plasma malondialdehyde (MDA) and intestinal 8-hydroxydeoxyguanosine (8-OHDG) levels, and increase plasma endogenous antioxidant levels. Qian et al. (7) also studied the protective effect of hydrogen-rich water on the hearts of mice damaged by ionizing radiation, and proved that hydrogen-rich water can protect myocardial degeneration, reduce myocardial MDA and 8-OHDG levels, and increase the content of endogenous myocardial antioxidants in the body.

In 2011, Zhao et al. (8) from China reported that mice could be induced to develop lymphoma after multiple irradiations. The incidence of lymphoma in the group injected with hydrogen-rich saline was significantly reduced, and the survival rate was significantly increased, while the group injected with normal saline had no such preventive effect.

In 2015, Runtuwene et al. (9) from Japan reported that the Colon-26 cell line can induce colorectal cancer in mice. Intraperitoneal injection of hydrogen water can improve the survival rate of tumor-bearing mice and induce apoptosis of cancer cells. The combined use of the chemotherapy drug 5-fluorouracil (5-FU) has a better tumor inhibition effect, indicating that the two methods have a synergistic effect in the treatment of colon cancer.

2. Basic Principles of Hydrogen Cancer Control

In 2007, Ota et al. (10) reported that surgical carotid artery clamping could induce an ischemia-reperfusion brain injury model in rats. Inhaled hydrogen could rapidly diffuse across cell membranes, buffering the effects of oxidative stress and significantly inhibiting brain damage. This groundbreaking research provided a theoretical basis for the application of molecular hydrogen in the treatment of clinical diseases.

Molecular hydrogen has therapeutic effects on many disease models and human diseases related to reactive oxygen species (ROS). This effect is mainly based on its selective antioxidant and anti-inflammatory properties. Many reviews have been published, such as the articles published by Huang et al. in China in 2010 and Ohta et al. in Japan in 2011 and 2014 (11-13).

Cancer is a multi-stage process defined by initiation, promotion, and progression, and oxidative stress contributes to all three stages of this process. ROS-mediated peroxidation and inflammation, as well as their mutual promotion, are key factors in the development and progression of cancer (14,15). It is generally believed that hydrogen may control the development and progression of cancer primarily through its antioxidant and anti-inflammatory properties. However, recent studies have shown that molecular hydrogen acts directly on the mitochondria of tumor cells and immune cells, exerting its tumor-killing and immune cell-rejuvenating effects.

1. Molecular hydrogen controls cancer by combating ROS

(1) ROS causes cancer

ROS are products formed by an imbalance between free radicals and reactive metabolites. These include oxygen free radicals (such as superoxide anion (O), hydroxyl (OH), peroxyl (RO), and alkoxyl (RO')) as well as non-oxygen free radicals. Molecules that can be converted into ROS and act as oxidants include hydrogen peroxide (H2O2), hypochlorous acid (HCl), ozone (O), and singlet oxygen ('O). ROS promote DNA synthesis, cell proliferation, cell survival, cell migration and invasion, as well as tumor metastasis and angiogenesis. Aerobic cells can produce a variety of ROS during endogenous metabolic reactions. Continuous exposure of mitochondria to high levels of ROS can lead to mitochondrial DNA damage and cell apoptosis (16-18). Damage to the mitochondria of normal stem cells in tissues can induce the generation of cancer stem cells, leading to tumor formation. If risk factors are not removed, the damage will gradually worsen, and the tumor will grow and become drug-resistant (see Figure 2).

Reactive nitrogen radicals (RNS) are formed by nitrogen-containing oxidants such as nitric oxide (NO) and peroxynitrite (ONOO). The mitochondrial respiratory chain can produce RNS under hypoxic conditions, and RNS can further produce other reactive substances. It is now known that cells continuously produce ROS and RNS as a result of multiple factors, including carcinogen exposure, inflammation, and mitochondrial respiration (19).

Radiation, smoking, air pollution, chemicals, mental stress, inflammation, strenuous exercise, myocardial infarction, blood flow arrest, organ transplantation, etc. can induce the body to produce ROS and RNS, of which OH and ONOO are the most toxic. Free radicals act on DNA, lipids, and proteins by inducing cell signal transduction pathways, causing DNA damage, lipid peroxidation, and protein denaturation, promoting cell mutation, and triggering the generation, proliferation, survival, and migration of cancer cells (20).

(2) ROS promotes tumor progression

Tumor cells produce more ROS than normal cells, leading to elevated oxidative stress. ROS damage to DNA is implicated in various chronic inflammatory diseases and multiple types of cancer, including bladder cancer, brain tumors, breast cancer, cervical cancer, gastric cancer, liver cancer, lung cancer, melanoma, multiple myeloma, leukemia, lymphoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, and sarcoma.

ROS initiates initiation and subsequent tumor progression by inducing DNA damage. Oxidative stress interacts with the initiation, promotion, and progression of cancer. In the initiation phase, ROS introduces genetic mutations and structural changes into DNA and produces DNA damage; in the promotion phase, ROS promote cancer cell proliferation or reduce apoptosis of cancer stem cells by causing abnormal gene expression, blocking cell communication, and modifying second messenger systems; finally, oxidative stress may increase DNA changes in the initiating cell population and promote cancer progression (21).

(3) ROS affects cancer by regulating gene expression

Under intracellular and extracellular environmental conditions, ROS stimulate cell signaling pathways, regulate gene mutations, and balance cell proliferation and apoptosis [16, 22]. Cancer signaling originates from various autocrine and paracrine components in the hypoxic microenvironment, including vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), hypoxia-inducible factor 1 (HIF-1a), NO, and H2O2, generating a positive feedback loop that activates protein kinase B (Akt) gene expression. Oxidative stress can activate a series of transcription factors, including NF-κB, p53, HIF-1, matrix metalloproteinases (MMPs), peroxisome proliferator-activated receptor γ (PGC-1a), catenin/Wnt signaling, and nuclear factor 2 (Nrf2). These effector molecules are activated under persistent ROS-related chronic inflammation and participate in the expression of genes involved in malignant transformation, immunity, inflammatory responses, and carcinogenesis and metastasis.

(4) Molecular hydrogen fights ROS

Dissolved H₂ in the culture medium selectively reduces the most potent oxidants involved in cell signaling (such as ·OH and ONOO) without interfering with O₂, NO, or H₂O₂ levels, nor does it affect redox reactions in cell-free systems (see Figure 3). Studies have shown that H₂ can neutralize ·OH produced by radiolysis or photolysis of water, significantly reducing OH levels in cultured cells and thereby protecting mitochondria. Because H₂ can penetrate biological membranes and diffuse into organelles, it can reduce the level of adenosine triphosphate (ATP) synthesis in mitochondria and the nucleus. H₂ can increase the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), reducing ROS levels and promoting the expression of phosphoinositide 3-kinase (PI-3K), Akt, and Nrf2 in human immortalized epidermal cells (HaCaT) induced by chronic UV irradiation. H₂ exerts neuroprotective effects by reducing cyclooxygenase-2 (Cox-2) activity in immunoreactive neurons.

2. Molecular hydrogen controls cancer by fighting inflammation

Metastasis is a hallmark of cancer cells. Over a century ago, British pathologist Paget proposed that cancer cells metastasize only when they encounter a suitable environment—this is known as the "seed and soil theory." Further research has revealed that cancer cell metastasis depends on the microenvironment (soil). The microenvironment is the breeding ground for cancer cell formation, development, and metastasis. Within the tumor microenvironment, at least four factors promote cancer cell growth: inflammation, hypoxia, macrophages, and immune cells. Inflammation is the most important factor in the microenvironment that promotes cancer (see Figure 4).

ROS can also cause chronic inflammation, leading to increased organ cell damage, increased cell division, and increased cell mutations, which in turn increases the formation of cancer cells. By inhibiting inflammatory cytokines and cell signaling factors, the molecule exerts anti-inflammatory and anti-allergic effects, thereby inhibiting tumor growth and progression.

H2 is known to reduce the expression of many proinflammatory cytokines, including tumor necrosis factor (TNF-α), interleukin (IL)-6, IL-1β, IL-10, IL-12, chemokine ligand 2 (CCL-2), intercellular adhesion molecule 1 (ICAM-1), NF-κB, high-mobility group protein 1 (HMG-1), and prostaglandin E2 (PGE2). Furthermore, H2 can reduce serum amine oxidase (DAO), TNF-α, IL-1, IL-6, tissue malondialdehyde (MDA), protein carbonyl group (PCO), and myeloperoxidase (MPO) activities, and inhibit pro-apoptotic factors, including JNK and caspase-3 [116,23]. In 2018, Zhang et al. (24) reported that in a mouse model of allergic asthma, hydrogen inhalation could significantly reduce the number of eosinophils and lymphocytes in bronchoalveolar lavage fluid, increase the levels of IL-4, IL-13, TNF-a and CCL-15, and alleviate airway inflammation.

3. Molecular hydrogen maintains the normal function of mitochondria

Mitochondria are the center of oxidative metabolism and the main site of ROS generation. Disorders in mitochondrial genomic DNA (mtDNA) or mitochondrial life functions (such as the production of ATP and ROS) have been shown to be associated with the occurrence of many diseases (25). Maintaining the mitochondrial function of normal cells can reduce the probability of their mutation into tumor cells, maintaining the mitochondrial function of tumor cells can reduce their invasiveness and drug resistance, and maintaining the mitochondrial function of immune cells can maintain the normal function of immune cells. In 2016, Otto et al. (26) in Germany observed that cancer ferments glucose in the presence of glucose and believed that mitochondrial respiratory defects may be the root cause of cancer. ROS induced by radiation, carcinogenic chemicals, viruses, chronic inflammation, etc. can damage mitochondria, thereby destroying aerobic respiration, activating fermentation genes, forming an energy generation process dominated by fermentation, and causing cancer cell formation. Some people believe that cancer is actually a "metabolic disease." Some people also call cancer a mitochondrial disease (27). This part will be discussed in detail in a separate chapter. H2 can quickly penetrate the cell membrane and enter the mitochondria under the drive of concentration gradient. In 2011, Ohta (12) of Japan reported that in addition to protecting mitochondria from the effects of ROS such as •OH, H2 also has a protective effect on mitochondrial function, including maintaining mitochondrial membrane potential, increasing ATP production, and reducing organelle swelling, thereby maintaining the health of mitochondrial bioenergy production (see Figure 5).

4. Molecular hydrogen directly regulates immune function

CD8+ T cells (cytotoxic T lymphocytes) are important immune killer cells that play an important role in the immune control of tumors. However, the exertion of their immune function is closely related to cell surface molecules. Programmed death receptor 1 (PD-1) is a marker of exhausted T cells. It is highly expressed in the circulation of CD8 T cells and tumor-infiltrating lymphocytes in cancer patients and is associated with poor prognosis in various cancers (including breast cancer, pancreatic cancer, and gastric cancer) (28). The mechanism by which H2 restores the function of exhausted T cells is still unclear, but this phenomenon was reported by Akagi and Baba (29) in Japan in early 2019. This part will be discussed in detail in a separate chapter.

3. Molecular hydrogen reduces the side effects of radiotherapy and chemotherapy

The three main treatments for cancer are surgery, radiotherapy, and chemotherapy. Patients undergoing these procedures often face short or long-term interruptions due to vomiting, diarrhea, hepatotoxicity, and low white blood cell and platelet counts to prevent potentially fatal side effects. In recent years, reports on the use of hydrogen to alleviate the side effects of radiotherapy and anti-cancer drugs have become increasingly numerous, with increasingly clear conclusions.

1. Molecular hydrogen reduces the side effects of radiotherapy

In 2011, Kang et al. (30) from China conducted a study on 49 patients undergoing liver radiotherapy and found that daily consumption of hydrogen-rich water could alleviate the oxidative stress caused by radiotherapy and improve the quality of life (using the QLQ-C30 Quality of Life Questionnaire). At the same time, the therapeutic effect on the radiotherapy site was no different from that in the control group, indicating that hydrogen-rich water would not affect the anti-tumor effect. The authors also tested the changes in liver function in patients undergoing liver irradiation and the changes in immune cells in patients undergoing spleen irradiation. They found that the indicators of the hydrogen water group were not much different from those before radiation, while the control group showed significant damage.

In 2014, Zhao et al. (31) from China reported that radiation can cause immune damage in mice. Intraperitoneal injection of hydrogen-rich saline has the following effects: 1. Increase the spleen index and alleviate radiation damage to the spleen; 2. Significantly reduce the expression level of ROS in the spleen, reduce the number of apoptotic cells, and reduce the expression level of pro-apoptotic proteins; 3. Increase the number of CD4* and CD8* T cell subsets in the spleen, so that the ratio between the two is close to normal; 4. Restore the polarization morphology and cytokine secretion level of CD4+ T cells in the spleen.

In 2016, Guo et al. (31) from China reported that low-dose, long-term radiation exposure can also cause cumulative damage to mice, as evidenced by significant changes in body mass index, forced swimming test, open-box test, chromosome aberration test, peripheral blood cell parameter analysis, sperm abnormality analysis, and lymphocyte deformation test. Long-term drinking of hydrogen-rich water by irradiated mice can gradually restore almost all indicators to normal, indicating that hydrogen can reduce low-dose, long-term radiation damage and has a protective effect on multiple systems throughout the body.

2. Molecular hydrogen reduces the side effects of chemotherapy

Cisplatin is a non-specific drug for the cell cycle. It is cytotoxic and can inhibit the DNA replication process of cancer cells and damage the structure on their cell membranes. It has a strong broad-spectrum anti-cancer effect. It has been clinically used for a variety of solid tumors such as ovarian cancer, prostate cancer, testicular cancer, lung cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck squamous cell carcinoma, thyroid cancer and osteosarcoma, and has shown efficacy. In 2009, Kamimura-Kamimura et al. (33) of Japan reported that mice injected with the chemotherapy drug cisplatin developed serious complications. Mice began to die on the second day, and only 60% of mice survived to the sixth day. The mortality rate of the hydrogen inhalation group was significantly reduced. All mice survived to the fifth day, and 80% survived to the ninth day. There was no significant change in body weight, and the nephrotoxicity was relatively low (serum creatinine and urea nitrogen levels were basically normal). The sensitivity of the two groups of tumor-bearing mice to cisplatin was not affected by hydrogen. In 2010, the same group (34) again reported the recovery effect of hydrogen-rich water gavage on chemotherapy in tumor-bearing rats, and similar results were observed.

Doxorubicin is one of the most effective anti-tumor drugs and is widely used in adult and pediatric tumors. However, due to its strong cardiac and renal toxicity, its clinical application is significantly limited. In 2016, Gao et al. (3) reported that intraperitoneal injection of hydrogen-rich saline can improve complications caused by doxorubicin in rats: 1. After 30 days of treatment, all 30 rats in the hydrogen-rich saline group survived, while only 18 rats in the normal saline group survived; 2. Cardiotoxicity, histopathological changes, liver function indicators, and ROS were also reduced; 3. Inflammation in the heart and liver was inhibited, and the expression of apoptosis-related proteins in organs was reduced.

From the above results, it can be concluded that hydrogen has the potential to become an auxiliary means to reduce the side effects caused by radiotherapy and chemotherapy in cancer patients.

Conclusion

Hydrogen medicine is a young but rapidly developing science. The discovery that molecular hydrogen can control cancer is older than the generally accepted "age" of hydrogen medicine. More than 40 years ago, the renowned American journal Science reported that the use of a high-pressure hydrogen and oxygen gas mixture effectively controlled cancer (1).

Perhaps due to technical difficulties in applying "high-pressure hydrogen," or perhaps due to a misconception that hydrogen therapy was too "simple," it wasn't until recent years, with the discovery of molecular hydrogen's antioxidant and anti-inflammatory effects, that people began to recall and take seriously the Science report, realizing that this simple, inexhaustible natural substance truly has an inhibitory effect on cancer. They also began to believe that using hydrogen to control cancer is not just nonsense, but has a profound scientific basis. Encouragingly, molecular hydrogen also has a role in immune function. By maintaining mitochondrial function, it can "rescue" exhausted T cells, restoring their anti-tumor efficacy and thus improving the prognosis for patients with advanced cancer.

Medicine is more than just a natural science, for it embodies a reverence for human life. Scientifically grounded medical technologies are bound to best serve and protect life. Hydrogen cancer control, as a technology, embodies this.

Xu Kecheng Lü Youyong Chen Jibing Du Duanming

References

[1] Dole M, Wilson FR,Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science, 1975,190(4210): 152-154.

[2] Roberts BJ, Fife WP, Corbett TH, et al. Response of five established solid transplantable mouse tumors and one mouse leukemia to hyperbaric hydrogen. Cancer Treat Rep, 1978, 62(7): 1077-1079.

[3] Saitoh Y, Okayasu H, Xiao L, et al. Neutral pH hydrogen-enriched electrolyzed water achieves tumor- preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression. Oncol Res, 2008, 17(6): 247-255.

[4] Saitoh Y, Yoshimura Y, Nakano K, et al. Platinum nanocolloid-supplemented hydrogendissolved water inhibits growth of human tongue carcinoma cells preferentially over normal cells. Exp Oncol, 2009, 31(3): 156-162.

[5] Liu C, Cui J, Sun Q, et al. Hydrogen therapy may be an effective and specific novel treatment for acute radiation syndrome. Med Hypotheses, 2010, 74(1): 145-146.

[6] Qian L, Cao F, Cui J, et al. Radioprotective effect of hydrogen in cultured cells and mice. Free Radic Res, 2010, 44(3): 275-282.

[7] Qian L, Cao F, Cui J, et al. The potential cardioprotective effects of hydrogen in irradiated mice. J Radiat Res, 2010, 51(6):741-747.

[8] Zhao L, Zhou C, Zhang J, et al. Hydrogen protects mice from radiation induced thymic lymphoma in BALB/c mice. Int J Biol Sci, 2011, 7(3): 297-300.

[9] Runtuwene J, Amitani H, Amitani M, et al. Hydrogen-water enhances 5-fluorouracil-induced inhibition of colon cancer. PeerJ, 2015, 3(e859).

[10] Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13(6): 688-694.

[11] Huang CS, Kawamura T, Toyoda Y, et al. Recent advances in hydrogen research as a therapeutic medical gas. Free Radic Res, 2010, 44(9): 971-982.

[12] Ohta S. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des, 2011, 17(22): 2241-2252.

[13] Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther, 2014, 144(1): 1-11.

[14] Kim J and Bae JS. ROS homeostasis and metabolism: a critical liaison for cancer therapy. Exp Mol Med, 2016, 48(11): e269.

[15] Kumari S, Badana AK, G MM, et al. Reactive Oxygen Species: A Key Constituent in Cancer Survival. Biomark Insights, 2018, 13(1177271918755391).

[16] Yang Y, Zhu Y,Xi X. Anti-inflammatory and antitumor action of hydrogen via reactive oxygen species. Oncol Lett, 2018, 16(3): 2771-2776.

[17] Liou GY and Storz P. Reactive oxygen species in cancer. Free Radic Res, 2010, 44(5): 479-496.

[18] Zhang G, Miura Y, Yagasaki K. Suppression of adhesion and invasion of hepatoma cells in culture by tea compounds through antioxidative activity. Cancer Lett, 2000, 159(2): 169-173.

[19] Lei XG, Zhu JH, Cheng WH, et al. Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications. Physiol Rev, 2016, 96(1): 307-364.

[20] Trush MA and Kensler TW. An overview of the relationship between oxidative stress and chemical carcinogenesis. Free Radic Biol Med, 1991, 10(3-4): 201-209.

[21] Wang J and Yi J. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol Ther, 2008, 7(12): 1875-1884.

[22] Klaunig JE, Xu Y, Isenberg JS, et al. The role of oxidative stress in chemical carcinogenesis. Environ Health Perspect, 1998, 106 Suppl 1(289-295).

[23] Sun H, Chen L, Zhou W, et al. The protective role of hydrogen-rich saline in experimental liver injury in mice. J Hepatol, 2011, 54(3): 471-480.

[24] Zhang N, Deng C, Zhang X, et al. Inhalation of hydrogen gas attenuates airway inflammation and oxidative stress in allergic asthmatic mice. Asthma Res Pract, 2018, 4(3).

[25] Giorgi C, Marchi S, Simoes ICM, et al. Mitochondria and Reactive Oxygen Species in Aging and Age- Related Diseases. Int Rev Cell Mol Biol, 2018, 340(209-344).

[26] Otto AM. Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism. Cancer Metab, 2016, 4(5).

[27] Sabharwal SS and Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Nature reviews. Cancer, 2014, 14(11): 709-721.

[28] Dermani FK, Samadi P, Rahmani G, et al. PD-1/PD-L1 immune checkpoint: Potential target for cancer therapy. J Cell Physiol, 2019, 234(2): 1313-1325.

[29] Akagi J and Baba H. Hydrogen gas restores exhausted CD8+T cells in patients with advanced colorectal cancer to improve prognosis. Oncol Report, 2018.

[30] Kang KM, Kang YN, Choi IB, et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Med Gas Res, 2011, 1(1): 11.

[31] Zhao S, Yang Y, Liu W, et al. Protective effect of hydrogen-rich saline against radiation-induced immune dysfunction. J Cell Mol Med, 2014, 18(5): 938-946.

[32] Guo J, Zhao D, Lei X, et al. Protective Effects of Hydrogen against Low-Dose Long-Term Radiation- Induced Damage to the Behavioral Performances, Hematopoietic System, Genital System, and Splenic Lymphocytes in Mice. Oxid Med Cell Longev, 2016, 2016(1947819).

[33] Nakashima-Kamimura N, Mori T, Ohsawa I, et al. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol, 2009, 64(4): 753-761.

[34] Kitamura A, Kobayashi S, Matsushita T, et al. Experimental verification of protective effect of hydrogen- rich water against cisplatin-induced nephrotoxicity in rats using dynamic contrast-enhanced CT. Br J Radiol, 2010, 83(990): 509-514.

[35] Gao Y, Yang H, Fan Y, et al. Hydrogen-Rich Saline Attenuates Cardiac and Hepatic Injury in Doxorubicin Rat Model by Inhibiting Inflammation and Apoptosis. Mediators Inflamm, 2016, 2016(1320365).

Hydrogen molecules maintain mitochondrial function and stability

Reading Key Points

Regarding hydrogen's cancer control, academics generally focus on its antioxidant and anti-inflammatory effects. Life is not merely a physical existence; it also relies on energy and information. The production of biological energy in the body relies on mitochondria. What role do mitochondria play in the development of cancer? What are the effects and functions of hydrogen molecules on mitochondria?

1. The Warburg Effect

In 1924, German physiologist Otto Warburg proposed a view that when mitochondrial function is impaired, cells provide energy by enhancing anaerobic glycolysis. After glucose is metabolized to pyruvate, it no longer undergoes aerobic oxidation through the mitochondrial tricarboxylic acid cycle, but is converted into lactate and excreted from the cell through lactate dehydrogenase (see Figure 1). He believed that the development of cancer was caused by enhanced anaerobic glycolysis of cells and reduced gas consumption. This view is called the Warburg effect. Although there has been much controversy about this view, the connection between cancer and mitochondria has been confirmed by many facts (2). Understanding this is of great significance for understanding the impact of hydrogen molecules on cancer and health.

What are mitochondria?

Mitochondria are the cell's powerhouses, located in the cytoplasm. Numerous in number, they break open the chemical bonds within food molecules to generate energy. Structurally, they consist of an outer membrane, an inner membrane, and a space within the membrane (see Figure 2, left). Chemical bonds are composed of positive charges called protons and negative charges called electrons, which are tightly bound to each other. Mitochondria remove electrons from protons, which then leak out through the "electron transport chain," generating an electric current. This electrical energy is used to produce adenosine triphosphate (ATP) molecules, each of which contains high-energy phosphate bonds. ATP acts like a miniature chemical battery. When the cell needs energy, it breaks apart the ATP phosphate bonds. Oxygen waits at the end of the ATP assembly line to capture the cascading electrons and then combines with them, forming water as a harmless byproduct. Because this process requires oxygen and produces high-energy phosphate bonds, it is called "oxidative phosphorylation," also known as "respiration" (see Figure 2).

3. Mitochondria in Cancer Cells

Compared with normal cells, the mitochondria of cancer cells have the following characteristics:

(1) The number of mitochondria in each cell is small.

(2) Often deformed and with an uneven inner surface.

(3) Low activity of key respiratory enzymes.

(4) Cardiolipin (a key mitochondrial fat) is less and deformed.

(5) The amount of DNA in mitochondria is small.

(6) Leakage: The electron transport chain is uncoordinated and energy is consumed as heat rather than ATP.

(7) The respiratory rate is significantly reduced.

What are the differences in energy production between normal and cancer cells?

The most important fundamental difference between normal and cancer cells is how they produce energy. Normal cells use a complex process called respiration to efficiently convert any type of nutrient (fats, carbohydrates, or proteins) into high levels of energy. This process requires oxygen and completely breaks down food into harmless carbon dioxide and water. Cancer cells use a primitive process called fermentation to inefficiently convert glucose (primarily from carbohydrates) or the amino acid glutamine (from protein) into small amounts of energy. This process does not require oxygen and only partially breaks down food molecules into the toxic waste products lactate and ammonia (3.4).

If normal cells temporarily experience a shortage of oxygen, they are sometimes forced to resort to fermentation. However, when there is sufficient oxygen, no cell will choose to ferment. Cancer cells, however, remain dominant even in the presence of abundant oxygen. This is the Warburg effect, described earlier, and is considered the "metabolic signature" of cancer cells (see Figure 3). This difference occurs because the mitochondria of cancer cells are damaged (5, 6).

5. ROS causes mitochondrial abnormalities

Radiation, carcinogenic chemicals, viruses, chronic inflammation, and other factors cause mitochondria to produce ROS, which impairs respiration and triggers a process called retrograde mitochondrial regeneration. Under normal circumstances, DNA in the cell nucleus issues commands that are transmitted to the mitochondria in the cytoplasm. However, if mitochondria are damaged and respiration is threatened, the mitochondria transmit information to the nucleus, activating fermentation genes, resulting in a fermentation-based energy production process (see Figure 4). ROS wreak havoc on surrounding molecules, activating genes most closely associated with cancer (oncogenes) and suppressing or mutating tumor suppressor genes.

6. Cancer is a “mitochondrial disease”

The result of mitochondrial damage is that the DNA in the cell nucleus becomes unstable, the cell loses its unique shape, the cytoskeleton and extensin (SNPH) become disordered, and it begins to replicate uncontrollably, thus forming cancer. Therefore, some people call cancer a mitochondrial disease (see Figure 5) (8). Reducing mitochondrial damage and protecting mitochondrial function can not only inhibit cancer cells, but also ensure the body has sufficient energy supply and improve the patient's symptoms and quality of life.

7. How does molecular hydrogen enter cells and mitochondria?

Molecular hydrogen is the simplest, lightest, and most abundant molecule in the universe, with a length of only 0.74 angstroms. Its small size allows H2 to rapidly penetrate cell membranes, transported to the cytoplasm, and then into the mitochondria, driven by a concentration gradient. This is a non-selective, rapid transport process. Experiments in rats have shown that myocardial hydrogen levels increase immediately within a few minutes of hydrogen inhalation. Besides molecular size, another factor that influences the entry of molecular hydrogen into mitochondria is its concentration gradient between the cytoplasm and the mitochondrial matrix. Inhaled molecular hydrogen first enters the bloodstream, so the greater the concentration gradient between the circulation and cells, and between the circulation and mitochondria, the faster the delivery of hydrogen to the mitochondria. This is why, in order to produce a rapid biological effect when treating a disease, the concentration and amount of hydrogen provided should not be too small (10).

Another factor that may affect the uptake of molecular hydrogen by mitochondria is its reactivity, which has the following characteristics:

(1) In theory, molecular hydrogen can react with many biologically relevant elements and compounds (e.g., active and transition metals, non-metals, organic compounds), but the reaction rates at room temperature or in the absence of a catalyst are usually so low that they can be ignored.

(2) Molecular hydrogen does not react with oxygen at room temperature and does not interfere with redox reactions. In the presence of hydroxyl radicals (OH), the biological reactivity of molecular hydrogen increases, effectively neutralizing •OH.

(3) Excessive elimination of OH in the cytoplasm will increase the consumption of hydrogen molecules and reduce their delivery rate to mitochondria.

(4) Molecular hydrogen introduced in vitro accumulates in the liver along with glycogen, which has a unique affinity for the accumulation and gradual release of molecular hydrogen. Since glycogen is primarily stored in the cytoplasm of many cell types, the ability of carbohydrates (including glycogen) to polymerize hydrogen may negatively affect the delivery of hydrogen to mitochondria (see Figure 6) (10)

8. Molecular Hydrogen Protects Mitochondria

Hydrogen can protect mitochondria and cell nuclei from acute oxidative stress damage. In 2017, Ostojic et al. (11) from Serbia reported that molecular hydrogen helps mitochondrial function by maintaining mitochondrial membrane potential, increasing ATP production, and reducing organelle swelling. Hydrogen molecules maintain the health of mitochondrial bioenergetics through a series of possible mechanisms (see Figure 7).

9. Mitochondria regulate immune function

Buck et al. (2016) and Angajala et al. (2018) (12,13) ​​in the United States have provided detailed and precise discussions on the relationship between T cells and mitochondrial function. T cell-mediated protective immunity plays a crucial role in anti-tumor immunity, possessing a unique ability to proliferate at an unparalleled rate in adult organisms. A single immature T cell can clone and expand into millions of "armed" effector T cells in just a few days. Mitochondria are crucial hubs for metabolic activity, anti-tumor immune responses, and cell death, constantly reshaping their structure according to varying needs. Effector T cells are associated with punctately fissured mitochondria, while memory T cells are associated with fused mitochondria. Like tumor cells, the former rely on aerobic glycolysis for energy, while the latter rely on oxidative phosphorylation. Once the antigen is cleared, most effector T cells die, but long-lived memory T cells persist and rapidly respond to cancer recurrence.

In 2014, Bonifaz et al. (14) from Mexico studied the relationship between antigen-presenting cells (dendritic cells and macrophages) and mitochondrial function.

A detailed discussion of this topic suggests that mitochondria regulate the functions of these two cell types. Dendritic cells are professional antigen-presenting cells that assist and promote T cell anti-tumor immunity. Macrophages are divided into M1 and M2 types. M1 macrophages play a crucial role in anti-tumor immunity, inhibiting tumor growth, while M2 macrophages have the opposite effect. However, given that healthy mitochondria are crucial for controlling cancer cell growth, mitochondria should be crucial for maintaining normal immune balance. Based on this perspective, it is clear that hydrogen molecules can regulate anti-tumor immunity by maintaining mitochondrial function.

Conclusion

From a therapeutic perspective, exogenous molecular hydrogen should be considered a valuable biomedical agent. Cancer, in a sense, is a metabolic disease, not a genetic one. Further research into the causal relationship between molecular hydrogen and metabolic abnormalities regulated by specific genes will undoubtedly contribute to the development of innovative cancer treatments.

Xu Kecheng Chen Jibing Lü Youyong Fei Sujuan

References

[1] San-Millan I and Brooks GA. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. Carcinogenesis, 2017, 38(2): 119-133.

[2] Grazioli S and Pugin J. Mitochondrial Damage-Associated Molecular Patterns: From Inflammatory Signaling to Human Diseases. Front Immunol, 2018, 9:832.

[3] Zong WX, Rabinowitz JD,White E. Mitochondria and Cancer. Mol Cell, 2016, 61(5):667-676.

[4] Sabharwal SS and Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Nature reviews. Cancer, 2014, 14(11): 709-721.

[5] Murphy MP. How mitochondria produce reactive oxygen species. Biochem J, 2009, 417(1): 1-13.

[6] Jia D, Park JH, Jung KH, et al. Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States. Cells, 2018, 7(3).

 

[7] Signorile A, Sgaramella G, Bellomo F, et al. Prohibitins: A Critical Role in Mitochondrial Functions and Implication in Diseases. Cells, 2019, 8(1).

[8] Altieri DC. Mitochondrial dynamics and metastasis. Cell Mol Life Sci, 2018.

[9] Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13(6): 688-694.

[10] Ostojic SM. Targeting molecular hydrogen to mitochondria: barriers and gateways. Pharmacol Res, 2015, 94:51-53.

[11] Ostojic SM. Does H2 Alter Mitochondrial Bioenergetics via GHS-R1alpha Activation? Theranostics, 2017, 7(5):1330-1332.

[12] Angajala A, Lim S, Phillips JB, et al. Diverse Roles of Mitochondria in Immune Responses: Novel Insights Into Immuno-Metabolism. Front Immunol, 2018, 9: 1605.

[13] Buck MD, O'Sullivan D, Klein Geltink RI, et al. Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming. Cell, 2016, 166(1): 63-76.

[14] Bonifaz L, Cervantes-Silva M, Ontiveros-Dotor E, et al. A Role For Mitochondria In Antigen Processing And Presentation. Immunology, 2014.

Hydrogen molecules "rescue" T cells and regulate immunity

Reading Key Points

In recent years, the role of hydrogen in controlling cancer has garnered significant attention. While molecular hydrogen's antioxidant and anti-inflammatory properties are generally believed to be the primary mechanisms for inhibiting cancer cells and their microenvironment, its immunomodulatory effects remain understudied. In 2019, our research group published a paper demonstrating that hydrogen can improve mitochondrial function, restore exhausted cytotoxic T cells, and relieve the body's immunosuppressive state, thereby controlling cancer progression.

1. What are immune cells?

The treatment effect and prognosis of cancer patients strongly depend on the patient's own immune function status.

The ideal and simple method is to draw blood to check the function of immune cells. The cells in human peripheral blood can be divided into red blood cells, white blood cells and

White blood cells are classified into three main groups: cells and platelets. Cells that carry out immune functions are found within this group. White blood cells can be further divided into granulocytes, monocytes, and lymphocytes based on their size, weight, and other parameters (see Figure 1). Granulocytes are primarily responsible for fighting infection and eliminating foreign pathogens. Monocytes act like scouts, constantly patrolling the body, primarily responsible for detecting tumors and then reporting them to lymphocytes. Lymphocytes then perform the surgery themselves, following the directions provided by monocytes to locate and eliminate tumor cells within the body. Lymphocytes are further divided into three categories based on their functions: T cells from the thymus, B cells from the bone marrow, and natural killer (NK) cells.

It takes 10 to 20 years for a tumor to form in the human body, from a single stem cell mutating into a cancer stem cell to dividing into billions of cells that can be seen by the naked eye. During this period, a constant battle of attrition between cytotoxic T cells and tumor cells occurs: if the tumor cells are exhausted first, the patient will recover without treatment; if the cytotoxic T cells are exhausted first, the tumor will grow rapidly and metastasize (2).

2. What are immune checkpoints and their ligands (PD-1/PD-L1)?

Human lymphocytes have evolved immune checkpoints (checkpoints) to identify friend and foe, allowing friendly cells to pass through while eliminating enemies. This is a homeostatic mechanism within the human immune system, preventing overactivation of T cells, which can lead to intense inflammation and harm the body. Tumor cells exploit this characteristic of the human immune system to disguise themselves as they pass through these checkpoints, evading immune surveillance and destruction. In 1992, Professor Tasuku Honjo of Kyoto University in Japan discovered the programmed death protein 1 (PD-1) protein on the surface of T cells, earning him the 2018 Nobel Prize in Medicine or Physiology. In 1999, Chinese-American scientist Professor Chen Lieping discovered the B7-H1 (also known as the PD-1 ligand, PD-L1) protein on the surface of tumor cells. This pivotal discovery laid the foundation for the use of PD-1 inhibitors in cancer immunotherapy. Once established, tumor cells exploit this inhibitory pathway to suppress T cell activation, thereby evading the immune system. Inhibiting immune checkpoint activity releases the immune brakes in the tumor microenvironment, reactivating cells' immune response to the tumor, thereby achieving an anti-tumor effect. The prerequisite for using this type of drug is to determine whether the enemy has disguised itself (i.e., performing immunohistochemical testing on tumor tissue), in order to achieve a powerful anti-tumor effect.

Lymphocytes are normally stored in the spleen and lymph nodes throughout the body, much like soldiers in barracks. When monocytes detect a tumor and report it to T lymphocytes, they are dispatched. After completing their mission, the T cells produce the T cell receptor tumor antigen PD-1 on their surface. Upon contact with cells expressing PD-L1, they are "destroyed on the spot," entering a state of apoptosis (exhaustion). Therefore, PD-1 is also considered a hallmark of exhausted T cells, acting like a "pigtail" that allows tumor cells to grab hold and attack them head-on (see Figure 2).

3. What effects does hydrogen have on immune cells in cancer patients?

If PD-1 is widely expressed on the surface of cytotoxic T cells, it usually indicates that the patient's immune system has completely collapsed and the patient's survival time is short.

Shorter. This conclusion has been proven in patients with breast cancer (4), pancreatic cancer (5) and gastric cancer (6). In 2016, Scharping et al. (7) from the United States reported that, whether in the tumor or in the blood, exhausted cytotoxic T cells have metabolic defects, with notable characteristics of easy aggregation of T cells, continuous decrease in mitochondrial function, and continuous decrease in PGC-1 expression level. In the same year, Kamimura et al. (8) from Japan reported that hydrogen can strongly activate the signaling molecule PGC-1x, thereby upregulating mitochondrial respiration in T lymphocytes. In 2006, Handschin and Spiegelman from the United States reported that PGC-1x signaling can enhance adaptive thermogenesis and gluconeogenesis, reversing the dysfunction of cytotoxic T cells. The next question is: If the function of cytotoxic T cells is restored, can the progression-free survival (PFS) of the tumor and the overall survival (OS) of the patient be prolonged?

What are the clinical results of hydrogen inhalation therapy for stage IV colon cancer?

In 2018, our research group (1) reported the results of a study on hydrogen inhalation therapy for patients with stage IV colon cancer. A total of 55 patients participated in the study. Each patient used a hydrogen inhaler for 3 hours per day and was followed up for 3 years. Blood was drawn regularly to check the expression level of PD-1 on the surface of cytotoxic T cells. Through continuous hydrogen inhalation, the proportion of PD-1°CD8+T cell subtypes in the patient's blood continued to decrease, and after a few months, it could be reduced by about 60%. The reason is that the PD-1* subtype cells are continuously induced to apoptosis by hydrogen, while PD-1 cells are continuously replenished. Patients with a high proportion of exhausted (PD-1) CD8+T cells in peripheral blood have shorter PFS and OS (both 18 months). Patients with a high proportion of non-exhausted (PD-1-) CD8+T cells have significantly longer PFS (>40 months) and OS (46 months) (see Figure 3).

5. What is the mechanism by which hydrogen regulates immune function?

After blood tests, we (1) found that hydrogen treatment led to a decrease in the proportion of PD-1* (exhausted) CD8+ T cells and an increase in the proportion of PD-1- (non-exhausted) CD8+ T cells in the peripheral blood of cancer patients (Figure 4). Hydrogen has two characteristics: one is that it can only remove OH from the four types of ROS. OH is known as the "villain" ROS, has the strongest oxidative capacity, and is associated with cancer, diabetes, and hypertension; the other characteristic is that it can enhance the function of lymphocyte mitochondria by activating PGC-1a. OH damages mitochondrial DNA, leading to mitochondrial dysfunction. Therefore, hydrogen maintains the state of PD-1 for a long time by removing OH and protecting CD8+ T cell mitochondria from DNA damage; as the proportion of PD-1 cells increases, the proportion of terminal PD-1 cells gradually decreases, thereby improving prognosis. This is due to hydrogen-induced mitochondrial activation.

Coenzyme (Co)Q10 is an essential electron carrier in the mitochondrial respiratory chain (see Figure 5). It transfers electrons from Complexes I and II to Complex II, catalyzing the binding of ·OH with molecules to form water molecules, which in turn eliminates the ·OH. Therefore, we believe that peripheral blood CoQ10 concentration can be considered a useful marker of mitochondrial function and is positively correlated with mitochondrial function.

We (1) subsequently selected 25 patients and tested the expression of CoQ10 in their blood. We found that after hydrogen treatment, 18 patients (72%) had elevated CoQ10 levels. Compared with patients with decreased CoQ10 (median OS = 8 months), patients with elevated CoQ10 had a significantly improved overall survival rate (>50 months), suggesting that hydrogen may improve T lymphocyte mitochondrial function by increasing CoQ10 levels, thereby improving patient survival (see Figure 6).

Conclusion

We have discovered for the first time immunological evidence that hydrogen inhalation prolongs survival in cancer patients. This is by increasing the number of highly active (PD-1) T cells in the blood, reducing the proportion of exhausted (PD-1) T cells, and prolonging the survival and killing capacity of cytotoxic T cells, thereby significantly extending patients' progression-free and overall survival. This effect may be achieved by increasing CoQ10 expression on the inner mitochondrial membrane of T lymphocytes, allowing more molecular hydrogen to enter the mitochondria, neutralizing ·OH and protecting normal mitochondrial function.

[Sun] Akagi Junji

(Note: This article was translated and compiled by Chen Jibing.)

References

[1] Akagi J and Baba H. Hydrogen gas restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis. Oncol Rep, 2019, 41(1): 301-311.

[2] Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 2006, 439(7077):682-687.

[3] Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood, 2009, 114(8): 1537-1544.

[4] Sun S, Fei X, Mao Y, et al. PD-1(+) immune cell infiltration inversely correlates with survival of operable breast cancer patients. Cancer Immunol Immunother, 2014, 63(4): 395-406.

[5] Zarour HM. Reversing T-cell Dysfunction and Exhaustion in Cancer. Clin Cancer Res, 2016, 22(8): 1856- 1864.

[6] Lu X, Yang L, Yao D, et al. Tumor antigen-specific CD8(+) T cells are negatively regulated by PD-1 and Tim-3 in human gastric cancer. Cell Immunol, 2017, 313:43-51.

[7] Scharping NE, Menk AV, Moreci RS, et al. The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. Immunity, 2016, 45(2): 374-388.

[8] Kamimura N, Ichimiya H, Iuchi K, et al. Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1alpha to enhance fatty acid metabolism. NPJ Aging Mech Dis, 2016, 2:

16008.

[9] Handschin C and Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev, 2006, 27(7):728-735.

Modifying cancer cells:

"Intimate" contact between hydrogen and cancer cells

Reading Key Points

The fear of cancer has become a commonplace in the world. Despite the continuous efforts of modern medicine, countless lives are still lost to cancer every day due to the invasion of cancer cells. Most cancer treatments still focus on how to kill cancer cells. However, common treatments such as chemotherapy and radiotherapy after surgical resection, while killing cancer cells, also greatly damage normal cells, causing serious toxic side effects. Multiple animal studies and preliminary studies in cancer patients have shown that hydrogen has potential important applications in assisting cancer treatment and reducing the side effects of chemotherapy and radiotherapy. So, how does hydrogen interact with tumor cells?

Tumors that look the same are actually composed of different types of cancer cells. Among them, there is a special type of cancer cell called cancer stem cells. Although they only account for a small part of the entire tumor, they play an important role in the survival, proliferation, metastasis and recurrence of the tumor. Cancer stem cells have a strong proliferation ability. On the one hand, they can generate new tumor stem cells by dividing.

On the other hand, cells can also give rise to other different types of tumor cells, namely differentiated cells or cells in the process of differentiation, thus forming what we call a tumor cell population. Cancer stem cells maintain the vitality of the tumor cell population through self-renewal and unlimited proliferation, and are also the culprit of tumor recurrence and metastasis (see Figure 1).

Cancer treatment generally relies on the principle that each tumor cell has the capacity to proliferate indefinitely. The goal is to kill as many tumor cells as possible, and if the tumor shrinks, the treatment is considered effective. However, most tumors recur after a period of time after treatment. From the perspective of cancer stem cells, traditional treatments do not completely eliminate them. Although cancer stem cells constitute only a small fraction of the tumor population, they survive due to their strong resistance to drugs. They retain their capacity for indefinite proliferation, laying the foundation for future recurrences. Cancer treatment requires finding a way to target cancer stem cells. If these cells are subdued, even if the tumor doesn't shrink, due to the limited proliferation of other cancer cells, the tumor will gradually regress and shrink, potentially leading to a true cure (see Figure 2).

We have conducted some research on cancer stem cells. Cancer stem cells have a characteristic: when cultured in a petri dish without the addition of nutrients such as serum, normal cancer cells will die over time due to lack of nutrients. However, cancer cells with stem cell characteristics will form spheres of cells called tumor spheres. Studies on their tumor-forming ability demonstrate the effects of hydrogen on cancer stem cells. Our study on ovarian cancer, published in Translational Cancer Research (2018), showed that hydrogen treatment significantly reduced the number and size of tumor spheres (see Figure 3). We also found that while cell growth remained largely unchanged in the presence of serum, the state of some cells differed from their original state. Similar phenomena have been observed in studies of various tumor cell types. Our current results suggest that hydrogen's intimate contact with cancer cells may modify them, causing them to lose some of their cancer stem cell properties. We are continuing our research into the long-term effects of this change, as well as the potential and practical application of hydrogen combined with other treatments for cancer stem cells.

The scavenging effect of hydrogen molecules on reactive oxygen species and their preventive and therapeutic effects on tumors

Reading Key Points

Compared with general antioxidants, hydrogen is selective, diffusible, and harmless, and may play a unique role in the prevention and treatment of tumors, such as avoiding the so-called "pro-oxidative effect" of some antioxidants.

Due to the heterogeneity of tumors, anticancer drugs have their scope of application, and the anti-tumor effects of hydrogen also show several situations: effective, ineffective, and potentially harmful.

In 1975, Dole et al. from Baylor University in the United States published a groundbreaking article in the internationally renowned academic journal Science. The authors found that hydrogen, at a concentration as high as 97.5%, could inhibit squamous cell carcinoma in mice, overturning the conventional wisdom that hydrogen was a physiologically inert gas. However, the molecular mechanism by which hydrogen inhibits cancer cells remained largely unresolved. It wasn't until 2007 that Shigeo Ohta et al. from the Institute of Gerontology at Nippon Medical School discovered that hydrogen could exert biological effects at a safe dose as low as 2%, and further demonstrated its selective antioxidant properties, sparking a wave of research into the biological functions of hydrogen molecules.

It is well known that the production and clearance of reactive oxygen species (ROS) in normal cells maintain a dynamic balance, with ROS levels being relatively low. However, tumor cells, due to genetic alterations, exhibit abnormal ROS metabolism. The high levels of ROS produced can promote tumor development and progression, raising the possibility that hydrogen could prevent and treat tumors through ROS clearance. In 2009, Itoh et al. (Japan) proposed the hypothesis that hydrogen could act as a second messenger, but this hypothesis was not widely accepted due to insufficient evidence. In fact, some ROS can actually act as second messengers to activate proliferation and antioxidant pathways within cells. Treatments targeting ROS in tumor cells are known as redox therapies. Further increasing intracellular ROS levels is oxidative therapy, while reducing ROS levels is reductive therapy. Broadly speaking, the effects of hydrogen on tumors fall under the category of reductive therapy. Because it is harmless to the human body and readily crosses various biological membranes, compared to other reducing agents, it is reasonable to speculate that hydrogen holds great promise in tumor prevention and treatment.

1. Hydrogen and ROS

It has long been believed that hydrogen is an inert gas, so hydrogen, when mixed with oxygen under pressure, has been used as a breathing gas for divers underwater. Ota Shigeo et al. (2) used cells and pure solutions without cells, combined with fluorescence probes, electron spin resonance and other methods, to clearly identify the target molecules of hydrogen as hydroxyl radicals (·OH·) and nitrite anions (ONOO-). The study of the latter was limited to pure solutions without cells, and the effect was relatively weak, so the target molecules of hydrogen are mainly ·OH. This result confirms the long-held speculation that hydrogen has a reducing effect in tissue cells. More importantly, the antioxidant effect of hydrogen is limited to the direct removal of ·OH· and ONOO. Hydrogen cannot remove other reactive oxygen molecules (such as O-2 and H2O2), nor can it reduce the oxidation products formed by the combination of OH- and other molecules. It also has no reducing effect on the oxidized molecules in the mitochondrial oxidative respiratory chain (i.e., it does not interfere with the function of mitochondria). It is speculated that hydrogen may have a certain effect on the free radical metabolism of cancer cells. Experiments using intestinal adenocarcinoma Caco-2 cells have shown that hydrogen not only significantly reduces the increase in intracellular OH induced by antimycin A but also significantly reduces the levels of OH and H₂O₂. This result, at least in malignant tumor cells, raises questions about the high selectivity of hydrogen in scavenging free radicals. Studies by Itoh et al. (3, 4) in Japan using inflammatory cells found that hydrogen inhibited the activation of mast cells by IgE and macrophages by LPS/IFNc. Although ROS levels increased in both cell types, hydrogen either had no effect on ROS elevation (macrophages) or, while primarily reducing O₂ and HO₂, inhibited NADPH oxidase activation (mast cells). According to the findings of Shigeo Ohta et al., hydrogen does not directly scavenge O₂ and H₂O₂, so the reduction in their levels is the result of hydrogen inhibiting NADPH oxidases/ROS and tumor oxidases. In summary, because hydrogen inhibits both signaling pathways involved in cell activation, and after ruling out the possibility that hydrogen directly scavenges ROS, Itoh et al. proposed that hydrogen, like CO, HS, and NO, serves as an intracellular second messenger. Unfortunately, due to the lack of a specific target molecule, this hypothesis remains to be proven. Given the complexity of intracellular signaling pathways, this is a formidable undertaking, which explains the limited research and satisfactory results to date.

 

In addition, according to the principles of biopathology, the fact that hydrogen increases the expression of antioxidant molecules such as Nfr2 and SOD in cells seems to contradict its role in scavenging free radicals, because the enhanced expression of the above proteins is a response of the cells to ROS. ROS are promptly scavenged by hydrogen, and Nfr2 and SOD should be reduced accordingly. It seems far-fetched to explain this experimental phenomenon by saying that hydrogen reduces oxidative damage and thus maintains the cell's ability to respond to ROS. Therefore, in addition to directly scavenging free radicals, hydrogen may have other mechanisms of action. Inspired by the fact that metals can directly combine with hydrogen molecules to form stable compounds in metallo-organic chemistry, Shi et al. (5) in China proposed that the target molecules of hydrogen may be metal ions in metalloproteins in the body. Because metalloproteins are widely present in the body, especially in the oxidative respiratory chain, the consequence of this hypothesis is that hydrogen will interfere with many metabolic processes in the body, especially the process of oxidative phosphorylation. This is inconsistent with the observation of Shigeo Ohta et al. that hydrogen does not interfere with the oxidative respiratory chain.

Viewing hydrogen from the perspective of ROS may help us understand experimental phenomena related to hydrogen. For example, ROS have a wide range of cellular effects, ranging from direct oxidative damage to indirect regulation of signaling pathways (6-8). The pathophysiological effects of hydrogen on various tissues and cells may ultimately require a rational explanation based on the biological effects of ROS. It is foreseeable that research on hydrogen and ROS will complement and promote each other.

2. ROS and Tumors

ROS are primarily products of the partial reduction of O₂, including O₂, H₂O, and OH. Mitochondria are the primary site of ROS production, but some biological oxidation reactions, such as peroxisomal β-oxidation, also generate ROS. Furthermore, cells possess ROS-scavenging systems, including enzymatic antioxidants such as superoxide dismutase (SOD) and non-enzymatic antioxidants such as NADPH, which primarily provide reducing equivalents for redox reactions. ROS interact with the intracellular redox potential. The ratio of GSH to its oxide GSSG (GSH/GSSG) is the primary buffering pair for maintaining redox potential. NADPH, primarily produced by the pentose phosphate pathway, is a crucial factor in maintaining a stable GSH/GSSG ratio. Biochemical processes such as the glucose pentose phosphate pathway (which produces NADPH), oxidative phosphorylation (which produces ROS), and protein anabolism (which consumes NADPH) coordinate to maintain intracellular redox equilibrium. Therefore, the regulation of intracellular ROS is a complex system (6-8).

(1) Abnormal ROS in some tumor cells: During the cell cycle, the level of ROS in cells increases steadily, and antioxidants can block cells in the late G1 phase (9,10). Early studies found that H and O levels in tumor cells increase steadily. Compared with progeny tumor cells, the ROS level in tumor stem cells is lower due to their strong antioxidant capacity. Gene mutation is the most important reason for abnormal (increased) ROS in tumor cells. Oncoproteins such as RAS and MYC increase the level of ROS in cells (11). For example, RAS increases ROS by enhancing NADPH oxidase (NOX) and reducing the antioxidant molecule sestrin1; excessive ROS increases the level of cyclin D1 through ERK1/2, and then promotes RB phosphorylation, releasing E2F1 and prompting cells to transition from G1 phase to S phase (12). Tumor suppressor protein B, BRCA1, etc. inhibit the production of ROS and promote its metabolism. For example, BRCA1 reduces the level of ROS in cells by upregulating the antioxidant gene glutathione S-transferase (13). Some oncoproteins and tumor suppressor proteins have a bidirectional regulation on ROS, playing a role in stabilizing ROS levels. Under non-stress conditions, the oncoprotein BCL-2 increases O-2 by enhancing mitochondrial oxidative phosphorylation; under stress conditions, BCL-2 has an inhibitory effect on excessive increases in O. Elevated ROS levels at low to moderate levels enhance P53 expression and activate the ROS scavenging pathway; when ROS levels are too high, P53 activates the ROS production pathway, inducing cell apoptosis by further increasing ROS levels (''). In addition, tumor cell infiltration and metastasis (EMT) can increase ROS levels due to changes in gene expression (10). Infiltration of inflammatory cells in the tumor microenvironment, hypoxia, and nutritional imbalance can all increase ROS levels in tumor cells (13-15).

(2) Effects of ROS on cells (cellular oxidative response): The signaling pathways activated by ROS not only regulate redox metabolism, but also have an effect on cell proliferation, apoptosis, and aging. Therefore, ROS has the function of a second messenger. Its important mechanism is that the cysteine ​​sulfhydryl groups in the key structural domains of some proteins are easily reversibly oxidized by ROS to form disulfide bonds (-SH+-SH→-S-S-). These proteins include transcription factors such as p53, signaling proteins such as RAS, proteasomes that inactivate proteins, etc. 19-11. The signaling molecules involved, such as HIF1, TGF-B/SMADs, and KEAP1/NRF2 complexes, activate cell stress pathways, which have the effects of protecting cells, inhibiting apoptosis, and promoting angiogenesis. The activation of NF-kB and the synthesis and release of inflammatory factors, and the PKC-MAPK pathway are related to the proliferation of cancer cells (I2). The synergistic activation of the proliferative pathway and the antioxidant pathway/stress pathway by ROS allows tumor cells to proliferate while avoiding apoptosis caused by excessive ROS. Therefore, some researchers consider antioxidant systems such as NRF2 within tumor cells to be oncoprotein components. In addition to activating apoptotic pathways, acutely elevated levels of ROS can directly damage cellular macromolecular structures and induce cell death. Tumor suppressor genes such as P53, some chemotherapy drugs, and radiotherapy all induce apoptosis by increasing ROS levels. 19-121 ROS have different effects on different tumor cell types and stages. For example, while a reduction in ROS has an inhibitory effect on melanoma, it enhances the invasiveness of fibrosarcoma cells. In early-stage tumors, elevated ROS induce apoptosis by activating pathways such as P53. In advanced and late-stage tumors, inactivation of these pathways increases tumor cell tolerance to ROS. Furthermore, refractory tumors or cancer stem cells, due to their strong antioxidant capacity, are also more tolerant to ROS.

(3) Using ROS to prevent and treat tumors: ROS promotes the occurrence and development of tumors, which provides a basis for reduction therapy. Compared with normal cells, the high level of ROS in tumor cells makes tumor cells more sensitive to further increases in ROS, and oxidation therapy becomes a viable option. Reduction therapy attempts to prevent the occurrence and development of tumors by reducing ROS levels, inhibiting the activation of proliferation channels and DNA mutations. ROS scavengers, ROS-promoting enzyme inhibitors, and anti-ROS enzyme activators (03-15) can be used. The effects of this therapy in cell and animal experiments are relatively obvious, but the results of clinical studies (taking vitamins A, E, selenium, and β-carotene) vary greatly. Some studies even believe that these antioxidants increase the incidence of cancer and weaken the effects of other anti-cancer treatments (13-15). This situation may be the result of the diversity of redox disorders in tumor cells. Oxidation therapy uses the cytotoxicity of ROS to directly kill tumor cells, including promoting the production of ROS and/or inhibiting the clearance of ROS. Low ROS levels in tumor stem cells may lead to insensitivity to treatment and survival (3); increasing ROS levels may also induce more mutations in tumor cells, or even normal cells, leading to drug resistance (1). These situations may limit the application of oxidative therapy. Theoretically, if tumor cells with disordered ROS are in the early stage without metastasis and DNA changes are minor, antioxidant therapy may prevent the occurrence and development of the tumor; if DNA changes are more severe and infiltration and metastasis have occurred, increasing ROS to promote apoptosis may be more effective (13). At present, some indicators that have a predictive effect on efficacy have been screened out, such as monitoring the plasma sulfoxidoreductase and VEGF levels in pancreatic cancer and liver cancer patients to evaluate the efficacy of sulfoxidoreductase inhibitors; PET scanning of tumor cells' glucose uptake rate and hypoxia degree can make ROS-promoting drugs related to metabolism and hypoxia more targeted. The screening and application of these indicators will make redox anti-tumor therapy more personalized (16).

3. Hydrogen and the Prevention and Treatment of Tumors

Some current research results have demonstrated the role of hydrogen in tumor prevention and treatment (17-20).

In terms of prevention, hydrogen water application reduced tumor incidence, decreased tumor size, and prolonged the incubation period in mouse models of thymic lymphoma, hepatocellular carcinoma, and renal cell carcinoma induced by Co, streptozotocin, and ferric nitrilotriacetate. Studies on renal cell carcinoma in Wistar mice induced by intraperitoneal injection of ferric nitrilotriacetate were conducted over short-term (1 week), medium-term (12 weeks), and long-term (49 weeks) observations. Short-term hydrogen treatment reduced the DNA uptake rate of 3-thymine and ornithine decarboxylase activity in renal homogenates; decreased OONO- and MDA production; and decreased the activities of enzymes such as NADPH oxidase, xanthine oxidase, and HO-1. Medium-term treatment reduced the expression of VEGF and PCNA, as well as STAT3 phosphorylation, in renal homogenates; and long-term treatment reduced the incidence of renal cell carcinoma and the average tumor size. These studies demonstrate that hydrogen can reduce the incidence and severity of tumors in animal models through antioxidant mechanisms.

Regarding treatment, as mentioned previously, as early as 1975, Dole et al. investigated the effects of high-pressure hydrogen (97.5% hydrogen, 2.5% oxygen, 8.28 atmospheres) in hairless albino mice after inducing cutaneous squamous cell carcinoma via ultraviolet irradiation. The results were astonishing: tumors shrank, and some detached cells disappeared, achieving a cure. Equally surprising, however, is the lack of similar reports since then. Recent studies have mostly used tumor cells, with a few using mice as experimental subjects. The tumor cell lines used include colon adenocarcinoma, human tongue carcinoma, human lung adenocarcinoma, human fibrosarcoma, and Ehrlich ascites tumor. Adding hydrogen to the culture medium reduced the metastatic capacity (number of colonies and number of cells per colony) and invasive capacity (number of cells traversing the reconstituted basement membrane) of tumor cells, while increasing cell degeneration and apoptosis rates. Importantly, hydrogen reduced the number of colonies and number of cells per colony of the human tongue cancer cell line HSC-4, but did not affect colony formation in normal human tongue epithelial-like cells (DOK), demonstrating its selective anti-tumor effect. The anti-cancer effect of hydrogen is related to reducing intracellular ROS levels, decreasing MAPK activity, and increasing the activity of apoptotic enzymes such as Caspase 3. Hydrogen also inhibits the transcription and secretion of VEGF in human lung adenocarcinoma cell line A549, reducing A549 culture medium-induced angiogenesis.

It is worth noting that although hydrogen promotes apoptosis in colon 26 cell lines, it does not increase the number and volume of tumors induced by colon 26 injection, nor does it increase the survival rate of tumor-bearing BALB/c mice (20). Hydrogen has no inhibitory effect on the liver cancer cell line HepG2; in the oxidative stress induced by antimycin A, hydrogen has a protective effect on intestinal adenocarcinoma Caco-2 cells. In addition, as an auxiliary intervention, hydrogen has the effect of reducing the side effects of other anti-tumor treatments. Hydrogen can reduce the renal toxicity of cisplatin-treated C57BL/6 mice transplanted with tumors and improve the physical condition and quality of life of patients with liver tumors receiving radiotherapy. In these studies, hydrogen did not affect the tumor itself.

The above studies show that hydrogen has preventive and therapeutic effects on some tumors and exhibits selectivity for tumor cells. For other tumors, hydrogen has no therapeutic effect; and under conditions of acute oxidative stress, hydrogen may even protect tumor cells.

Conclusion

Studies on hydrogen's potential for preventing and treating tumors are limited, involving only a limited number of tumor cells and animals, and no randomized controlled clinical trial reports exist. Future work should focus on the following areas: 1. Strengthen cellular research, using a wider variety of tumor cell types to investigate oxidative stress and antioxidative stress conditions, focusing on therapeutic efficacy and categorizing it as effective, ineffective, or harmful. 2. Strengthen holistic animal research, exploring the biomedical effects of hydrogen at different stages of tumor development and progression, including genetics and phenotypes. 3. Strengthen clinical research, focusing on the actual situation of tumor populations, especially those with malignant tumors, and conducting real-data studies. This involves fully recording the treatment history of each individual, accumulating a sufficient number of case records, and obtaining a true reflection of the efficacy of treatment for a specific type of tumor. 4. Explore the combined application of hydrogen with other anti-tumor therapies, such as hydrogen combination therapy trials based on chemotherapy, radiotherapy, and hyperthermia (19-21). Some animal and human trials involve a wide range of topics and require collaborative efforts by researchers from multiple disciplines.

Qin Shucun Zhou Xiao

References

[1] Dole M, Wilson FR,Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science, 1975, 190(4210): 152-154.

[2] Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13(6):688-694.

[3] Itoh T, Fujita Y, Ito M, et al. Molecular hydrogen suppresses FcepsilonRI mediated signal transduction and prevents degranulation of mast cells. Biochem Biophys Res Commun, 2009, 389(4):651-656.

[4] Itoh T, Hamada N, Terazawa R, et al. Molecular hydrogen inhibits lipopolysaccharide/interferon gamma- induced nitric oxide production throuh modulation of signal transduction in macrophages. Biochem Biophys Res Commun, 2011, 411(1):143-149.

[5] Shi P, Sun W,Shi P. A hypothesis on chemical mechanism of the effect of hydrogen. Med Gas Res, 2012, 2(1): 17. [6] Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature, 2009, 458(7239): 780-783.

[7] Kopnin PB, Agapova LS, B.P. K, et al. Repression of sestrin family genes contributes to oncogenic Ras- induced reactive oxygen species up-regulation and genetic instability. Cancer Res, 2007, 67(10): 4671- 4678.

[8] Chen ZX and Pervaiz S. Bcl-2 induces pro-oxidant state by engaging mitochondrial respiration in tumor cells. Cell Death Differ, 2007, 14(9): 1617-1627.

[9] Vousden KH and Ryan KM. p53 and metabolism. Nature reviews. Cancer, 2009, 9(10): 691-700.

[10] Watson J. Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol, 2013, 3(1): 120-144.

[11] Kurz EU, Douglas P,Lees-Miller SP. Doxorubicin activates ATM-dependent phosphorylation of multiple downstream targets in part through the generation of reactive oxygen species. J Biol Chem, 2004, 279(51): 53272-53281.

[12] Dempsey EC, Newton AC, Mochly-Rosen D, et al. Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol, 2000, 279(3): L429-L438.

[13] Gorrini C, Harris IS,Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov, 2013, 12(12): 931-947.

[14] Church SL, Grant JW, Ridnour LA, et al. Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells. Proc Natl Acad Sci USA, 1993, 90(7): 3113-3117.

[15] The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. The ATBC Cancer Prevention Study Group. N Engl J Med, 1994, 4(1): 1-10. [16] Marinho HS, Real C, Cyrne L, et al. Hydrogen peroxide sensing, signaling and regulation of transcription factors. Redox Biol, 2014, 2(23): 535-562.

[17] Kawai D, Takaki A, Nakatsuka A, et al. Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. Hepatology, 2012, 56(3): 912-921.

[18] Saitoh Y, Yoshimura Y, Nakano K, et al. Platinum nanocolloid-supplemented hydrogendissolved water inhibits growth of human tongue carcinoma cells preferentially over normal cells. Exp Oncol, 2009, 31(3): 156-162.

[19] Runtuwene J, Amitani H, Amitani M, et al. Hydrogen-water enhances 5-fluorouracil-induced inhibition of colon cancer. PeerJ, 2015, 3: e859.

[20] Zhao P, Jin Z, Chen Q, et al. Local generation of hydrogen for enhanced photothermal therapy. Nat Commun, 2018, 9(1): 4241.

Reflection on "Qi Circulating Blood" and Hydrogen Ion Transfer

Reading Key Points

1. The biological significance of “Qi” supporting hydrogen ion transport and ATP synthesis

The character "qi" (qi) is composed of "qi" (qi) and "mi" (mi). Qi refers to the air of heaven, mostly oxygen; mi refers to the air of earth, mostly the essence of water and grain, namely water, trace elements, sugar, protein, and fat. Qi supports the hydrogen ion transport and ATP synthesis of the mitochondrial respiratory chain.

Oxygen enters the alveoli through the trachea, passes through the alveolar epithelium, interstitial tissue, and pulmonary capillaries, enters the bloodstream, and enters red blood cells, where it binds to hemoglobin. Under the spleen's transportation and transformation, food and water are transformed into food essences. These essences pass through the epithelium and interstitial tissue of the small intestine, entering the lacteals and capillaries. In the lungs, these food essences and oxygen form Zong Qi, which circulates throughout the body along the vascular system, diffusing through the capillaries to the tissues and cells surrounding the microvessels.

In cells with mitochondria, oxygen and water-grain essence undergo catabolism to produce acetyl-CoA, which enters the tricarboxylic acid cycle for decarboxylation and dehydrogenation to produce CO, which reduces nicotinamide adenine dinucleotide (NAD') and flavin adenine dinucleotide (FAD) to reduced nicotinamide adenine dinucleotide (NADH) and reduced flavin dinucleotide (FADH).

The respiratory chain in the inner mitochondrial membrane consists of five complexes. Complex I is NADH-Q2 reductase (also known as NADH oxidase), Complex II is succinate-Q2 reductase, Complex III is cytochrome reductase, Complex IV is cytochrome oxidase, and Complex V is ATP synthase. Prosthetic groups that transfer hydrogen and electrons include NAD, FMN, FAD, and CoQ2, while electron transfer occurs through Fe-S and heme Fe and Cu, which transfer electrons through the gain and loss of electrons. Hydrogen is transferred via two pathways: through Complex I and through Complex II.

1. Hydrogen transfer via Complex I

Most dehydrogenases within mitochondria use NAD' as a coenzyme. Under dehydrogenase catalysis, the hydrogen removed from the substrate's SH domain is transferred to NAD* to generate NADH2. Under the action of Complex I, NADH transfers the hydrogen atom to FMN to form FMNH2, which in turn transfers the hydrogen to Q to form QHz. At this point, the two hydrogen atoms dissociate into two protons and two electrons. The two protons become free in the medium, while the two electrons are transferred to cytochrome C via Complex III. Complex IV then transfers the two electrons from cytochrome C to oxygen to form O, which combines with 2H+ to form water.

2. Hydrogen transfer via Complex II

Succinate-Q reductase dehydrogenates succinate to produce FADH, and then transfers the hydrogen on FADH to Q to produce QH. The subsequent transfer process, such as NADH respiratory chain complexes I, III, and IV, has a proton pump function, and the oxidation potential energy of complex II to transfer electrons is too small to pump out protons.

The oxidative potential energy from electron transfer pumps hydrogen ions (H+) from the mitochondrial matrix into the intermembrane space outside the inner membrane, creating a negative proton gradient across the inner membrane, which provides the potential energy for ATP synthesis. The ATP synthase complex, composed of proteins including subunits a, b, and 8, has a proton channel. When protons flow back through the intermembrane space through the proton channel, ATP synthase is activated, driving ATP synthesis. This method of ATP synthesis is called oxidative phosphorylation, the process in which the electrochemical potential generated by the redox reactions accompanying hydrogen ion transfer in the respiratory chain drives the phosphorylation of ADP to ATP. Oxidative phosphorylation is the primary method of ATP synthesis in cells; another method is substrate phosphorylation. Oxidation of NADH via the respiratory chain produces 2.5 ATP molecules, and oxidation of FADH via the respiratory chain produces 1.5 ATP molecules.

In summary, "qi" (qi) contains oxygen and grain essence, and it produces NADH and FAD2 through the tricarboxylic acid cycle. NADH is converted into NADH' by the mitochondrial respiratory chain complexes, transferring H' to mitochondrial complex I. Then, via coenzyme Q10, H' is transferred to mitochondrial complex III. FADH2 is transferred to mitochondrial complex II, and via coenzyme Q10, H' is transferred to mitochondrial complex III. H' transferred through these two pathways passes through cytochrome C and is transferred to complex IV. H' ions escape from complex IV and combine with oxygen to produce water. The potential energy accumulated during H ion transfer is used by mitochondrial complex V, or ATP synthase, to convert adenosine diphosphate (ADP) into ATP. Qi provides the basis for hydrogen ion transfer, and the potential energy accumulated from hydrogen ion transfer provides the basis for ATP synthesis (see Figure 1). When mitochondrial complex activity decreases, hydrogen ion transfer is impaired, causing hydrogen ions to escape from mitochondrial complexes I and III, combining with oxygen to produce negative oxygen anions. ATP has a high affinity for the cytoskeleton, assembling individual cytoskeleton components (G-actin) into actin (F-actin). Cardiac F-actin is a substructure of the myocardial thin and thick filaments, maintaining contraction and relaxation, and fulfilling the role of blood circulation. Heart Qi and blood circulation refer to the oxygen and food essence entering the myocardial mitochondria, which, through the tricarboxylic acid cycle and the new mitochondrial respiratory chain, generate ATP, promoting the assembly of F-actin, maintaining myocardial thin and thick filaments, fulfilling contraction and relaxation, and fulfilling the role of blood circulation.

2. Considerations of Heart Qi Deficiency, Insufficient Blood Circulation, Abnormal Hydrogen Ion Transfer, and Insufficient ATP Production

Heart Qi deficiency often occurs when there is insufficient supply of oxygen and water and grain essence in the blood due to ischemia, hypoxia, or ischemia-reperfusion. Blockage or semi-blockage of the coronary vessels of the heart leads to insufficient supply of oxygen and water and grain essence, and combined with reduced expression and activity of ATP synthase in the mitochondrial complex, this can lead to reduced myocardial ATP production, myocardial F-actin depolymerization, myocardial thin and thick filament rupture, and cardiac dysfunction (4).

Thrombolysis or interventional revascularization can restore the supply of oxygen, grain essence, and water. However, the abnormal energy metabolism pathway caused by ischemia and the low expression of mitochondrial complexes II, III, IV, and V have not yet recovered. After reperfusion, the transmission of hydrogen ions is impaired, overflowing through I and III, producing negative oxygen anions (5). In addition, the accumulated potential energy decreases, and the expression of the ATPase subunit ATP5D is low, resulting in reduced ATP production (6). Excessive peroxide production damages DNA and induces cell apoptosis. On the other hand, it damages membrane structure through lipid peroxidation (7); the reduction of ATP leads to the rupture of myocardial F-actin, myocardial thin filaments, and thick filaments, which in turn leads to cardiac dysfunction and blood loss.

3. Qishen Yiqi Dropping Pills' Qi-tonifying and Blood-promoting Effects and Comprehensive Regulation of the Mitochondrial Respiratory Chain in Cardiac Cells

Qishen Yiqi Dropping Pills are a compound Chinese herbal preparation for invigorating qi and activating blood circulation, consisting of Astragalus, Salvia, Panax notoginseng, and Dalbergia odorifera. Astragalus is the main ingredient of Qishen Yiqi Dropping Pills, with astragaloside IV as one of its main ingredients; Salvia is the main ingredient of Qishen Yiqi Dropping Pills, with danshensu as one of its main ingredients; Panax notoginseng is also the auxiliary ingredient of Qishen Yiqi Dropping Pills, with ginsenosides Rb1, Rg1, and notoginsenoside R1 as its main ingredients. In 2003, Qishen Yiqi Dropping Pills were approved as a new drug for the treatment of Qi deficiency and blood stasis type coronary heart disease, and are clinically used for the treatment of angina pectoris in Qi deficiency and blood stasis type coronary heart disease (8). Multicenter large-sample clinical studies have also demonstrated that Qishen Yiqi Dropping Pills have clinical efficacy in the secondary prevention of coronary heart disease. Our study confirmed that Qishen Yiqi Dropping Pills can improve myocardial ischemia-reperfusion injury, and its Qi-invigorating and blood-activating effects are related to its regulation of the myocardial mitochondrial respiratory chain.

Qishen Yiqi Dropping Pills and their main Qi-tonifying ingredient, astragaloside IV, can inhibit the low expression of mitochondrial complex V, suppress the decrease in ATP/ADP and ATP/ADP ratios, and improve myocardial energy metabolism. They also inhibit the decrease in myocardial tissue cTnI levels and the increase in peripheral blood cTnI levels, improving myocardial structure and function. The Qi-tonifying and blood-activating ingredient, Rb1, in Qishen Yiqi Dropping Pills can also inhibit the low expression of mitochondrial complex V and the decrease in ATP levels, improving myocardial structure and function. Qishen Yiqi Dropping Pills exert their Qi and blood-tonifying effects during ischemia, with their main Qi-tonifying ingredients, astragaloside IV and Rb1, fulfilling this role.

Qishen Yiqi Dropping Pills also have an ameliorative effect on myocardial injury caused by ischemia-reperfusion in rats. A rat myocardial ischemia-reperfusion injury model was established by ligating the anterior descending coronary artery of the rat heart for 30 minutes, removing the ligation, and reperfusing for 90 minutes. Pre-administration of Qishen Yiqi Dropping Pills can inhibit myocardial infarction caused by ischemia-reperfusion and improve cardiac function and cardiac perfusion volume. This effect is related to its upregulation of ATP5D, a subunit of myocardial mitochondrial complex V, improving myocardial energy metabolism, and inhibiting the rupture of myocardial actin and myocardial fibers (6).

Astragaloside IV can inhibit the low expression of ATPSD, a subunit of the respiratory chain V, in the myocardium of rats with 30 minutes of ischemia and 30 minutes of ischemia/90 minutes of reperfusion, improve myocardial energy metabolism, inhibit the decrease of cTnI content in myocardial cells and the increase of cTnI content in peripheral blood, inhibit the cleavage of F-actin in myocardial cells and the phosphorylation of MLC2, reduce the area of ​​myocardial infarction, improve cardiac function and myocardial perfusion (10), and play a role in replenishing qi and blood.

(1) Rb1 can inhibit myocardial infarction caused by ischemia-reperfusion in rats, inhibit myocardial cell apoptosis, myocardial actin F-actin and myocardial fiber rupture, inhibit the decrease of troponin cTnI content in myocardial cells, and inhibit the increase of cTnI content in peripheral blood.

Rb1 can inhibit the activation of RhoA-ROCK1 of the small G protein family and relieve its inhibitory effect on ATP5D (11).

(2) Rg1 can alleviate myocardial infarction caused by ischemia-reperfusion in rats, reduce myocardial damage, and improve cardiac function and cardiac flow. Rg1 can inhibit the activation of RhoA-ROCK1 and relieve its inhibition on ATP5D. Rg1 can also inhibit the increase of aldolase and embryonic enolase in the myocardial glycolysis pathway caused by ischemia-reperfusion, inhibit the decrease of wild-type enolase and coenzyme dienoyl-CoA isomerase in the fatty acid metabolism pathway, and improve the myocardial energy metabolism pathway (12).

(3) Rg1 can inhibit myocardial infarction in rats induced by ischemia-reperfusion, inhibit cardiomyocyte apoptosis, and inhibit the rupture of myocardial actin and myocardial fibers. This effect is related to its inhibition of ROCK1 overexpression and MYPT1 phosphorylation, relieving its inhibition on myocardial mitochondrial ATP5D, inhibiting AMPK phosphorylation, and improving myocardial energy metabolism (13).

Danshensu can improve myocardial infarction caused by ischemia-reperfusion in rats, improve cardiac function and cardiac perfusion volume. Danshensu can improve the expression and activity of myocardial mitochondrial complex I and its subunit NDUFA10 by upregulating the expression of Sirt-1 deacetylase, promote the transfer of hydrogen ions, inhibit the production of superoxide, and provide potential energy for ATP production (14)

Rg1 in Qishen Yiqi Drops improves the energy metabolism pathway: Danshensu regulates Sirt-1, the expression and activity of the mitochondrial complex and its subunit NDUFA10, promotes the transfer of hydrogen ions, and provides potential energy for ATP production; Rb1 and R1 inhibit the activity of the small G protein family RhoA/Rock1, restore the expression of ATP5D, and astragaloside IV upregulates ATPSD, comprehensively regulating the mitochondrial respiratory chain and the transfer of hydrogen ions, reducing the production of peroxidation, promoting ATP production, and comprehensively playing the role of replenishing qi and activating blood circulation) (see Figure 2).

References

[1] Han Jingyan, ed. Ischemia-reperfusion injury and traditional Chinese medicine, China Traditional Chinese Medicine Press, 2019: 6-7.

[2] Letts JA and Sazanov LA. Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain. Nature structural & molecular biology, 2017, 24(10):800-808.

[3] Pollard TD and Borisy GG. Cellular motility driven by assembly and disassembly of actin filaments. Cell, 2003, 112(4): 453-465.

[4] Cui YC, Yan L, Pan CS, et al. The Contribution of Different Components in QiShenYiQi Pills(R) to Its Potential to Modulate Energy Metabolism in Protection of Ischemic Myocardial Injury. Front Physiol, 2018, 9: 389.

[5] Pell VR, Chouchani ET, Murphy MP, et al. Moving Forwards by Blocking Back-Flow: The Yin and Yang of MI Therapy. Circ Res, 2016, 118(5): 898-906.

[6] Lin SQ, Wei XH, Huang P, et al. QiShenYiQi Pills(R) prevent cardiac ischemia-reperfusion injury via energy modulation. Int J Cardiol, 2013, 168(2): 967-974.

[7] Bagheri F, Khori V, Alizadeh AM, et al. Reactive oxygen species-mediated cardiac-reperfusion injury: Mechanisms and therapies. Life Sci, 2016, 165: 43-55. [8] Zhu Linping, Li Xia, Zhu Mingdan, et al. Clinical research progress on the prevention and treatment of cardiovascular diseases with Qishen Yiqi dripping pills. Journal of Practical Traditional Chinese Medicine, 2015, 31(12): 1203.

[9] Shang H, Zhang J, Yao C, et al. Qi-shen-yi-qi dripping pills for the secondary prevention of myocardial infarction: a randomised clinical trial. Evid Based Complement Alternat Med, 2013, 2013: 738391.

[10] Tu L, Pan CS, Wei XH, et al. Astragaloside IV protects heart from ischemia and reperfusion injury via energy regulation mechanisms. Microcirculation, 2013, 20(8): 736-747.

[11] Cui YC, Pan CS, Yan L, et al. Ginsenoside Rb1 protects against ischemia/reperfusion-induced myocardial injury via energy metabolism regulation mediated by RhoA signaling pathway. Sci Rep, 2017, 7: 44579.

[12] Li L, Pan CS, Yan L, et al. Ginsenoside Rg1 Ameliorates Rat Myocardial Ischemia-Reperfusion Injury by Modulating Energy Metabolism Pathways. Front Physiol, 2018, 9: 78.

[13] He K, Yan L, Pan CS, et al. ROCK-dependent ATP5D modulation contributes to the protection of 3notoginsenoside NR1 against ischemia-reperfusion-induced myocardial injury. American journal of physiology. Heart and circulatory physiology, 2014, 307(12): H1764-1776.

[14] Yang XY, He K, Pan CS, et al. 3, 4-dihydroxyl-phenyl lactic acid restores NADH dehydrogenase 1 alpha subunit 10 to ameliorate cardiac reperfusion injury. Sci Rep, 2015, 5: 10739.

[15] Han JY, Li Q, Ma ZZ,Fan JY. Effects and mechanisms of compound Chinese medicine and major ingredients on microcirculatory dysfunction and organ injury induced by ischemia/reperfusion. Pharmacol Ther, 2017, 177: 146-173.

[16] Han Jingyan, The scientific connotation of heart qi deficiency and blood stasis and the mechanism of action of Qishen Yiqi Dropping Pills in replenishing qi and activating blood circulation, World Science and Technology - Modernization of Traditional Chinese Medicine, 2019.

Reading Extension

Jiuhua Mountain

Mount Jiuhua is one of the four famous Buddhist mountains in China. Li Bai praised it, "Once, from the Jiujiang River, I gazed at the Jiuhua Peak from afar. The Milky Way hangs over the green water, and its beauty resembles that of lotus flowers." From the foothills of Mount Jiuhua to Tiantai Peak, renowned temples and ancient monasteries abound, each boasting rare historical sites. The relics are particularly renowned for their whole-body relics, representing the remains of highly accomplished monks who, after their passing, have remained intact, their original form remaining vivid and lifelike. Master Haiyu lived in a cave on Mount Jiuhua for a full 100 years, never leaving the mountain, never seeing anyone, and never taking a disciple, until he was 126 years old. He maintained strict discipline, spending his entire life surrounded by mist and clouds, cultivating the pure and dispensing the turbid, abstaining from worldly pleasures. When hungry, he ate Polygonatum sibiricum and Pueraria root, and when thirsty, he drank mountain spring water. Legend has it that a single serving of raw Polygonatum sibiricum could keep him from feeling hungry for seven days.

Zhang Xichun, a famous Qing Dynasty physician, wrote in his book "Medical Records of Combining Chinese and Western Medicine": "There is hydrogen in the furnace core and in the human abdomen. The yellow one can draw hydrogen up to the lungs, where it combines with inhaled oxygen to transform into water. It can also encourage the upward movement of body fluids in the stomach and regulate the transformation of qi in the lower part of the body, preventing frequent urination. Therefore, it can cure thirst." Master Haiyu "ate Polygonatum when he was hungry." Is Polygonatum the "yellow one" that "draws hydrogen up" and thus relieves the master's hunger?

(Photo courtesy of Ni Shengpei)

Praise of Mount Jiuhua

Zhongzimei

Legend of the Immortal

It is a metaphor for the physical relics

Or is it just a shock of reality?

The mountain is clear and the wind is also clear

Thousands of years can never be completed

The clarity and wonder of the soul

Unstained, undefiled, and indestructible

It is persistence and non-attachment

It's the same as your Jiuhua Mountain

condescendingly

Insight into the mundane world

Chapter 3

Experimental studies

Experimental study on hydrogen cancer control

Reading Key Points

Tumor cells produce large amounts of ROS, far more than normal cells. These ROS can promote their own proliferation, DNA synthesis, and angiogenesis, leading to cancer cell infiltration and growth and distant metastasis (1-3). The earliest report on hydrogen directly inhibiting tumor cell growth was in 1975, when Dole et al. in the United States found that high-pressure hydrogen could cause squamous cell carcinoma cells inoculated on mouse skin to regress (4). Literature reports on hydrogen directly inhibiting tumor occurrence or progression have continued to appear in professional medical journals at home and abroad in recent years. This article summarizes them below.

In 2009, Saitoh et al. (5) of Japan reported that hydrogen-rich water and cisplatin were used alone or in combination to intervene in the in vitro growth of human tongue cancer cells (HSC-4). They used hydrogen-rich water and cisplatin as the experimental group and normal tongue epithelial cells (DOK) as the control group. They found that: 1. Hydrogen-rich water alone or hydrogen-rich water combined with cisplatin (combination group) could accelerate the clearance of ROS in HSC-4, with the combination group being faster; 2. The combination group could inhibit the growth rate and growth area of ​​HSC-4 cells and inhibit the growth of DOK cells. It can be seen that with the help of hydrogen-rich water, cisplatin has a stronger killing effect on tumors, indicating that cisplatin and hydrogen-rich water have a significant synergistic effect in suppressing tumors; cisplatin combined with hydrogen-rich water only kills tumors but not normal cells, indicating that hydrogen-rich water can offset the side effects of chemotherapy drugs on normal cells. From a mechanistic perspective: 1. Since ROS is associated with the pathogenesis of almost all tumors (6), hydrogen-rich water alone or in combination with cisplatin can accelerate the clearance of ROS in HSC-4, which may be the reason why hydrogen-rich water inhibits tumor mutation and metastasis and enhances anti-tumor effects (7); 2. Hydrogen-rich water alone is not enough. The effect of hydrogen-rich water alone in treating tumors is not good, and the anti-tumor effect of the combined method is significantly better than that of hydrogen water alone; 3. The reason why chemotherapy drugs such as cisplatin cause side effects is mainly because they induce normal cells to produce a large amount of ROS (8), which in turn produces cytotoxicity. This reflects from another aspect that chemotherapy patients need antioxidant therapy for recovery.

In 2011, Zhao et al. (9) in China used multiple radioactive particle irradiation to induce thymus tumors in mice. At the same time, hydrogen saline was injected intraperitoneally to observe the incidence of thymic lymphoma. After 30 weeks, they found that: 1. The tumorigenicity rate of mice in the hydrogen saline injection group (38%) was significantly lower than that in the simple irradiation group (60%), and most tumors did not occur; 2. Different methods were used to detect the intracellular and extracellular ROS levels of hydrogen saline-treated mice and the control group 4 hours after irradiation. Blood was drawn and peripheral blood mononuclear cells were isolated. It was found that the intracellular ROS level of hydrogen saline-treated mice was significantly lower than that of the control group. The serum SOD and total GSH concentrations of the hydrogen saline group were significantly higher than those of the control group, and the MDA concentration was significantly lower than that of the control group, indicating that the antioxidant status of the hydrogen saline group was significantly improved, thereby reducing the degree of DNA damage. Mechanistically, 1. Since radiotherapy-induced tumors are achieved through the continuous and massive production of toxic ROS in normal cells (10-12), hydrogen-rich saline, by controlling ROS, inhibits tumor mutation and metastasis, which may be an important reason for the reduction in radiation-induced mortality (13-15). 2. The simple use of hydrogen-rich water can significantly reduce the level of irradiation-generated ROS in peripheral blood leukocytes and plasma, thereby delaying tumor formation or even preventing it altogether. This indicates that molecular hydrogen has a strong ability to resist radiation damage and protect normal tissues.

In 2012, Kawai et al. (16) from Japan reported that STAM mice were induced to develop fatty liver and liver cancer models by drinking hydrogen-rich water and pioglitazone (PGZ, an anti-diabetic anti-inflammatory drug that can prevent fatty liver) alone or in combination, and the MCD diet was used as a blank control group. After 8 weeks, they found that: 1. The liver function damage in the hydrogen-rich water and hydrogen-rich water + PGZ groups was significantly milder than that in the control group, and the combined group had better effects, with the least obvious increase in transaminase; 2. The liver tumor volume in the hydrogen-rich water and hydrogen-rich water + PGZ groups was significantly smaller than that in the control group, and the hydrogen-rich water group had better effects, with the largest tumor size smaller than that in the other two groups, indicating that hydrogen-rich water has an antagonistic effect on oxidative stress, apoptosis, inflammation and tumorigenesis of liver cells. From the perspective of mechanism: 1. Although hydrogen water is not as good as PGZ in lowering cholesterol, it is more effective in anti-oxidation and preventing liver cancer, indicating that hydrogen water is a new method for preventing fatty liver. Similar effects have also been reported in models of acute liver injury induced by diabetes and carbon tetrachloride (17,18); 2. In the hydrogen water group, the lipid metabolism-related genes AOX and FAT of the model animals were significantly downregulated, indicating that hydrogen water may exert its effect by inhibiting the PPAR signaling pathway, thereby inhibiting mitochondrial oxidase and enhancing fatty acid oxidation (19); 3. Since the tumor inhibition ability of the hydrogen water + PGZ group is stronger than that of the simple PGZ group, it shows that there is a synergistic effect between the two methods. As for why the tumor inhibition effect of hydrogen water alone is better than that of the combined group, it may be because hydrogen has more targets and sometimes interacts with PGZ. For example, the simple hydrogen water group has the best effect in reducing liver 8-OhdG and peripheral blood ROM, indicating that hydrogen water alone is more effective in protecting DNA oxidative damage. Stronger than combined use with PGZ; 4 Since TNF-a (20) and IL-6 (21) play a core role in hepatocyte apoptosis and fatty liver formation, the mechanism of action of hydrogen water also includes inhibiting the gene expression of these two cytokines; 5 The expression of PCNA can reflect the proliferation activity of hepatocytes. Among all the groups, only the PCNA expression level of hepatocytes in the hydrogen water group was significantly reduced, indicating that hydrogen water has a strong effect of resisting cell proliferation.

In 2013, Li et al. (22) from China reported that drinking hydrogen-rich water could prevent kidney damage and renal cancer in rat models induced by ferrous nitrilotriacetate (Fe-NTA). The results showed that: 1. The degree of kidney damage in the hydrogen-rich water group was significantly reduced, and serum creatinine and urea nitrogen levels remained normal. 2. The mechanism of its protective effect on renal function is: first, it reduces the formation of lipid peroxidase and peroxynitrate, inhibiting oxidative stress; second, it activates NAPDH oxidase and xanthine oxidase, enhances the activity of catalase, and restores the function of mitochondria in renal cells; third, it reduces the expression of NF-kB, IL-6, and MCP-1 in renal cells, reduces the accumulation of macrophages in the kidneys, and thus inhibits Fe-NTA-induced inflammation. 4. It inhibits the expression of VEGF and PCNA in renal cells and inhibits STAT3 phosphorylation. 3. The incidence of renal cancer in the hydrogen-rich water group (22%) was lower than that in the control group (54.8%), and the onset rate was also slower than that in the control group. From the perspective of the pathogenesis of renal cancer: 1. The mechanism of the Fe-NTA-induced model is the continuous iron deposition in the renal tubular cells (23), while in this study, hydrogen water can reduce the iron content in the kidneys of model animals, and at the same time reduce the levels of OONO- and MDA in the kidneys, showing a strong ability to resist oxidative stress; 2. The HO-1 gene is highly expressed in a variety of tumor models and can promote angiogenesis, tumor proliferation and metastasis241. The significant decrease in HO-1 gene expression in the kidneys of animals injected with hydrogen water is very indicative; 3. Inflammation plays a core role in the pathogenesis of renal cancer (25). The significant decrease in IL-6 and MCP-1 expression in the kidneys of model animals after drinking hydrogen-rich water best reflects its anti-cancer ability; 4. Abnormal increase in VEGF in tissues is related to the accelerated growth and metastasis of renal cancer. The decrease in VEGF expression in the kidneys of model animals after drinking hydrogen-rich water may be another mechanism of hydrogen; 5. Activation of STAT signals is also widely present in a variety of tumor cell lines and primary tumors (27,28). After hydrogen water treatment, model animals also showed a decrease in STAT expression, which led to a decrease in IL-6 levels, which should also be a mechanism of hydrogen action.

In 2015, Runtuwene et al. (29) from Japan reported that drinking high-pressure hydrogen-rich water and 5-fluorouracil (5-FU) alone or in combination intervened in the in vitro growth of colon cancer cell line (Colon26) and in vivo tumor induction model. The model animals without intervention were used as the control group. The results showed that: 1. Drinking high-pressure hydrogen water alone can promote the apoptosis of Colon 26 tumor cells. The reason is that the expression of p-AMPK, AIF and Caspase 3 that induce cell apoptosis in cells is significantly increased. Combined with 5-FU, high-pressure hydrogen water can further enhance the killing effect on cancer cells in vitro; 2. The animals in the group drinking ordinary water survived for an average of 9 days, while those drinking ordinary hydrogen water survived for 11 days.

The survival time of the animals was significantly prolonged (30.31) when the high-pressure hydrogen water was used for 13 days, and when combined with 5-FU, the survival time was extended to 18-20 days. The above results indicate that: 1. The tumor in this model progresses rapidly, and hydrogen water alone is insufficient to achieve an effect. It must be combined with 5-FU to significantly prolong the survival time of the animals (30.31);

2. At low hydrogen doses, the free radical scavenging effect of this antioxidant can protect various cells, including tumor cells. At high hydrogen concentrations, because the free radicals in tumors are significantly more than those in normal cells (32, 33), it can induce tumor cell apoptosis. 3. In in vitro experiments, both hydrogen waters increased the expression of p-AMPK, AIF, and Caspase 3 in Colon 26 cells, which may be the mechanism by which hydrogen water induces apoptosis in these cells (34). It is likely that the tumor produces a large amount of ROS, which are scavenged by H, and then rely on the Caspase 3 pathway and lipid oxidative stress to induce tumor cell apoptosis (35).

In 2018, Wang et al. (36) reported that: 1. Using a hydrogen-oxygen nebulizer, different concentrations of hydrogen-oxygen mixed gas were introduced into two lung cancer cell culture systems (A549 and H1975). It was found that the cell division, migration and invasion abilities were significantly inhibited, and cell apoptosis was accelerated. The reason was that the expression of NIBPL, SMC3/5/6, Cyclin D1, and CDK4/6 genes in the cells was reduced. 2. Lung cancer mice were treated with a hydrogen-oxygen nebulizer (2 hours per day for 4 weeks) and intraperitoneal injection of the chemotherapy drug cisplatin, respectively. Saline injection served as the control group. Compared with the control group, the tumor size in the cisplatin-treated group was 75%, and that in the H1975-treated group was 25%. The expression of proteins Ki-67, VEGF, and SMC3, which are positively correlated with tumor growth, was reduced in both treatment groups, with the expression being more pronounced in the cisplatin-treated group.

Chen Jibing Mu Feng

References

[1] Gunther S, Ruhe C, Derikito MG, et al. Polyphenols prevent cell shedding from mouse mammary cancer spheroids and inhibit cancer cell invasion in confrontation cultures derived from embryonic stem cells. Cancer Lett, 2007, 250(1):25-35.

[2] Maulik N and Das DK. Redox signaling in vascular angiogenesis. Free Radic Biol Med, 2002, 33(8): 1047- 1060.

[3] Nonaka Y, Iwagaki H, Kimura T, et al. Effect of reactive oxygen intermediates on the in vitro invasive capacity of tumor cells and liver metastasis in mice. Int J Cancer, 1993, 54(6): 983-986.

[4] Dole M, Wilson FR,Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science, 1975, 190(4210): 152-154.

[5] Saitoh Y, Yoshimura Y, Nakano K, et al. Platinum nanocolloid-supplemented hydrogendissolved water inhibits growth of human tongue carcinoma cells preferentially over normal cells. Exp Oncol, 2009, 31(3): 156-162.

[6] Szatrowski TP and Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res, 1991, 51(3): 794-798.

[7] Dhar A, Young MR,Colburn NH. The role of AP-1, NF-kappaB and ROS/NOS in skin carcinogenesis: the JB6 model is predictive. Mol Cell Biochem, 2002, 234-235(1-2): 185-193.

[8] Yao X, Panichpisal K, Kurtzman N, et al. Cisplatin nephrotoxicity: a review. Am J Med Sci, 2007, 334(2): 115-124.

[9] Zhao L, Zhou C, Zhang J, et al. Hydrogen protects mice from radiation induced thymic lymphoma in BALB/c mice. Int J Biol Sci, 2011, 7(3): 297-300.

[10] Little JB. Radiation carcinogenesis. Carcinogenesis, 2000, 21(3): 397-404.

[11] Siegler R, Harrell W,Rich MA. Pathogenesis of radiation-induced thymic lymphoma in mice. Journal of the

National Cancer Institute, 1966, 37(2): 105-121.

[12] Barcellos-Hoff MH, Park C,Wright EG. Radiation and the microenvironment - tumorigenesis and therapy. Nature reviews. Cancer, 2005, 5(11): 867-875.

[13] Liu C, Cui J, Sun Q, et al. Hydrogen therapy may be an effective and specific novel treatment for acute radiation syndrome. Med Hypotheses, 2010, 74(1): 145-146.

[14] Qian L, Cao F, Cui J, et al. Radioprotective effect of hydrogen in cultured cells and mice. Free Radic Res, 2010, 44(3): 275-282.

[15] Qian L, Cao F, Cui J, et al. The potential cardioprotective effects of hydrogen in irradiated mice. J Radiat Res, 2010, 51(6): 741-747.

[16] Kawai D, Takaki A, Nakatsuka A, et al. Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. Hepatology, 2012, 56(3): 912-921.

[17] Kamimura N, Nishimaki K, Ohsawa I, et al. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity (Silver Spring), 2011, 19(7): 1396-1403.

[18] Sun H, Chen L, Zhou W, et al. The protective role of hydrogen-rich saline in experimental liver injury in mice. J Hepatol, 2011, 54(3): 471-480.

[19] Yakaryilmaz F, Guliter S, Savas B, et al. Effects of vitamin E treatment on peroxisome proliferator- activated receptor-alpha expression and insulin resistance in patients with non-alcoholic steatohepatitis: results of a pilot study. Intern Med J, 2007, 37(4): 229-235.

[20] Wigg AJ, Roberts-Thomson IC, Dymock RB, et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non- alcoholic steatohepatitis. Gut, 2001, 48(2): 206-211.

[21] Anty R, Bekri S, Luciani N, et al. The inflammatory C-reactive protein is increased in both liver and adipose tissue in severely obese patients independently from metabolic syndrome, Type 2 diabetes, and NASH. The American journal of gastroenterology, 2006, 101(8): 1824-1833.

[22] Li FY, Zhu SX, Wang ZP, et al. Consumption of hydrogen-rich water protects against ferric nitrilotriacetate- induced nephrotoxicity and early tumor promotional events in rats. Food Chem Toxicol, 2013, 61(248-254. [23] Toyokuni S. Iron-induced carcinogenesis: the role of redox regulation. Free Radic Biol Med, 1996, 20(4):

553-566.

[24] Nuhn P, Kunzli BM, Hennig R, et al. Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo. Mol Cancer, 2009, 8(37).

[25] Mantovani A. Molecular pathways linking inflammation and cancer. Current molecular medicine, 2010, 10(4): 369-373.

[26] Li C, Liu B, Dai Z, et al. Knockdown of VEGF receptor-1 (VEGFR-1) impairs macrophage infiltration, angiogenesis and growth of clear cell renal cell carcinoma (CRCC). Cancer Biol Ther, 2011, 12(10): 872- 880.

[27] Huang M, Page C,Reynold RK. Constitutive activation of STAT3 oncogene product in human ovarian carcinoma cells. Gynec Oncol, 2000, 79(67-73).

[28] Lin TS, Mahajan S,Frank DA. Stat signaling in the pathogenesis and treatment of leukemias. Oncogene, 2000, 19(2496-2504).

[29] Runtuwene J, Amitani H, Amitani M, et al. Hydrogen-water enhances 5-fluorouracil-induced inhibition of colon cancer. PeerJ, 2015, 3(e859).

[30] Ishikawa T, Tanaka Y, Ishitsuka H, et al. Comparative antitumor activity of 5-fluorouracil and 5'-deoxy-5- fluorouridine in combination with radiation therapy in mice bearing colon 26 adenocarcinoma. Japanese journal of cancer research: Gann, 1989, 80(6): 583-591.

[31] Tominaga T, Yoshida Y, Kosaki G, et al. Effect of 5-fluorouracil and UFT on experimental liver metastasis model of colorectal cancer using mouse colon 26 cells. Japanese journal of cancer research: Gann, 1993, 84(7): 783-786.

[32] Nakashima-Kamimura N, Mori T, Ohsawa I, et al. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol, 2009, 64(4): 753-761.

[33] Simone CB, 2nd, Simone NL, Simone V, et al. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, Part 2. Altern Ther Health Med, 2007, 13(2): 40-47.

[34] Jin C and Reed JC. Yeast and apoptosis. Nat Rev Mol Cell Biol, 2002, 3(6): 453-459.

[35] Farmer EE and Mueller MJ. ROS-mediated lipid peroxidation and RES-activated signaling. Annual review of plant biology, 2013, 64(429-450).

[36] Wang D, Wang L, Zhang Y, et al. Hydrogen gas inhibits lung cancer progression through targeting SMC3. Biomed Pharmacother, 2018, 104(788-797).

Experimental study on the inhibition of lung cancer by hydrogen in cellular and animal models

Reading Key Points

Experiment 1: Effects of Hydrogen on Experimental Tumor Formation

Methods: Six BALB/C nude mice were divided equally into two groups, A and B, which were the normal group and the hydrogen inhalation group (inhalation of hydrogen and oxygen mixed gas), respectively.

Tumor Cell Injection: After A549 cells were expanded to a certain number, they were digested with trypsin and harvested. The nude mice were observed for 3 days in an SPF environment. If they were in good condition, they were ready for cell inoculation. In a cleanroom, the skin at the injection site was disinfected with 75% alcohol. A cell suspension containing 5 x 10 cells was injected into the hind limb of the nude mouse. The insertion point was approximately 1 cm from the injection site, forming a raised skin bump to prevent fluid leakage. The skin was then disinfected and the tumor formation was observed.

Intervention method: After tumor formation, the nude mice in group A were not treated in any way and were kept in a normal environment; after tumor formation, the nude mice in group B were given a hydrogen and oxygen mixed gas (66.7% H2+33.3% O) to inhale for 6 hours a day at a flow rate of 3 liters/minute for a total of 14 days.

Experimental results: The growth rate of tumor in the normal group of nude mice showed a slow increasing trend in the first 3 weeks, and then a rapid growth trend after 3 weeks; compared with the normal group, the growth rate of tumor in the hydrogen inhalation group appeared to be continuously slow (see Figure 1).

The size of the tumor mass finally formed in the hydrogen inhalation group of nude mice was significantly smaller than that in the normal group (see Figure 2).

During the experiment, it was found that the nude mice in the normal group ate significantly less than those in the hydrogen inhalation group. Grossly, the lungs, livers, and intestines of the nude mice in the normal group were significantly enlarged, while the organs of the nude mice in the hydrogen inhalation group were relatively normal (see Figure 3).

In addition, it was found that the normal group had more microvascular proliferation in the tumor growth area, while the hydrogen inhalation group did not have this phenomenon and had fewer microvessels (see Figure 4).

 

Experiment 2: Cell morphology observation

Methods: After A549 cells were expanded to a certain number, they were digested with trypsin and collected; they were replated in two 35-well dishes and divided into two groups: cultured in a normal cell culture incubator and cultured in a hydrogen-oxygen mixed gas incubator (66.7% H2+33.3% Oz); the medium was changed every two days, and the cells were passaged after they were fully grown; the passaged A549 cells continued to be cultured according to the culture environment of the parent culture; and the two groups of cells were observed until the 10th generation.

Results: At the first passage, there was no significant difference between the cells cultured in the two gas environments, with similar proliferation and good cell health (see Figure 5a). At the fifth passage, the proliferation of A549 cells in the hydrogen-oxygen mixed gas group was inhibited, with increased cell volume and more cell death (see Figure 5b). At the tenth passage, cells in the hydrogen-oxygen mixed gas group showed more vacuolation (see Figure 5c).

Experiment 3: Cell immunofluorescence observation

Methods: A549 cells in the logarithmic growth phase were collected, counted, and the cell suspension diluted to 5 × 10⁻¹/mL in complete serum medium. The cells were seeded onto 6-well slides. The cells were cultured in a CO2-treated cell culture incubator for 24 hours. Depending on the experimental group, each well was replaced with either standard medium or hydrogen-containing medium for another 24 hours. Diluted anti-Vimentin antibody (PBS for blank control and antibody for experimental groups) was added, followed by diluted fluorescent secondary antibody, and nuclear staining with Hoechst. The slides were removed, observed, and photographed under a fluorescence microscope.

Results: This experiment demonstrates the effects of hydrogen molecules on the growth of A549 cells. Compared to the control group cultured in standard culture medium, hydrogen-treated cells slowed their growth. Red fluorescence (BrdU staining) significantly decreased from the first to the tenth generation, indicating that hydrogen inhibits cell growth (see Figure 6).

Experiment 4: A549 cell cycle detection

Methods: Cells in the logarithmic growth phase were collected, counted, and the cell suspension was diluted to 2×10°/mL with full serum medium.

Cells were seeded in 6-well plates and cultured in a CO2-free cell culture incubator for 24 hours. Depending on the grouping, each well was then replaced with either standard culture medium or hydrogen-containing culture medium and cultured for another 24 hours. The fixed cells were removed and centrifuged, the fixative removed, and 200 μL of cell cycle detection reagent was added for flow cytometry analysis.

Results: As shown in Figure 7, compared with those cultured in ordinary culture medium, the number of S phase cells of A549 cells treated with hydrogen was significantly reduced, and the number of G2/M phase cells was significantly increased, suggesting that hydrogen may affect the cell cycle, inhibit cancer cell proliferation and promote cell apoptosis by reducing S phase division and G2/M phase arrest.

Experiment 5: Cell migration observation

Methods: A cell scratch test was performed. Cells in logarithmic phase growth were digested, counted, and cultured in a humidified incubator with 5% CO. Once cells had completely covered the bottom of the plate, a 200 μL yellow pipette tip was used to create a linear scratch perpendicular to the plate, ensuring that each scratch was uniform in width. Standard culture medium supplemented with 1% FBS and hydrogen-containing culture medium were added to the plates, and the plates were placed in the incubator for further culture. Images were taken at 0 and 24 hours after the scratch. Time-lapse videos of cell migration were recorded from 0 to 24 hours to investigate the effect of hydrogen on tumor cell migration.

Results: After 24 hours of culture, the cells began to move toward the middle, and the migration ability of A549 cancer cells was significantly reduced after adding hydrogen culture medium.

in conclusion

This experiment tested the effects of hydrogen-oxygen mixed gas prepared by a hydrogen-oxygen atomizer produced by Shanghai Mei Company on human lung adenocarcinoma cell A549 from the aspects of cell proliferation, tumorigenesis, cell activity, cell cycle and apoptosis, cell metastasis and invasion. The results showed that hydrogen can significantly change the morphology of tumor cells, change the cell cycle, promote apoptosis, and inhibit tumor cell growth, movement, invasion and migration.

Attachment

Wang Dongchang et al. conducted a similar experiment in China using a Shanghai-based oxygen-hydrogen nebulizer to investigate the inhibitory effects of hydrogen on the growth and invasiveness of non-small cell lung cancer. Since they used the same oxygen-hydrogen nebulizer as this study, the abstract is reprinted below with the author's permission (originally published in International Journal of Respiratory Medicine, 2018, 38: 561-565):

Methods: A tumor-bearing nude mouse model was established. A suspension of cultured human lung cancer cell line A549 was inoculated subcutaneously on the dorsal forearm of BALB/c male nude mice. When the transplanted tumors reached an average diameter of approximately 4 mm, the mice were divided into a control group and a hydrogen group. The control group inhaled air; the hydrogen group inhaled 66% hydrogen + 34% oxygen (USA, model AMS-H-01) for 2 hours daily. After 4 weeks, the nude mice were sacrificed, and the tumors were removed. Tumor volume and weight were recorded, and tissues were collected for histological, immunohistochemical, and various molecular analyses.

result:

(1) Growth and weight of transplanted tumors: In the first week after tumor cell inoculation, there was no statistically significant difference in tumor size between the control group and the hydrogen group. As the hydrogen intervention time prolonged, differences in tumor volume gradually appeared, and by the second week, the difference between the two groups was statistically significant. After four weeks of intervention, the tumors in the hydrogen group were significantly smaller than those in the control group (see Figure 8), and the difference in tumor growth also increased with time (see Figure 9).

(2) Histological and immunohistochemical changes of the tumor: HE staining of the tumor tissue in the control group showed that the cells were closely arranged, the cell density was relatively large, and the morphological heterogeneity was significant, which was a typical manifestation of cancer; the cell density in the hydrogen group was relatively small, and its heterogeneity was lower than that in the control group, which showed that the "cancerousness" of the tumor was lower than that in the control group (see Figure 10).

(3) The Ki-67, COX-2, and VEGF protein contents in tumor tissues were detected. The control group had a higher content of nuclear dark staining, while the hydrogen group had relatively less dark staining of these three proteins (see Figure 11).

Conclusion: Hydrogen can inhibit the growth of non-small cell lung cancer and reduce cancer invasiveness. This inhibitory effect is related to the downregulation of Ki-67, COX-2 and VEGF expressions.

Wang Ying Lai Peizhen

Experimental study on the inhibition of ovarian cancer by hydrogen

Reading Key Points

Ovarian cancer is often considered a "hidden killer" of female cancers. Because the ovaries are located deep in the pelvis and are hidden, initial symptoms are mild, and routine gynecological examinations typically only reveal ovarian cysts. However, ovarian cysts can have many causes, including irregular menstrual cycles. These cysts typically return to normal after menstruation. However, cysts with underlying disease often persist after menstruation, requiring further examination to determine whether they are normal ovarian cysts or ovarian cancer. In many cases, even in the late stages of ovarian cancer, the ovaries themselves do not enlarge, making it easy to overlook them. By the time ovarian cancer is confirmed, it's already too late, and optimal treatment is no longer possible. Globally, over 220,000 women develop ovarian cancer each year, and approximately 60% of these patients die. In the West, gynecologists have a saying: If "cancer" is one of the scariest words in the English language, then for most women, "ovary" is the worst adjective. In China, the current state of ovarian cancer treatment is equally bleak, with a five-year survival rate of less than 40%. While most cancer treatments have seen rapid advancements and the emergence of new drugs, ovarian cancer has seen no new first-line medications in nearly 30 years. Difficulty in detection, diagnosis, and treatment are the three most important factors contributing to the low survival rate for ovarian cancer.

The potential therapeutic effect of hydrogen on cancer has actually been studied for a long time. As early as 1975, a study from the United States showed that high-pressure hydrogen has a therapeutic effect on skin squamous cells (1). The researchers exposed tumor-bearing mice to 97.5% hydrogen at 8 atmospheres for 16 consecutive days and found that hydrogen had a very significant anti-tumor effect. Within 10 days of hydrogen treatment, it was found that the tumor tissue of some mice turned black, the tumor volume of some mice was significantly reduced, and the tumor of some mice even fell off. At the same time, all mice did not show any adverse consequences. The study was published in the famous Science magazine. However, because high-pressure hydrogen requires special equipment for storage and there are safety risks, there are few subsequent reports on high-pressure hydrogen treatment for cancer. Since Professor Shigeo Ota of Japan discovered in 2007 that trace amounts of hydrogen can exert biological effects (2), research on hydrogen in the field of cancer has gradually begun. Our research group's animal and cell experiments have found that hydrogen has potential application value in the treatment of ovarian cancer. This research result has been published in Transl Cancer Res (3). The following is a brief introduction to our research results.

To study the effects of hydrogen on ovarian cancer, we first established an ovarian cancer mouse model. Two ovarian cancer cell lines, Hs38.T and PA-1, were subcutaneously inoculated into the mice. Tumor growth was observed after two weeks. These tumor-bearing mice were then randomly divided into two groups: one group received hydrogen inhalation three times daily for 30 minutes each time for six weeks (using a Shanghai Mei Hydrogen Oxygen Atomizer, with the inhaled gas containing 66% hydrogen and 34% oxygen); the other group served as a control group, breathing normal air. Aside from the different respiratory conditions, the two groups of mice were housed under identical conditions. The experimental results, as shown in Figure 1, show that six weeks of hydrogen inhalation significantly inhibited tumor growth, with an average reduction of 32.3% in tumor volume. The expression of Ki67, a marker of tumor malignancy, decreased by 30%, indicating a significant suppression of tumor growth. Furthermore, we found that CD34, a marker of tumor angiogenesis, decreased by 74%, indicating that hydrogen can reduce tumor angiogenesis. Blood vessels are responsible for transporting oxygen and nutrients. The body's organs and tissues are densely woven with blood vessels, and tumors are no exception. Because cancer cells grow and multiply so rapidly, they have a particularly high demand for oxygen and nutrients. Therefore, as tumors grow, they release signals that promote angiogenesis, allowing more blood vessels to extend into the tumor and deliver more oxygen and nutrients. We hypothesize that hydrogen inhalation therapy significantly reduces these tumor blood vessels, resulting in a decrease in the supply of oxygen and nutrients to the tumor, ultimately slowing tumor growth. This may be one of the reasons why hydrogen inhalation inhibits ovarian cancer growth.

In addition to their extraordinary reproductive capacity, tumor cells possess many abilities not possessed by normal cells, such as the ability to invade adjacent tissues and metastasize to distant sites. This ability is a major cause of tumor recurrence and metastasis, ultimately leading to death in cancer patients. So, besides inhibiting tumor growth, does hydrogen also have other ways of targeting tumor cells? We conducted cell-based experiments to investigate the effects of hydrogen on the biological functions of tumor cells. First, we prepared a hydrogen-enriched cell culture medium and then cultured ovarian cancer cells in both normal and hydrogen-enriched medium. The results, shown in Figure 2, show that hydrogen significantly inhibited tumor cell growth in vitro, consistent with previous animal studies. Furthermore, cell invasion (see Figure 2, C and D) and migration (see Figure 2, E and F) experiments showed that ovarian cancer cells cultured in hydrogen-enriched medium significantly decreased their invasive and migratory abilities, suggesting that hydrogen may inhibit metastasis. Tumor recurrence and metastasis are the main causes of death, and inhibiting this recurrence and metastasis remains a major challenge in cancer treatment. Although our research has found that hydrogen can inhibit the invasion and migration of tumor cells, further experimental evidence is needed, particularly from animal models and clinical trials. If it can be confirmed in the future that hydrogen can inhibit tumor recurrence and metastasis, it will undoubtedly bring new hope to cancer patients.

Another important discovery in our cell-based experiments is that hydrogen has a significant inhibitory effect on cancer stem cells. As shown in Figure 3, in vitro tumor sphere formation experiments show that hydrogen treatment significantly reduces the number and size of tumor spheres, suggesting a potential inhibitory effect of hydrogen on cancer stem cells. Cancer stem cells are a type of cell within tumors that possess stem cell characteristics. They possess both high proliferation and self-renewal capabilities and multipotential differentiation potential. This means they can not only replicate themselves but also transform into other cell types under external stimulation. Current cancer stem cell theory holds that tumors are actually composed of multiple different cell types, with only cancer stem cells possessing strong carcinogenicity and high invasiveness. Although these cells only constitute a small proportion of tumor cells, they play a crucial role in tumor recurrence and metastasis. The formation of new tumors following tumor recurrence and metastasis requires the involvement of cancer stem cells. In addition to ovarian cancer cells, we have also observed the inhibitory effect of hydrogen on cancer stem cells in cervical cancer cells. As shown in Figure 4 , the in vitro tumor sphere formation experiment showed that the number and size of tumor spheres of HeLa cells derived from cervical cancer cultured in hydrogen-rich medium were significantly reduced compared with those of normal cultured cells ( 4 ).

Combined with the current research on hydrogen in other tumors, we believe that hydrogen may be used as an alternative to existing tumor treatments.

Auxiliary treatments play an important role.

First, hydrogen can directly affect tumor cells themselves. Our experimental results above demonstrate that breathing hydrogen can significantly inhibit tumor growth in mice with ovarian cancer. This anti-cancer effect of hydrogen may be closely related to its ability to inhibit angiogenesis, reduce tumor cell invasion and migration, and inhibit the growth of tumor stem cells. It should be noted that our research is limited to animal and cell studies. Because ovarian cancer is a diverse and complex disease, and the pathological process of each patient is diverse and complex, the efficacy of hydrogen therapy for ovarian cancer requires further experimental evidence, particularly clinical research.

Secondly, hydrogen may also enhance patients' immunity and help them overcome cancer. Clinical research by Japanese scholars has found that the T lymphocytes responsible for killing cancer in cancer patients are prone to aging and exhaustion. Inhaling hydrogen can reactivate these cells, increasing the proportion of T lymphocytes capable of killing cancer (5). This change is closely related to the patient's prognosis. In other words, the anti-cancer effect of hydrogen may be achieved by improving the patient's immunity.

Third, hydrogen can alleviate the toxic side effects of chemotherapy and radiotherapy. There are many reports on this aspect of research. For example, clinical studies have long proven that hydrogen can alleviate the side effects of radiotherapy and chemotherapy (6). There is even more evidence from animal experiments, such as hydrogen's ability to counteract the toxic damage to the kidneys caused by the chemotherapy drug cisplatin.

In short, the role of hydrogen in cancer prevention and treatment is promising, but we must avoid exaggerating its effects. In the future, we need to conduct more in-depth and systematic basic and clinical research on hydrogen in cancer prevention and treatment. This will have important significance and value both for hydrogen medical research and for cancer patients.

Xie Fei Zhao Pengxiang Ma Xuemei

References

[1] Dole M, Wilson FR,Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science, 1975,190(4210): 152-154.

[2] Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13(6):688-694.

[3] Shang L, Xie F, Li JL, et al. Therapeutic potential of molecular hydrogen in ovarian cancer. Transl Cancer Res, 2018, 8(1).

[4] Shang Lei, Li Jiala, Su Zehua, et al. Effects of hydrogen molecules on cervical cancer cells Hela. Progress in Biotechnology, 2018, 8:1-9.

[5] Akagi J and Baba H. Hydrogen gas restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis. Oncol Rep, 2019, 41(1): 301-311.

[6] Nakashima-Kamimura N, Mori T, Ohsawa I, et al. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol, 2009, 64(4):753-761.

Chapter 4
Case Study

A "real world" investigation of hydrogen cancer control:

Follow-up report of 82 patients with progressive cancer undergoing hydrogen inhalation

Summary

Background and Purpose: The treatment of progressive cancers presents a significant challenge, necessitating new approaches and strategies. Non-drug approaches are being explored. Hydrogen has been shown to have antioxidant and anti-inflammatory effects. Cancer development and progression are closely linked to peroxidation and inflammation, so hydrogen may play a role in controlling cancer.

Patients and Methods: Using the "real-world evidence" (RWE) research method, a retrospective and prospective follow-up study was conducted on patients with cancer, primarily progressive cancers, who recovered through self-inhalation of hydrogen. A total of 82 patients with stage III and IV cancer who underwent self-inhalation of hydrogen were observed. The tumors followed up were mainly lung cancer, liver cancer, gynecological malignancies, pancreatic cancer, gastrointestinal malignancies, and urinary malignancies, and all met the following criteria: (1) patients with a clear diagnosis and pathologically confirmed stage III and IV cancer; (2) patients who had received conventional treatment, including surgery, radiotherapy, and/or chemotherapy, but did not respond well or relapsed, or were unable to receive the above treatment due to systemic conditions or comorbidities, or refused treatment; (3) patients with different symptoms, such as poor appetite, fatigue, insomnia, and pain; (4) patients with existing tumors or/and abnormal tumor markers; (5) patients aged 20 to 80 years, without obvious heart, brain, lung, or kidney failure or mental abnormalities, and who could express symptoms; (6) patients who used a hydrogen-oxygen nebulizer to inhale a hydrogen-oxygen mixed gas with a hydrogen concentration of 66.7% and oxygen of 33.3% at a gas flow rate of 3000 mL/min. The inhalation lasted at least 1.5 hours per day for more than 3 consecutive months.

Results: (1) The follow-up time was 3 to 46 months, with a median follow-up time of 6 months. During the follow-up period, 12 patients died, all of whom were stage IV patients, including 4 patients with pancreatic cancer. The causes of death were: tumor progression in 5 cases, infection in 2 cases, liver failure, intestinal obstruction, upper gastrointestinal bleeding, PD-1 antibody drug-related pneumonia, and euthanasia in 1 case each. (2) The EORTC QLQ-C30 quality of life measurement scale was prospectively evaluated in 30 patients. With the extension of hydrogen inhalation time, the improvement of patients' functional areas and symptoms became more and more obvious. After 4 weeks of hydrogen inhalation, all areas showed improvement, with the most significant improvement in patients' fatigue, insomnia, loss of appetite, and pain. (3) All patients were assessed for physical fitness according to the Zubrod-ECOG-WHO (ZPS, 5-point system). 41.5% of patients had improved physical fitness, 34.1% of patients had stable physical fitness, and 24.4% of patients had deteriorated physical fitness. There was no significant difference in the improvement rate between patients who received hydrogen inhalation alone and those who received hydrogen inhalation combined with other treatments, or between patients in stage III and IV. However, there were significant differences between the tumor groups, with lung cancer patients having the highest improvement rate and pancreatic cancer and gynecological cancer patients having the lowest. (4) Tumor markers including alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA19-9, CA125, CA153, and CA724 were followed up. Among the 58 patients with elevated tumor markers, 36.2% of the patients had a decrease in markers after hydrogen inhalation, 15.5% had no change, and 48.3% had worsening. The time for markers to begin to decrease was 13 to 45 days, with a median time of 23 days. There was no significant difference in the marker decrease rate between patients who received hydrogen inhalation alone and those who received hydrogen inhalation combined with other treatments, but there were significant differences between the groups of patients with different tumor types, with lung cancer having the highest decrease rate and pancreatic and liver malignant tumors having the lowest decrease rate. (5) Among the 80 patients with visible tumors on imaging, 1 patient achieved complete remission (CR) after hydrogen inhalation, accounting for 1.3%; 15 patients achieved partial remission (PR), accounting for 18.8%; 30 patients achieved stable disease (SD), accounting for 37.5%; and 34 patients achieved progressive disease (PD), accounting for 42.5%, with a disease control rate of 57.5%. The time for CR and PR in patients ranged from 21 to 80 days, with a median time of 55 days. There was no statistically significant difference in disease control rate between patients receiving hydrogen inhalation alone and those receiving hydrogen inhalation combined with other treatments. The disease control rate was 83.0% for stage III patients and 47.7% for stage IV patients, and the difference was significant. Except for pancreatic cancer, there was no significant difference in disease control rate between other tumor types. Pancreatic cancer had the lowest disease control rate. (6) Adverse reactions: No hematological toxicity was observed. Some patients experienced stomach discomfort, dizziness, headache, and epistaxis in the early stages of hydrogen inhalation, which all disappeared quickly.

Conclusion: This follow-up observational study suggests that hydrogen inhalation (a mixture of hydrogen and oxygen) can improve quality of life and physical fitness, and control cancer progression, in patients with advanced cancer. To ensure effective inhalation, the inhaled hydrogen should be of sufficient concentration to ensure rapid tissue penetration and for a sufficient duration to produce a cumulative dose effect. Simultaneous inhalation of oxygen may also have a synergistic effect. Considering the significant challenges of treating advanced cancers and the high safety profile of hydrogen, this simple method warrants further study and rapid expansion into clinical rehabilitation and even treatment.

"Real World" Survey of Hydrogen-Controlled Cancer: Follow-up Report of 82 Cases of Advanced Cancer with Hydrogen Inhalation

Background and purpose: Advanced cancer treatment is a huge challenge and new ideas and strategies must be in place. Means other than drugs have become the target of people's exploration. Hydrogen has been shown to have antioxidant and anti-inflammatory effects, and the occurrence and progression of cancer is closely related to peroxidation and inflammation, so hydrogen may play a controlling role in cancer.

Cases and Methods: A retrospective and prospective follow-up study of cancers with self-hydrogen inhalation rehabilitation, mainly advanced cancer, was performed with reference to the "Real World Evidence" (RWE) study. A total of 82 patients with stage III and IV cancer who were self-hydrogenated were observed. The tumors that were followed up were mainly lung cancer, liver cancer, gynecological malignant tumor, pancreatic cancer, gastrointestinal malignant tumor and urinary malignant tumor, all of which met the following conditions: (1) patients with stage III and IV cancer with clear diagnosis and pathological confirmation; (2) have received routine treatment, including surgery, radiotherapy and / or chemotherapy,but did not get a good response or recurrence, or because of systemic conditions, combined disease can not accept the above treatment, or patients refused to accept; (3) have different symptoms, such as poor appetite, fatigue, insomnia, pain; (4) existing tumors, or/and tumor markers abnormal; (5) age 20-80 years old, no significant heart, brain, lung and kidney failure and mental disorders; (6) using hydrogen and oxygen nebulizer, inhalation of hydrogen and oxygen mixed gas, the concentration of hydrogen in the gas is 66.7%, oxygen 33.3%; gas flow 3000mL/min. Inhale at least 1.5 hours a day for more than 3 months.

Results: (1) follow-up time: 3-46 months, median time of 6 month. During the follow-up period, 12 patients died in stage IV, including 4 patients with pancreatic cancer. The causes of death were tumor progression in 5 cases, infection in 2 cases, and liver failure, intestinal obstruction, upper gastrointestinal bleeding, PD-1 antibody-associated pneumonia and euthanasia in one case, respectively. (2) The life quality of 30 patients were prospectively evaluated by the EORTC QLQ-C30. With the prolonged hydrogen inhalation time, the functional areas and symptoms of patients improved significantly. All areas improved after 4 weeks of hydrogen inhalation, with the most significant improvement in patient fatigue, insomnia, loss of appetite and pain. (3) A physical fitness assessment was performed on all patients according to Zubrod-ECOG- WHO (ZPS, 5-point method). 41.5% of patients had improved physical status, 34.1% were stable, and 24.4% were worse. There was no significant difference in the improvement rate between patients who hydrogen inhalation alone and hydrogen inhalation plus other therapies, and between patients with stage III and IV, but there was a significant difference between the tumor groups. Among them, lung cancer patients had the highest improvement rate, pancreatic cancer and gynecologic cancer patients had the lowest. (4) Follow-up of tumor markers including alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA19-9, CA125, CA153, and CA724 changes, was followed-up. Among the 58 cases who had an increase of one or more tumor markers, the decrease in markers after hydrogen inhalation was 36.2%, the stable was 15.5%, and the worsening was 48.3%. The marker began to fall for 13-45 days with a median time of 23 days. There was no significant difference in the bus bru rate of decrease in markers between the patients with hydrogen alone and those treated with hydrogen plus other therapies, but there were significant differences among the patients with different tumor types. The highest rate of the marker decrease was in lung cancer and the lowest was in pancreatic and hepatic malignancies. (5) In the 80 cases of visible imaging tumors the tumor response after hydrogen inhalation was complete response (CR) in 1 cases, accounting for 1.3%; partial response (PR) 15 cases, 18.8%; stable disease (SD) 30 cases, 37.5%; progressive disease (PD) 34 cases, 42.5%, with the total disease control rate of 57.5%. CR and PR appeared for 21-80 days with a median time of 55 days after hydrogen inhalation. There was no statistically significant difference in disease control rates between patients who received hydrogen alone and hydrogenation in combination with other treatments. The disease control rate was 83.0%, and 47.7% in stage III and IV patients, respectively, and the difference was significant. Except for pancreatic cancer, there was no significant difference in disease control rates between different tumor types. Pancreatic cancer has the lowest disease control rate. (6) Adverse reactions: No hematological toxicity was observed. The stomach upset, dizziness, headache, and snot at the beginning of hydrogen inhalation were seen in individual cases and quickly disappeared spontaneously.

Conclusion: The results of follow-up observations show that in patients with advanced cancer, inhaled hydrogen (hydrogen and oxygen mixed) can improve patients' quality of life and physical fitness, and control cancer progression. In order to ensure the hydrogen effect, the inhaled hydrogen should have sufficient concentration to ensure that it enters the tissue as soon as possible, and that it has a sufficient time to produce a dose accumulation. At the same time, inhaled oxygen may have a synergistic effect. Considering the great difficulty of progressive cancer treatment and the high safety of hydrogen, the simple method of inhaling hydrogen is worthy of further study and will be extended to clinical rehabilitation and even therapeutic applications as soon as possible.

introduction

Cancer has become the leading cause of death in humans, and its incidence continues to rise (1). Over the past half century, significant progress has been made in basic and clinical cancer research, and the incidence and mortality of some cancers have decreased, but this is mainly due to primary prevention (such as smoking cessation) and early cancer screening, and rarely to any specific drug (2).

Treatment is a double-edged sword. All commonly used treatments, including radiotherapy, chemotherapy, fine needle aspiration, and surgery, can increase circulating tumor cells, promoting cancer progression and distant metastasis (3-6). Precision therapy strategies based on molecular testing have not benefited the majority of cancer patients, with only 3% to 13% of patients receiving targeted medication (7.8). Furthermore, studies have shown that targeted therapy can lead to cancer metastasis by inducing a large secretome of proteins.

To change the harsh reality of current cancer treatment, new ideas and strategies must be developed. Means other than drugs have become the target of people's exploration.

Hydrogen molecular biology and hydrogen medicine are very young but rapidly developing disciplines (10-12). Hydrogen has been shown to have antioxidant and anti-inflammatory effects. The occurrence and progression of cancer are closely related to peroxidation and inflammation, so hydrogen may play a role in controlling cancer.

In recent years, many cancer patients have self-inhaled hydrogen. Using the "real-world evidence" (RWE) research methodology (13-14), we conducted a retrospective and prospective follow-up study of patients with cancer, primarily progressive cancers, who recovered through hydrogen inhalation. The results are reported below.

Cases and methods

Follow-up subjects: It includes two parts. (1) A retrospective survey was conducted on patients who inhaled hydrogen at home from 2014 to April 2018. The main method was to visit the patients' homes and review relevant data in the hospital to conduct a retrospective study. There were 14 cases who underwent the retrospective survey. (2) For cases after May 2018, hydrogen inhalation was mainly carried out in studios and rehabilitation associations, and some were self-inhaled at home. Specialized doctors provided care and guidance to them as "volunteers", reviewed relevant data as needed, and conducted a "prospective" observational study. A total of 68 cases underwent the prospective study.

The patients who were followed up and included in the statistical analysis met the following conditions: (1) patients with a clear diagnosis and pathological confirmation of stage III and IV cancer; (2) patients who had received conventional treatment, including surgery, radiotherapy and/or chemotherapy, but did not get a good response or relapsed, or were unable to receive the above treatment due to systemic conditions or comorbidities, or refused treatment; (3) patients with different symptoms, such as poor appetite, fatigue, insomnia, and pain; (4) patients with existing tumors and/or abnormal tumor markers; (5) patients aged 20 to 80 years, without obvious heart, brain, lung, or kidney failure and mental abnormalities, and who could express symptoms.

Hydrogen inhalation method: Use a hydrogen-oxygen nebulizer [AMS-H-01 hydrogen-oxygen nebulizer (Shanghai Asclepius Meditec Co., Ltd., China)]. The patient sits or lies down and inhales a hydrogen-oxygen mixture through a nasal cannula or mask with spontaneous breathing. The hydrogen concentration is 66.7% and the oxygen concentration is 33.3%; the gas flow rate is 3000 mL/min. (5) The hydrogen inhalation time should be no less than 1.5 hours per day for more than 3 consecutive months.

Tumor staging: according to TNM.

Tumor size change: evaluated according to RECIST criteria based on imaging findings. Complete response (CR): All target lesions disappear, no new lesions appear, and tumor markers remain normal, maintained for at least 4 weeks. Partial response (PR): The sum of the maximum diameters of target lesions decreases by ≥30%, maintained for at least 4 weeks. Stable disease (SD): The sum of the maximum diameters of target lesions decreases but does not reach PR, or increases but does not reach PD. Progressive disease (PD): The sum of the maximum diameters of target lesions increases by ≥20%, or new lesions appear. Disease control rate (DCR): CR + PR + SD.

Quality of life was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 scale. The QLQ-C30 consists of 30 items, including five functional subscales: physical function, role function, cognitive function, emotional function, and social function; three symptom scales: fatigue, pain, and nausea/vomiting; six individual measurement items; and an overall quality of life scale. Assessments were conducted before and every other week after hydrogen inhalation. Interviews were conducted by a third party who was unaware of the patient's condition.

The performance status score was calculated according to the Eastern Cooperative Oncology Group Zubrod-ECOG-WHO (ZPS, 5-point scale), ranging from 1 to 5. A decrease of 1 point or more was considered improvement; an increase of 1 point or more was considered worsening; and no change was considered stable.

Statistical analysis: SPSS data statistical analysis tool was used.

For patients who were followed up "prospectively", they all signed an "informed consent form", stating that they were recovering through "hydrogen inhalation" on their own, not "clinical treatment", and that they voluntarily accepted the follow-up.

result

1. General

(1) A total of 82 patients were followed up, including 29 males and 53 females with an average age of 56 years, including 8 patients aged 20-40 years, 48 ​​patients aged 41-60 years, and 26 patients aged 61-85 years.

(2) The types of tumors in the patients were mainly lung cancer (19 cases, 23.2%), liver cancer (11 cases, 13.4%), gynecological malignancies (16 cases, 19.5%), pancreatic cancer (10 cases, 12.2%), breast cancer (6 cases, 7.3%), gastrointestinal tumors (6 cases, 7.3%), urinary system tumors (6 cases, 7.3%), and other malignancies (8 cases, including 2 oral malignancies, 1 case each of lymphoma, basal cell carcinoma, gallbladder cancer, thymoma, leiomyosarcoma, and mediastinal inflammatory myofibroblastic tumor).

(3) Tumor stage: All patients were in stage III or IV, including 21 patients in stage III, accounting for 25.6%; and 61 patients in stage IIV, accounting for 74.4%.

(4) Combined treatment: 28 cases received hydrogen inhalation alone or did not receive any anticancer treatment during hydrogen inhalation, and the remaining 54 cases received

He received chemotherapy, targeted therapy, endocrine therapy and other anti-tumor treatments.

The follow-up conditions of the patients are summarized as follows (Table 1).

2. Follow-up time and survival

All patients were followed up for 3 to 46 months, with a median follow-up of 6 months, including 45 patients (54.9%) who were followed up for 3 to 6 months, 33 patients (40.2%) who were followed up for 7 to 12 months, and 1 patient each who was followed up for 13, 14, 26, and 46 months.

During the follow-up period, 12 patients died, all of whom were stage IV patients, including 4 patients with pancreatic cancer, 2 patients with liver cancer, 1 patient with lung cancer, 3 patients with gynecological tumors, 1 patient with gastrointestinal tumor, and 1 patient with other diseases. The causes of death are shown in Table 2.

3. Changes in quality of life and physical fitness

Thirty patients were prospectively assessed using the EORTC QLQ-C30 quality of life questionnaire. Results showed that after two weeks of hydrogen inhalation, shortness of breath and appetite improved, and physical function, role function, emotional function, fatigue, nausea and vomiting, and insomnia significantly improved. After four weeks of hydrogen inhalation, cognitive function, pain, appetite, constipation, and diarrhea also significantly improved (Table 3).

Physical fitness was assessed in all patients, including those in the retrospective study who were assessed based on their medical history. Three months after hydrogen inhalation, 41.5% of patients experienced improvement in their physical fitness, 34.1% experienced stability, and approximately 24.4% experienced deterioration. The improvement rate for patients receiving hydrogen inhalation alone was 32.1%, while the improvement rate for patients receiving hydrogen inhalation combined with other treatments was 44.4% (Table 4). The improvement rate in the combined treatment group was higher than that in the hydrogen inhalation group alone, but there was no statistically significant difference between the two groups.

Three months after hydrogen inhalation, physical status scores were assessed. Compared to pre-treatment, the improvement rate for stage III patients was 57.1%, and for stage IV patients was 36.1%. The improvement rate for stage III patients was higher than that for stage IV patients, but the difference was not statistically significant (see Table 5).

After three months of hydrogen inhalation, improvements in physical fitness varied among patients with different tumor types. Lung cancer patients had the highest improvement rate (68.4%), while pancreatic cancer (0%) and gynecological cancer patients (12.5%) had the lowest (see Table 6). Compared to lung cancer patients, patients with gynecological and pancreatic cancer showed significant differences in improvement rates. Lung cancer patients showed the best improvement in physical fitness, while patients with gynecological and pancreatic cancer had the worst results.

 

4. Changes in tumor markers

Tumor markers, including alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA19-9, CA125, CA153, and CA724, were followed up. Before hydrogen therapy, 58 patients had elevated tumor markers (one or more), while 24 had normal levels. For patients with elevated tumor markers, 36.2% experienced a decrease in tumor markers after three months of hydrogen inhalation, while 15.5% experienced no change and 48.3% experienced worsening. The onset of tumor marker decline ranged from 13 to 45 days, with a median of 23 days. Compared to pre-treatment levels, the decrease in markers after three months of hydrogen inhalation was 22.2% in patients receiving hydrogen inhalation alone and 42.5% in patients receiving hydrogen inhalation combined with other treatments. The decrease in tumor markers was higher in patients receiving hydrogen inhalation combined with other treatments, but the difference was not significant (see Table 7). No patients with normal tumor markers before treatment experienced an increase in markers after hydrogen inhalation.

Fifty-eight patients with elevated serum markers before hydrogen inhalation were analyzed based on different tumor types. Three months after hydrogen inhalation, lung cancer patients experienced the highest tumor marker reduction rate (75%), while no patients with pancreatic or liver cancer experienced a reduction (see Table 8). Significant differences were observed between lung cancer patients and those with gynecological, liver, and pancreatic cancers. Lung cancer patients showed the best results in reducing serum marker levels, while those with gynecological, liver, and pancreatic cancers showed the worst results.

5. Tumor Response

Of the 82 patients enrolled, 80 still had tumors before enrollment, while the remaining two only had elevated tumor markers. Three months after hydrogen inhalation, one (1.3%) patient achieved complete remission (CR), 15 (18.8%) achieved partial remission (PR), 30 (37.5%) achieved stable disease (SD), and 34 (42.5%) achieved progressive disease (PD), resulting in a disease control rate of 57.5%. CR and PR occurred within 21 to 80 days, with a median of 55 days. Three months after the start of hydrogen inhalation, the disease control rate was 53.8% for hydrogen inhalation alone and 59.3% for hydrogen inhalation combined with other treatments, with no statistically significant difference between the two groups (see Table 9).

From the perspective of tumor staging, the disease control rate of patients in stage IIV was 83%, and that in stage IIV was 47.7%, with significant differences (see Table 10).

In terms of tumor pathology, lung cancer had the highest disease control rate (78.9%), while pancreatic cancer had the lowest (20%). Only pancreatic cancer showed a statistically significant difference compared to lung cancer (see Table 11).

6. Adverse Reactions

Among 29 patients treated with hydrogen inhalation alone, no hematologic toxicity was observed. One patient experienced gastric discomfort and chills, and one experienced dizziness (which resolved spontaneously after a few days). No other symptoms were reported. Among 53 patients treated with hydrogen inhalation combined with other treatments, one patient experienced a headache, which resolved spontaneously within 3–5 days; one experienced occasional epistaxis, which was minimal and resolved spontaneously; one experienced nasal dryness, which occurred during inhalation and resolved several hours after cessation of inhalation; and one patient reported sinusitis without obvious symptoms, but a CT scan revealed it.

discuss

1. The Control Effect of Hydrogen on Cancer Baibu Zhoushui As early as 1975, Dole et al. (17) discovered that hydrogen can inhibit cancer. When nude mice with skin squamous cell carcinoma inhaled a mixture of 97.5% hydrogen and 2.5% oxygen at 8 atmospheres, the tumors significantly regressed after 2 weeks, while the control group and the model mice receiving hyperbaric oxygen-helium did not show the above changes. In 2008, Saitoh et al. (18) of Japan reported that neutral pH hydrogen-rich electrolyzed water inhibited the colony formation efficiency or colony size of human tongue cancer cells HSC-4, but had no significant inhibitory effect on normal human tongue epithelial cells; hydrogen had the same effect on the growth and migration ability of human fibrosarcoma cells HT-1080. In 2009, Saitoh et al. (19) reported that enhanced platinum colloidal hydrogen-containing water had an inhibitory effect on the colony formation and size of human HSC-4 tongue cancer cells. In 2011, Chinese scholars Zhao et al. (20) found that hydrogen can prevent the occurrence of radiation-induced lymphoma. In 2015, Runtuwene et al. (21) reported that hydrogen could improve the survival rate of colon 26-induced tumor-bearing mice, induce cancer cell apoptosis, and enhance the sensitivity of colon cancer cells to 5-fluorouracil.

Wang Dongchang et al. (22) studied the effects of inhalation of a mixture of 66% hydrogen and 34% oxygen on human lung cancer cell line transplanted tumors. The volume and weight of the tumors in the hydrogen group were significantly reduced, and the mRNA and protein expressions of Ki-67, COX-2, and VEGF were significantly reduced. In terms of its pathological morphology and cellular heterogeneity, the tumors showed lower invasiveness compared with the control group. Similarly, Shang et al. (23) studied the effects of hydrogen and oxygen inhalation on ovarian cancer model mice. They found that 6 weeks of hydrogen inhalation could significantly inhibit tumor growth. The expression of Ki67, an indicator of tumor malignant proliferation, and CD34, an indicator of tumor angiogenesis, were significantly decreased, suggesting that hydrogen reduces the invasion and migration ability of tumor cells and may have an anti-tumor angiogenesis effect.

Our observations on 82 patients with stage III and IV progressive cancer who self-inhaled hydrogen showed that hydrogen has the following four main effects:

(1) Improved quality of life. After 2 weeks of hydrogen inhalation, shortness of breath and appetite improved, and fatigue and insomnia were significantly improved. After 4 weeks of hydrogen inhalation, pain, constipation, and diarrhea were significantly improved (see Table 3).

(2) Improve physical fitness. After three months of hydrogen inhalation, lung cancer patients showed the most significant improvement in physical fitness, while gynecological and pancreatic cancer patients showed the worst effect (see Table 6).

(3) Reduce tumor markers. After 3 months of hydrogen inhalation, the markers of lung cancer patients decreased most significantly, while the effect was the worst in patients with gynecological, liver, and pancreatic cancer (see Table 8).

(4) Control cancer progression. After 3 months of hydrogen inhalation, the tumor control rate of stage III patients was much higher than that of stage IV patients (see Table 10). Lung cancer had the best effect, while pancreatic cancer had the worst effect (see Table 11).

The treatment of advanced cancer is a great challenge. Of the anticancer drugs approved by the United States and the European Medicines Agency, 67% and 57%, respectively, have not shown evidence of long-term survival and improvement in quality of life (24, 25). Studies have shown that neoadjuvant chemotherapy can induce breast cancer metastasis through TMEM-mediated mechanisms (4); chemotherapy can increase the formation of metastatic niches and promote liver metastasis; radiotherapy can promote the metastasis of residual liver cancer after surgery by inducing epithelial-mesenchymal transition (6); Liang et al. (26) found that in the environment of chemotherapy and radiation, the malignancy of cancer cells increased and turned into stem-like cancer cells; Amelot et al. (27) analyzed 413 patients with brain metastases of various causes and found that anticancer drugs, especially paclitaxel and its derivatives, can promote brain metastasis and reduce patients' disease-free survival. A recent review believes that all commonly used treatments, including radiotherapy, chemotherapy, fine needle aspiration and surgery, can cause an increase in circulating tumor cells, promote cancer progression and distant metastasis (28).

Considering the above facts, the beneficial effects of hydrogen on cancer patients are very encouraging.

2. Factors related to cancer control

According to our follow-up observations, the control effect of hydrogen inhalation on cancer is not only related to the type of tumor, but also to the factors and application of hydrogen itself.

(1) Hydrogen concentration: The hydrogen concentration inhaled in this group of patients was 66% at a flow rate of 3000 mL/min. Since Ota et al. (2) reported in 2007 that inhaling a low concentration of 2% hydrogen could prevent brain ischemia/reperfusion injury, most researchers have used 1% to 4% positive pressure hydrogen to study the biological effects of hydrogen molecules. As for the effects of high-pressure hydrogen or high-concentration hydrogen, there are limited reports. Only Dole et al. (17) reported that the use of 97.5% hydrogen at 8 atmospheres successfully inhibited skin squamous cell carcinoma. In the two experimental studies by Wang Dongchang (22) and Shang Lei (23), 60% and 66.7% hydrogen were used respectively. It was found that the effect of hydrogen was dose-dependent, whether it was inhibiting cancer cells in vitro or inhibiting tumor growth in vivo in vivo. That is, the higher the hydrogen concentration, the greater the effect.

(2) Hydrogen inhalation time: The patients in this group generally inhaled hydrogen for more than 3 hours per day, and some even inhaled hydrogen for 8 hours. The time for tumor markers to begin to decline was 13 to 45 days, with a median of 23 days. The time for CR and PR to occur was 21 to 80 days, with a median of 55 days. In the aforementioned experimental study, the hydrogen inhalation time of mice lasted for 4 weeks and 6 weeks respectively (22.23). Yamamoto et al. (30) studied the distribution of hydrogen in mice after continuous inhalation of 3% hydrogen. The time it took for hydrogen in the muscles to reach saturation was significantly longer than that in other organs, which was after 20 minutes, and the hydrogen concentration in the muscles gradually increased over time. By organ, the hydrogen concentration was highest in the liver and lowest in the kidneys.

(3) Inhalation of a hydrogen-oxygen mixture, not pure hydrogen. Hypoxia can cause metabolic modifications, which in turn adaptively support the progression of malignant tumors (31,32). Improving oxygen supply and hypoxia can inhibit cancer progression. Some studies suggest that hydrogen can "load" oxygen. Because hydrogen molecules are extremely small, they can carry oxygen to the deepest part of the tumor. Inhaling oxygen while inhaling hydrogen clearly helps control cancer progression.

(4) Ways to introduce hydrogen into the body. Currently, in experiments and clinical practice, the methods of introducing hydrogen into the body include hydrogen inhalation, drinking hydrogen-rich water, and injecting hydrogen-rich saline. Drinking hydrogen water is difficult to ensure a sufficiently high hydrogen concentration in the tissues. There are reports that hydrogen in the brain cannot be measured after administering hydrogen-rich water (33). Although injecting hydrogen saline can quickly increase the hydrogen concentration in the blood, the method is "minimally invasive" and continuous infusion of large amounts of saline will cause water and salt retention. Hydrogen inhalation is the simplest method, which can quickly increase the hydrogen concentration in the tissues, generally reaching a peak after 30 minutes, and maintaining a high level of balance during the continuous hydrogen inhalation process (34). In theory, after inhaling 55.7% hydrogen, the equilibrium hydrogen concentration is about 520M, which is equivalent to the hydrogen concentration of 600M that inhibits cancer cells in vitro. The disadvantage of hydrogen inhalation is that it is easily affected by the operation. For example, the nasal tube method is not as good as the mask method in ensuring sufficient hydrogen inhalation. Whether the patient's breathing is even and stable, as well as the basic lung function status, can affect the amount of hydrogen inhaled.

While it's impossible to precisely measure the amount of hydrogen inhaled by patients, their experiences suggest that to ensure therapeutic efficacy, hydrogen must be present at a sufficient concentration to ensure rapid penetration into tissues and persist for a sufficient period of time to produce a sufficient cumulative dose. The hydrogen-oxygen nebulizer used in this follow-up group generally met these requirements. The effectiveness of other hydrogen generators remains to be seen.

3. Evaluation of Hydrogen Cancer Control Products

In 2014, Haines (35) criticized the Lancer magazine for continuing to use the term “cancer war”, arguing that the metaphor of cancer treatment as war has led to many incurable solid cancers receiving highly toxic and overly aggressive chemotherapy, and has also prevented many patients with advanced cancer from receiving early palliative care, including treatments that have strong evidence to show are beneficial. He believes that it is time to change the term “cancer war” (36). Tang Zhaoyou (37) advocated that the term “cancer control” should be abandoned and replaced with “cancer control”, proposing that the treatment of cancer should be “elimination and transformation”, the former including surgery, radiotherapy and chemotherapy, and the latter including transformation of cancer cells themselves, microenvironment and the entire body (38).

Hydrogen has selective antioxidant, anti-inflammatory, and signal-regulating effects (3). While direct effects on cancer cells cannot be ruled out, hydrogen may primarily improve the microenvironment and play a "transforming" role. Recent discoveries have also linked hydrogen molecules to the body's immune function, potentially saving exhausted T cells by maintaining mitochondrial function and restoring their anti-tumor efficacy, thereby improving the prognosis of patients with advanced cancer (40). Therefore, hydrogen also has the effect of "transforming" the body.

Hydrogen is very easy to use, inexpensive, and has almost no adverse reactions. This is an important step towards achieving the ideal of truly patient-centered, family-based home rehabilitation.

4. Problems

This article presents only observations and descriptions, not typical "evidence-based medicine" research. Furthermore, this article emphasizes "rehabilitation" and "assistance," not "treatment" in the conventional sense. Further research is needed, including: The true mechanism of hydrogen's cancer control: Is it simply scavenging reactive oxygen species and controlling inflammation? Currently, the most researched topic is hydrogen molecules; do hydrogen ions play a role? What is the optimal dosage for introducing hydrogen into the body? What is the most effective treatment course? How does hydrogen rehabilitation complement mainstream treatments? What are its long-term effects? This requires us to broaden our thinking and strengthen experimental and clinical research.

in conclusion

Follow-up observations in this study suggest that hydrogen inhalation (a mixture of hydrogen and oxygen) can improve quality of life and physical fitness, and control cancer progression, in patients with advanced cancer. Besides tumor-specific factors, to ensure the hydrogen inhalation effect, the inhaled hydrogen must be of sufficient concentration to ensure rapid tissue penetration and for a sufficient duration to produce a cumulative dose effect. Furthermore, inhaled oxygen may have a synergistic effect. Considering the significant challenges of treating advanced cancers and the high safety profile of hydrogen, this very simple method warrants further study and rapid expansion into clinical rehabilitation and even treatment. Given the extensive research demonstrating the beneficial effects of hydrogen on various body systems, the research prospects are encouraging.

Xu Kecheng Kong Xiaofeng Lu Tianyu Chen Jibing

References

[1] Brawley OW. Avoidable cancer deaths globally. CA Cancer J Clin, 2011, 61(2): 67-68, pods JS (09)

[2] Siegel RL, Jemal A, Wender RC, et al. An assessment of progress in cancer control, CA Cancer J Clin,home 2018, 68(5): 329-339.

[3] Neeman E and Ben-Eliyahu S. Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement. Brain Behav Immun, 2013, 30 Suppl: $32-40.

[4] Karagiannis GS, Pastoriza JM, Wang Y, et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Science translational medicine, 2017, 9(397).

[5] Zenitani M, Nojiri T, Hosoda H, et al. Chemotherapy can promote liver metastasis by enhancing metastatic niche formation in mice. J Surg Res, 2018, 224: 50-57.

[6] Li T, Zeng ZC, Wang L, et al. Radiation enhances long-term metastasis potential of residual hepatocellular carcinoma in nude mice through TMPRSS4-induced epithelial-mesenchymal transition. Cancer gene therapy, 2011, 18(9): 617-626.

[7] Hodson R. Precision medicine. Nature, 2016, 537(7619): S49.

[8] Tannock IF and Hickman JA. Limits to Personalized Cancer Medicine. N Engl J Med, 2016, 375(13): 1289- 1294.

[9] Obenauf AC, Zou Y, Ji AL, et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature, 2015, 520(7547): 368-372.

[10] Sano M, Suzuki M, Homma K, et al. Promising novel therapy with hydrogen gas for emergency and critical care medicine. Acute Med Surg, 2018, 5(2): 113-118.

[11] Ge L, Yang M, Yang NN, et al. Molecular hydrogen: a preventive and therapeutic medical gas for various diseases. Oncotarget, 2017, 8(60): 102653-102673.

[12] Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther, 2014, 144(1): 1-11.

[13] Booth CM, Karim S,Mackillop WJ. Real-world data: towards achieving the achievable in cancer care. Nat Rev Clin Oncol, 2019.

[14] Krause JH and Saver RS. Real-World Evidence in the Real World: Beyond the FDA. American journal of law & medicine, 2018, 44(2-3): 161-179.

[15] Clarke LP, Sriram RD,Schilling LB. Imaging as a Biomarker: Standards for Change Measurements in Therapy workshop summary. Academic radiology, 2008, 15(4): 501-530.

[16] Bjordal K, de Graeff A, Fayers PM, et al. A 12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC Quality of Life Group. Eur J Cancer, 2000, 36(14): 1796-1807.

[17] Dole M, Wilson FR,Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science, 1975, 190(4210): 152-154.

[18] Saitoh Y, Okayasu H, Xiao L, et al. Neutral pH hydrogen-enriched electrolyzed water achieves tumor- preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression. Oncol Res, 2008, 17(6): 247-255.

[19] Saitoh Y, Yoshimura Y, Nakano K, et al. Platinum nanocolloid-supplemented hydrogendissolved water inhibits growth of human tongue carcinoma cells preferentially over normal cells. Exp Oncol, 2009, 31(3): 156-162.

[20] Zhao L, Zhou C, Zhang J, et al. Hydrogen protects mice from radiation induced thymic lymphoma in BALB/c mice. Int J Biol Sci, 2011, 7(3): 297-300. BA is Debrew local 14 box? S

[21] Runtuwene J, Amitani H, Amitani M, et al. Hydrogen-water enhances 5-fluorouracil-induced inhibition of colon cancer. PeerJ, 2015, 3: e859. what is east bon ragu?

[22] Wang Dongchang, Zhao Yunxia, ​​Zhao Zhifang, et al. Study on the effect and mechanism of hydrogen intervention in inhibiting the growth of non-small cell lung cancer, International Journal of Respiratory Diseases, 2018, 38(8): 561-565.

[23] Shang L, Xie F, Li J, et al. Therapeutic potential of molecular hydrogen in ovarian cancer. Tranl Cancer Res, 2018, 7: 988-995.

[24] Prasad V. Do cancer drugs improve survival or quality of life? BMJ, 2017, 359: j4528.

[25] Prasad V, De Jesus K,Mailankody S. A further strategy to combat the high price of anticancer drugs. Nat Rev Clin Oncol, 2017, 14(10): 629.

[26] Liang Y, Zhong Z, Huang Y, et al. Stem-like cancer cells are inducible by increasing genomic instability in cancer cells. J Biol Chem, 2010, 285(7): 4931-4940.

[27] Amelot A, Terrier LM, Mathon B, et al. Can anticancer chemotherapy promote the progression of brain metastases? Med Oncol, 2018, 35(3): 35.

[28] Martin OA and Anderson RL. Editorial: Therapy-induced metastasis. Clin Exp Metastasis, 2018, 35(4): 219-221.

[29] Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13(6): 688-694.

[30] Yamamoto R, Homma K,Suzuki K. Hydrogen gas distribution in organs after inhalation: real-time monitoring of tissue hydrogen concertration in rat. Sci Rep, 2019, 9(1): 1255.

[31] Kakkad S, Krishnamachary B, Jacob D, et al. Molecular and functional imaging insights into the role of hypoxia in cancer aggression. Cancer Metastasis Rev, 2019.

[32] Al Tameemi W, Dale TP, Al-Jumaily RMK, et al. Hypoxia-Modified Cancer Cell Metabolism. Front Cell Dev Biol, 2019, 7: 4.

[33] Fujita K, Seike T, Yutsudo N, et al. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. PLoS One, 2009, 4(9): e7247.

[34] Ono H, Nishijima Y, Adachi N, et al. A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. Med Gas Res, 2012, 2(1): 21.

[35] Hanahan D. Rethinking the war on cancer. Lancet, 2014, 383(9916): 558-563.

[36] Haines I. The war on cancer: time for a new terminology. Lancet, 2014, 383(9932): 1883.

[37] Tang Zhaoyou. Chinese anti-cancer. Shanghai Science and Technology Publishing House, 2015, Shanghai.

[38] Xu Kecheng. Practicing Chinese-style cancer control. Yangcheng Evening News Publishing House, 2018, Guangzhou.

[39] Iida A, Nosaka N, Yumoto T, et al. The Clinical Application of Hydrogen as a Medical Treatment. Okayama Acta Medical, 2016, 70(5): 331-337.

[40] Akagi J and Baba H. Hydrogen gas restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis. Oncol Rep, 2019, 41(1): 301-311.

The “real world” of hydrogen cancer control:

Case Listing and Commentary

This article cites patients whose lesions were either inoperable, recurred after surgery, or failed radiotherapy or chemotherapy. After inhalation of a hydrogen-oxygen mixture (or combined with mild radiotherapy or chemotherapy), their tumors became resectable, shrank, or even disappeared (complete remission), or stabilized, allowing the patients to survive and "coexist with cancer." The following describes the timing and purpose of hydrogen application.

1. Before surgery, "adjuvant" neoadjuvant therapy

Case 1: Squamous cell carcinoma of the lung

A 54-year-old female patient developed chest discomfort, a dry cough, and shortness of breath in October 2016. On October 27, she underwent a PET-CT scan in Taiwan, which revealed a 4-cm space-occupying lesion in the right lung with a standardized uptake value (SUV) of 18.57. The tumor was connected to the pericardium and had metastases to the mediastinal lymph nodes. Bronchoscopy revealed obstruction of the right lobe bronchus by the tumor (Figure 1). A local biopsy was obtained, and pathological examination and immunohistochemistry revealed squamous cell carcinoma. Genetic testing was negative for mutations.

The patient underwent 30 radiation treatments and three cycles of chemotherapy. He also practiced hydrogen inhalation for at least four hours daily. After a week, his cough subsided and his breathing became smoother. Two and a half months later, on January 13, 2017, a PET-CT scan revealed that the previous lung lesions had disappeared. On February 23, 2017, the patient underwent a thoracoscopic right upper lobectomy, along with exploration of the pericardium and mediastinum, and removal of lymph nodes (LN2, 4, 7, and 10). Postoperative pathological examination revealed no cancer cells. To date, the patient has been disease-free for nearly two and a half years.

 

Figure 1. PET-CT and endoscopic examinations of Case 1. A, PET-CT scan performed on October 27, 2016, shows a right mid-lobe mass with hilar invasion; regional lymph node involvement is noted in the right hilar N1 lymph node (black arrow). B, Bronchoscopy reveals bronchial mucosal edema and obstruction of the right middle lobe bronchus by the mass. C, Biopsy reveals squamous cell carcinoma. D and E, PET-CT scans performed on January 13, 2017: regional lymph nodes N1, 2, and 3 in the right mid-lobe are absent (black arrows). Compared to the high-end PET-CT scans performed on October 27, 2016, the original lesion in the right lung is no longer evident. Commentary: The patient was diagnosed with squamous cell carcinoma of the lung. Due to pericardial and mediastinal involvement, surgical resection was not possible at the time. After chemoradiotherapy, the preoperative tumor was completely eliminated, resulting in a complete response (CR). Although surgery was performed, no further tumor was found. Generally, chemotherapy is the primary treatment for stage IIb squamous cell lung cancer, primarily using platinum-based or platinum-based combination chemotherapy. However, regardless of the regimen, the survival benefit is limited. A meta-analysis of six RCTs reported on 847 patients with non-small cell lung cancer (including squamous cell carcinoma) receiving chemotherapy found no difference in efficacy between single-agent and combination chemotherapy, with median overall survival of only 37.3 and 34.7 weeks, respectively, and median progression-free survival of 14 and 11.7 weeks, respectively. Radiation therapy, while effective for early-stage isolated lung cancer, has a very limited effect on non-small cell lung cancers larger than 5 cm. Although this patient received both chemotherapy and radiotherapy, these treatments alone are unlikely to achieve a CR (complete remission) of the disease. Hydrogen inhalation certainly played a role.

Example 2: Esophageal cancer

A 62-year-old male patient experienced difficulty eating in February 2017 and underwent a gastroscopy at Beijing xxx General Hospital. The findings revealed a mass on the posterior esophageal wall, 31-35 cm from the incisors, which was brittle, oozing blood, and easily bleeding. An endoscopic ultrasound revealed an ulcerated mass in the 31-35 cm segment of the esophagus, primarily located in the muscularis propria, with invasion of the adventitia. A CT scan revealed a mass in the lower esophagus and possible lymph node metastasis in the left gastric region. A biopsy of the esophageal mass revealed squamous cell carcinoma. On March 12, he received neoadjuvant chemotherapy with liposomal paclitaxel and cisplatin, administered in 21-day cycles for two cycles. He also self-inhaled hydrogen peroxide (H2O) for three hours daily, achieving concentrations of 66% H2O and 34% H2O, respectively. A follow-up CT scan on May 11 revealed no significant space-occupying lesions or stenosis throughout the esophagus, and no significant enlarged lymph nodes were found in the mediastinal interspaces. On May 15, the patient underwent radical resection for esophageal cancer. Postoperative pathology: The resected esophagus had a hard area measuring 2.5×1.0×0.8 cm. Histology showed squamous cell carcinoma grade II, with cancer cells regressing and invading the fibrous tissue.

Membrane, accompanied by lymphocyte reaction.

Comment: A report indicates that neoadjuvant chemotherapy for resectable advanced esophageal cancer has a clinical response rate of 76% and a pathological response rate of 33%. This patient had esophageal cancer. Preoperative endoscopic ultrasound and CT scans revealed an ulcerated tumor up to 5 cm in the lower esophagus, involving the esophageal adventitia. Two months after chemotherapy combined with hydrogen inhalation, the tumor shrank to 2.5 cm, and pathological examination revealed that the lesion had only invaded the fibrous membrane. This effect is difficult to achieve with chemotherapy alone, and molecular hydrogen may have played a role. Furthermore, the patient reported few adverse reactions during chemotherapy. Studies have shown that hydrogen inhalation can reduce chemotherapy side effects.

Second, "adjuvant" chemoradiotherapy, used simultaneously with chemoradiotherapy:

Example 3: Gastric cancer

The patient was an 84-year-old woman. In February 2014, she began experiencing choking and vomiting during meals. On May 21st, she underwent a gastroscopy, which revealed a 3-4 cm subcardial mass with erosion and bleeding. A biopsy revealed poorly differentiated adenocarcinoma. A concurrent abdominal CT scan revealed a subcardial bulge, suggestive of a gastric neoplasm. Her blood tumor marker CA19-9 was 1450 units. She declined surgery and radiotherapy. She self-inhaled hydrogen for 3-4 hours daily.

A month later, the patient's dysphagia improved, and a follow-up CA19-9 test in August had dropped to 307 units. The doctor recommended oral Xeloda. A follow-up gastroscopy on October 26th revealed a white scar at the site of the original tumor. Xeloda was used until May 2015, a total of nine months. It was discontinued due to adverse reactions, but hydrogen inhalation therapy continued. CT scans are performed every six months. Recent CT scans have shown a patent cardia, and the original signs of the tumor have disappeared. CT scans and other tests have revealed no metastasis (see Figure 2).

More remarkable, his blood CA19-9 level gradually decreased, reaching 307 U/L in August 2014 and continuing to decline until, in May 2017, three years after the onset of the disease, it reached 17.68 U/L, returning to normal (see Figure 3). As of a follow-up visit in February 2019, the patient still reported being "perfectly healthy."

Comment: A Korean study compared the efficacy of Xeloda alone and the combination of Xeloda and oxaliplatin for advanced gastric cancer. The median progression-free survival and overall survival were 2.6 months and 6.3 months, respectively, in the Xeloda alone group and 7.1 months and 11.1 months, respectively, in the combination group. The patient, who did not undergo surgery but received Xeloda alone, experienced rapid symptom improvement, with virtually no lesions on endoscopy, and a gradual decrease in the tumor marker CA19-9 to normal levels. The patient has remained disease-free for four years. This efficacy is clearly related to hydrogen.

Example 4: Hepatocellular carcinoma

A 54-year-old male patient experienced right upper abdominal pain in October 2016 and underwent a CT scan, which led to a diagnosis of liver cancer. A biopsy revealed hepatocellular carcinoma. The intrahepatic tumor was 14 cm in size and associated with a portal vein tumor thrombus. He received intravenous chemotherapy once weekly for six sessions and underwent three hepatic artery chemoembolizations. He also self-inhaled hydrogen for two to three hours daily. Five months later, on March 23, 2018, a follow-up CT scan revealed a 7.8 × 7.5 cm, round, low-density lesion in liver segments S7 and S8. The lesion had clear margins, minimal iodized oil deposits, and minimal enhancement, exhibiting liquefaction necrosis (see Figure 4). The portal vein tumor thrombus had resolved. The patient's general condition and liver function remained normal, and he resumed normal work. As of follow-up in February 2019, the patient reported being "healthy."

Comment: For advanced, massive liver cancer, transarterial chemoembolization (TACE) and targeted therapy are the mainstays of treatment (5.6). Systemic chemotherapy has not been proven to prolong patient survival. TACE can shrink tumors, primarily serving as a bridge to radical treatment (surgical resection, ablation); it does not provide a survival benefit when used alone. Based on nine published studies, the median progression-free survival (PFS) after TACE ranges from 2.4 to 6.7 months. TACE is ineffective for portal vein tumor thrombi. This patient has been progression-free for two and a half years, and the liver cancer tissue is now essentially necrotic and liquefied, with the portal vein tumor thrombus disappearing. The role of hydrogen cannot be underestimated.

3. After surgery, "auxiliary" adjuvant treatment

Example 5: Non-small cell lung cancer

A 64-year-old male patient underwent a right middle lobectomy (stage LC) on November 6, 2017, for a nodule (approximately 2.5 cm in diameter) in the inner segment of the right middle lobe. Pathology revealed poorly differentiated lymphoepithelioid carcinoma (a subtype of large cell lung cancer). Genetic testing revealed no mutations other than TP53, and no targeted therapy was available. Circulating tumor cell monitoring revealed five single cells, and a large 10 x 6 mm nodular shadow was located at the left anterior margin of the T12 vertebra. Three weeks after surgery, a course of TP chemotherapy (Taxol + Platinum) was initiated. Follow-up examination revealed that the T12 lesion had enlarged to 17 x 9 mm and showed significant enhancement, suggesting an oligometastatic lesion. Chemotherapy was switched to a course of pemetrexed plus neroxaline, followed by 18 fractions of TOMO radiotherapy (approximately 45 Gy). However, his white blood cell and platelet counts were severely decreased, and further chemotherapy was discontinued. Starting from April 30, he inhaled hydrogen for 6 hours every day, and his appetite increased after inhalation. One month later, a PET-CT reexamination showed calcification at the original lesion on chest 12, and no F-18 deposition was observed (see Figure 5).

After surgery, his blood CA125 level was 200 U/L. After chemotherapy and radiotherapy, it dropped to 45 U/L. One month after hydrogen inhalation, it remained at 45 U/L, but after 50 days, it dropped to 24 U/L, and after 60 days, it dropped further to 18 U/L (see Figure 6). As of early 2019, the patient reported being "stable" and "without recurrence."

Comment: For patients with non-small cell lung cancer without EGFR mutations and ALK negativity, platinum-based combination chemotherapy is generally used (8). Gridelli et al. (9) reported that the median overall survival of patients treated with chemotherapy with or without cisplatin was 9.6 and 7.5 months, respectively, and the progression-free survival was 4.6 and 3 months, respectively. The group treated with cisplatin had more severe hematological toxicity and fatigue. Socinski et al. (10) reported similar results, with median progression-free survival and overall survival of 6.3 and 12.1 months, respectively. During the 5-month chemotherapy period, the patient's CA125 level remained elevated and thoracic vertebrae metastases developed. After 2 months of hydrogen inhalation alone, the metastatic lesions calcified and CA125 gradually returned to normal. It is worth noting that tumor markers remained unchanged within one month after hydrogen inhalation and returned to normal only after 50 days, suggesting that the effect of hydrogen may have a dose-accumulating effect.

Case 6: Postoperative ovarian cancer

The patient, a 28-year-old woman, underwent surgery in December 2017 for left ovarian cancer, including hysterectomy and uterine appendage removal. The postoperative diagnosis was ovarian adenocarcinoma (IA). In the past three months, two consecutive tumor marker tests had elevated. On May 9, 2018, she began hydrogen inhalation therapy, 3-4 hours daily. Two weeks later, a follow-up examination revealed that the tumor markers had completely returned to normal (see Figure 7). A blood test one month later revealed CEA levels of 1.9 μg/L and CA19-9 levels of 10.3 μg/L. She was asymptomatic, and CT scans and endoscopic ultrasound revealed no evidence of cancer. As of early 2019, there has been no recurrence.

Comment: Elevated CA19-9 and CEA levels after ovarian cancer surgery should primarily be considered as residual ovarian cancer or occult metastasis (11,12). Chemotherapy is generally recommended, but due to adverse reactions, the patient was reluctant to undergo it. Hydrogen inhalation, a simple and safe treatment, produced miraculous results in this patient, a matter of great relief to both patient and physician.

Example 7: Thymic carcinoma

A 51-year-old male patient presented with chest tightness of unknown etiology on June 29, 2017, to a Shandong cancer hospital for a CT scan. CT scans revealed irregular nodules and masses in the anterior mediastinum, the largest measuring 101 x 38 mm in cross-section; multiple nodules and masses in the left pleura; and linear shadows in the left lower lobe. On July 5, 2017, a thoracoscopic biopsy of the mediastinal mass was performed under general anesthesia at a Beijing hospital. During the procedure, multiple firm, white nodules were found on the surface of the visceral and parietal pleura, along with a mass measuring approximately 6 x 5 x 5 cm in the anterior mediastinum, closely adherent to the left lung tissue. The nodules on the surface of the parietal pleura were initially locally resected and sent for frozen biopsy, which revealed thymoma (predominantly type B2). G-shaped resection of the nodules on the surface of the visceral pleura in the left lower lobe was performed using a linear stapler. Given the patient's extensive pleural metastasis of the thymoma, radical resection was not feasible, and the surgery was terminated. The patient received chemotherapy after surgery, but stopped taking the drug after 4 cycles due to severe adverse reactions, including insomnia, loss of appetite, extreme fatigue, and rapid weight loss.

In early October 2017, hydrogen inhalation therapy was initiated, lasting 8 to 10 hours daily. Four months later, a follow-up CT scan revealed a reduction in the tumor size by 0.1 × 0.3 cm, and the pleural effusion had decreased. Ten months later, a follow-up CT scan showed further reduction in the tumor size, the pleural effusion had disappeared, and the patient resumed normal work. A follow-up CT scan in July 2018 revealed a reduction in the mediastinal lesion (at least stable), with no evidence of metastasis (see Figure 8). Follow-up in early 2019 indicated the patient's condition was stable.

Comment: According to the WHO classification, thymoma is divided into subtypes A, AB, B1, B2, and B3 based on thymic epithelial morphology. Thymic carcinomas primarily present as squamous cell carcinomas. Surgery is the sole curative treatment option. 50%-60% of B2 and 60%-80% of B3 thymic carcinomas are classified as stage III-IV. Unresectable thymic tumors are often progressive and difficult to treat. Radiotherapy and chemotherapy are the main palliative options. The objective response rate after chemotherapy is 47.7%, and the median progression-free survival is 6.5 months. There is little difference between different chemotherapy regimens. Two phase II trials using imatinib, a tyrosine kinase inhibitor targeting KIT, for the treatment of thymic carcinomas have failed to demonstrate beneficial effects. In another phase II trial, bevacizumab combined with erlotinib in 11 thymomas and 7 thymic carcinomas failed to observe tumor responses (14.15). This patient's thymic tumor pathologically belongs to the B2 subtype, and its biological behavior is unequivocally malignant. The patient's mediastinal tumor stabilized after hydrogen inhalation. The overall survival from onset was 23 months, and the survival from the start of hydrogen inhalation was 19 months, suggesting that hydrogen has an inhibitory effect on thymic tumors.

IV. Alternative treatment (“adjuvant” palliative treatment) is used for patients who cannot undergo surgery, radiotherapy or chemotherapy, or for patients who have failed radiotherapy or chemotherapy.

Example 8: Pancreatic cancer

An 84-year-old male patient presented in May 2017 with poor appetite, abdominal distension, and jaundice of the skin and sclera. CT scan revealed a 7-8 cm space-occupying lesion in the pancreatic head, dilated pancreatic ducts in the pancreatic body and tail, and multiple small lymph nodes surrounding the pancreas and blood vessels. The common bile duct and intrahepatic bile duct were also dilated. He was diagnosed with pancreatic cancer and underwent endoscopic common bile duct catheterization. Jaundice gradually subsided postoperatively. The patient self-inhaled hydrogen for at least 5 hours daily, and his appetite improved during this period. A PET-CT scan in January 2018 revealed a 6-7 cm space-occupying lesion in the pancreatic head. A stent was found in the common bile duct. A 2 cm, round, highly reactive tumor was detected in the left lobe of the liver, suggesting liver metastasis.

The patient did not receive any anti-cancer treatment except continuing hydrogen inhalation.

A follow-up CT scan on March 23, 2018, revealed a 5.9 × 3.2 cm space-occupying lesion in the pancreatic head and a common bile duct stent. Compared with the PET-CT scan two months prior, the mass was stable and appeared to have shrunk. The metastatic lesion in the left lobe of the liver was no longer visible (see Figure 9). The patient's appetite and spirits were excellent, and he had gained 2 kg in the past two months. The patient's circulating tumor cells were only 1 cell/mL; all lymphocyte types and cytokines in his blood, which reflect immune function, were completely normal.

Comment: Inoperable pancreatic cancer relies mainly on chemotherapy. Gemcitabine combined with albumin-bound paclitaxel or FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) is the most commonly used treatment regimen, with a median overall survival of approximately 11 months. However, once liver metastasis occurs, the median overall survival drops to 7.4 months (16). Moreover, a retrospective study showed that less than half of 224 patients were able to receive full-dose chemotherapy (17). For metastatic pancreatic cancer, as one American doctor said: One loser may be better than another, but ultimately, no one regimen is a winner.

This patient did not receive any anti-tumor treatment, yet one year later, the tumor remained stable, liver metastases had even disappeared, and overall health, including appetite and weight, improved. The patient inhaled hydrogen alone, which undoubtedly played a key role.

Case 9: Recurrence of hepatocellular carcinoma after liver transplantation

A 54-year-old male patient developed liver pain in July 2017. A CT scan revealed a large liver mass. Three months after liver transplantation, multiple metastases developed in the "new liver," lungs, spine, bones, brain, and subcutaneous tissue. One metastasis emerged from the left nostril, ulcerating and bleeding, obstructing the nasal cavity and impairing breathing. He experienced generalized pain, was unable to walk, had little appetite, and experienced rapid weight loss. He received no special treatment and, starting in March 2018, had been self-inhaling hydrogen for three to four hours daily.

In May 2018, the patient reported less pain, an improved appetite, and was able to walk. The metastatic tumor in the left nostril gradually shrank and then disappeared (see Figure 10).

Comment: Treatment for recurrent liver cancer after liver transplantation is extremely difficult (8). This patient had extensive metastasis of hepatocellular carcinoma throughout the body after liver transplantation, making surgery and chemotherapy impossible. To prevent rejection after the transplant, immunotherapy was also not possible. After hydrogen inhalation, the patient's overall condition improved, and the progression of the cancer stabilized. Particularly notable was the disappearance of nasal metastases. The effect of hydrogen is evident.

Example 10: Rectal cancer

An 84-year-old female patient complained of blood in the stool and a feeling of incomplete defecation for two years, along with sacrococcygeal pain for one year. In early 2016, she developed blood in the stool with no apparent cause, consisting of mucus and blood. She sought medical attention at a hospital in Jinhua, Zhejiang Province. Digital rectal examination revealed a cauliflower-shaped mass, approximately 500 ml in size, 2 to 6 cm from the anal verge, while in the left lateral decubitus position. She declined surgery. In May 2016, she developed copious amounts of blood in the stool, consisting of clots of blood, and subsequently experienced similar bloody stools three times, all without specific treatment. In September 2016, a mass developed at the anal opening, accompanied by worsening sacrococcygeal pain. A CT scan revealed a right upper mediastinal mass, an infectious lesion in the right upper lobe of the lung, and rectal cancer. Small lymph nodes were observed adjacent to the abdominal aorta, suggesting mediastinal metastasis of rectal cancer and pulmonary infection. Anorectal examination from the knee-chest position revealed a cauliflower-like mass protruding from the anus, approximately 3 x 2 cm in size, with a rough surface and minimal surface bleeding. A plain and contrast-enhanced abdominal CT scan in February 2018 reported: thickening of the rectal wall and soft tissue mass in the distal rectal and anal regions; unclear adhesions to the bilateral levator ani muscles and posterior vaginal wall; and multiple small and slightly larger lymph nodes bilaterally adjacent to the iliac vessels and in the groin (see Figure 11).

Colonoscopy revealed a broad-pedunculated polyp, approximately 1 x 0.6 cm, 10 cm from the anus, with hyperemia, edema, and erosion. The rectal mucosa within 4 cm of the anus was hyperemia, edema, and erosion, with a cauliflower-like appearance, involving three-fifths of the anal perianal area (see Figure 12). A biopsy revealed moderately differentiated adenocarcinoma.

Since May 2018, he has been inhaling hydrogen for at least four hours daily. Before treatment, he was in excruciating pain, unable to defecate, and confined to bed. After more than a month of hydrogen inhalation, the pain was significantly reduced, he could defecate, and he could go out for walks. The swelling at his anal opening disappeared. As of early 2019, the patient remained "stable."

Comment: This patient suffered from low rectal cancer with metastasis to the perirectal lymph nodes and mediastinum. The tumor was incarcerated in the anus, causing severe pain. Surgery was impossible. Conventional treatment options included radiotherapy and chemotherapy, but the patient's advanced age and poor general condition made these treatments difficult. The patient also refused both chemotherapy and radiotherapy. After one month of hydrogen inhalation, the pain subsided and the local tumor regressed. Therefore, the improvement in her symptoms was undoubtedly due to the effects of hydrogen.

Case 11: Non-small cell lung cancer with brain metastasis

A 47-year-old female patient developed a sudden, increasingly severe dry cough in September 2015. CT scans revealed right lung cancer with metastases to the hilar, mediastinal, and left supraclavicular lymph nodes, right lower lung carcinomatous lymphangitis, and an abnormally enhancing nodule in the right occipital lobe. Bronchoscopy and biopsy revealed adenocarcinoma, EGFR mutation, and ALK (2p23) chromosomal translocation (ALK positive) by fluorescent in situ hybridization. Chemotherapy began on September 29th. From October 21, 2015, to February 8, 2017, she received a combination of two drugs, then a single drug for maintenance, then another combination of two drugs, and then a single drug for maintenance, for a total of 15 months. She then underwent radiotherapy, a total of 32 times over 48 days. During this period, a follow-up CT scan eight months after chemotherapy showed "stability," followed by another CT scan two months later, which showed "significant progression." Follow-up CT and MRI scans five months later revealed "progression" of brain metastases and concurrent cerebral hemorrhage (see Figure 13).

In May 2017, the patient began taking the active pharmaceutical ingredient "crizotinib" orally, while also inhaling hydrogen for 8-10 hours daily. A follow-up CT scan three months later showed reductions in the lung tumor and lymph node metastases, and the disappearance of pleural and pericardial effusions. However, a new metastasis had appeared in the brain. A follow-up CT scan six months later revealed smaller lung and brain metastases. A year later, a CT scan revealed further reductions in the lung tumor and brain metastasis (see Figure 14). The patient's general condition gradually improved, and he returned to normal work. As of early 2019, his condition remained stable.

Comment: The patient received chemotherapy for 15 months and was once "stable," but his condition quickly progressed. Because he was ALK-positive, he was also treated with the unconventional drug "crizotinib" (an unconventional API). Shaw et al. (20) reported that the median survival in the crizotinib group was 7.7 months, which was better than the 3 months in the chemotherapy group, but there was no significant difference in overall survival. The adverse reactions of crizotinib should not be ignored. Common adverse reactions include visual impairment, liver damage, and gastrointestinal reactions. Fatal interstitial pneumonia has been reported.

Lung cancer with ALK fusion mutations progresses more rapidly. The incidence of brain metastasis in patients with ALK-positive non-small cell lung cancer is 20%-30%, and the incidence of brain metastasis during treatment is 60%-90% (21). Due to the low blood-brain barrier passage rate of crizotinib, the central nervous system remains the main site of acquired resistance to crizotinib, regardless of whether the patient has brain metastases. Most patients will inevitably develop acquired resistance within 1 year, and 40%-50% will first manifest as intracranial progression (22-23).

The patient had brain metastases at the time of onset. Crizotinib has limited efficacy against brain metastases due to its difficulty crossing the blood-brain barrier. During treatment, the patient suffered a cerebral hemorrhage and was placed under emergency care. With the addition of hydrogen inhalation therapy, the patient's condition gradually improved. Since the start of hydrogen inhalation, he has been "progression-free" for over 20 months, clearly demonstrating the effectiveness of hydrogen.

Case 12: Right upper lobe adenocarcinoma cT2aN2M1b stage IV with

Brain metastases

A 43-year-old female patient presented to a hospital in Xinjiang in late November 2015 with complaints of dizziness and unsteadiness for two weeks. She underwent resection of a left cerebellar metastasis on November 27, 2015. Postoperative pathology revealed metastatic lung adenocarcinoma; genetic testing revealed a positive EGFR fragment 19 mutation. She underwent whole-brain radiotherapy from December 2015 to January 2016. A lung CT scan on April 20, 2016, revealed a space-occupying lesion in the right upper lobe. She began receiving targeted therapy with Iressa (gefitinib tablets). A follow-up examination at a local hospital on September 11, 2017, revealed disease progression, and she began combination therapy with pemetrexed and erlotinib. However, she developed grade III myelosuppression during chemotherapy. Chemotherapy was discontinued on October 13, 2017, but oral erlotinib was continued. A head MRI performed on March 6, 2018, showed changes following resection and radiotherapy of a left cerebellar hemisphere metastasis. Compared to the previous radiograph (September 18, 2017), the residual cavity in the surgical area remained largely unchanged, but the abnormally enhancing nodule at the margin of the residual cavity had increased in size. The lesion in the left frontal and parietal lobes had decreased in size, with more pronounced nodular enhancement at the margin, suggesting disease progression. Multiple abnormal signals were present in the rest of the brain, suggesting new metastases. A chest CT scan revealed an enlarged lesion in the right upper lobe and a nodule in the basal segment of the right lower lobe, suggesting metastasis. Multiple lymph nodes in the mediastinum and hilum were also enlarged, and a metastatic nodule in the left adrenal gland was also enlarged. The patient was switched to oral icotinib hydrochloride. Two weeks later, due to side effects, the patient discontinued the drug on her own. She experienced shortness of breath, dyspnea, chest tightness, palpitations, discomfort, incoherent speech, and difficulty walking. She initiated hydrogen inhalation for 3 to 4 hours daily. Subsequently, her symptoms gradually improved. Five months later, on August 30, 2018, a follow-up examination revealed significant reductions in the brain metastases and right lung lesions (see Figure 15). The patient gradually regained the ability to walk independently, breathing normally, remaining conscious and answering relevant questions. As of a follow-up call in February 2019, the patient's condition remained stable.

Comment: This patient presented with neurological abnormalities as the initial symptom. Brain metastases were first discovered, and lung lesions were discovered six months later. He underwent brain surgery, radiotherapy, chemotherapy, and targeted drug therapy. Over two years later, both lung and brain lesions worsened. Symptoms gradually improved after hydrogen inhalation therapy. A follow-up brain MRI six months after hydrogen inhalation showed significant improvement in the metastatic lesions, reduction in the lung lesions, and overall good condition. This case demonstrates that hydrogen inhalation has a significant effect on brain metastases.

Hydrogen molecules are extremely small and highly diffusible, easily penetrating the blood-brain barrier. Brain tissue and cell damage are more easily induced by oxidative stress and inflammation. Therefore, hydrogen may have a special therapeutic effect on brain lesions, including brain metastases (24).

Case 13: Gallbladder cancer

A 73-year-old female patient presented to the hospital in November 2017 with right upper abdominal distension and pain. Gallbladder cancer was diagnosed, with metastases to the liver, hepatic hilum, and pancreatic head. A biopsy confirmed stage III gallbladder adenocarcinoma (see Figure 16). She underwent ablation and oral tegafur, but with no significant effect. On September 21, 2018, she was admitted to the ICU with wheezing, shortness of breath, and vomiting. At the time, she was severely anemic, with a hemoglobin level of only 37 g/L, serum albumin of 25.6 g/L, an erythrocyte count of 1.49 x 10₂/L, and a hematocrit of 0.14%. Tumor markers were elevated: CA19-988.18 U/mL, AFP 14.11 IU/mL, and CEA 39.68 ng/mL. She also presented with cardiac insufficiency. Tumor compression of the duodenum caused tumor-enteric fistula and intestinal obstruction, and the liver was largely occupied by metastatic tumors. Emergency symptomatic treatment was given, including oxygen inhalation, red blood cell and plasma transfusion, fasting, gastric tube insertion for gastrointestinal decompression, parenteral nutrition, etc. Given the extremely serious condition, the ward repeatedly explained the condition to the family, but the family insisted on emergency treatment in the hospital.

In early October, the patient received an anti-PD-1 drug. After one injection, he developed severe fatigue, diarrhea, itchy skin, and hypokalemia, forcing him to discontinue the drug. Seeing conventional treatments unable to save him, his family requested a trial of hydrogen inhalation therapy and brought a hydrogen-oxygen nebulizer (66% hydrogen, 34% oxygen, manufactured by Shanghai Demei). The patient inhaled via a nasal cannula at a rate of 3 liters/minute. Initially, he inhaled for two hours daily, increasing to four and then eight hours over a few days. Aside from life-sustaining treatments, the patient received no other anti-cancer treatments.

After two weeks of hydrogen inhalation, the patient's overall condition gradually improved. After 51 days of gastric tube intubation, the tube was removed and he began to eat, sit up, and then walk. Anemia gradually improved, with increases in red blood cells and hemoglobin, and serum albumin returning to normal (see Figure 17).

At the same time, the three tumor markers in the patient's blood gradually decreased until they fell into the normal range (see Figure 18).

Follow-up CT scans showed that both the gallbladder tumor and the liver metastases had shrunk (see Figure 19). The primary gallbladder tumor had shrunk by two-thirds, and the liver metastases had shrunk by over 40%. On January 18, 2019, after nearly four months in the hospital, the patient was discharged on foot.

Comment: Gallbladder cancer has a poor prognosis. Surgical resection is the only cure. Due to the lack of specific symptoms in the early stages, it often coexists with benign lesions (such as gallstones) and is often misdiagnosed as a chronic gallbladder disease, so that the chance of surgical cure has been lost by the time the disease is diagnosed. There is a lack of effective adjuvant therapy. Prognosis is closely related to the stage at diagnosis. According to statistics from the United States, the 5-year survival rate of gallbladder cancer is 50% for stage I patients, 28% for stage II, 8% for stage IIIa, 7% for stage IIIb, and 4% and 2% for stages IVa and IVb, respectively. A report from the United Kingdom also showed that the later the stage, the shorter the survival time. The median survival time of patients with stage Ia and IIIb is only 5 and 4 months, respectively (25). A Canadian review in 2014 showed that the overall median survival time of patients with gallbladder cancer is only 6 months, and the 5-year survival rate is only 5%260. The main reason for the poor prognosis is the lack of a serous membrane between the gallbladder and the liver, so gallbladder cancer is very easy to invade or metastasize to the liver at an early stage.

This patient's gallbladder cancer had metastasized to the liver, hepatic hilum, and pancreatic head at onset, resulting in stage IVa. Surgery was not an option. Although he had received a single dose of anti-PD-1 therapy, the side effects were severe and he was unable to continue treatment. Without any anti-tumor treatment and relying solely on hydrogen and oxygen inhalation, his symptoms significantly improved, with red blood cell and albumin levels rising, tumor markers returning to normal, and significant reductions in both the primary and metastatic tumors, indicating that hydrogen was playing a control role.

The patient returned to the hospital for a follow-up examination on April 13, 2019, and was in good general condition and walking freely. Blood tumor markers remained normal, and a follow-up CT scan showed further shrinkage of the liver, gallbladder, and nearby metastatic lymph nodes. Immunohistochemistry of the tumor tissue revealed low microsatellite instability (MSI+IHC), suggesting insensitivity to PD-1 antibodies, further suggesting that the patient's improvement was primarily due to the effects of hydrogen.

Case 14: Ureteric adenocarcinoma

An 84-year-old female patient presented with hematuria for three months. A CT scan in December 2016 revealed a 3x4 cm mass at the junction of the right proximal ureter and renal pelvis. A biopsy revealed ureteral epithelial carcinoma. Twelve years prior, due to a drug allergy, her left kidney was damaged and atrophied, leaving only 25% of its function. Her blood creatinine level was 170 μmol/L. She declined nephrectomy and, in March 2017, underwent a right ureteral conduit followed by CT-guided irreversible electroporation ablation of the tumor. Postoperatively, her blood creatinine level dropped to 110 μmol/L, and a CT scan revealed shrinkage of the ureteral tumor. Six months later, the tumor recurred at the right proximal ureter and invaded the renal pelvis. Repeat CT-guided irreversible electroporation ablation was performed. She subsequently inhaled a hydrogen (66%) and oxygen (34%) mixture at home for three to four hours daily. A follow-up MRI in January 2019 revealed shrinkage of the right kidney and adjacent metastatic lymph nodes (see Figure 20). The patient is in good general condition, with serum creatinine stable below 150 umol/L.

Comment: The standard treatment for unresectable advanced or metastatic ureteral malignancies is systemic chemotherapy. Platinum-based combination chemotherapy is the gold standard (2). In a phase III clinical trial, 248 patients after nephroureterectomy were randomized to gemcitabine-cisplatin or monitoring therapy, with 2-year disease-free survival rates of 70% and 51%, respectively (28). However, data on chemotherapy for upper ureteral cancer, particularly in advanced cases, are limited.

A phase II trial of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, reported an overall survival of 13.9 months in the combination therapy with gemcitabine-carboplatin compared with 9 months in the chemotherapy alone group (29).

The patient's advanced age and impaired renal function made chemotherapy difficult, and he received only local tumor ablation. He suffered from severe fatigue at one point. Six months prior, he developed dermatomyositis and received corticosteroid (prednisolone) treatment. However, the primary tumor showed no significant progression, metastatic lymph nodes did not increase in number, and existing metastatic lymph nodes shrank. His overall condition is currently good. The patient has been using hydrogen inhalation for over a year, and the effects of hydrogen cannot be ignored.

Conclusion

Based on the above "real-world" case studies, the effects of hydrogen inhalation (a mixture of 66% hydrogen and 34% oxygen) are encouraging. Hydrogen can be used in at least five areas of cancer control, including:

(1) Before surgery, neoadjuvant therapy, used with chemotherapy or alone, attempts to shrink the tumor so that surgery can be performed more easily.

(2) After surgery, adjuvant therapy, combined with radiotherapy or chemotherapy, or used alone, aims to eliminate residual tumors and reduce recurrence. For patients with asymptomatic elevated tumor markers (such as AFP, CEA, CA19-9, CA125, CA153, PSA, etc.) or increased circulating tumor cells (CTC), if there is no indication for chemotherapy, hydrogen inhalation can be used for rehabilitation.

(3) "Adjuvant" radiotherapy and chemotherapy, which are used simultaneously with radiotherapy and chemotherapy to try to reduce the adverse reactions of radiotherapy and chemotherapy.

(4) For patients with advanced cancer who cannot undergo surgery or whose cancer cannot be removed by surgery and for whom chemotherapy and radiotherapy are inappropriate, hydrogen can be used as a palliative measure to improve symptoms and quality of life and prolong survival.

(5) Cancer patients who have received effective treatment can use it preventively (tertiary prevention) to try to reduce long-term recurrence. Of course, this is just a "case study" and to become a high-level "evidence", a large amount of long-term clinical observation and research, especially multicenter research, is still needed. The final version of the 21st Century Cures Act of 2016 approved the use of "real-world evidence" (RWE) to replace traditional clinical trials to expand indications. RWE is a patient-centered research that does not impose special restrictions on subjects. It pays special attention to listening to the patient's voice and emphasizing the communication between patients and doctors, and then directly applies it to clinical practice.

The above cases seem to be the "voice of patients."

Xu Kecheng Kong Xiaofeng Lu Tianyu Chen Jibing Qian Wei

References

[1] Di Maio M, Chiodini P, Georgoulias V, et al. Meta-analysis of single-agent chemotherapy compared with combination chemotherapy as second-line treatment of advanced non-small-cell lung cancer. J Clin Oncol, ovil 2009, 27(11): 1836-1843. for AM rom (81)

[2] Tekatli H, van't Hof S, Nossent EJ, et al. Use of Stereotactic Ablative Radiotherapy (SABR) in Non-Small Cell Lung Cancer Measuring More Than 5 cm. J Thorac Oncol, 2017, 12(6):974-982. 1881-181

[3] Hayata K, Ojima T, Nakamori M, et al. Neoadjuvant Chemotherapy with Docetaxel, Cisplatin and S-1 for Resectable Advanced Esophageal Cancer. Anticancer Res, 2018, 38(9): 5267-5273. A landgame-non

[4] Peng J, Tan C, Zeng X, et al. Cost-effectiveness analysis of capecitabine monotherapy versus capecitabine a plus oxaliplatin in elderly patients with advanced gastric cancer. PLoS One, 2018, 13(6): e0199553.

[5] Lee EW and Khan S. Recent advances in transarterial embolotherapies in the treatment of hepatocellular 电话:carcinoma. Clinical and molecular hepatology, 2017, 23(4): 265-272.

[6] Li L, Zhao W, Wang M, et al. Transarterial chemoembolization plus sorafenib for the management of unresectable hepatocellular carcinoma: a systematic review and meta-analysis. BMC Gastroenterol, 2018, 18(1): 138.

[7] Liu X, Wang Z, Chen Z, et al. Efficacy and Safety of Transcatheter Arterial Chemoembolization and Transcatheter Arterial Chemotherapy Infusion in Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Oncol Res, 2018, 26(2): 231-239.

[8] Carmichael JA, Wing-San Mak D,O'Brien M. A Review of Recent Advances in the Treatment of Elderly and Poor Performance NSCLC. Cancers, 2018, 10(7).

[9] Gridelli C, Morabito A, Cavanna L, et al. Cisplatin-Based First-Line Treatment of Elderly Patients With Advanced Non-Small-Cell Lung Cancer: Joint Analysis of MILES-3 and MILES-4 Phase III Trials. J Clin Oncol, 2018, 36(25): 2585-2592.

[10] Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small- cell lung cancer: final results of a phase III trial. J Clin Oncol, 2012, 30(17): 2055-2062.

[11] Zhang W, Wang L,Xin Z. Combination of serum CA19-9 and CA125 levels and contrast-enhanced ultrasound parametric data facilitates to differentiate ovarian serous carcinoma from ovarian malignant Waepithelial cancer. Medicine (Baltimore), 2018, 97(16): e0358.

[12] Moro F, Pozzati F, Mascilini F, et al. Ultrasound characteristics of ovarian metastases from low-grade appendiceal mucinous neoplasms. Ultrasound Obstet Gynecol, 2018, 51(5): 699-700.

[13] Xu XL and Mao WM. Current Drug Targets for Thymic Neoplasms. Curr Cancer Drug Targets, 2015, 15(7): 593-603.

[14] Girard N. Chemotherapy and targeted agents for thymic malignancies. Expert Rev Anticancer Ther, 2012, 12(5): 685-695.

[15] Merveilleux du Vignaux C, Maury JM,Girard N. Novel Agents in the Treatment of Thymic Malignancies. Curr Treat Options Oncol, 2017, 18(9): 52.

[16] Vivaldi C, Caparello C, Musettini G, et al. First-line treatment with FOLFOXIRI for advanced pancreatic cancer in clinical practice: Patients' outcome and analysis of prognostic factors. Int J Cancer, 2016, 139(4): 938-945.

[17] Jean M, Yoo-Joung K,Akmal G. STANDARD CLINICAL PRACTICE OF FOLFIRINOX IN ADVANCED/ METASTATIC PANCREATIC CANCER (PC) PATIENTS: A CANADIAN REGISTRY. Annals of Oncology, 2015.

[18] Zimmerman MA, Ghobrial RM, Tong MJ, et al. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg, 2008, 143(2): 182-188; discussion 188.

[19] Holliday EB, Allen PK, Elhalawani H, et al. Outcomes of patients in the national cancer database treated non-surgically for localized rectal cancer. J Gastrointest Oncol, 2018, 9(4): 589-600.

[20] Shaw AT, Kim TM, Crino L, et al. Ceritinib versus chemotherapy in patients with ALK-rearranged non- small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol, 2017, 18(7): 874-886. 2 mains WB [1 [21] Loganadane G, Dhermain F, Louvel G, et al. Brain Radiation Necrosis: Current Management With a Focus on Non-small Cell Lung Cancer Patients. Front Oncol, 2018, 8(336).

[22] Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med, 2014, 371(23): 2167-2177.

[23] Yang P, Kulig K, Boland JM, et al. Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. J Thorac Oncol, 2012, 7(1): 90-97.

[24] Liu CL, Zhang K,Chen G. Hydrogen therapy: from mechanism to cerebral diseases. Med Gas Res, 2016, 6(1): 48-54.

[25] Smith GC, Parks RW, Madhavan KK, et al. A 10-year experience in the management of gallbladder cancer. HPB (Oxford), 2003, 5(3): 159-166.

[26] Hundal R and Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clinical epidemiology, 2014,

6(99-109.

[27] Bianconi M, Cimadamore A, Faloppi L, et al. Contemporary best practice in the management of urothelial carcinomas of the renal pelvis and ureter. Ther Adv Urol, 2019, 11(1756287218815372).

[28] Birtle AJ, Chester JD,Jones RJ. Results of POUT: a phase III radonised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). J Clin Oncol, 2018, 36(Suppl 6): 407.

[29] Bialar AV, Aoplo AB,Ostrovnaya I. Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. J Clin oncol, 2013, 31(724).

Reading Extension

Rudong Seaside

My beautiful hometown, Rudong Coast, lies where the Yangtze River meets the Yellow Sea. The boundless coastal wetlands exude a dreamlike mystery. Clam fishermen, walking together under the rising sun, offer a glimpse into the boundless wonder and romance of this pristine environment. Countless wind turbines dot the coast, providing an inexhaustible source of electricity and adding a touch of modern beauty to Rudong's ecology.

Chapter 5 Hydrogen Cancer Control: A "Real World" Story

Hydrogen and "cancer pain": relieving pain and bringing joy

The pain of cancer

On the afternoon of November 13, 2018, I accompanied Professor Wu, a renowned expert from a domestic cancer hospital, to visit my studio (Xu Kecheng Care for Health Studio in Guangdong Province). As soon as we entered, Ms. Yingzi, a volunteer serving there, pulled me aside and asked me to see Mr. Liu, a Hong Kong businessman in Changsha, Hunan. She said he was a friend she had known for 20 years.

Next to a hydrogen-oxygen nebulizer, a thin man wearing a cap and a nasal cannula sat. He was inhaling hydrogen. When he saw Professor Wu and me, he immediately stood up, shook hands with us, and said hello.

His wife came over and held me, saying "thank you" repeatedly. She seemed to be from Hunan Province, and tears streamed down her face as she spoke: "Now his pain has eased, he can eat and sleep, and he sleeps very soundly..."

In April 2018, Mr. Liu was diagnosed with tongue cancer. He refused surgery and continued to take traditional Chinese medicine. In October, his condition worsened, with pain, blisters, swelling, and ulcers forming on his tongue. He couldn't open his mouth or move his tongue, and could only eat liquid food. He also suffered from insomnia, irritability, and weight loss. With a "try your luck" mentality, they traveled to Guangzhou and came to my studio for hydrogen inhalation. After a week of hydrogen inhalation, their sleep improved, their appetite improved, their energy level improved, their breathing became smoother, and they had more energy to walk.

Professor Wu and I examined Mr. Liu's tongue and suggested that he be hospitalized and receive conventional treatment including surgery or minimally invasive surgery after his general condition, especially nutritional status, further improved. Mr. Liu accepted the treatment.

Mrs. Liu told us that they had given up hope and did not want any medical treatment. Mr. Liu had already written his will, chosen a burial plot, and made all the necessary arrangements. Mrs. Liu said, "We've all endured the pain of facing death."

As a cancer survivor, I know full well the suffering that cancer patients experience, which is "suffering": the suffering of pain, anorexia, fatigue, insomnia, treatment, fear, anxiety, helplessness, lack of respect, loneliness, being cheated, and having no money, as well as the "helplessness" of facing death, as Mrs. Liu described.

Mrs. Liu said: "Now he can eat, sleep, and walk, and he has the confidence to live. This hydrogen inhalation method is really amazing. At least it has relieved our suffering for the time being, and we now have the confidence to seek treatment in the hospital."

The original intention of hydrogen absorption

After hearing Mrs. Liu's words, I felt very relieved and even a sense of accomplishment. The Guangdong Xu Kecheng Care for Health Studio is a public welfare organization established under the care of Guangdong provincial leaders and approved by the Provincial Civil Affairs Department. My goal is to use this platform to do more for society. As both a doctor and a cancer patient, I hope to do something beneficial for the recovery of cancer patients.

Practicing "Chinese-style cancer control" and finding and researching effective cancer rehabilitation methods are the main contents of the studio's "Caring for Health" program.

 

I found "Hydrogen." It's for the studio, of course, but also for myself.

I've been suffering from cancer for 13 years, and I constantly worry about the possibility of a recurrence. We often talk about "5-year" and "10-year" survival rates for cancer, rather than "cure rates," because cancer is a chronic disease that can relapse at any time. Even breast cancer, with a 70% 5-year survival rate, can still recur 20 years later. My cancer is much more aggressive than breast cancer, so I must take extra precautions against recurrence. I've read extensive literature, particularly Japanese research on hydrogen and health, and have discovered that molecular hydrogen is beneficial to health, preventing and treating many diseases and conditions, and helping to prevent cancer recurrence.

Hydrogen is the most abundant gas in nature, but because it's so light, it's found at high altitudes, colorless and odorless, making it imperceptible to humans. Some say that perhaps the greatest contribution of "natural medicine" over the past 20 years has been the discovery that molecular hydrogen is a "mysterious substance" that promotes health.

The experiment began with me. I began inhaling hydrogen for at least an hour daily, often while running on a treadmill, watching TV, or listening to music. I call this the "three-in-one home rehabilitation program." After a while, I noticed my sleep was better and more restful, my appetite improved, and I felt less fatigued. Colleagues and friends commented that my skin had become more supple, and I somewhat believed this, as the Japanese use hydrogen water for beauty treatments.

I've traveled to Taipei, Shanghai, Beijing, Shandong, Xinjiang, and Tokyo, interviewing over 100 cancer patients who have been inhaling hydrogen for months or even years. Witnessing some patients' miraculous recoveries and hearing their inspiring stories, I was thrilled and deeply moved. This is the background and original intention behind setting up the hydrogen inhalation experience room in my studio.

Hydrogen has captivated the public, including cancer patients, those with common chronic illnesses, the healthy and those in suboptimal health. The hydrogen and oxygen atomizers in the hydrogen inhalation room operate non-stop from morning till night. I asked my patient, Peng Ximei, to volunteer to serve those who come for hydrogen inhalation. Ximei was a terminal ovarian cancer patient who was rescued in December 2009 from Zhanjiang, Guangdong, where she underwent surgery to remove 55 kilograms of tumor and cyst fluid. She has fulfilled her promise: to remain a lifelong volunteer for as long as she lives.

Peng Ximei and other volunteers set up a WeChat group called "Sunshine Hydrogen Health" specifically for hydrogen users. Almost every day, the WeChat group receives exciting news:

"It rained heavily today, but it couldn't stop the three of us from being enthusiastic about hydrogen inhalation. One of us came for the first time yesterday and after two hours of hydrogen inhalation, his cough improved and his throat felt much better."

"Hydrogen has improved my sleep quality, thank you."

"My allergic rhinitis has healed and I haven't had an attack for a week."

"Thanks to hydrogen inhalation. The joint pain that tormented me for four to five years was gone after just four hydrogen inhalations. It's truly miraculous. I'm so grateful!"

One afternoon, I was working in the hospital's outpatient clinic when suddenly there was a commotion outside. The nurse announced that a woman hadn't registered and insisted on seeing me. Before she'd finished speaking, the woman entered, grabbed my hand, and said, "Professor, what do you say? I just felt so much better, and I can't stop inhaling hydrogen!"

I recall a time when she was a patient with recurrent uterine cancer after surgery and had come to my clinic. She had numerous symptoms, and I urged her to be hospitalized for cryotherapy and vascular interventional chemotherapy. She explained that she had already undergone dozens of chemotherapy treatments, which had left her with a loss of appetite, exhaustion, and mental and physical devastation. She also suffered from constant abdominal pain and didn't want to be hospitalized again.

She complained that there were too many people coming to the studio to experience hydrogen inhalation and she couldn't get in line. I comforted her and said, "Hydrogen inhalation is just an auxiliary method. For your cancer, you can't ignore conventional treatment."

"I know that, and I will definitely listen to you in the future. Do you know how much suffering I went through before because of the pain, constipation and urination? After inhaling hydrogen, I finally got rid of this suffering. Professor, you are a good person, please help me again!" The lady cried.

Thinking carefully about the life of a cancer patient, it is filled with so much sadness and helplessness, and it has also moved to a "remote" place - the left nostril.

Cancer is an internal conflict within the body, and it's impossible to completely eradicate all cancer cells. "Coexisting with cancer" is the goal of cancer treatment and the strategy for controlling cancer. Eliminating cancerous tumors is essential for survival, but beyond survival, living is also important.

In a sense, effectively alleviating the various symptoms suffered by cancer patients is also a form of "treatment", creating conditions for "cancer treatment".

We often say: It is better to live a good life than a miserable one. This is what we mean.

Meritorious journalist "satisfied"

Mr. T, a distinguished journalist with a division-level rank, was only 50 years old. A year ago, he suddenly developed upper abdominal pain. Examination revealed a massive liver cancer, and he quickly underwent a liver transplant at a renowned Beijing transplant center. However, his fate was unfortunate. Three months later, the cancer recurred, rapidly metastasizing to the "new liver," as well as the lungs, bones, subcutaneous tissue, and brain. Perhaps due to the pressures of "modern treatment," cancer metastasis has become less predictable. For example, liver cancer typically metastasizes outside the liver primarily to the lungs and bones, which are the closest points. However, in our patient's case, the tumor not only metastasized to multiple organs but also grew deep within the nasal cavity, emerging from his nostrils like a snake, a sight both heartbreaking and terrifying.

Mr. T was in excruciating pain: nasal metastases obstructed his nasal passages, making it difficult to breathe; bone metastases caused periosteal pain; brain metastases caused headaches and dizziness; and subcutaneous abdominal metastases ruptured, leading to local infection and fever. What could medicine do for him? Surgery was impossible, and chemotherapy was ineffective for hepatocellular carcinoma. He only received radiotherapy, which targeted brain metastases. Because it was a post-transplant procedure, immune defenses were needed to prevent rejection, making the now-hyped immunotherapy impossible.

In early 2018, I visited Beijing. Mr. T, supported by his wife, came to see me. I reviewed his medical records, and almost all of his prescriptions were for painkillers. As a physician with decades of clinical experience in digestive and hepatic diseases, I was helpless. Finally, in desperation, I offered a suggestion: hydrogen inhalation—more accurately, inhaling a mixture of hydrogen and oxygen, which contains both hydrogen and oxygen.

A month later, he arrived in Guangzhou by high-speed rail, accompanied by his wife. The next morning, I visited his ward with a sense of trepidation. A glance at his nostrils revealed that the metastatic tumor had essentially disappeared, and his nasal cavity was largely unobstructed. The CT and MRI scans he brought with him showed the tumor was still present. However, he said, "The pain has lessened, my spirits have improved, my strength has increased, I'm hungry again, and I can now walk a hundred meters."

"Hydrogen inhalation has relieved many of my pains. I am satisfied." Mr. T spoke slowly and with emotion.

"Professor Xu, in recent years, I've been playing a game of life and death, and my greatest hope is to coexist with cancer." His wife took out my book, "Coexisting with Cancer," and said, "I read it to him, and he's listened to it several times."

"Coexisting with cancer" is the "normal" part of life, but this coexistence must be of high quality.

I held Mr. T's hand and said, "Time is priceless. Whether it's a month, a year, or ten years, it's worth cherishing. I will definitely help you and fight this disease together. Let's encourage each other!"

Due to brain metastasis, Mr. T's eye movements were restricted. He stood up, tilted his head slightly, looked at me, and said, "Let's encourage each other. I believe that when we face death with joy, life continues to extend."

Two weeks later, before being discharged from the hospital, Mr. T, accompanied by his wife, came to my office. We had a heart-to-heart talk. He said he didn't care about living a long life, but simply wanted to live a life without too much pain. He believed hydrogen inhalation was a good method and would continue to do so. He hoped I could offer some advice on how to proceed with hydrogen inhalation.

I say there is no consensus at present. According to my research, it is best to do the following:

(1) Inhalation of a mixture of hydrogen and oxygen is not simply hydrogen, as hydrogen and oxygen travel together. Hydrogen molecules are small and can easily enter cells, potentially bringing oxygen with them. Hypoxia promotes the proliferation and progression of cancer cells, while oxygen can inhibit cancer cells.

(2) Ensure that sufficient amount of gas is inhaled to allow the gas to enter deep into the tissue, and the gas flow rate should not be too small.

(3) Equipped with a nebulizer, drugs that need to be inhaled through the respiratory tract can be taken through this channel.

(4) The selected machine has stable performance, can be operated continuously for 24 hours, and the gas production fluctuation is less than 1%.

Mr. T smiled and said, "Only those who understand the true meaning of life can constantly generate wisdom and strength. Let's take a photo together. I will always remember your words." His voice was not loud, and tears rolled in his eyes when he finished speaking.

As I was leaving, Mr. T suddenly turned around and grabbed me, saying, "Professor Xu, study it carefully. From my own experience, the role of hydrogen may have a deeper meaning."

Mr. T is not only a journalist, but also a philosopher. Our life is not a superficial existence. The source and power of thought will make our life endless.

Conclusion

Writing these words is not easy, because I am always worried about those patients. Their cancer is impossible to cure, and even difficult to improve in the long term. I just hope they can suffer less from cancer.

What is happiness? It's a feeling. Savoring happy moments is happiness, as is facing pain and overcoming difficulties. The essence of medicine is care. Dr. Trudeau, buried on the shores of Saranac Lake in northeastern New York, has a tombstone inscribed: "Sometimes to heal, often to help, always to comfort."

I remembered Mr. Le Junren, President of the Shanghai Putuo District Cancer Rehabilitation Association. He once sent me a letter saying that he was deeply moved after listening to my lecture on "Practicing Chinese-style Cancer Control and Hydrogen Medicine Research" at the Yangtze River Delta Cancer Rehabilitation Forum held in Wuxi, Jiangsu.

Covenant of Life

One stick of heart-scented fragrance

Relieve suffering and gain joy

Living towards death

Relieve suffering and bring joy! This is tolerance to doctors, as well as encouragement and motivation.

When I was almost done writing this article, I saw a child swinging on a swing in the courtyard outside the window, and I couldn’t help but think of the poem “Swinging” by the poet Han Yu.

The pond rains at night,

The courtyard is dust-free and close to the flower garden.

The five-wire rope is tied out of the wall late,

I was exhausted before I could see my neighbor in the garden.

I couldn't adjust my panting.

I leaned against the red railing for a long time without saying a word.

Speechless and filled with sorrow,

In the blink of an eye, I looked up at the sky and vomited.

The moment the swing swings high, the view opens up. Perhaps the view has only expanded a little, perhaps the distance seen is an incurable chronic disease, but the distance always leads to the farther distance.

Like swinging on a swing, human horizons gradually broaden. Inhaling hydrogen, or hydrogen-oxygen inhalation, is a distant step in the quest for cancer recovery. But now that we've reached this point, why not "turn our eyes and exhale"?

Xu Kecheng

Commentary by Tang Zhaoyou

After reading Professor Xu's article, especially the remission of Mr. T's extensive liver cancer metastasis, I was deeply moved. I've been studying liver cancer for half a century, and only in the 1960s and 1970s did I see patients with such extensive metastatic disease. Back then, high-dose chemotherapy (such as methotrexate) rapidly shrank the tumors, but they re-expanded at an even faster rate a few weeks later, soon leading to unprecedented widespread metastasis, leaving us helpless. Mr. T's significant reduction in metastatic disease after hydrogen inhalation is truly incredible. Nowadays, people prioritize so-called expensive "miracle drugs" over simple, easy-to-use treatments, which is worth reflecting on. Another impression Professor Xu left on me is his commitment to seeing new things through to the end, both with cryotherapy and now with hydrogen inhalation. This article has given me a lot of basic knowledge about hydrogen inhalation.

Hydrogen and lung cancer: a surgery in vain

Taipei is so close

Guangzhou and Taipei are so close. On the morning of March 5, 2018, my secretary, Tianyu, and I boarded a China Southern Airlines flight and landed at Taoyuan Airport in less than two hours. Shortly after exiting the plane, I was greeted by Director Zhang of Shanghai Mei. He had arrived earlier than us on China Eastern Airlines from Shanghai and had skipped customs, having come to meet me from another terminal. There were long lines at customs, but my age allowed me to take the easy route. Mr. Lin, CEO of Hui Mei, and Dr. Wang from Tongji University in Shanghai, who had arrived earlier, met us at the exit. Mr. Lin, born in Taiwan, has been an entrepreneur in Shanghai for 26 years. Early in his career, he built a world-renowned business in auto parts manufacturing. In recent years, he has transitioned to the health industry, passionate about hydrogen molecule health and rehabilitation, attracting a group of experts to participate in his research. Dr. Wang is young and naturally beautiful. This was her first time in Taiwan, and her face was filled with excitement and curiosity.

After getting in the car, Mr. Lin excitedly recounted how he and several classmates had gone hiking the previous day at a resort with incredibly clean air. One of his female classmates, who had lung cancer and had once given up hope of survival, is now remarkably active and healthy. Looking at Mr. Lin's expression as he spoke, I suspected this student's recovery was related to his research on hydrogen molecules.

Meeting with Taiwanese experts

That evening, in a red-themed private room at the Taipei Grand Hotel, Mr. Lin invited several renowned Taiwanese medical experts to dine with me. Professor Liu, Vice President of Linkou XX Hospital and a renowned thoracic surgeon, showed me the WeChat account of Dr. Niu Lizhi from our hospital. I opened the video, and Niu excitedly greeted Professor Liu. Dr. Niu praised Professor Liu as a pioneer of thoracoscopic surgery across the Taiwan Strait. Mr. Lin remarked that Professor Liu was innovative and his passion for hydrogen molecules bordered on obsession.

This introduction immediately dispelled the unfamiliarity between the group and provided common topics. Naturally, everyone started chatting about stories of "hydrogen cancer control." The most remarkable story was about a lung cancer patient at XX Hospital who, after undergoing "hydrogen inhalation plus chemotherapy," ultimately underwent surgery for nothing. Professor Liu explained that surgeons' greatest fear during surgery is leaving a gap. Fortunately, the patient, far from complaining, expressed gratitude.

Mr. Lin said that the patient who "underwent surgery in vain" and thanked the doctor was a classmate who went hiking with him and was "particularly active and healthy."

What a magical story that makes people look forward to it! The next morning, we finally met this amazing person in the "Hydrogen Molecule Experience Area" near the National Taiwan University Hospital.

She was diagnosed with lung cancer

ZYJ, 54, experienced chest discomfort, a dry cough, and shortness of breath in October 2016. On October 27, she underwent a PET-CT scan at Linkou XX Hospital. A 4-cm mass lesion in the right middle lobe was detected, with a Standardized Uptake Value (SUV) of 18.57. The tumor was connected to the pericardium and had metastasized to the mediastinal lymph nodes. A bronchoscopy revealed a tumor obstructing the right middle lobe bronchus. A local biopsy was performed, and pathological examination revealed non-small cell lung cancer. Immunohistochemistry staining also revealed squamous cell carcinoma. Genetic testing revealed no mutations.

Ms. Z first went to the respiratory department, where the doctor told her that a Standardized Uptake Value (SUV) greater than 2.5 indicated a malignant tumor. The SUV value is correlated with the malignancy of the tumor; if it is greater than 10, the tumor is highly malignant. Her tumor's SUVF value was close to 20, indicating a very malignant tumor that had invaded the pericardium and mediastinal lymph nodes, making surgical removal of the tumor difficult. Molecular targeted therapy could have been used, but her tumor was a squamous cell carcinoma, and genetic testing did not find a target. Chemotherapy could be done, but the effect would not be good. She made an appointment with a senior respiratory specialist. After carefully reviewing the various tests, the specialist said, "Do radiotherapy and chemotherapy to try to control the disease." He seemed a little helpless, and then said, "Hydrogen inhalation, maybe it will help."

Linkou Hospital is a renowned institution in Taiwan. Even this specialist was stumped, so who else could she turn to? Ms. Z returned home, feeling a weight of worry and disappointment. She didn't tell her family the truth. She was still young, with elderly parents and young children to support, and she didn't want to leave this world like this.

Friendship between classmates

As the saying goes, friendships last after years of school. When Mr. Lin, who was far away in Shanghai, learned that his old classmate, Ms. Z, had a tumor, he immediately flew back to Taiwan and sent her the hydrogen-oxygen atomizer he was developing. He told Ms. Z, "No matter what treatment the doctor prescribes, follow the experts' advice and start with hydrogen inhalation. It's free and harmless." He presented her with a stack of literature on the cancer-inhibiting effects of hydrogen molecules and displayed three video images on a computer: one showed normal cells, moving in regular patterns and arranged in an orderly fashion; the second showed cancer cells, varying in size, running amok, constantly dividing, and multiplying rapidly; the third also showed cancer cells, but unlike them, they seemed to have calmed down, forming rows, a sign of a return to goodness.

After the 2011 March 11 earthquake in Japan, Mr. Lin accompanied Tzu Chi from Taiwan to provide disaster relief. He observed rescue workers at the Fukuoka nuclear power plant bathing in hydrogen-containing water, claiming it was to eliminate radiation and prevent cancer. Afterward, he visited Professor Shigeo Ohta of Nippon Medical University in Tokyo. In 2007, Ohta published an article in the prestigious journal Nature Medicine, demonstrating that molecular hydrogen is a selective antioxidant with therapeutic effects on many diseases associated with reactive oxygen species. This article captivated the global biomedical community and earned him the title "the founder of molecular hydrogen medicine."

Perhaps it was fate, but Ota was particularly delighted to meet Mr. Lin. He lamented that he had been dreaming of creating a hydrogen generator for years, but realization seemed elusive. Mr. Lin, a mechanical engineer by training, understood his vision and returned to Taiwan. Three months later, he successfully developed a hydrogen-oxygen atomizer that produced hydrogen from water. When he presented the prototype to Professor Ota, this pioneer in hydrogen research stroked the machine, repeatedly exclaiming, "This is the best in the world," while wiping his moistened eyes with a tissue.

Ms. Z inhaled hydrogen for at least four hours daily. After a week, her coughing lessened, her breathing became smoother, and her spirits seemed to improve. A month later, she underwent radiation therapy for a total of 30 sessions, concurrently with chemotherapy. Her home was not far from the hospital, and she rushed home after each treatment to inhale hydrogen. Because hydrogen inhalation is currently limited to civilian use, she didn't tell the ward doctor about it. The doctor constantly praised her, saying she had a strong constitution and, despite the high doses of radiation each time, she hadn't vomited or experienced a decrease in her white blood cell count. She also noticed that her fellow chemotherapy patients in the same room had almost no appetite, some vomited constantly, and constantly needed "leukocyte-boosting injections" (biological products to increase white blood cell counts). She figured it must be the hydrogen! She was grateful to the specialist who suggested hydrogen inhalation and to her old classmate who had sent her the hydrogen-oxygen nebulizer.

The tumor is gone?

Two and a half months later, on January 13, 2017, Ms. Z went to Linkou XX Hospital for a follow-up visit and another PET-CT scan. A few days later, she went to see the results with great trepidation. The doctor reviewed the results, then looked at Ms. Z for several minutes. He paused and asked, "Have you only had chemotherapy?" He asked slowly and carefully.

"Yes." Ms. Z panicked, her heart pounding with anxiety: Could it be that her illness had worsened and she couldn't survive?

"It's almost impossible that there is no tumor in your lungs." The doctor didn't seem to believe his own judgment and asked her to go to the clinical department.

She went to the respiratory medicine and surgery departments. The doctors met and told her they were planning surgery. She asked why surgery was necessary since there was no tumor. The doctors said they didn't believe it, as there was almost no precedent. They needed to remove the tumor and see what was happening. A doctor who appeared to be more senior patted her on the shoulder and said, "You have a very aggressive form of lung cancer. We're worried if we don't have surgery."

"Bai Kai" a knife

On February 23, 2017, Ms. Z underwent a thoracoscopic right lobectomy, which went smoothly. Linkou Hospital is renowned for its thoracoscopic surgery, and Dr. Liu, the aforementioned director, is a renowned thoracoscopic specialist there.

After the operation, the doctor told her: the upper and middle lobes of the right lung were removed, and the lymph nodes were also removed, but no tumor was found. Whether there is really no cancer or not, we have to wait for the pathology report. After all, pathology is the "gold standard".

Perhaps the pathologist was also in a dilemma, as the pathology examination results came out 12 days later (March 7, 2017): no tumor was found.

Linkou xx pathology report (S2017-012×××) dated March 7, 2017: "Tissue received: right upper lobe, two lung tissue sections, sections. Microscopically, foreign body giant cells and reactive organizing pneumonia were observed. No tumor was found."

"I verified the magic of hydrogen'

On the morning of March 6, 2018, Ms. Z appeared particularly happy when she met us. Her expression and demeanor suggested she was in her forties. She described her illness in detail. I asked her, "Do you regret having the surgery for nothing?"

"A little, but I'm so happy because I verified the magic of hydrogen!" She held my hand and continued, "It also verified your book 'Practicing Chinese-Style Cancer Control'. The book talks about 'elimination' and 'transformation' going hand in hand. My treatment is to 'transform' first and then 'elimination'. Inhaling hydrogen is 'transformation'." Ms. Z's words are full of wisdom.

I gave her a book I'd written three years earlier, "Living with Cancer," and signed my name on it. She took the pen and wrote on the title page: "I have put into practice Professor Xu's 'Living with Cancer.'"

Patients are the best teachers. Ms. Z's life-or-death experience illustrates at least two effects of hydrogen on cancer: first, it "transforms" cancer cells, making them more compliant and enhancing the effectiveness of chemotherapy and radiotherapy, as has been demonstrated experimentally; second, it reduces the side effects of chemotherapy and radiotherapy. Ms. Z said she was able to go mountain hiking during her chemotherapy treatments, likely due to the hydrogen.

Hequ News

Xu Kecheng

Commentary by Tang Zhaoyou

This article resonated deeply with me. Three years ago, a relative of mine was diagnosed with non-small cell lung cancer with mediastinal lymph node metastasis. I watched helplessly as he passed away two weeks after being hospitalized. However, this patient's surgery confirmed the complete disappearance of the tumor, a truly incredible feat. The history of modern cancer treatment is one of "eliminating" tumors—a remarkable success, but not complete victory. This is because cancer has been viewed as an invading enemy, prioritizing only "elimination" and neglecting "transformation." This patient may offer some insight into the simultaneous pursuit of both "elimination" and "transformation."

Hydrogen and lung cancer: living again

Worried about Lao Wang

During Labor Day in 2018, I was at home in Shanghai on vacation. Waking up that morning, I suddenly thought of Lao Wang, because a week earlier, he'd said he'd be back at the hospital for a checkup. Oddly enough, I picked up my phone to send him a message, but I got halfway through and stopped myself: What if his condition worsened?

Lao Wang used to be a senior official in my hometown, but that’s secondary. What’s important is that in recent years, because of his lung cancer, on the one hand, I have been very worried, and on the other hand, I have also enjoyed the joy of success.

It was the morning after New Year's Day 2017. Lao Wang, laughing heartily, walked quickly into my office, handed me a lab report and a stack of CT scans, and kept asking, "Is this true? Is this true?"

I saw on the test results that the tumor marker CA153 had dropped to within the normal range, and the original tumor in the left lung was no longer visible on the CT scan. The report stated that "no obvious evidence of tumor was found."

Mr. Wang has been suffering from non-small cell lung cancer for eight years. Initially diagnosed with bone metastasis and an EGFR mutation, he improved after receiving the TK1 inhibitor Tarceva, but developed resistance within a year. He then tried another inhibitor, which also developed resistance soon after. In August 2016, he traveled thousands of miles to our hospital. By then, the tumor in his left upper lung had grown to 8 centimeters. He underwent cryoablation and thoracoscopic surgery, which removed 80% of the tumor. He also received nonspecific immunotherapy for the remaining tumor.

He returned to his hometown to recuperate. Everyone thought he would not survive, but unexpectedly, his tumor disappeared. Is this true? I could hardly believe my eyes for a moment.

Look at the test reports and CT scans he brought, all of which were from Shanghai Chest Hospital. They were not only "real" but also "substantial"! I remember we were all very excited at the time and asked our hospital's photographer to take many photos to share that happy moment.

Developed another cancer

Mr. Wang's lung cancer recurred in 2018. Strangely, the recurring tumor wasn't in the lung, but in the cervical lymph nodes—a form of lymph node metastasis. Lung cancer, especially adenocarcinoma, is characterized by heterogeneity, meaning that the cancer cells contain many different genotypes. Mr. Wang's lymph node metastasis was actually a different type of cancer. The metastasis grew rapidly, initially the size of a soybean, but within a month, it had grown to the size of a walnut. The left side of his neck became red, swollen, shiny, and hot. His neck felt frozen in place by the tumor, making it difficult to move and extremely painful. A bacterial culture was negative, and experimental antibiotics were used without response.

This is a typical inflammatory cancer or cancerous inflammation. In fact, there is a theory that cancer is an unhealed inflammatory wound.

Cancer cells are "traitors" formed when normal cells undergo genetic mutations during replication due to genetic defects or the influence of the microenvironment. The number of cancer cells produced = the number of cell divisions multiplied by the number of mutated genes generated during each division. Inflammation increases organ cell damage, cell division, and mutations, leading to an increase in the formation of cancer cells. Therefore, controlling inflammation can theoretically help control cancer.

Have a heart-to-heart talk again

Old Wang was deeply concerned and wanted to have another heart-to-heart talk with me. It was during this heart-to-heart talk two years earlier that the decision to pursue nonspecific immunotherapy was made, leading to the aforementioned "moment of joy" on January 2, 2017 (see my book, "Practicing Chinese Cancer Control," pp. 125-132).

I went to his bedside and sat down. Lao Wang's eyes welled up, and he clutched my hand tightly, refusing to let go. "Save me! You've already given me more than two extra eight months of life." Before he came to our hospital in 2016, some estimated he had only eight months to live; now he's lived 18.

Wang: "Professor, I still want to live for at least another eight months! You saved me two years ago. Do you have any other good ideas? I don't want chemotherapy anymore."

Xu: "It is recommended to take tissue samples for genetic testing to see if there are any new mutations, and then use targeted drugs if necessary."

Wang: "We've already done it, but no new targets have been found. Targeted drugs have been used for generations, but they haven't been very effective. I heard hydrogen can control cancer. How does that work?"

Xu: "It is being explored and studied all over the world, and is currently used as a means of 'natural recovery' and control."

I introduced the relationship between inflammation and cancer, and between inflammation and free radicals. According to the free radical theory, many carcinogenic factors, including smoking, environmental pollution, chemicals, radiation, chronic infections, and obesity, can trigger the body to produce toxic reactive oxygen free radicals, particularly hydroxyl radicals. Hydroxyl radicals are highly unstable and can react rapidly and indiscriminately with most biological molecules, causing DNA mutations within the cell nucleus, abnormal mitochondrial energy metabolism, and mitochondrial DNA mutations. This, in turn, contributes to the growth and progression of cancer cells, particularly promoting metastasis.

Wang: "Then wouldn't eliminating free radicals help control cancer? I've been taking a lot of health supplements, including large doses of vitamins C and E, as well as antioxidants I bought from abroad."

Xu: “General antioxidants are not necessarily effective. A few years ago, the New England Journal of Medicine published a short paper in which two doctors reported that some antioxidants are not only ineffective against cancer, but can actually promote tumor growth.

Wang: "Really? But the instructions for these health supplements clearly state that they can fight active free radicals.

Xu: "Reactive free radicals are not all bad. Normal cells produce oxidants such as hydrogen peroxide, which are necessary for normal human metabolism. General antioxidants can eliminate these normal oxidative free radicals, interfering with human energy metabolism, especially mitochondrial function, which is obviously harmful."

Wang: "What about hydrogen? I've read a lot of articles saying hydrogen is an antioxidant."

Xu: "Yes. Hydrogen molecules have characteristics that other antioxidants don't have: first, they are highly specific, protecting only against toxic reactive oxygen species, such as hydroxyl radicals, while leaving normal free radicals unaffected. Second, they are highly permeable. Once hydrogen enters the body, it can freely enter the mitochondria and nucleus within cells, and can also pass through the blood-brain barrier, making it particularly effective against brain lesions. The establishment of hydrogen molecular medicine began with Professor Ota of Japan publishing a paper on how hydrogen molecules can alleviate cerebral infarction."

Wang: "Will it be toxic? I've been ill for years and I'm terrified of the side effects of medication."

Xu: "The third characteristic of hydrogen is its high safety. The bacteria in our large intestines produce hydrogen all the time. An American expert determined that the average person produces over 1,200 liters of hydrogen per day after a meal."

Wang: "Oh, I understand. Then when was the earliest paper on hydrogen cancer control published?"

Xu: "In 1975, the first paper on hydrogen cancer control was published in the journal Science, reporting the successful treatment of squamous cell carcinoma of the skin using high-pressure hydrogen."

Start absorbing hydrogen

Perhaps honed by decades of leadership, Lao Wang is extremely cautious about any treatment. For example, he had already purchased a PD-1 inhibitor from abroad, but after reading an article warning that patients with EGFR mutations should use it with caution, he never used it. Although hydrogen is not a drug but a "natural substance," Lao Wang personally visited several cancer patients who were inhaling hydrogen at home. He eventually borrowed a hydrogen-oxygen nebulizer and began inhaling a hydrogen-oxygen mixture at home for at least four hours daily. The mixture contains 66.6% hydrogen and 33.4% oxygen.

“Maybe I’m saved again.”

I finally mustered the courage to text Lao Wang, asking how the tumor in his neck was doing. Two hours later, he called back, repeatedly saying "thank you so much," and then explained his condition: there were three "heads" (metastatic lymph nodes) in his neck, one of which had already subsided, while the other two, which had previously been bleeding, had been gradually disappearing over the past week.

He'd been inhaling hydrogen for over two months. I asked him to keep going, and he readily replied, "Of course, that's the most important thing." He added, "Thank you so much, Professor. Maybe there's hope for me!" His voice was a little hoarse, probably from the metastatic lymph nodes compressing the nerves in his neck. But judging by his laughter and the emotion in his speech, he could definitely survive, and beyond the "eight months" he'd hoped for.

Postscript

More than five months after this article was completed, news suddenly came: "Old Wang's condition has worsened and he is in critical condition." When asked why, the family replied: After using PD-1 inhibitors, "the side effects were extremely severe and it completely defeated him."

Not long ago, The Lancet reported complications of anti-PD-1 therapy. Most patients developed immune inflammation, and 101 cases developed severe myocarditis. The mortality rate was as high as 46%. Among them, the mortality rate of patients using PD-1 inhibitors alone was 36%, and the mortality rate of patients receiving PD-1 inhibitors combined with ipilimumab was as high as 67%.

Why did this complication happen to Lao Wang?

I dug out the photos of him taken in my office, and recalled what I had repeatedly told him over the years: Don't hope for "eradication," just hope to "coexist with cancer"; no matter how big or small the "tumor" is, survival is the bottom line.

He once had concerns about using PD-1, but perhaps the hype surrounding the "miracle drug" finally won him over...

Xu Kecheng

Commentary by Tang Zhaoyou

After reading Professor Xu's article, I noticed another difference between Eastern and Western thinking. Western thinking often proceeds from mechanism to practice. Molecular targeted therapy involves first identifying the relevant molecules, then designing drugs targeting them, and finally conducting practical testing. Eastern thinking often begins with practice, and when practice proves effective, the mechanism is then clarified when conditions permit. Arsenic was effective in treating one type of leukemia, and then the mechanism was determined to be "differentiation induction," meaning a shift from an evil to a good. Acknowledging only the former mindset will disregard numerous proven results. Hydrogen's effectiveness in treating cancer, while the principle behind it was introduced from abroad, has been successfully implemented in China. Combining Eastern and Western thinking is the approach we should adopt.

Hydrogen and lung cancer with bone metastasis: surviving the cold

Ask for help from colleagues

Director Y is a radiologist and director of the Radiology Department at a hospital affiliated with a renowned medical university in China. On May 27, 2018, he called me to say he was diagnosed with lung cancer on November 6, 2017, and underwent surgery, chemotherapy, and radiotherapy. During this time, a single metastasis developed in the 12th thoracic vertebra. He began hydrogen inhalation on April 30, 2018, for six hours daily. He wanted my advice.

Doctors with cancer have even more to consider. In 1986, the McGill Cancer Center in Canada conducted a survey of physicians: "If you were a 60-year-old oncologist diagnosed with non-small cell lung cancer with liver and bone metastases, would you be willing to use chemotherapy?" Reportedly, 81% of the physicians surveyed chose not to use cisplatin. Eleven years later, in 1997, the US National Comprehensive Cancer Network (NCCN) conducted another identical survey, and the percentage of physicians willing to use cisplatin increased from 19% to 64.5%, while the percentage of nurses was 67%.

Clearly, Director Y was a very "professional" doctor. He received all the necessary and possible treatments, including cisplatin chemotherapy. However, Director Y's problem was the development of bone metastases, which occurred during chemotherapy. This "harsh" treatment likely induced genomic disruption in the cancer cells, creating new genomes that resist chemotherapy, ultimately turning them into drug-resistant "outliers," or causing some previously slow-growing cancers to become more aggressive. Further chemotherapy is generally ineffective.

I could tell from the phone call that Director Y was very anxious. I encouraged him not to despair. If the main road was blocked, why not try another route?

Metastatic progression

Director Y sent me a WeChat message to introduce his treatment process (see Figure 1).

In early November 2017, a physical examination revealed a nodule approximately 2.5 cm in diameter in the inner segment of the right middle lobe. A complete right middle lobectomy was performed. Pathology revealed poorly differentiated lymphoepithelioid carcinoma (a subtype of large cell lung cancer). Genetic testing revealed no mutations other than TP53, and no targeted drugs were available. The disease stage was IC. Circulating tumor cell (CTC) monitoring revealed five single cells, with no invasive tumor cell clusters or stromal cells. A CT scan revealed a 10 x 6 mm nodule at the left anterior margin of the 12th thoracic vertebra, which was indeterminate preoperatively. Chemotherapy began three weeks after surgery with the TP regimen (Taxol plus Nedaplatin) for two cycles.

CT scan reexamination revealed that the lesion at the 12th thoracic vertebra had increased to 17×9 mm and was significantly enhanced. It was considered to be an oligometastatic lesion, so two courses of pemetrexed + neroxazolidinone chemotherapy were used, and 18 TOMO radiotherapy sessions, about 45 Gy, were used. Because the white blood cell count dropped to 1800 and the platelet count dropped to a minimum of 49,000, the white blood cell count was still only 2400 after more than a month of "white blood cell injection", so chemotherapy was stopped.

In mid-March 2018, one month after the end of radiotherapy, a follow-up MRI enhanced scan showed no change in the lesion at the 12th thoracic vertebra. A follow-up MRI scan in mid-April showed the lesion was slightly smaller than in mid-March, but still showed moderate enhancement, indicating that the metastasis had not been controlled.

Director Y said that after reading my article on follow-up hydrogen therapy in Taiwan, he managed to obtain a hydrogen-oxygen nebulizer. Since April 30th, he has been inhaling hydrogen for six hours daily. He said, "I'm happy that my appetite has increased after inhaling hydrogen."

I advised him to persist in hydrogen inhalation, paying attention to his inhalation technique to ensure sufficient hydrogen enters his body. I also recommended that he read a 1975 experimental study published in Science magazine on the successful treatment of skin cancer with hydrogen. I also shared with him our upcoming animal model and cellular research results, both of which show that high-concentration hydrogen has a stronger inhibitory effect on cancer than low-concentration hydrogen. Within a certain range, the inhibitory effect is directly proportional to the cumulative hydrogen dose.

Before hydrogen absorption

Director Y sent me photos of the metastasis at the 12th thoracic vertebra before hydrogen inhalation via WeChat. These were PET-CT scans performed in early November 2017 (before surgery and chemoradiotherapy), and MRI (plain scan + enhanced scan) and bone scans performed at the end of December. They showed significant enhancement of the left anterior lesion at the 12th thoracic vertebra; the bone scan also showed significant isotope deposition (after two rounds of TP chemotherapy). The tumor marker CA125 was low before surgery, but it rose one month after surgery, reaching a peak of 200 units, and remained at 45 units during chemotherapy.

After 23 days of hydrogen inhalation

Director Y informed me via WeChat: Bone metastasis is still present on PET-CT and CA125 has not decreased, remaining at 45 units.

After 50 days of hydrogen absorption

On July 2, 2018, Director Y sent me a WeChat message and told me happily that the CA125 had dropped to 24 units (normal value is less than 35 units), and the MRI enhanced scan showed that the lesion of the thoracic vertebra 12 had shrunk and the enhancement was slightly reduced.

After 65 days of hydrogen absorption

Two weeks later, Director Y sent another PET-CT scan, which showed calcification in the lesion area. The CA125 level had further dropped to 18 units, completely returning to normal.

Luck and heartbreak

Director Y suffers from a poorly differentiated lymphoepithelioid carcinoma, a highly aggressive form of the disease with no targetable targets and limited therapeutic agents. The oligometastasis at the 12th thoracic vertebra likely existed before surgery and was clearly insensitive to chemotherapy, leading to increased metastasis during chemotherapy. Despite receiving radiotherapy, the disease remained uncontrolled. After 50 days of hydrogen inhalation, the tumor marker CA125 returned to normal, and the metastatic lesions calcified. This is a remarkable result and a truly fortunate event.

Judging from the relationship between hydrogen absorption, transfer and CA125, the contribution of hydrogen can be confirmed.

But despite his fate, Director Y couldn't be happy. He was deeply troubled by fatigue. He wrote on WeChat that he was extremely tired, and the unbearable fatigue made it difficult for him to sleep or eat, and even made walking difficult. He anxiously hoped that I could provide "treatment."

Director Y's WeChat messages also made me anxious. That day, I sat in my office, lost in thought, and the image of Director Y's exhausted face suddenly appeared before my eyes.

What can I do for him?

Suddenly, I saw a book on the table called "Random Thoughts." It was a gift from a Beijing writer suffering from pancreatic cancer. I flipped open a page and a short article titled "Heartbeat" jumped out at me. One paragraph read:

Life's unexpected events come one after another, and even after the rain, the traces remain. After all, a violent storm will always break something, and the tyranny of a rainstorm will always leave some scars. Thus, sadness is destined to remain in my heart, like an indelible thorn, deeply embedded in my heart...

Cancer metastasis is a "storm" for anyone, let alone an experienced expert who has been treating similar diseases for decades! Director Y has endured the tyranny of the "storm" and there must be a thorn in his heart that is difficult to remove and an indelible "heartbeat".

He told me that he was under too much psychological pressure and might be suffering from depression.

Fatigue, especially cancer-related fatigue, is primarily related to an increase in toxic free radicals and inflammation in the body. Recent research suggests that depression is not only a psychological disorder but is also accompanied by an increase in inflammatory factors and inflammatory responses. Hydrogen can eliminate toxic free radicals, provide antioxidant and anti-inflammatory properties, and is theoretically effective in alleviating fatigue and depression. Animal studies have shown that inhaling hydrogen can significantly alleviate stress-induced depression and anxiety-like behaviors in mice.

It's likely that the "heart palpitations" exacerbate fatigue, and fatigue promotes "heart tribulations." Hydrogen inhalation seems to kill two birds with one stone. I encouraged him to continue inhaling hydrogen and persevere, as hydrogen has a cumulative dose effect.

After 7 months of hydrogen inhalation

On November 20, 2018, Director Y sent me a WeChat message, telling me that he now practices Guolin Qigong in the morning, swims 1,000 meters in the afternoon, and inhales hydrogen in the evening. He is feeling much better than before, and his appetite has returned to pre-illness levels. The metastasis to chest X-ray remains stable, and tumor markers remain normal.

"The sky is cold and its color is blue; the north wind rustles the withered mulberry trees" (Meng Jiao's "Song of Bitter Cold"), I hope Director Y has gotten through the cold and "good rain knows when to fall, it comes in spring" (Du Fu's "Joyful Rain on a Spring Night"), and is now enjoying the spring of life.

Xu Kecheng

Commentary by Tang Zhaoyou

This radiologist developed metastasis after lung cancer surgery, and chemotherapy was ineffective. After 50 days of hydrogen inhalation, his tumor markers returned to normal, and the bone metastases calcified. The timing suggests hydrogen has definitely been effective, suggesting its potential as an adjuvant therapy. Since Virchow proposed the cellular origin of cancer in 1863, all efforts have been directed toward "eliminating" cancer cells. However, cancer differs from other diseases.

Cancer is not an invasion by an external enemy, but rather an internal disturbance caused by an imbalance between the internal and external environment. Therefore, both eradication and transformation are necessary (cancer control, not cancer treatment). These two approaches complement each other. Cancer is a chronic disease, and the fight against cancer is a protracted battle of both eradication and transformation. Hydrogen therapy is not a traditional "elimination" approach to cancer treatment; it should be considered a "transformation" approach, and therefore requires sustained attention.

Hydrogen and lung cancer brain metastasis: "Ten times better"

Fly to Xinjiang covered in snow

On the morning of September 5, 2018, my secretary, Tianyu, and I boarded a China Southern Airlines flight to Urumqi. As the plane ascended over Xinjiang, the pristine blue sky shone brightly. Outside, white clouds rolled in waves, surging and surging in a patchwork of rhythmic movements. In the distance, snow-capped mountains loomed. This wonderland, sculpted by nature's uncanny craftsmanship, is enchanting and captivating. This vast and mysterious land harbors the profound Kunlun Loess Civilization.

I had been looking forward to this trip to Xinjiang. Six months ago, I received a call from a friend in Shanghai, asking me to check on Ms. Chen, who was hospitalized at my hospital. I went to a ward in Ward 3. Ms. Chen lay huddled in her bed, gasping for breath. Her mother was by her side. Upon seeing me, the elderly woman burst into tears and said, "You are our last hope."

Ms. Chen's speech was slurred and her vision was blurry. Sometimes she saw two objects, a condition called double vision. I helped her get up, but she had trouble standing. Her mother said, "The brain metastasis is too extensive."

From the airport to the hospital, it was your hospital staff who pushed her in a wheelchair."

Ms. Chen's lung cancer

I reviewed her medical history. In late November 2015, she visited a hospital in Xinjiang due to dizziness and unsteadiness. CT and MRI scans revealed a space-occupying lesion in the left cerebellum. On November 27, 2015, she underwent brain tumor resection. Postoperative pathology revealed metastatic lung adenocarcinoma, and genetic testing revealed a positive EGFR19 mutation.

From December 2015 to January 2016, he underwent whole-brain radiotherapy for a total of 18 sessions. On April 20, 2016, a lung CT scan revealed a space-occupying lesion in the right upper lobe. He took Iressa (gefitinib tablets) until his disease progressed in September 2017. He then received combination therapy with pemetrexed and erlotinib. Due to grade III myelosuppression, he discontinued chemotherapy on October 13, 2017, and continued oral erlotinib targeted therapy.

On March 6, 2018, a head MRI revealed an abnormally enhancing nodule at the margin of the residual cavity in the left cerebellar hemisphere. There was also significant nodular enhancement at the margin of the original lesion in the left frontal and parietal lobes, suggesting progression and the development of new metastases. A CT scan revealed an enlarged lesion in the right upper lobe, a nodule in the basal segment of the right lower lobe, and multiple lymph nodes in the mediastinum and hilum, some of which were enlarged compared to before. A metastatic nodule in the left adrenal gland was also enlarged compared to before. The patient was switched to oral icotinib hydrochloride, which he discontinued voluntarily after 20 days due to side effects.

She was admitted to our hospital in April 2018 with difficulty breathing, chest tightness, palpitations, incoherent speech, and difficulty walking. Her admission diagnosis was cT2aN2M1b stage IV right upper lobe adenocarcinoma with brain metastasis. She also had cerebral edema. A week later, after receiving dehydration treatment, her speech became clearer.

She received no special treatment, and when she was discharged, I recommended that she continue taking AZD9291 orally and inhaling hydrogen for at least six hours daily. I asked her to keep us informed of her condition and promised her that I would visit her in Xinjiang in a few months.

In the past two months, she sent WeChat messages to my secretary Tianyu every few days, saying that she was “much better” and hoped that we would go to Xinjiang. She also said that “the grapes are ripe, so fragrant and sweet, come and eat some grapes.”

"I've gotten better, haven't I?

As the plane approached Urumqi, I seemed to smell the sweet, juicy aroma of grapes, but a sense of unease welled up in my head: What if Ms. Chen's condition wasn't "much better" as she'd claimed, but had worsened? How would I cope?

After getting off the plane, a friend picked us up and drove directly to Ms. Chen's home. The wide, flat streets were bustling with cars of all shapes and sizes, flowing like a colorful river. The golden fallen leaves lining the road adorned the streetscape with their fleeting beauty. An hour later, the car arrived at Ms. Chen's apartment complex. Ms. Chen's mother was waiting for us outside a building. Following her, we hurried up to the third floor. The door was open, and Ms. Chen stood on the threshold. Seeing the rain, we embraced each other tightly.

This was a two-bedroom, two-living-room apartment. On the living room coffee table lay bunches of crystal-clear grapes, resembling agates. Ms. Chen and her mother pulled us to the sofa and eagerly handed us the grapes. I couldn't help but pick one and put it in my mouth, savoring it carefully. The delicious juice was a tart and sweet tang, and the unique aroma of grapes filled my nostrils and invigorated my soul.

I studied Ms. Chen. She looked at me, smiled, and said, "How are you? Doctor Xu, am I feeling better?" Then she began to walk around the room. I approached, took her hands, and tested her strength: she was quite strong! I also performed the finger-push test: her coordination was basically normal. I also checked her eye movements and performed the cheek-puff test, but found no corresponding neurological abnormalities.

I reviewed her five CT and MRI scans from October 2015 to August 2018. On August 27, 2018, the MRI showed a significant reduction in the brain metastasis, and the CT scan showed the right lung space-occupying lesion was essentially stable.

"The 9291 I'm taking is a 'raw material' I bought online, and I'm not sure if it works," Ms. Chen said. "Regular medicine is too expensive."

She told us that she actually started inhaling hydrogen in October 2017, using a hydrogen-oxygen nebulizer. Initially, she didn't do it every day, but she really started using it after being discharged from our hospital in April 2018. She continues to inhale for 6-8 hours daily, both during the day and before bed. "I often fall asleep after just a few minutes," she said. Since starting hydrogen inhalation, she's never had insomnia, whereas she used to suffer from frequent headaches and difficulty falling asleep.

Brain is a 'safe haven' for lung cancer

Approximately half of patients with non-small cell lung cancer will develop brain metastases. Once brain metastases develop, patients experience a significant decline in quality of life, often accompanied by neurological and cognitive impairment. The prognosis is poor, with a median survival of three to six months. Traditional treatment includes surgery and radiotherapy. Because a layer of endothelial cells separates the blood and brain tissue, forming a tight junction structure known as the blood-brain barrier, this barrier prevents the free passage of larger molecules. Therefore, chemotherapy drugs in the bloodstream, whether administered orally or intravenously, have difficulty penetrating this barrier, preventing them from entering the brain parenchyma and effectively targeting metastatic cancer cells within the brain. Consequently, the brain is often referred to as a "safe haven" for cancer cells to avoid chemotherapy.

Although molecularly targeted EGFR-TK inhibitors (TKIs) have prolonged survival in patients with non-small cell lung cancer (NSCLC), their effectiveness is limited in those with brain metastases. Studies have measured erlotinib and its metabolite concentrations in the cerebrospinal fluid of patients with NSCLC and brain metastases and found them to be only 5.1% and 5.8% of plasma concentrations, respectively. Gefitinib has an even lower penetration rate, with CSF concentrations at only 1.1% to 1.3% of plasma concentrations (J Thorac Oncol, 2015; Mol Cancer. 2018; 17: 38).

AZD9291 (osimertinib, Tagrisso) is a third-generation TK inhibitor, and literature reports indicate that it can cross the blood-brain barrier (Medicine [Baltimore], 2017). However, its actual effectiveness is limited.

Ms. Chen is full of confidence

Ms. Chen's treatment was standard and comprehensive. She first underwent brain metastasis surgery and radiotherapy, then received the targeted drug erlotinib for 17 months. After developing resistance to gefitinib, she took icotinib for 6 months. However, due to intolerance to its adverse effects, she stopped taking it after only 20 days. Her condition progressed, and she began taking "9291" five months ago.

Ms. Chen has been suffering from lung cancer for three years. She is very satisfied and said to us, "Thank you for coming all the way to see me. I am getting better and better. I am very happy and have the confidence to continue with treatment." (See Figure 5)

The median duration of response for EGFR-TKI therapy is 10-14 months. Ms. Chen achieved a 23-month response after taking erlotinib and gefitinib, which is consistent with general guidelines. Furthermore, these drugs have difficulty crossing the blood-brain barrier, so the progression of her brain metastases was predictable. She later received "9291," a non-standard medication, but its potential therapeutic effect on lung tumors, particularly brain metastases, cannot be ruled out.

Was the improvement in Ms. Chen's brain metastasis due to AZD9291 or hydrogen inhalation?

As the saying goes, long illness makes a good doctor. I asked Ms. Chen to evaluate her treatment. She said, "The hydrogen is effective. At least now I can eat, sleep well, and have strength." She stretched out her hand and compared it with mine.

Since I started my "Hydrogen Journey" in 2017, I have sincerely hoped to obtain "positive" results, and I am always happy for "positive" results. However, the foundation of medicine is science. As an honest doctor, I also hope to obtain "negative" results, that is, the results show that hydrogen is "ineffective".

It is difficult to determine whether hydrogen has a beneficial effect on Ms. Chen based on the existing data alone, but given its high safety, the use of hydrogen as an auxiliary measure is not without benefits.

One of the greatest characteristics of hydrogen is its selective neutralization of toxic reactive oxygen free radicals, which can promote the formation and progression of cancer. Hydrogen is also highly diffusible and can penetrate the blood-brain barrier. Therefore, for patients like Ms. Chen, hydrogen has at least the following benefits:

Function

(1) Improve brain damage. As early as 2007, Japanese researchers Shigeo Ohta et al. discovered that hydrogen can improve cerebral ischemic reperfusion injury and reduce cerebral infarction. In 2017, Ohta's team published an article proving that hydrogen has a protective effect on brain damage caused by trauma, bleeding, inflammation, radiation, and tumors.

(2) It has an inhibitory effect on metastatic cancer cells. Researchers from Chongqing Medical University found that hydrogen can downregulate Akt phosphorylation, inhibit the PI3K pathway, enhance the effect of PI3K specific inhibitors on the proliferation of non-small cell lung cancer cells, and promote cancer cell apoptosis (Mol Med Rep, 2018). Scholars from Hebei Medical University also found that hydrogen can inhibit the growth, proliferation, invasiveness, and migration of non-small cell lung cancer cells through animal models and cell culture (Biomed Pharmather, 2018).

3. Improve immune function. CD8+ cytotoxic T lymphocytes have the ability to kill tumors and play a crucial role in anti-tumor immunity. However, increased expression of the inhibitory receptor PD-1 on T cell surfaces suppresses T cell anti-tumor activity, leading to T cell exhaustion. In cancer patients, the number of T cells expressing PD-1 increases. Akagi Junji of Noda, Japan, recently measured the number of CD8+ T cells/PD-1-positive cells in the peripheral blood of 55 patients with stage IV colorectal cancer and found that 39 of them had increased numbers of these cells. After hydrogen treatment, these numbers decreased in 35 of these patients, suggesting that hydrogen can "rescue" exhausted T cells and enhance their immune function (Oncol Report, 2018).

This is a very gratifying research result. We have already found in our experimental studies that hydrogen can inhibit PD-1 (unpublished data).

(4) Improve systemic symptoms, including increased appetite, and the elimination of insomnia and fatigue. Korean researchers found in animal experiments that animals that ingested hydrogen had enhanced swimming endurance and were less prone to fatigue (Biomed Res, 2018). Data from American researchers show that hydrogen can effectively reduce the various adverse reactions caused by radiotherapy and chemotherapy in patients (International J Clin Med, 2016).

Postscript

Nearly two months after I finished writing this article, I received a WeChat message from Ms. Chen, forwarded by Mr. Lin in Shanghai: "My complexion has been getting better and better recently. My face is rosy and rosy. My colleagues think I look no different from a normal person. They say my complexion is at least ten times better than in the first video."

Tsui Hark-cheng and Lu Tianyu

Commentary by Tang Zhaoyou

Reading this brings back a lot of thoughts. My wife had HER2-positive breast cancer with axillary lymph node metastasis. She didn't receive chemotherapy or radiotherapy after surgery, and she stopped using Herceptin midway due to cardiotoxicity (which later led to a cerebral infarction). She persisted in swimming and oxygen therapy after surgery, and died 11 years later without recurrence. I wouldn't rule out a role for Herceptin (the literature suggests half-dose is ineffective), but swimming and oxygen therapy are equally difficult to rule out. I also can't rule out a role for AZD9291 in this patient's improvement, but with such a significant improvement, I can't rule out a role for hydrogen inhalation either. Cancer is a chronic disease involving multiple genes, so a long-term, comprehensive approach is essential. Combining "elimination" therapy with "transformation" therapies (such as hydrogen inhalation) may have a complementary effect. As Mao Zedong said, "In a long and brutal war, guerrilla warfare will demonstrate its great power."

Hydrogen and lung cancer with brain metastasis:

Farewell to Suffering

Fly to Dongying

On July 20, 2018, my secretary Xiao Lu and I flew from Guangzhou to Jinan, and from there to Dongying.

Few people know the city of Dongying, but everyone knows the Shengli Oilfield, a boomtown that emerged with the oil gushing out. In recent years, a prime-time CCTV advertisement, "Where the Yellow River meets the sea, magnificent wetlands," promoted Dongying.

The Earth's climate has indeed changed. Summers in China seem to get hotter the further north you go. As we exited Jinan Airport, a wave of heat washed over us. Lao Shao, who had come all the way from Dongying, greeted us loudly, helped us with our luggage, and led us to the parking lot. As soon as we got in the car, Lao Shao couldn't wait to tell me: Sister Wang's cotton shop is open again.

I'm here at the invitation of the Dongying Medical Association and the Dongying Cancer Hospital to present a talk on "Practicing Chinese Cancer Control." But I'm particularly interested in meeting Sister Wang. I've been worried about her condition: Are her brain metastases under control? Has the enlarged lymph node above her left clavicle disappeared?

I clearly remember the first time I met her at the end of March 2018. It was at a medical center near Zhongguancun in Beijing. Sister Wang, accompanied by her husband, came to consult me. Her first question was, "How many months do I have left to live?"

Miraculous Survival

On the morning of the second day after arriving in Dongying, just after breakfast, Mr. and Mrs. Shao drove to the hotel and took us to Dongcheng.

Dongying's mornings are a scene of tranquil beauty. The straight avenues and the distinctive shade of ginkgo trees captivate the imagination of first-time visitors. The ginkgo trees sway gracefully along the roadside, while morning exercisers stroll or jog. The weather forecast predicts an impending typhoon, and the air is exceptionally fresh, with a hint of coolness. Wisps of soft mist slowly drift away.

After a 20-minute drive, we arrived at a shop facing the main street. Sister Wang was already there, welcoming us at the door. She helped me open it and then, taking me in, we walked quickly inside. Inside, the tables were piled high with various cotton fabrics, and the walls were covered in curtains of varying sizes. Sister Wang told me that she had reopened her shop after recovering in the past few months. I asked her how business was going, and she smiled and said, "For some reason, business is much better than before I got sick."

Old Shao smiled and said, "Dongying is a small place, and we often see each other. Now that Sister Wang's cotton shop has reopened, people come to buy things, partly to help her, and partly to see this miraculous survivor."

I looked at Sister Wang. Her complexion was rosy and she looked much plumper than when I met her a few months ago in Beijing. I asked if she had a cough or a headache, and then checked her left supraclavicular lymph nodes. She said, "All the symptoms you mentioned are gone." She smiled and pointed to a sewing machine in the room. She explained that she was busy from morning till night and had no time to think about her illness. It was only because of my visit that she had gone to the hospital for a follow-up checkup.

I reviewed the hospital's CT and MRI reports, which showed significant improvement compared to March. The X-rays showed that the lung tumor, hilar lymph nodes, and brain metastases were still present, but had indeed shrunk.

I held Sister Wang's hand tightly and said, "Congratulations! Your experience and results have given me great support." I was talking about the support for the concept of "coexisting with cancer" that I proposed.

Sister Wang's eyes welled up as she said, "A year ago, when I was in the ICU, the doctor said I only had a few dozen days to live. My husband prepared my burial clothes." Pointing at the elderly couple, she said, "Without them, I would have died long ago. It was they who allowed me to start hydrogen inhalation on June 6, 2017."

The elderly couple and Sister Wang were middle school classmates. Mrs. Shao said, "At that time, seeing her unable to eat or walk, and constantly eating due to a severe headache, our hearts ached." Knowing there was no better solution, they borrowed a hydrogen-oxygen nebulizer from a friend in Shanghai and sent it to Sister Wang's home, where she had to inhale it for at least six hours a day.

Lao Shao is a hydrogen enthusiast. Originally a chemical engineer, he's become obsessed with it in recent years and has applied for five patents related to hydrogen applications. He once showed me a photo of a pair of daffodils. The one on the left is short and flowerless, while the one on the right is twice as tall, with dazzling, vibrant buds. It turns out the one on the left was watered with tap water, while the one on the right was watered with hydrogen-rich water.

I asked Sister Wang: "Aren't you taking crizotinib?" Her ALK is positive, and crizotinib should be a specific drug.

Sister Wang said, "I started taking crizotinib in May 2017. A month later, my cough improved, but my headaches worsened. I was diagnosed with a brain tumor hemorrhage. That was the most dangerous time since I became ill. The doctor later told me that crizotinib is ineffective for brain metastases." She pulled out a pill bottle with the label "Crizotinib" and "270mg x 60" handwritten in pen. There was no batch number, place of origin, or production date. Sister Wang said it was a "raw material" from the black market. She said somewhat embarrassedly, "I have no money, so I can only take this medicine. I don't know if it's real or fake."

Lao Shao told us: Three months after inhaling hydrogen, on September 6, 2017, Ms. Wang underwent a follow-up CT scan. The results showed that the lung cancer and metastatic lymph nodes had shrunk, and the previous right pleural effusion and pericardial effusion had disappeared. The only disturbing thing was that a new brain metastasis had appeared. Lao Shao and his team's only solution at the time was to ask her to extend her hydrogen inhalation time. "She inhaled hydrogen for more than 10 hours a day. There may be a barrier between her brain and the outside world, so it may take longer for the hydrogen to enter the brain," Lao Shao said with a smile. "I'm not a doctor, so please don't laugh if I'm wrong."

"You make sense. There is a natural barrier between the brain and the blood, called the blood-brain barrier. The reason why crizotinib is ineffective for brain metastases is because it cannot penetrate the blood-brain barrier. Hydrogen molecules are small, so they may be able to pass through this barrier." I explained.

"Then what do you think caused the turn for the better in your condition?" I asked Sister Wang, trying to make sense of her complicated treatment process.

"It was hydrogen, hydrogen, it was definitely hydrogen, without a doubt." Sister Wang said firmly, with gratitude, "After a week of hydrogen inhalation, I was able to eat, and after two weeks I could stand up and go shopping, and my headaches were relieved.

The pain of treatment

For several years, 47-year-old Wang has run a cotton shop, selling and processing curtains. She's both the owner and an employee, earning only a few thousand yuan a month. Her husband works in logistics, but also doesn't make much. They have two children, both in school, and their life is simple, yet warm and harmonious.

In September 2015, Ms. Wang suddenly developed a dry cough that became increasingly severe. On September 21, she went to Dongying Hospital for a checkup, first undergoing a chest X-ray and then a CT scan. After reviewing her medical records and CT scans, the radiologist referred her to the oncology department.

Oncology? She panicked, carefully examining the report: right lung cancer with metastasis to the hilar, mediastinal, and left supraclavicular lymph nodes, right lower lung carcinoma lymphangitis, and abnormally enhancing nodules in the right occipital lobe. She was truly panicked, feeling a sense of impending disaster, tears streaming down her face.

She was hospitalized for a bronchoscopy and a biopsy, which revealed adenocarcinoma. Chemotherapy began on September 29th. Three weeks later, her husband returned from out of town and took her by train to Beijing the next day. After several days of waiting, she was finally admitted to the Cancer Hospital of the Chinese Academy of Medical Sciences.

A few days later, she continued chemotherapy. From October 21, 2015, to February 8, 2018, she began with a two-drug combination, then continued with a single drug, then switched to another two-drug combination, and then continued with a single drug, for a total of 17 months. She then underwent radiotherapy, undergoing 32 chemotherapy sessions over 48 days. A CT scan eight months after chemotherapy showed "stability," but another CT scan two months later showed "significant progression." A follow-up CT scan and MRI five months later revealed "progression" combined with "cerebral hemorrhage"...

I looked at the medical history summary provided by the People's Hospital here, and the list is as follows:

Sister Wang said that on July 7, 2016, she saw the CT review results and the doctor told her that she was "stable". She was so happy. Although all her hair fell out and vomiting after chemotherapy made her feel miserable, the doctor said that "stable" meant success, and she seemed to see hope.

"How could it progress so quickly?" Sister Wang was referring to the CT scan on September 7, 2016, two months later, which showed "obvious progression." "I went through so much hardship with chemotherapy, but it still progressed in the end. I'm so sad."

Change lanes

Ms. Wang's question is a common one. According to literature, for patients with advanced lung cancer like her, the median survival is no more than one year, and the only treatment options are chemotherapy and radiotherapy. The treatments she received were all standard and in line with guidelines. While these treatments can prolong median survival, the final outcome is still progression. Therefore, median survival is also called survival to progression. Ms. Wang's "stability" after chemotherapy puts her in the survival to progression stage. From the start of chemotherapy in September 2015 to her progression in May 2017, she lived for 18 months, a remarkable achievement.

Fortunately, her ALP was positive. ALP stands for anaplastic lymphoma kinase. Due to a chromosomal inversion, a gene called epidermal microtubule-associated protein 4 (EML4) rearranges with the ALK gene (EML4-ALK), contributing to the development and progression of lung cancer. This condition primarily occurs in non-small cell lung cancer, with an incidence of 3% to 5%. People with this rearranged gene are prone to brain metastases, and Ms. Wang had brain metastases when she became ill. Crizotinib is a targeted drug for ALP-positive lung cancer, with an efficacy rate of 40% to 50%, extending median survival to 12 months. However, due to its difficulty crossing the blood-brain barrier, it has little effect on brain metastases. At the June 2018 ASCO Annual Meeting, it was reported that alectinib, a third-generation ALP-targeted drug that can cross the blood-brain barrier, is currently undergoing a global multicenter Phase 3 clinical trial. However, for Ms. Wang, this is currently out of reach.

In order to allow patients like Sister Wang to survive for a long time and live a good life, the treatment must "change lanes" and change the thinking: it does not depend on whether the tumor disappears, but on the overall health of the patient, that is, "coexisting with cancer."

Academician Tang Zhaoyou proposed the "Chinese-style cancer control," which calls for both "elimination" and "transformation" of cancer. The treatments Ms. Wang received were all aimed at "elimination," which was effective, but limited. Her survival and her current life as a normal person are due to "transformation." Hydrogen inhalation is a form of "transformation." Hydrogen molecules selectively combat and eliminate toxic free radicals (reactive oxygen species), transforming cancer cells, the microenvironment, and the entire body. Hydrogen allows her to "coexist with cancer."

Conclusion

Sister Wang's shop reopened, bidding farewell to hardship. That evening, the day I met Sister Wang, I stood on the hotel's top-floor corridor. White clouds drifted across the blue sky. I looked toward the Yellow River, the mother river of the Chinese nation, as it radiated the splendor of thousands of years of traditional Chinese culture.

"Chinese-style cancer control" is rich in Chinese elements and embodies Chinese philosophy. Hydrogen molecule "transformation" is a key strategy and means of implementing "Chinese-style cancer control," offering a "change of approach" for treating the most difficult and challenging patients.

“If you want to see a thousand miles away, you must climb to a higher level…” Success belongs to the wise and brave who have the courage to innovate and climb.

Xu Kecheng

Commentary by Tang Zhaoyou

No one would dispute the statement that "Practice is the sole criterion for testing truth," and the notion that "necessity often lies in chance" is equally understandable. However, when faced with specific problems, Western-trained doctors (including me) often question whether there is evidence-based medicine, thus preventing many promising innovations from being realized. Scientific progress is often the result of continuous development based on the work of predecessors. For over a century, the "elimination strategy" for cancer has yielded significant progress, but not complete victory. These cases, which have achieved unexpected results after "renovation," deserve attention and study.

Hydrogen and liver cancer: unexpected

Mr. Zeng came to Guangzhou

Mr. Zeng Congxian is a resident of Taiwan. I invited him to Guangzhou for a check-up because I think that if his liver cancer has really been "cured" as he said, it would prove that the "Chinese-style cancer control" view is correct.

He flew from Taipei to Guangzhou on March 22, 2018. That afternoon, the Yangcheng Evening News Publishing House held a press conference for my new book, "Practicing Chinese-Style Cancer Control." It was well-attended, and Academician Tang Zhaoyou traveled all the way from Shanghai to give a lecture on "Chinese-Style Cancer Control." I had hoped Mr. Zeng would attend Academician Tang's lecture, as he had been in Taipei for several months practicing hydrogen inhalation. Academician Tang advocated that the main strategy for Chinese-Style cancer control be "elimination" plus "transformation," with hydrogen inhalation potentially serving as the "transformation." However, the flight was delayed that day, and Mr. Zeng missed the opportunity, a fact he expressed deep regret for not being able to make. Accompanying him were Taiwanese entrepreneur Mr. Lin and Mr. Fu Daren, a renowned Taiwanese host. Fu Daren had pancreatic cancer and had been planning to seek euthanasia in Switzerland. Mr. Lin and I urged him to abandon the idea and instead invited him to our hospital for treatment.

Mr. Zeng's trip to Guangzhou wasn't easy. He said it was his first time stepping outside the "island gate." Seeing the size and beauty of Baiyun Airport and Guangzhou's stunning skyscrapers, he said, "If it weren't for your invitation, how could a country boy like me have come here to broaden my horizons?"

Visit Taoyuan, Taiwan

March 7, 2018, was our "Hydrogen" team's last day in Taipei during our visit to Taiwan. We had originally planned to go shopping in the afternoon, as several of us were visiting Taiwan for the first time. However, we heard about a liver cancer patient whose tumor, once large, was now almost completely gone, and we were inspired to visit. Our host, Mr. Lin, said it was a small, far-flung place and asked us not to overwork it. We were eager to see how ordinary Taiwanese people lived, so we said, "Please let the driver take the trouble." We then headed straight for Zhongli City, Taoyuan County, 50 kilometers from Taipei, a typical multi-ethnic area in Taiwan.

Perhaps the weather was about to change, as the afternoon was hot and muggy, with occasional drizzles. After driving for over an hour, the car stopped in front of a shop on a side street. Mr. Zeng came up to us, shook our hands, and greeted us. Inside, he invited us to sit at a simple square table. Mr. Zeng had already set out the teacups, and the kettle was boiling on the electric stove. The tea was the famous Taiwanese high mountain tea. He poured us tea, following the same tea-making rituals as in Guangdong. I said, "It feels like I'm back in Guangdong." Mr. Lin smiled and said, "Descendants of the Dragon, we're one family on both sides of the Taiwan Strait."

It's a two-story townhouse, about 50 square meters, facing the street. Inside, there are piles of wood planks and several tool benches covered with various woodworking tools. Mr. Zeng told us that he used to run a sofa shop, but in recent years he's specialized in advertising and decorative signs. Business has been slow, so even when he's sick and hospitalized, he'd sneak back home to do some work.

Found a huge liver cancer

Mr. Zeng's medical history was uncomplicated. In October 2016, he experienced pain in his right upper abdomen and went to Linkou Hospital for an examination, where he was diagnosed with liver cancer. The tumor in his liver was 14 centimeters in diameter, with a portal vein thrombus. He was treated with chemotherapy, administered intravenously weekly, and underwent three hepatic artery embolization procedures. A few months ago, a doctor confirmed that the tumor was very small and no treatment was necessary.

"Are there any other treatments?" we asked simultaneously. Dr. Wang from Tongji University widened his eyes in amazement, smiled knowingly at me, and added, "Is it really that magical?

Mr. Zeng retrieved his medical records from the XX Hospital. Liver function tests revealed slightly elevated transaminases and alkaline phosphatase, while albumin and bilirubin were within normal ranges. Hepatitis B virus infection markers were positive. Alpha-fetoprotein, a key marker for hepatocellular carcinoma, was not elevated, which is not surprising; 30% of patients experience false negative results. Most importantly, the liver biopsy showed hepatocellular carcinoma. Therefore, the diagnosis was unquestionable.

"Oh, I inhale hydrogen every day." Mr. Zeng pointed at Mr. Lin and said, "Brother Lin helped me. Thank you!"

Mr. Zeng's brother, who used to work for a Taiwanese-funded company in Shanghai, knew Mr. Lin and told him about another Taiwanese businessman whose mother, in her 80s, had stomach cancer. She steadfastly avoided surgery and relied solely on hydrogen inhalation. Four years later, she was still doing well. Mr. Lin, therefore, hoped Mr. Lin would also offer his help. Mr. Lin recommended Mr. Zeng to the hydrogen inhalation experience center next to Linkou Hospital. Mr. Zeng was very dedicated, visiting the center daily for two to three hours of inhalation, even during chemotherapy, as soon as treatment ended. He said, "The staff at the hydrogen inhalation center were so kind! Not only did they let him inhale for free, they sometimes even treated him to meals."

"Can you handle secretly coming back to do business during chemotherapy?" I asked.

"I'm not feeling any discomfort. I can eat, sleep, and do my work just fine. People say chemotherapy is tough, but I find it smooth sailing." He pointed to the half-finished boards in the room. "Life is tough for people in Taiwan right now. How can we survive without working? I have to support my family!"

In recent interviews, nearly all interviewees reported improved appetite, better sleep, and increased energy after hydrogen inhalation. They also reported no hair loss and less vomiting during chemotherapy. Mr. Zeng now appears remarkably healthy, with a sturdy build and rosy complexion. His handshake with me was incredibly strong, and this seems to be due to hydrogen inhalation. But my biggest concern is the progress of his tumor.

I asked him to go to the hospital for a follow-up checkup, at least a CT scan. He looked hesitant and hesitated. Is it a money issue? Taiwan's National Health Insurance! Mr. Lin whispered to me, "Taiwan's National Health Insurance isn't all-inclusive."

He also knew that Mr. Lin was researching hydrogen medicine. He heard me holding Mr. Zeng's hand and saying, "Have you been to the mainland?"

He shook his head and said, "Where's the chance?"

"Mr. Lin and I would like to invite you to Guangzhou for a CT scan, ultrasound, and blood test at our hospital." Seeing his hesitation, I made the decision for Mr. Lin. "Mr. Lin will pay for your plane tickets, and I'll cover your hospital check-up fees, okay?" I shook Mr. Zeng's hand tightly and said, "Guangzhou is so beautiful right now. Say yes. See you in Guangzhou."

 

As I mentioned earlier, my book launch had already concluded when Mr. Zeng, Mr. Lin, and Mr. and Mrs. Fu Daren arrived in Guangzhou. I treated them to dinner at the Sunshine Hotel and then admitted them to my hospital. Because I had a meeting in Beijing the next day, I worked with the ward doctor that evening to develop a checkup plan for Mr. Zeng.

The re-examination results were surprising

The next evening, just after the meeting in Beijing ended, I was having dinner with a friend when I received a WeChat message from the ward doctor: "Mr. Zeng's CT scan is complete, and the lesion has been found to be significantly smaller and its activity has been significantly reduced. It seems that the treatment is very effective." Everyone present couldn't help but stand up and cheer.

The next day, I couldn't wait to fly back to Guangzhou. Upon returning to the hospital, I immediately met with a radiologist to review the scans. The CT scan showed a quasi-round, low-density lesion in liver segments S7 and 8, measuring 7.8 x 7.5 cm. The lesion had clear margins, minimal iodized oil deposition, and minimal enhancement, appearing to be liquefaction necrosis. Compared to Mr. Zeng's CT scan in Taiwan in November 2016, the tumor had shrunk significantly, and its activity had decreased significantly.

Seems to be "disease-free"

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in my country, and surgical resection is the preferred treatment. However, due to the absence of symptoms in the early stages, patients often miss the opportunity for surgery by the time they are diagnosed. Minimally invasive ablation procedures (such as cryosurgery and irreversible electroporation, also known as nanoablation) can achieve a "curative" cure for some inoperable HCC patients. However, over 60% of patients are neither suitable for surgery nor for ablation. For these patients, chemotherapy fails to prolong life. Percutaneous hepatic arterial chemoembolization and targeted drugs (such as Nexavar) are the mainstays of treatment, but are generally believed to only prolong progression-free survival, not overall survival. Studies have shown that these treatments can promote tumor growth even after a period of "effectiveness."

Mr. Zeng's liver cancer was pathologically confirmed to be hepatocellular carcinoma. The initial CT scan revealed a massive liver cancer, complicated by cirrhosis and portal vein thrombosis, making surgery inoperable. In Taiwan, he received only chemotherapy and hepatic artery chemoembolization. Typically, patients like him have a survival rate of about six months, but miraculously, he is not only alive, but also in excellent general condition, seemingly "disease-free." The original liver cancer site has almost completely liquefied and necrotic. While we can't claim to be cured, the significant improvement is undeniable. Importantly, based on experience, this result seems unlikely given his limited experience with chemoembolization and systemic chemotherapy. Mr. Zeng also inhaled hydrogen. Could the hydrogen molecules have played a role?

As early as 1975, Dole et al. published an article in Science magazine reporting that continuously breathing 97.5% hydrogen at 8 atmospheres effectively inhibited cutaneous squamous cell carcinoma in animals, proposing for the first time that hydrogen inhibits tumor growth through its antioxidant properties. Japanese researchers have found that giving animals with cirrhosis hydrogen-containing water can prevent liver cancer. Others have used hydrogen water to treat cancer cells and found that their growth was inhibited. Researchers at Shanghai Jiao Tong University have found that hydrogen can inhibit intestinal cancer in animal models by regulating the redox microenvironment and interfering with the expression of genes associated with cancer cell proliferation, thereby promoting cancer cell apoptosis and inhibiting cancer cell proliferation.

Hydrogen has been proven to be a selective, non-toxic, residue-free, and extremely inexpensive antioxidant. In the Chinese approach to cancer control, both through "elimination" and "transformation," hydrogen molecules appear to play a role in transforming cancer cells and reshaping the microenvironment. While hydrogen cannot be the primary treatment for cancer, including liver cancer, it can play a supporting role in comprehensive treatment.

Mr. Zeng's liver cancer was unresectable. He received conventional treatment, and surprisingly, the cancer was brought under control. The entire treatment process was also very smooth. Hydrogen played a crucial role in this.

(On March 5, 2019, exactly one year after our visit to Mr. Zeng in Taiwan, we called him. He was very happy and said that he went to the hospital for an ultrasound every three months and that "he was still doing well, just like before.")

Xu Kecheng

Commentary by Tang Zhaoyou

When treating cancer today, people often hope for a "one-shot" solution, unaware that cancer is a chronic, systemic, and dynamically changing disease. A cold takes a few days to develop and usually takes a few days to recover. Cancer, on the other hand, often takes decades to develop and recover from. Therefore, while eradicating the tumor, "transformation" is essential, both simultaneously and afterward. This is why I advocate complementing the "quick battle to eradicate tumors" with a "protracted battle of eradication and transformation." Hydrogen, through its antioxidant and anti-inflammatory properties, inhibits cancer cells. I believe that "inhalation" will play a role in this "protracted battle of eradication and transformation."

Hydrogen and cholangiocarcinoma:

"The death of the clams turns into pearls"

Wuyi Mountain's "Heartbeat"

I've long wanted to write about hydrogen and cholangiocarcinoma, but I delayed it because I wanted to visit my teacher in Yunnan. Recently, I attended a cancer rehabilitation conference in Wuyishan, Fujian, and two things struck me, so I immediately started writing.

First, meeting Miaoxuan was incredibly exciting. She's bright, lively, and cheerful. She embraced me the moment she saw me, unfazed by the usual "intimate contact between men and women." As the saying goes, beauty is unparalleled; it's the beauty that pleases the eye. Miaoxuan is my patient, but today, seeing her, she's truly a feast for the eyes. She held my hand, dancing like a girl, and said lovingly, "Thank you, thank you so much, my benefactor!"

The second was meeting a beautiful female writer. She was tall, and though she'd gained weight, her artistic presence remained undiminished. Her thick black hair, paired with a long coat, embodied the words of an ancient poem: "Her demeanor was graceful and her thoughts were profound, her skin was delicate and her bones were evenly proportioned." She gave me a copy of "The Death of the Clam, the Pearl," telling me it chronicled her experiences, thoughts, and feelings about her encounter with "Mr. Tumor." Her surname was also Xu, and her pen name was Xu Niang. "Five hundred years ago, we were one family," and the distance between us suddenly narrowed.

The death of the oyster creates a pearl

I quickly read the preface to "Frogs' Death Become Pearls," then flipped through the entire book with my mind. Like the author's graceful demeanor, the book is filled with flowing ideas, brilliant writing, and each word is as beautiful as a pearl. This "Mei Niang" from the Xu family was diagnosed with breast cancer in 2013. Her book chronicles her "over four-year battle with the cancer," undergoing only surgery and no chemotherapy. "To this day, her elegance remains undiminished," using her "life as a mirror and the book as a guide," documenting her "countless insights and experiences," offering readers a ray of sunshine amidst the gloom of a tragic fate.

Xu Niang loves pearls because she believes that "only the story of pearls and clams can provide the most appropriate interpretation and the most accurate analogy for those who have dealt with tumors."

A clam swims freely in the water, occasionally opening its vast shell. Suddenly, a grain of sand, carried by the crashing waves, enters its body. Unable to expel the invading sand, the poor clam mobilizes all its strength, pouring out blood and tears to envelop the sand, coexisting and growing together. Finally, one day, the sand grain transforms into a beautiful pearl, "like a cloud, carried by the gentle breeze into the mortal world, emitting a dazzling brilliance."

Xu Niang used her wisdom to mobilize her entire body's "strength" and "qi" to conquer the cancer cells that had invaded her body, allowing herself to wander in a realm of health, sunshine, elegance, and comfort. She thus became "a precious pearl formed by the death of the oyster."

Miaoxuan's Game

On the morning of December 2, 2018, Miaoxuan and I, shoulder to shoulder, holding the "Light of Life" banner, joined hundreds of others in a brisk walk along the lush, forested mountain roads of Wuyi Mountain. This was the "10,000-meter Walk" organized by the conference. We breathed in the refreshing mountain air, and amidst the natural beauty of emerald waters and verdant mountains, we admired the supreme unity of man and nature.

Miaoxuan, the woman who makes my heart flutter, has no signs of cancer at all. Isn't she the brilliant pearl described in Xu Niang's book?

The next morning, Miaoxuan joined experts on the podium at the Wuyishan Honglin Hotel for a cancer rehabilitation forum. She said, "In 2010, I underwent surgery for cholangiocarcinoma. The cancer recurred every year, requiring further surgery. Three surgeries and three rounds of chemotherapy nearly tore me apart. But in the past four years, my CT scans, MRIs, ultrasounds, and blood tumor markers have all been normal. I'm full of energy and happy every day." She looked at me in the audience and said, "This is all thanks to the correct rehabilitation strategy Professor Xu Kecheng developed for me."

Compared to the breast cancer Xu Niang suffered, Miao Xuan's tumor was ten times more aggressive. I remember one day in 2014, while I was at a specialist clinic, a tall woman approached me, hands over her past hospitalization records. She was Miao Xuan, from Shenzhen. Before she could even share her medical history, tears rolled down her cheeks like pearls from a broken string. She whispered, "Look, is there any hope?"

Like me, she also suffered from cholangiocarcinoma. For several years, every time I saw this patient, I felt a pang of pain, a kind of "heartache." On the one hand, it touched me personally. We are not plants or trees. I remember seeing a patient with cholangiocarcinoma during my ward rounds who had relapsed 12 years later. My heart sank for days. On the other hand, almost every time I saw a specialist outpatient, there were always several patients with cholangiocarcinoma who came to see me. They either relapsed shortly after surgery or had already metastasized by the time the disease was discovered. People call pancreatic cancer the "king of cancers," but in reality, cholangiocarcinoma and pancreatic cancer are closely related. Less than 10% of patients survive for five years.

Cancer recurrence can have many causes, and it's extremely difficult to determine the specific cause for each patient. Besides the possibility of residual cancer cells, I suspect, at least in Miaoxuan's case, that it's related to chemotherapy. In total, Miaoxuan has undergone over 20 chemotherapy sessions, using over 10 different medications. On the one hand, cholangiocarcinoma is inherently insensitive to chemotherapy; on the other hand, it's possible that it can become desperate after chemotherapy. Cancer cells are derived from normal cells that have "mutated." Chemotherapy drugs can induce further mutations in cancer cell genes, creating "outliers" and making the cancer cells more malignant.

Miaoxuan continued, "Professor Xu, are there any other treatments? Professor, is he suffering from mixed cholangiocellular and hepatocellular liver disease?"

I said: "No chemotherapy!"

"No need for medicine?" Miaoxuan opened her eyes wide, and it was unclear whether her expression was one of despair or surprise.

"Yes! 'No chemotherapy' is treatment." As a doctor, making treatment decisions for patients requires wisdom and courage. But this decision seems a bit unconventional. After I finished speaking, I felt a brief moment of regret, but quickly regained my composure—I was speaking the truth.

One day a year ago, Miaoxuan’s image suddenly appeared in my memory. I sent her a message, not daring to ask about her “illness”, but only about her “health”.

She quickly replied: "I'm fine! No illness or pain. Thank you."

"Have you received any treatment?"

"Didn't you tell me not to have chemotherapy? After listening to you, the tumor has not recurred since then." You can see that she is very happy.

Six months ago, I went to Shenzhen to give a lecture on "Chinese Cancer Control and Hydrogen Molecular Medicine." As the lecture concluded, a woman approached the stage and grabbed my hand. It was Miaoxuan. Her rosy complexion, matched by her red top, radiated joy. Miaoxuan said, "Professor Xu, you've got another great gift for us. I absolutely must try this hydrogen you talked about!"

When I saw Miaoxuan in Wuyishan this time, she excitedly told me that she felt great after hydrogen inhalation: she slept well, ate well, and had plenty of energy. But she was also worried, considering her disease had only been recurrence-free for four years. Cholangiocarcinoma is terrifying. Miaoxuan said, "It's a real gamble. Several patients in Shenzhen with the same liver cancer died within two years." She asked if I had any examples of hydrogen inhalation controlling cholangiocarcinoma.

I told her that I was planning to visit my teacher who lived in Yunnan. He was suffering from mixed cholangiocarcinoma and hepatocellular carcinoma, which had shown signs of recurrence after surgery. He had been taking hydrogen inhalation for four months and called to say that his condition had "improved."

Teacher Chen's misfortune and luck

Mr. Chen and his wife are both teachers, having worked for many years at a middle school in a Yunnan city. In September 2017, his wife was diagnosed with breast cancer and underwent surgery. In November, he was diagnosed with a 5-centimeter liver cancer. A month later, he underwent a lobectomy. Pathological examination of the surgical specimen revealed mixed liver cancer, poorly differentiated. He underwent six rounds of chemotherapy. Mr. Chen, a Chinese language teacher with a keen understanding, knew from medical textbooks that this type of liver cancer is not sensitive to chemotherapy and has a high recurrence rate.

Tumor markers are early indicators of recurrence. Sure enough, in May 2018, several tumor markers in his blood began to rise. CA19-9 rose to 99 units, nearly three times the upper limit of the normal range and exceeding the 57 units before surgery. Alpha-fetoprotein also rose to double the normal level. He was genuinely concerned and came to see me in Guangzhou. I asked him what the doctors in Yunnan had said. He told me that the local doctors recommended "continuing chemotherapy," but he refused. He said, "I've read the literature, and the conclusion is that it can achieve a 'tumor response,' but it won't prolong life."

I examined him and found no "space-occupying lesions" in his liver, making ablation unsuitable. He urged me to "find a treatment plan for him, no matter what." He explained that he had two sons: the elder was in the United States, about to complete his postdoctoral research, and the younger was studying in China, neither of whom had started a family. Over the past few years, both he and his wife had been ill, spending all their savings and incurring hundreds of thousands of yuan in debt.

He was nearly in tears as he spoke, his wife weeping beside him. What else could I do? He had accepted almost all the conventional treatments for liver cancer.

I suggested that he go back and get an interferon injection, and added: "Also, there is a rehabilitation treatment. I can't say it's sure, but you can try it." I asked him to go to my studio to inhale hydrogen.

He and his wife rented an apartment nearby and visited the "Xu Kecheng Care for Health Studio" daily for hydrogen inhalation. A month later, he returned home and rented a hydrogen inhalation machine. Two months later, he excitedly sent a WeChat message, saying his CA19-9 had dropped to 38 units, and a CT scan of his liver showed no recurrence.

I was excited by Dr. Chen's success. Perhaps it was because we shared a common sympathy, but also because I wanted to learn from him, as such a result is generally unattainable. I knew the nature of cholangiocarcinoma all too well. I immediately sent him a WeChat message, asking what treatments he had received. He said he had been taking interferon injections twice a week, as prescribed by my doctor, but the reaction was so severe that he stopped after a few weeks. He mainly inhaled hydrogen, at least six hours a day. He also emphasized his diet, focusing on a vegetarian diet, avoiding red meat and fried foods, and maintaining a balanced energy diet.

I once heard an expert in integrated Chinese and Western medicine explain the concept of "Qi flowing through the blood." He believed that "Qi" is particularly important. When Qi flows freely, the meridians and blood flow smoothly. When these three things are well-functioning, positive Qi strengthens while negative Qi weakens. The traditional Chinese character for "Qi" is composed of "qi" (qi) plus "mi" (rice). With "qi" and "mi" (nutrition), the body connects the heavens above and the earth below, harmonizing the five internal organs and ensuring smooth functioning of the six bowels.

Isn't the hydrogen and nutrients that Teacher Chen inhales the combined form of "qi"?

While this is a philosophical and psychological speculation, whether it's "scientific" still requires further study. Practice is the sole criterion for testing truth. I decided to visit Mr. Chen's home in Yunnan to see how he truly practices life. I remember a statistician saying: The way to evaluate a patient's recovery isn't in the hospital, but in society, in the patient's home. My visit was a source of comfort. I thought so.

I've already booked my flight to Yunnan, but back-to-back meetings in Guangzhou have forced me to postpone my departure. Recently, my publisher's editor called, urging me to submit my manuscript, saying the only missing article is for the soon-to-be-published book, "Hydrogen Cancer Control: Theory and Practice."

Coincidences are like this. That day, I was on a business trip in Xi'an, planning to head to Yunnan upon my return, aiming to complete my patient visits before New Year's Day. The next morning, my secretary, Tian Yu, immediately said, "I have something unpleasant to tell you."

I was stunned. What happened? Xiao Lu whispered: "Maybe there is no problem, don't worry too much." Tianyu has been my secretary for 10 years. He often knows what I am thinking and always shares my worries.

She said: "Mr. Chen from Yunnan will fly to Guangzhou to see you tomorrow. He is bleeding from his mouth."

"Is it bright red or black? Did he vomit or cough it up? How much?" I was getting really anxious. Mr. Chen has a chronic liver disease. He's bleeding, and he's rushed all the way to Guangzhou to see me. It can't be good news. Maybe his liver cancer has relapsed.

The next day after returning to Guangzhou, I rushed to the ward as soon as I got to work. Teacher Chen beamed upon seeing me and quickly explained, "It was a false alarm"—it turned out to be bleeding gums. Perhaps it was a lot of bleeding, as he'd coughed up a lot of bright red blood when he woke up that morning. He'd been experiencing bleeding gums for years, and he'd never taken it seriously. But now, with liver cancer, he was paranoid.

Mr. Chen underwent a full set of blood biochemistry and tumor marker, CT and MRI examinations, and no evidence of disease recurrence was found.

I want Teacher Chen to "relax," "see through," live in the present, and live with death in mind. Inside Hangzhou's Lingyin Temple, there's a couplet: "How can life be completely perfect? ​​In everything, only seek half-satisfaction." In reality, "half of life is within oneself, the other half is left to nature." I want him to learn from Miao Xuan in Shenzhen. Look at her: she inhales hydrogen at home every night and dances for charity at the Rehabilitation Association during the day. We are all "fellow travelers," but with different mindsets, our life circumstances vary greatly. Happiness is seeing the magic in the ordinary; happiness is finding true meaning in the ordinary. Everyone experiences ups and downs; just dust yourself off and keep going.

Teacher Chen seemed like a completely different person. He and his wife visited relatives and friends, reminiscing about the past with fellow travelers in a warm and joyful atmosphere.

Entering 2019's New Year's Day with a yearning for the new year, I opened my phone early in the morning and the first WeChat message popped up. Teacher Chen said, "When you're surrounded by mountains and rivers, you might think there's no way out, but when you bend the willows and flowers, you'll find another village." He looked forward to seeing Yunnan again and insisted I visit Yunnan's beautiful Yuxi.

Teacher Chen lives in a scenic city, a place with neither severe winter cold nor scorching summer heat, four seasons like spring, and distinct dry and wet seasons. It's also the hometown of the great musician Nie Er. I seem to hear Nie Er's "Pioneer"—"I'm not afraid of your thousands of mountains and rivers, thousands of years of fossils have accumulated to form peaks on the ground!" Cholangiocarcinoma is a dangerous disease, but if we not only "combine with the right" but also "win with the unconventional," we can achieve "the mutual growth of the right and the unconventional" (quoted from "The Art of War"), and our remaining years will not be filled with sorrow and desolation. We will surely be like the beautiful writer Xu Niang, mentioned by Ai Mendou at the beginning of this article: "Pure as a clam, bright as a pearl."

In March 2019, Dr. Chen returned to Guangzhou for a follow-up examination due to "liver pain." The results were positive, and his tumor markers had further decreased. He jokingly said he was "too sensitive" and "saw danger everywhere."

Xu Kecheng

Commentary by Tang Zhaoyou

Professor Xu's writing is a delight, his prose flowing smoothly, his witty remarks brimming with insightful, yet profoundly insightful philosophical insights. Some say these are merely "chance" events, devoid of evidence-based medical support. However, necessity often resides in chance, and ignoring chance often leads to significant discoveries slipping by. The metaphor of "a pearl emerging from the shroud of a clam" is a fitting one. For nearly 200 years, the battle against cancer has been aimed at "eliminating" tumors, ideally eradicating them completely. Few have considered the possibility of peacefully coexisting with cancer, "living with it." It's worth noting the implicit methods for achieving "living with it" in his article: open-mindedness and enjoying life, "no longer resorting to chemotherapy," a balanced diet, hydrogen inhalation, and so on. The reason these "minor interventions" have been overlooked is because of the "humanities." I recently published "Western Learning, Chinese Medicine: Creating a New Chinese Medicine." The "Chinese" here refers not only to the principles of traditional Chinese medicine, but also to the essence of Chinese civilization. Lao Tzu said, "The soft overcomes the strong." Isn't the taming of cancer through "minor interventions" a case in point?

Hydrogen and Colorectal Cancer: Infinite Relief

Going to Jinhua, Zhejiang, has been something I have been looking forward to in recent months, not because I have never been to the city famous for its "Jinhua Ham", but because I seem to have a sense of guilt towards Mrs. Yang and her son Mr. Shen.

Mrs. Yang is 84 years old and suffers from rectal cancer. My feelings are not because of the medical malpractice we had, nor because of the complaints from her and her son, but because of my inner self-reflection.

Old Mrs. Yang is hospitalized

On February 10, 2018, the director of the fifth ward of our hospital came to me and said that a patient from Zhejiang Province had come to the hospital because of my reputation and insisted on seeing me to get a treatment plan. I went to the ward and looked through the patient's medical records. The medical history was as follows:

Two years ago, the patient had blood in the stool without any obvious cause. The stool was mucus and bloody, accompanied by a feeling of incomplete defecation, and the stool became thinner in shape, without pain or abdominal distension. He went to the Central Hospital of Jinhua City, Zhejiang Province for treatment. A cauliflower-shaped mass was found 2 to 6 cm away from the anal margin during digital rectal examination. The patient refused surgical treatment and took oral Chinese medicine for treatment, but the symptoms of blood in the stool did not improve significantly. A year ago, he developed paroxysmal pain in the sacrum and coccyx, and he took herbal medicine on his own, but it did not work. In May 2016, he had a large amount of blood in the stool, about 500 mL. After that, he had similar blood in the stool three times, but no special treatment was given. In September 2016, a mass appeared perianal, accompanied by worsening pain in the sacrum and coccyx. He was hospitalized in a hospital in Hangzhou for treatment and underwent CT examination. The results showed a space-occupying lesion in the right upper mediastinum, an infectious lesion in the right upper lobe of the lung, and rectal cancer; a small

Lymph nodes were found, and mediastinal metastasis of rectal cancer and lung infection were considered. After taking Chinese medicine for more than 5 months, there was no significant improvement in the condition.

On the second day after admission to our hospital, the patient underwent whole abdominal CT scan with plain scan and enhanced scan. The results showed: (1) thickening of the intestinal wall and soft tissue mass in the distal rectum and anal area; (2) unclear adhesions of the bilateral levator ani muscles and the posterior vaginal wall; (3) multiple small and slightly larger lymph nodes beside the bilateral iliac vessels and inguinal area; (4) small shadows in the right lower lung, which was considered to be an inflammatory lesion; (5) multiple small cysts in the liver.

Colonoscopy revealed a broad-pedunculated polyp measuring approximately 1.0 x 0.6 cm, 10 cm from the anus. The surface was congested, edematous, and eroded. The rectal mucosa within 4 cm of the anus was congested, edematous, and eroded, with a cauliflower-like appearance, involving three-fifths of the perianal area. A biopsy revealed moderately differentiated adenocarcinoma.

Caught in a dilemma

The patient's attending physician, Dr. Shi, had over a decade of clinical experience treating cancer and was known for overcoming challenges. However, she was torn between a rock and a hard place when it came to this elderly woman's case. She had low rectal cancer. Surgery was difficult due to her advanced age and poor general condition, and the tumor had invaded the perirectal structures and pelvic cavity. Chemotherapy was a firm objection from the family. Worst of all, the tumor was growing outward, protruding from the anus and becoming lodged there, causing severe pain, especially during bowel movements.

I arrived at Room 524, where a white-haired elderly woman lay on the bed by the window, moaning continuously. Standing beside the bed were a man and a woman—her son and daughter. The elderly woman's son, upon seeing me, excitedly grasped my hand and said, "I'm finally here. Please save my mother! She's in so much pain." He paused, tears welling in his eyes. "As long as we can relieve her pain, we'll be satisfied."

What special methods do I have?

In order to reduce the tumor "burden", on February 14, 2017, under intravenous general anesthesia, the doctor performed cryoablation on Mrs. Yang's rectal and anal tumor in an attempt to eliminate part of the tumor.

The next day, I visited her. The old lady's pain hadn't subsided; the freezing had only melted the part of the tumor exposed at the anus. I remained silent, feeling only guilt.

On February 16, I went to visit her again. The old lady's son, Mr. Shen, looked solemn as he handed me a discharge bill, saying that they were "discharged voluntarily" and were preparing to return to their home in Zhejiang.

Three months of telephone communication

Over the next three months, Mr. Shen called every few days. I was speechless, but my job as a doctor compelled me to answer.

Shen: "Professor Xu, the tumor at my mother's anus has grown again. What should I do?"

Xu: "Let's put a stent in the anus. We can go to a hospital in Shanghai or Hangzhou for that."

Shen: "Professor Xu, my mother is in so much pain that she screams every day and can't sleep. What should I do?"

Xu: “You can use morphine…”

............

By late May, Mr. Shen's calls were getting more urgent: "Professor Xu, my mother's pain is no longer relieved by morphine.

You must help me find a solution..."

My heart was actually aching. I was silent for a few minutes on the phone, then I said, "Breathe some hydrogen. Every day, at least four hours a day. Keep doing it, and maybe..."

A treasure that fell from the sky

On June 30, 2018, Mr. Qin’s WeChat suddenly popped up on my phone:

Yang, the 84-year-old mother of Shen ×× in Jinhua, Zhejiang (a colorectal cancer patient), has been inhaling hydrogen for at least 4 hours a day for over a month. Before the treatment, she was in unbearable pain, unable to defecate, and confined to bed. Now the pain has been significantly reduced, she can defecate, and since yesterday she has been able to walk to the street to buy groceries.

Afterwards, he sent two short videos, recording Mrs. Yang inhaling hydrogen and practicing Tai Chi outdoors.

Mr. Qin is a friend of Mr. Shen's. He managed to rent the oxygen-hydrogen atomizer that Old Lady Yang uses for hydrogen inhalation. For me, this news was like a treasure dropped from the sky. I sent Mr. Shen a WeChat message, expressing my joy and hope, hoping his mother would continue with the hydrogen inhalation, and saying I'd try to visit her in Jinhua.

Mr. Shen replied immediately, saying that besides feeling lucky, he also hoped that I could go to Jinhua to visit his mother and give her encouragement.

The atmosphere and mood of this WeChat conversation with Mr. Shen were worlds apart from our previous phone calls. As a doctor, I always consider my patients' recovery my greatest reward. The medical value of hydrogen requires further research; perhaps it will offer us a completely new scientific approach to treating illnesses. I sincerely thank him for his courage to accept my suggestion, and I also thank his mother. It was her "good luck" that gave me the confidence to research hydrogen cancer control.

I must visit Mrs. Yang and thank her in person.

Jinhua Interview

On August 11, 2018, my secretary, Tianyu, and I boarded a northbound high-speed train. Soft music played in the carriage, and the rhythmic clatter of the wheels against the rails brought endless joy and reverie. Life is like a constantly moving train. Each stage of life is like a station. As a doctor, my mission is to accompany my patients through every stage of their battle against disease, never leaving them.

Six hours later, dusk descended like a vast gray net, and the train pulled up at Jinhua Station. It was already 8 p.m., and the glittering lights on the streets shone like a multicolored display of fireworks, strings of bright car lights flowing like a river of glitter.

Mr. Shen was waiting for us at the exit. Once we got on the bus, I couldn't wait to ask about his mother. Mr. Shen replied, "She's been looking forward to seeing you for a long time. She was so happy to hear you were coming that it almost made her feel better."

Mr. Qin, who arrived from Shanghai an hour early, greeted us at the hotel. The patient's family, Mr. Qin, their assistant, and us, the doctors, were all delighted to meet. Everyone congratulated each other, and the scene felt like a commando unit winning a victory.

The next morning, just after breakfast, Mr. Shen met us at the hotel. Jinhua, located in central Zhejiang, boasts a 2,200-year history, named for its location where Venus and Nüwa compete for brilliance. The streets, lined with ancient and modern buildings, complement each other beautifully. This scene reminded me of the famous line by the Ming Dynasty poet Feng Chun describing Jinhua: "Golden towers and pavilions in the sky, northward gazes at lotus flowers and lush green grass."

After walking a little over 200 meters, we arrived at Mr. Shen's multi-story home. Mr. Qin said Mr. Shen was a filial son. His own home was in a luxurious residential area in the new district, but he had moved here for the past two years to care for his mother.

We went up to the third floor, the door was open, and we walked straight into the room. Old Mrs. Yang was half-reclining on the sofa, inhaling hydrogen. She immediately sat up and greeted us warmly. Mr. Shen's wife was from Jiangsu, and seeing us, her fellow Jiangsu people, she was particularly friendly and hurried to make tea for us.

I examined the old woman carefully. Her complexion was pale, but much better than when she was admitted to our hospital. A simple physical examination revealed no superficial lymphadenopathy, no abdominal masses, and no tenderness. Secretary Tianyu examined her anus, and the protruding mass was gone.

I wanted to suggest that the old lady go to the hospital for a CT scan and colonoscopy. Perhaps my husband understood my intention and said, "She can eat, sleep, and walk now, and she has gained a full 15 pounds. We don't want her to go through the pain of those tests again."

Mr. Shen's point makes sense. The fundamental purpose of cancer treatment is to prolong the patient's life and improve their quality of life. As long as an 84-year-old can "coexist with cancer," why should he be overly concerned about the size of his tumor?

The old lady took me to the living room and chatted with us. She praised her son and daughter-in-law for their filial piety and told us what to eat every day. She said she wanted to thank us very much. We had lunch. I said, "You're welcome. Your recovery is our greatest thanks."

From my "voluntary discharge" six months ago and my regretful apology, to my subsequent three months of phone conversations with Mr. Shen and my frustration, to the video I saw of the old lady strolling in the garden a month and a half ago, to her invitation to dinner right now, it's truly like "the mist and moon are unaware of the changes in human life, as if in a dream." Life is a temporary stay, and a sense of happiness arises spontaneously!

People say that the profession of doctor is noble. At this moment, I appreciate my profession as a doctor. This profession can make us feel the unforgettable happiness from the meaning of life.

Mr. Shen also insisted on inviting us to lunch, but we declined. We were heading to Lanxi Town, over 40 kilometers from Jinhua, where an elderly woman was waiting for us. She had a massive mediastinal tumor and was also receiving hydrogen therapy. Her daughter called this morning, excitedly reporting that her mother's condition had improved after two weeks of hydrogen therapy.

Conclusion

Mrs. Yang's rectal cancer persists, but the improvement in her condition, which previously involved a tumor embedded in her anus and caused severe pain that even morphine couldn't alleviate, is now miraculous: she can eat, sleep, and walk. Is this a "spontaneous" improvement in the tumor, or is hydrogen playing a role?

There are cases of cancer being cured without treatment, but they are extremely rare, estimated at around one in 100,000. These cases primarily occur in children. Elderly woman Yang's rectal cancer had invaded the perirectal area and pelvic cavity. It was not in the early stages, and she had not received chemotherapy or radiotherapy. Her condition improved one month after hydrogen inhalation, demonstrating its effectiveness.

Follow-up studies of cancer patients receiving hydrogen inhalation have shown that the effects of hydrogen often become apparent after one month. Like anticancer drugs, the effects of hydrogen appear to be dose-dependent. The effects are particularly slow to manifest in "distant" tumors, as hydrogen travels a longer distance from the nose to the lungs and bloodstream. In other cases, we have found that directing the hydrogen outlet directly at the tumor wound resulted in tumor regression and wound size reduction after several days.

How should hydrogen be administered? What is the effective dose? How does hydrogen control cancer? What are the long-term effects? These all require further research. The human heart is a stage for dreams. While it may be considered unrealistic, it is like a bamboo root. Though buried underground and invisible, it will never stop exploring and emerging new things.

Xu Kecheng Lu Tianyu

Commentary by Tang Zhaoyou

Professor Xu, nearly eighty years old and a cancer survivor, remains so dedicated and passionate about his patients—a truly commendable achievement. A few days ago, I saw a report in Reference News titled, "Sky-high Prices of Life-Saving Drugs Become a Hidden Pain in American Society." Gene therapy costs $470,000 per session, while targeted therapy costs $150,000 annually (approximately 1 million RMB). Given China's current situation, I believe we should promote both "high-tech, cutting-edge, and innovative" treatments and "faster, better, and more economical" treatments. Currently, even patients often find it difficult to afford inexpensive medications. Furthermore, "practice is the sole criterion for testing truth." As long as clinical efficacy is effective, it deserves attention. This patient's treatment has clearly shown positive results: their tumor has shrunk, they are living with the disease, and their quality of life has significantly improved. Modern medicine often demands "cancer-free survival," a goal difficult to achieve. Therefore, winning the war against cancer depends not only on new weapons but also on new thinking.

Hydrogen and ovarian cancer: initial elimination of “pre-disease”

Cure disease

The best time to treat or intervene in cancer is before or just after cancer cells form. As an ancient book (Book of the Later Han Dynasty, Biography of Ding Hong) states: "If the government is self-disciplined and prevents the onset of disease, then the evil will be eliminated, harm will be eliminated, and blessings will come."

Cancer cells evolve from normal cells in the body. Under the long-term influence of various internal and external factors, normal cells mutate and gradually accumulate, eventually becoming cancer cells. This is a long, gradual, multi-stage process, starting with abnormal proliferation, then developing into precancerous lesions, then progressing to carcinoma in situ, early cancer, invasive cancer, and finally lymph node metastasis and distant tissue and organ metastasis. This process typically takes 10, 20, 30 years, or even longer.

For patients who have already developed cancer and received effective treatment, preventing recurrence and metastasis is paramount. Recurrence can arise from residual cancer cells, circulating cancer cells, pre-existing dormant cancer cells, particularly cancer stem cells, or re-emerging cancer cells. The course of recurrence depends on the source and can take from as little as a few months to several years or longer.

Over 2,000 years ago, the Yellow Emperor's Classic of Internal Medicine proposed the principle that "the best doctor treats illness before it occurs, the middle doctor treats impending illness, and the lowest doctor treats existing illness." "Preventing illness before it occurs" involves inhibiting abnormal growth and precancerous lesions, preventing primary tumors, preventing the recurrence of treated cancer, and inhibiting residual or dormant cancer cells.

Women with "no disease"

Every month or so, Professor L would call and say, "My child's in trouble," and he wanted me to help him. Professor L is a renowned professor at a prestigious hospital affiliated with a prestigious university in Guangzhou. We've been friends for many years, and it was my duty to help him.

A few days later, Professor L came to our hospital. The child he was talking about was his daughter-in-law, Ms. Y. Her demeanor and face were just like what the poem says, "sorrowful as a mountain, gloomy as the sea, sorrowful as a mountain."

Ms. Y was diagnosed with left ovarian cancer and underwent surgery in December 2017, which removed her uterus and uterine appendages. The postoperative diagnosis was ovarian adenocarcinoma type Ia. In the past three months, she had three consecutive tumor marker tests, all of which were elevated. The most recent test showed blood levels of CEA at 13.7 micrograms/liter and CA19 at 947.4 units/liter, three times and 27% higher than the upper limit of the normal range, respectively.

Substances produced and released by tumor cells often exist in the host's body fluids in the form of antigens, enzymes, and other metabolites. Measuring these tumor markers can diagnose tumors or assess their progression. CEA, or carcinoembryonic antigen, and CA19-9, or carbohydrate antigen 19-9, can detect a variety of cancers. For those who have had cancer, elevated levels of these markers indicate recurrence or an impending recurrence.

Ms. Y's tumor markers were elevated. Although this could be a normal "mutation", for cancer patients, it should be considered as a recurrence of the tumor, or residual cancer cells in the body, especially dormant cancer cells that existed before, or the emergence of a new type of cancer cell. Before the surgery, her CEA and CA19-9 were normal. Elevated levels of these two markers are generally seen in the digestive system.

Cancers, such as colon cancer and pancreatic cancer, can also occur in ovarian cancer. She underwent tests including PET-CT and colonoscopy, but no tumor was found. However, abnormalities in these markers can occur six months or even years before a tumor is clinically detected. Perhaps this is a "pre-existing" cancer?

This undoubtedly buried a "time bomb" in the body!

"The child is in great pain, but mainly because of her heart." Professor L gave a wry smile, looking helpless. "She doesn't want chemotherapy. It's really a dilemma!"

”

I said, "Then wait and follow up." I felt helpless. I knew this "standardized" answer wouldn't satisfy them; otherwise, why wouldn't they go to their own prestigious hospital for treatment?

Sure enough, Professor L was not satisfied with my "standard" answer and said, "Old friend, we are here today to hear your truth." He must have read my book "I Tell the Truth to Cancer Patients".

"Professor Xu, judging by your energy and spirit, you must have a secret weapon! Your book, 'Daily Talks on Rehabilitation,' is considered a bible by many." Ms. Y spoke up, full of anticipation. "Can I try that hydrogen you mentioned?"

Her words reminded me that hydrogen might help her, or at least it wouldn't do her any harm.

I have been in contact with hydrogen for two years. First I drank hydrogen-rich water, and then I inhaled hydrogen gas. Now I seem to have become "addicted" to it.

Professor L said, "My child wants to follow you in your fight against cancer!" He smiled and said he'd read my other book, "Follow Me in the Fight Against Cancer." I said, "To be precise, it's not 'fighting cancer,' it's 'controlling cancer.' Controlling cancer isn't just about eliminating cancer cells; more importantly, it's about 'transforming' them. To prevent cancer cells from growing and spreading, we first need to transform the 'microenvironment.'"

Many studies have shown that hydrogen molecules can transform the microenvironment.

If chemotherapy is the "right path" for treating "pre-illness" conditions like Ms. Y's, then hydrogen may be the "curve" or "side road." We can "overtake on the curve" or "change lanes to overtake."

I suggested: If she's willing, she could inhale hydrogen. She could inhale hydrogen while watching TV or checking her phone, as a way to prevent illness. I recommended hydrogen inhalation because, compared to other methods of hydrogen ingestion, inhalation produces a rapid effect. Reports indicate that for a 60-kilogram person, inhaling 2% hydrogen can achieve a 24-hour hydrogen saturation level 10 times or more higher than oral intake of saturated hydrogen-rich water. Within a certain range, blood hydrogen concentration is dose-dependent: the more hydrogen is inhaled, the higher the blood concentration, and the more hydrogen enters the tissues.

Studies have shown that the biological effects of hydrogen molecules are positively correlated with tissue hydrogen concentration. Hydrogen levels in plasma reach their peak approximately 30 minutes after inhalation and return to baseline approximately 60 minutes after cessation of inhalation. Therefore, the inhaled hydrogen concentration should be high. my country has developed a hydrogen-oxygen nebulizer that rapidly produces a gas mixture containing 66.7% H and 33.3% CO, and it has been approved by the government as an innovative product.

The device is very safe and can be used continuously. I asked her to inhale hydrogen for 2 to 4 hours every day, because the experience of other patients has shown that the inhibitory effect of hydrogen on cancer seems to have a critical point, which occurs after a cumulative inhalation of hydrogen for about 80 to 120 hours.

Initial recovery of “pre-disease”

As a cancer patient myself, I've always viewed other cancer patients as comrades in the same trench, fighting the cancer together. In the more than half a month since Ms. Y and Professor L left, their worried and helpless expressions have surfaced in my mind from time to time, and I've also been constantly worried: Will hydrogen be effective?

Around 9 p.m. on May 25, 2018, I had just finished a party in Beijing when my phone rang. It was a WeChat message from Ms. Y: "...I've been inhaling (hydrogen) for half a month and feel very good. Yesterday's test results showed everything was normal...I didn't expect it to have such a magical effect...Thank you very much." At the same time, she sent photos of three test results, which showed: CEA 3.3 micrograms/liter, CA19-918.8 units/liter, completely normal.

That night, I suffered a rare bout of insomnia. I was to teach a doctoral class at Peking University the following day, and in preparation, I spent the afternoon discussing "what is innovative thinking" with several expert friends in Beijing. Everyone mentioned hydrogen, citing a 2007 article in the prestigious journal Nature Medicine that reported the remarkable therapeutic effects of a molecule on a rat model of cerebral infarction. We pondered a common question: hydrogen, the smallest element in the upper left corner of the periodic table, had long been used only in hydrogen balloons. Only then did Professor Ota of Japan discover its broad biological significance, attracting worldwide attention. Isn't that innovation?

I'm so happy for my cancer patient, Ms. Y. If hydrogen therapy is innovation, then this is the fruit of that innovation!

Two days later, I sent a WeChat message to Ms. Y, asking her to confirm the "effect" again. As a doctor, I hope to get the "most authentic" results.

One month later, Ms. Y reported the re-examination results: CEA 1.9 micrograms/liter, CA19-9 10.3 units/liter, which further decreased.

Ms. Y's "preventive treatment" achieved "miraculous" results. Although this is a case that needs further verification, based on my interviews with patients with other types of cancer and the literature, her result was both unexpected and expected.

Hydrogen is amazing

Hydrogen is truly amazing. On a grand scale, it powers the sun's fusion energy; on a more detailed scale, hydrogen molecules are part of nearly every molecule in the body: DNA, proteins, sugars, fats. In the human body, hydrogen primarily binds to carbon, oxygen, and nitrogen, and is crucial for ATP production within mitochondria. While our understanding of hydrogen biology is still in its infancy, rigorous scientific research reveals that hydrogen not only has the ability to function at the cellular level but can also cross the blood-brain barrier, enter the mitochondria, and ultimately, penetrate the cell nucleus.

Hydrogen molecules can inhibit cancer cells, generally believed to be due to their antioxidant and anti-inflammatory properties. The most powerful and toxic oxidants in the body are OH and ONOO, which can act on nucleic acids, lipids, and proteins, causing DNA damage, lipid peroxidation, and protein denaturation. Smoking, air pollution, chemicals, stress, and inflammation, among other factors, can induce these peroxidants, triggering cell mutations and the development of cancer cells. H2 is a specific scavenger of these two oxidants.

Some people in Japan say that hydrogen is effective against 67 diseases; an American scholar published an article saying that hydrogen molecules can improve at least 170 kinds of poor health conditions and diseases; another American expert said that among the top ten causes of death in the United States, except for suicide and traffic accidents, hydrogen can

be improved.

Renowned respiratory disease expert Academician Zhong Nanshan believes that the use of hydrogen allows disease treatment to be moved "front-end," effectively addressing the underlying causes. He advocates for "preventive treatment." Ms. Y's "miraculous results" are a case in point.

Professor Sun Xuejun, a renowned hydrogen research expert, believes that hydrogen "has broad application prospects" and can "make all potentially effective diseases and problems amenable to research." He even exaggerates: "How can an affordable, safe, and effective disease treatment not have a global impact?"

Xu Kecheng

Commentary by Tang Zhaoyou

Professor Xu advocates the "ABC principle" of cancer control: effective (A), simple (B), and cheap (C), and I agree with it. In 2008, one of my doctoral students conducted an experimental study that found that aspirin helped reduce the spread of residual cancer after radiotherapy. I suggested that the professors involved conduct a randomized controlled clinical trial, but perhaps because the drug was so common, they weren't interested. In 2015, CA-Cancer J Clin, a journal with the highest impact factor, published an article claiming that "aspirin helps reduce mortality in prostate cancer with a high risk of recurrence." While everyone acknowledges that "practice is the sole criterion for testing truth," in today's world of cutting-edge technology, "accidental" events like hydrogen inhalation are likely to slip by.

Hydrogen and esophageal cancer: A personal trial of hydrogen

“Old friends” and cancer patients

On the evening of November 17, 2018, I arrived in Beijing for a meeting. The next morning, still half asleep, I suddenly thought of checking on Lao Wang: How is he doing now?

This morning, in the vast exhibition hall of the Beijing International Convention Center, I was touring the various booths with a doctor from Beijing when someone suddenly tapped my shoulder. I turned and saw: "Isn't that Lao Wang?" A friend is like a moving song. I'd thought of him that morning, and sure enough, he was here. Naturally, we shook hands, hugged, and asked about each other's well-being. Lao Wang said, "Old friend, I missed you!"

"Are you okay?" I asked, naturally asking about his health.

"Do you think I'm okay?" He patted my back hard, then held my hand tightly and said, "I'm fine! I have meetings every day, play ball every day, and inhale hydrogen every day!"

I saw him, full of energy, with his graying hair and a ruddy, slightly dark square face, framed by a pair of intelligent eyes. I wrestled with him again, his skin tight and his muscles toned. I jokingly said, "You're really strong! Congratulations, old friend!"

In fact, we, two "old friends," had only known each other for a little over six months. Some say that meeting, reuniting, and reuniting is a matter of fate, seemingly unrelated to time. Lao Wang and I became old friends primarily because we were cancer patients, comrades fighting the cancer together. It was like a brief, life-or-death battle in war that transformed us into lifelong friends.

We became "old friends" because we both used a protective weapon: hydrogen. My cancer history is much longer than his, but his unwavering belief in hydrogen's effects and his time inhaling it surpass mine.

A friend is like a book; through him you can open up the whole world. It was he who urged me to enter the research field of "hydrogen cancer control" with greater confidence.

Around the end of March 2018, a friend told me about a "rehabilitation expert" in Beijing—a renowned rehabilitation specialist who was obsessed with treatment. One evening, at a hotel in Guangzhou, a friend connected me with Lao Wang. A loud, cheerful voice came from the other end. After a few pleasantries, he said, "Hydrogen cancer control has a scientific basis. I've personally experienced it. You must conduct thorough research and strive for us Chinese to achieve something remarkable!"

Although we had never met, his few words revealed his identity: researcher, expert, cancer patient, and long-term leader. From the volume and momentum of his voice, I knew he must be a well-off beneficiary of hydrogen.

He is indeed a prominent leader, the director of the xx Rehabilitation Research Center. More than a year ago, he underwent surgery for esophageal cancer.

Trying out hydrogen

Two weeks after our phone call, I arrived in Beijing for a meeting. As soon as I checked into the State Council's No. 2 Hotel, I was greeted by the sound of cheerful voices and laughter in the hallway. I hurried to the door and was greeted by Old Wang, a man of medium build, neither thin nor fat, accompanied by a friend. He approached me and shook my hand tightly. As he entered the room and sat down on the sofa, he pulled a stack of hospital records and CT scans from his briefcase and said quickly, "You're a gastroenterologist. Please take a look. Is this surgery worth it?"

I opened my medical records. In February 2017, Mr. Wang experienced difficulty eating and underwent a gastroscopy at Beijing General Hospital. A mass was found on the posterior wall of the esophagus, 31 to 35 centimeters from the incisors. The mass was brittle and easily bleeds. An endoscopic ultrasound revealed an ulcerated mass in the 31 to 35 centimeter segment of the esophagus, primarily located in the muscularis propria, penetrating the outer membrane. A CT scan revealed a mass in the lower esophagus and possible left gastric lymph node metastasis. A biopsy of the esophageal mass revealed squamous cell carcinoma. On March 12, Dr. Wang was admitted to the hospital for two 21-day cycles of neoadjuvant chemotherapy: paclitaxel esters and cisplatin. He also self-inhaled hydrogen (using a hydrogen-oxygen nebulizer) for at least three hours daily.

CT review report on May 11, 2017: No obvious space-occupying lesions or stenosis were found in Mr. Wang's esophagus, and no obvious enlarged lymph nodes were found in the intrinsic spaces of the mediastinum.

Lao Wang said, "I was very happy at the time. On the one hand, I could eat smoothly, and on the other hand, the tumor was no longer visible on the CT scan. At least the 'big cancer' had become a 'small cancer.'" He asked to continue hydrogen inhalation and undergo 2 to 4 more cycles of chemotherapy.

But his family disagreed, and neither did his superiors. As mentioned earlier, Lao Wang was a leader, a high-ranking official. His body and health were no longer entirely his own, and his superiors' opinions weighed heavily on his treatment.

On May 15th, Mr. Wang underwent radical resection for esophageal cancer. The esophagus was resected, revealing a hard area measuring 2.5 x 1.0 x 0.8 cm. Postoperative pathology revealed grade II squamous cell carcinoma, with cancer cells regressing and invading the fibrous membrane, accompanied by a lymphocytic reaction.

Comparing the endoscopic and CT findings before the operation with the pathological changes after the operation, his esophageal cancer had changed from a "big cancer" to a "small cancer" before the operation.

After reading the report, I said, "Lao Wang, I think surgery is suitable and necessary for you."

"That's not necessarily true! What if I continue with hydrogen inhalation and chemotherapy?" Lao Wang seemed very persistent and raised his voice. "Look, my tumor was originally 5 centimeters long and deep into the outer lining of the esophagus. Can just two cycles of chemotherapy, with a small dosage, shrink the tumor by half? You are a gastroenterologist, have you ever seen a case like mine? This must be the effect of hydrogen!"

Cases like this are rare, and hydrogen inhalation appears to be effective. Given our ongoing research into hydrogen's effects on cancer, I genuinely hope it's the cause. However, as a doctor within our own field, I must be extremely rational and not easily deviate from tradition. As a researcher, I must be even more rational and not assume things; I must have evidence. I held Lao Wang's hand, deeply impressed by his courage and dedication, and said, "But if I were your attending physician, I wouldn't dare make such a choice for you."

"Why not? This is also a form of innovation. How can our medicine advance if we don't try? Honestly, at the time, I wanted to test the effects of hydrogen on myself, but I couldn't help myself..." Old Wang smiled somewhat helplessly. I understand. It was said that the minister had ordered him to undergo the surgery.

He is full of confidence

The next day, Lao Wang took my colleagues and me on a tour of the "Green Rehabilitation Studio." He's past retirement age, but as a rehabilitation specialist, he still hopes to serve patients on another platform. There are various rehabilitation devices, including a hydrogen and oxygen nebulizer. He said this is also a way to give back to society, as he himself "lives a good life."

Lao Wang summarized the benefits of hydrogen inhalation in his experience: First, it complements chemotherapy and can make surgery easier when used before surgery. However, he hopes to further investigate whether hydrogen inhalation alone is effective. Second, it reduces chemotherapy side effects. He said he experienced almost no adverse reactions during chemotherapy.

Third, it promotes postoperative recovery. He returned to work shortly after surgery. Fourth, it prevents recurrence. He said he is confident that if he continues to inhale hydrogen, his esophageal cancer will not recur.

Regarding his fourth point, due to the short time, it is difficult to draw a conclusion and further follow-up is needed. However, considering the wide range of biological effects of hydrogen molecules and seeing his excellent "spirit", the role of hydrogen cannot be underestimated!

More than three months after our meeting in Beijing, I wanted to assess Lao Wang's hydrogen inhalation results again, so I sent him a WeChat message, asking him to further comment on "the contribution of hydrogen." He immediately replied, believing that his treatment results were "directly related to hydrogen inhalation."

Xu Kecheng

Commentary by Tang Zhaoyou

The expert patient mentioned in the article reported positive results from hydrogen inhalation. This also raises a significant question: hydrogen may be effective before, during, and after treatment, potentially serving as a "neoadjuvant therapy." The goal of this treatment is to shrink the tumor and prepare for surgery. Sun Tzu's Art of War advocates "avoiding forceful attacks," and this also applies to cancer treatment. If the tumor is large and the patient is weak, forcing a forceful attack will not be beneficial. I once compared a drowning person desperately trying to survive, but would drown if they were only a foot from shore. A gentle push could save them. Don't underestimate the power of that gentle push. Hydrogen is that "push."

Hydrogen and Gastric Cancer: Live Freely

A writer worried about stomach cancer

Gastric cancer treatment is simple, if not straightforward. Early-stage gastric cancer, defined as tumors confined to the gastric mucosa or submucosa, can be easily detected by experienced gastroenterologists through gastroscopy. After surgical or endoscopic resection, the five-year survival rate exceeds 80%, and no additional treatment is generally necessary. However, treatment for advanced gastric cancer is more complex, especially for those with metastases, which can be extremely difficult to manage.

In recent months, I can't forget the expectant gaze of a writer. It was during an outpatient clinic. A thin, pale-faced, middle-aged man approached me and solemnly handed me two signed books. He was from Shandong, and from the author bios on the title pages, I knew he was a great writer. He said he had just returned from treatment in Taiwan and Hong Kong. He had stomach cancer, which had metastasized extensively to the abdominal cavity and had ascites. He shook my hand and said, "Professor Xu, you are the savior I've been waiting for!" My heart trembled as I grasped his bony hand.

I often feel anxious, distressed, and confused about the treatment of similar patients. The goal of cancer treatment is to prolong the patient's life. Everyone will die, but no one wants to die prematurely, suffer in agony, or die a miserable death. This writer expects me to be his "savior," which is too much, and I dare not accept it. However, as a doctor, saving lives is my duty.

I fantasize about finding a "magic pill" to treat this writer. An interview in Taipei on March 6, 2018, left me incredibly excited. Perhaps hydrogen could be the "magic pill" that aids this writer's treatment.

A "young" old lady in Taipei

This was the second day of our study tour in Taiwan, hosted by Mr. Lin, a Taiwanese entrepreneur specializing in hydrogen molecule research. Before leaving, the weather forecast predicted Taipei's air would be somewhat polluted. But today, we were treated to a glorious blue sky and white clouds, with temperatures hovering just over 20 degrees Celsius—a perfect balance between hot and cold, a feeling of harmony between man and nature. Our spirits were remarkably high.

The Hydrogen Experience Center is right next to the National Taiwan University Hospital. As soon as I entered and sat down at a clean white workbench, an elderly woman approached. She was of medium build, dressed in traditional Chinese attire, with a rosy complexion and gentle eyes, exuding kindness and sincerity. Her name was Lin Yang Yueying, and she was from Taoyuan. I shook her hand and asked, "How old are you this year?"

The old woman looked at me, her face beaming. The young man accompanying her immediately said, "I'm sorry, Grandma doesn't speak Mandarin. She's 86 years old."

I couldn't believe my eyes. I thought she was only in her 70s, younger than me. She was really a "young old lady".

She has advanced gastric cancer.

Her grandson took out a stack of hospital documents and a CD from his handbag. The old lady was a patient with subcardia gastric cancer. After the Spring Festival in 2014, she began to have difficulty swallowing when eating, and later she often vomited after eating dry rice. On May 21 of that year, she underwent a gastroscopy at Taipei XX Memorial Hospital and found a raised mass under the cardia, 3 to 4 cm in size, with erosion and bleeding on the image. Biopsy: poorly differentiated adenocarcinoma. Abdominal CT found a raised neoplasm under the cardia, the lesion was deep into the serosal layer, indicating advanced gastric cancer. The blood tumor marker CA19-9 was 1450 units, which was lower than normal.

It increased nearly 40 times.

Doctors recommended surgery and chemotherapy, but she refused, not because of financial reasons, as Taiwan's national health insurance program covers her. Her grandson said, "Grandma is afraid of surgery. In fact, our whole family doesn't agree with it because she still has a pacemaker. We just want her to live a few more years in peace and comfort, without pain."

"Hydrogen +" treatment

Following the advice of a friend, the old man began to inhale hydrogen, two hours each in the morning and afternoon, plus oral administration of a rice preparation called "nano-mushroom" and a mixed fruit paste, which was a "hydrogen +" treatment.

The hydrogen is produced by a device called a hydrogen atomizer.The device, equipped with special electrodes, decomposes pure water to produce 66.6% hydrogen and 33.4% oxygen, which is colorless and odorless. The device automatically controls the gas flow rate, typically 3 liters per minute when inhaled through a nasal cannula. Inhalation is extremely convenient, just like inhaling oxygen in a hospital. Elderly people can enjoy the comfort of inhaling hydrogen while watching TV at home.

She miraculously recovered

After a month of hydrogen inhalation, the patient's dysphagia improved, and a follow-up check in August 2014 revealed a CA19-9 level of 307 units. The doctor recommended oral Xeloda. A follow-up gastroscopy on October 26th revealed that the original tumor had disappeared, leaving behind "shallow ulcers and erosions." Xeloda was used until May 2015, a total of nine months, when it was discontinued due to adverse reactions. However, hydrogen inhalation continued. CT scans were performed every six months. Recent CT scans showed a patent cardia, and the original signs of the tumor had disappeared. CT scans and other tests revealed no metastasis.

Even more remarkable is that blood CA19-9 levels gradually decreased until they returned to normal. In August 2014, the month after the "Hydrogen + 2" treatment, CA19-9 had dropped to 307 units. By February 2015, it had further decreased to 40.62 units, approaching normal (normal is no more than 37). It continued to decrease thereafter, reaching 17.68 units in May 2017, three years after the onset of the disease. CA19-9 is a highly sensitive tumor marker, reflecting the presence and recurrence of tumors.

I asked the old man about his daily life, and his grandson said, "Every day I cook, do laundry, and clean at home. I'm very busy."

I asked the old man to weigh himself: 64 kg. The grandson said: Four years ago when he was sick, he weighed 58 kg. I did a simple physical examination for the old man, and his abdomen

There was no palpable mass on the forehead, but the supraclavicular lymph nodes were swollen. I shook the old woman's hand and felt that her hand was very strong.

I have been working in the field of gastroenterology for over 40 years and have never seen a patient with advanced gastric cancer live comfortably for four years without surgery. She is currently in good general condition. I advised her to undergo another gastroscopy, but she refused, saying that she was having trouble eating, sleeping, and being energetic.

Well, she lived a comfortable life and she thought "the cancer was gone".

The elderly man had taken Xeloda orally, a prodrug of fluorouracil, which is mainly used to treat metastatic colorectal cancer and breast cancer, but has limited effect on gastric cancer. It is impossible for Xeloda to have such an effect on the elderly man's gastric cancer.

So, is this the effect of "hydrogen plus"? Hydrogen molecules have been shown to inhibit cancer cells. While we can't attribute this entirely to hydrogen, it certainly played a significant role, perhaps a synergistic effect. If further evidence is available, "hydrogen plus low-dose chemotherapy" may become a treatment option for gastric cancer (and other cancers) patients who are inoperable or unwilling to undergo surgery.

Hydrogen molecules control cancer

That night, I couldn't fall asleep, so I got up and searched online for over 20 papers on the clinical applications of molecular hydrogen. I discovered that hydrogen actually has therapeutic effects on dozens of diseases, including one on cancer: molecular hydrogen can inhibit the growth and invasion of cancer cells while being harmless to normal cells. The mechanism by which it inhibits cancer is described as follows:

Reduce excessive reactive oxygen free radicals (oxidative stress), downregulate key cell division-related growth factors (ERK), inhibit vascular endothelial growth factor, and thus inhibit tumorigenesis.Tumor progression and division. Tumor progression and division.

MMP proteins are involved in multiple cellular functions (cell proliferation, apoptosis, and angiogenesis). Cancer cells overexpress MMP genes, leading to tumor invasion and angiogenesis. Hydrogen molecules reduce MMP gene overexpression, thereby inhibiting tumor invasion and growth.

● Hydrogen molecules can shorten the telomerase in cancer cells (telomerase is the "end cap" of DNA), thereby promoting apoptosis of cancer cells.

● Hydrogen molecules can improve the body's immune function, thereby enhancing the body's immune surveillance against cancer cells.

● For cancer patients undergoing radiotherapy and chemotherapy, hydrogen inhalation can reduce side effects, prevent a decrease in white blood cell count, and improve quality of life.

I sent a WeChat message to a Shandong writer I'd been thinking about that night, telling him I'd found a method for assisting the treatment of advanced cancer that might be effective for his stomach cancer. He immediately replied, "Thank you! I'll go to Guangzhou as soon as possible."

Commentary by Tang Zhaoyou

Coincidentally, many years ago, a relative of mine had undifferentiated gastric cancer and also underwent chemotherapy after surgery, but passed away a little over a year later. I was deeply surprised to read this short article. Three years later, the patient had gained weight, the gastric tumor had disappeared, and tumor markers had returned to normal. The diagnosis was correct, and the efficacy was evident. I immediately took a closer look at the treatment, which turned out to be "hydrogen combined with low-dose chemotherapy." Modern medicine inevitably asks whether there is evidence-based medical evidence and what exactly worked: hydrogen, oxygen, chemotherapy, or a combination of these. "Practice is the sole criterion for testing truth." If something works, it must have a reason. I couldn't help but think of Sun Tzu's famous saying, "Use the right approach to achieve unity, and the unusual approach to achieve victory." While the current emphasis on "using the right approach to achieve unity" (diagnostic and treatment standards) is correct, without "using the unusual approach to achieve victory," medical progress will remain.

Hydrogen and Thymic Cancer: Conquered by Hydrogen

The remaining thymic cancer was conquered by hydrogen?!

Mr. Z has been very busy and happy over the past six months. He's busy with his medical device business, and he's happy because he never imagined he'd be back in business, seemingly having waved goodbye to death.

On July 24, 2018, I first met Mr. Z in a ward on the third floor of Shandong xx Cancer Hospital. He was tall, with a ruddy complexion and sparkling eyes. He spoke with a strong Shandong accent, but his voice was loud and clear, and he got straight to the point, reflecting the straightforwardness typical of Shandong men.

"You never thought I'd make it back here alive, did you?" Mr. Z had been hospitalized in this ward and was familiar with the medical staff. He heard I was seeing a patient here today and came all the way here. He said, "After I was diagnosed with a thymic tumor at this hospital, I immediately went to Beijing for surgery. But the tumor was too large to be removed." He handed me a discharge certificate from Peking University Hospital.

On June 29, 2017, a CT scan was performed at ×× Cancer Hospital due to unexplained chest tightness. The scan revealed irregular nodules and masses in the anterior mediastinum, with the largest cross-section measuring 101 × 38 mm; multiple nodules and masses in the left pleura; and linear shadows in the left lower lobe. On July 5, 2017, a thoracoscopic biopsy of the mediastinal mass was performed under general anesthesia. During the procedure, multiple firm, white nodules were found on the surface of the visceral and parietal pleura. A mass measuring approximately 6 × 5 × 5 cm was also seen in the anterior mediastinum, closely adherent to the left lung tissue. The nodules on the surface of the parietal pleura were initially locally resected. The biopsy revealed thymoma (predominantly type B2), with the possibility of localized thymic carcinoma not ruled out. Further biopsy of the nodules on the surface of the visceral pleura in the left lower lobe was performed, with a linear pattern.

The patient's thymoma had multiple metastases in the pleural cavity and could not be radically removed.

So the surgery ended...

After surgery, he underwent chemotherapy. The first round was bearable, but after the second, he felt weak in his limbs, had trouble sleeping, couldn't eat, and was extremely tired. The 180-pound man had suddenly lost over 30 pounds. He really didn't want to endure this hardship again, so he searched for painless treatments. He went to a "center" and spent tens of thousands of yuan on "stem cell immunotherapy."

"Can stem cells cure cancer?" I was a little surprised.

"I was desperate and tried every possible method! I knew the tumor had metastasized to multiple sites in the chest cavity and chemotherapy was useless, so I had no choice but to ask around for any good treatments," said Mr. Z.

"Is chemotherapy still being continued? Only three times is not a 'course of treatment'!" I said.

"Yes, my doctor said so too. Fortunately, I met a kind person," he continued, looking at Mr. S standing beside him.

"It was him who sent me a hydrogen-oxygen nebulizer. I work in the medical device business, and I saw that it was an innovative medical product that would be approved by the state, so I used it.

"We are friends. Seeing how weak he was and not wanting to continue chemotherapy, I suggested that he inhale hydrogen while undergoing chemotherapy. I saw a report in the literature that hydrogen can reduce the side effects of chemotherapy." Mr. S, a hydrogen research enthusiast, chimed in.

"It's amazing! Hydrogen helped me a lot. Before the fourth chemotherapy, on October 1, 2017, National Day, I started inhaling hydrogen." Mr. said to Mr. S, "He asked me to inhale it for 4 hours a day, but I inhaled it for 6 hours. After a few days, my sleep improved, I wanted to eat, and I felt more energetic. During the fourth chemotherapy, the side effects were basically gone. The attending physician was also puzzled: Why didn't I have leukopenia during this chemotherapy, and didn't need to take 'white blood cell boosting'?

Needle'?"

"Does your doctor know that you are taking hydrogen?" I asked curiously.

"I don't know. At that time, they didn't know that hydrogen could cure diseases." Mr. Z said with a smile.

"Then why only four chemotherapy sessions?" I asked.

"I looked it up online and found that chemotherapy is ineffective for thymic cancer, and the doctor who treated me said so too.

Mr. Z went to the Proton and Heavy Ion Therapy Center in Shanghai.The doctor at the hospital took one look at the discharge report from Beijing, took a quick look at the CT scan, and answered bluntly, "Not suitable."

In November 2017, he went to Linkou xx Hospital in Taiwan to find Professor Liu.

"Will Professor Liu agree to another surgery?" I asked. Professor Liu is a thoracoscopy expert in chest surgery, well-known on both sides of the Taiwan Strait.

Mr. Z looked at me and said, "Professor Liu is very serious. He repeatedly reviewed the film and did a physical examination. He said that it is OK to open the"We'll open the chest and take a look, but we're not sure we can eradicate the tumor... Even such a famous doctor said that. I'm disappointed with modern medicine." There was bitterness in his voice.

Mr. Z simply stopped thinking about his tumor and spent the next week traveling around Taiwan by train and car.

He traveled a total of more than 2,000 kilometers. Strangely enough, he felt full of energy and did not feel tired or unwell. He attributed this to the hydrogen inhalation.

Mr. Z became excited as he spoke. He took out the CT scan he had just checked and the report showed that the tumor had shrunk by 2 cm and the left chest cavity had

There is a small amount of fluid accumulation, but it is significantly reduced compared with before.

"Mr. Z, do you think hydrogen inhalation is truly effective for you?" I asked in a serious tone. I say the same thing to almost every patient who undergoes hydrogen inhalation. As a hydrogen medicine enthusiast, emotionally, I certainly hope for positive, affirmative responses from patients. However, as a researcher, science and truth are paramount. Especially as a clinician, I have a responsibility to my patients. Therefore, I prefer to hear truthful responses, but I also rationally hope to hear negative, opposing responses.

"It definitely works, I have no doubt about it! Professor Xu, I came to see you today to tell you this truth, hoping others will benefit too." Mr. Z's tone was serious and earnest. He continued, "A few days after hydrogen inhalation, my energy improved. My fourth chemotherapy session didn't have the side effects of my second and third chemo treatments. If that wasn't the effect of hydrogen inhalation, what else could it be? Four months after hydrogen inhalation, a follow-up CT scan showed the tumor had shrunk by 0.1 x 0.3 cm—at least it's stable. The pleural effusion I had previously had has also decreased. I didn't receive any other treatments during this time!"

What's the next step in treatment?

Thymic epithelial tumors encompass a heterogeneous group of anatomically, clinically, histologically, and molecularly diverse tumors arising in the thymus. According to the World Health Organization (WHO) classification, thymomas are divided into subtypes: A, AB, B1, B2, and B3, based on thymic epithelial morphology. Thymic carcinomas primarily present as squamous cell carcinomas, and surgery is the only curative option.

Prognosis is closely related to stage. 50%-60% of B2 and 60%-80% of B3 thymic carcinomas fall into stage III-IV. Unresectable thymic tumors are often progressive and difficult to treat. Radiotherapy and chemotherapy are the main palliative treatments.

Mr. Z's thymic tumor was pathologically classified as subtype B2. Although the frozen biopsy did not confirm that it was thymic carcinoma,Judging from the biological behavior of multiple metastases, it is definitely "malignant".

"Professor Xu, are there any other treatments?" Mr. Z askedMy eyes are full of anticipation.

"You can repeat chemotherapy. 50% to 70% of thymoma recurrences are suitable for chemotherapy. Paclitaxel and pemetrexed are less toxic and can be used." I turned on my computer and found a paper. It was a retrospective study conducted by Dr. Song from Zhejiang Cancer Hospital. From 2000 to 2012, a total of 86 patients with advanced thymic carcinoma were treated. The objective response rate after chemotherapy was 47.7%, and the median progression-free survival was 6.5 months. There was little difference between different chemotherapy regimens (Clinics [Sao Paulo], 2015).

A sudden silence fell, and I suddenly realized that this article might be too pessimistic. I saw Mr. Z's expression was gloomy, and I thought to myself, "Maybe I hurt his confidence," feeling a little guilty.

"But, take a look at this article. It talks about prognostic factors. The general condition, histological grade and the presence of liver metastasis are the most relevant. Mr. Z is in such good health now. He looks healthier than a healthy person. His liver is clean and there is no sign of metastasis. His future will definitely be bright." In order to change the atmosphere, I asked several doctors present to look at the literature and compare it with Mr. Z's CT scan, which made everyone laugh.

"Can targeted therapy be used?" asked Dr. Wang, the director of the XX Cancer Hospital, who was present. "This disease is so rare that we're not familiar with it. Are there any reports of this type of treatment in the literature?"

I casually browsed online and came across an article published in the 2013 European Respiratory Review. Two phase II trials reported that imatinib, a tyrosine kinase inhibitor targeting KIT, failed to show beneficial effects in the treatment of thymic carcinoma. Another phase II trial, combining bevacizumab with erlotinib in 11 thymomas and 7 thymic carcinomas, failed to observe any tumor response.

"Can radiotherapy be used?" I asked Dean Wang, who is a second-level professor at ×× Medical College and a radiology expert.

Is it true that Mr. Z's remaining thymic tumor is being broken down by the tiny amount of hydrogen?

Director Wang shook his head and said, "The original lesion was too extensive, so radiotherapy is unlikely to be effective. I hope he continues to inhale hydrogen. Once the lesion is further controlled, radiotherapy may be considered."

Xu Kecheng

Conclusion

I agree with Dean Wang's opinion: continue to inhale hydrogen. Mr. Z has been inhaling hydrogen for 19 months. He said that no matter what new method

Method, never give up on hydrogen absorption!

When clinicians are at their wits' end when faced with patients, they often consider alternative treatments. Is hydrogen inhalation an alternative? Mr. Z himself isn't worried, thinking, "Since it's non-toxic and so easy to use, why not use it?"

But as a clinical study, we seem to be more concerned about data. Moreover, the dosage of hydrogen inhalation, the course of treatment, and how to coordinate with other treatments all need further research.

The 21st Century Cures Act, enacted in the United States in 2016, calls for a "real-world data" (RWE) research approach. This involves conducting non-interventional, observational studies based on clinical practice and outcomes to investigate treatment safety, efficacy, and modalities. Why not apply this approach to the study of hydrogen inhalation, a "natural" treatment?

Commentary by Tang Zhaoyou

Why are "reconstructive" therapies (such as the inhalation therapy in this case) often overlooked? The reason is simple. Ever since Virchow proposed the "cellular origins of cancer," all efforts have been directed toward "eliminating" tumors, yet reconstructive therapies do not directly eliminate them. Therefore, to prioritize both "elimination and transformation," we must begin at the source, which means renewing our understanding of the nature of cancer. In reality, cancer is not an "invasion by foreign enemies (bacteria and viruses)" like infectious diseases. Rather, it is an "internal disturbance" caused by an imbalance between the internal and external environments, as cancer cells evolve from normal cells. Just as with criminal cases, the death penalty alone is not enough; "imprisonment" is necessary, and the criteria for assessing "imprisonment" cannot be applied to "death penalty" measures. This requires recognizing that "survival with cancer" with a good quality of life should also be another "end point" in cancer treatment.

Hydrogen and Pancreatic Cancer: The Miracle of Da Ren (Part 1)

Advising Against Euthanasia

Celebrities are ultimately celebrities. Although the "fans" of celebrities are mainly young people, I, an elderly person, have surprisingly become a "fan" of Taiwan's Fu Da Ren. This is partly because he is a well-known figure on both sides of the Taiwan Strait; on the other hand, he is suffering from pancreatic cancer and is preparing for euthanasia. More importantly, it is said that he is inhaling hydrogen, which relates to my profession and research. Recently, an idea has been swirling in my mind: could inhaling hydrogen be effective for him? Perhaps I could persuade him not to go through with euthanasia?

A Truly Famous Person

Fu Da Ren is undoubtedly famous across the Taiwan Strait. He was once a basketball expert and coach in Taiwan, winning a silver medal at the Asian Games and broadcasting over 10,000 NBA and other events. He hosted the TV variety show "Da Jia Le," winning the Golden Bell Award for excellent variety programs. At the 1990 Beijing Asian Games, he provided commentary alongside the renowned sports broadcaster Song Shi Xiong from the mainland. On New Year's Eve in 1991, Fu Da Ren and his wife participated in the CCTV Spring Festival Gala, performing a segment called "Shandong Da Shi Hua." His eloquent words have captivated countless "fans."

Fu Da Ren is also notable for being a descendant of anti-Japanese heroes. His father, Fu Zhong Gui, was a major general in the National Revolutionary Army, hailing from Changqing, Shandong. He died fighting against Japanese invaders in 1938 along the Yellow River in Shandong. His mother passed away early as well, leaving Fu Da Ren an orphan at a young age. He faced many hardships before being taken in by Soong Mei Ling and arriving in Taiwan at the age of 15.

Even More Famous: He Has Advanced Pancreatic Cancer and Applied for Euthanasia

In recent years, Fu Da Ren has become a legendary figure in Taiwan because he hopes to personally experience euthanasia, only to be miraculously "brought back" from it! In May 2017, 84-year-old Fu Da Ren was diagnosed with pancreatic cancer, losing weight from 74 kg to 58 kg within three months. He urged Taiwan's leaders to establish a "Euthanasia Act for Those with Terminal Illnesses," stating, "If the bill can pass, I am willing to be the first to accept euthanasia." He even planned to change his new book launch into a "farewell" memorial service.

He found Dignitas, the only organization that provides euthanasia services for international clients, and became a qualified member. In November 2017, he traveled to Switzerland, obtaining a "green card" for euthanasia in a country where it is legislated, preparing to go there a few months later. On November 19, 2017, Taiwan's United Daily News reported: "Fu Da Ren has obtained permission for euthanasia and 'is going home.'"

At 84 years old, Fu Da Ren, a veteran sports broadcaster from Taiwan diagnosed with terminal pancreatic cancer and given only two months to live, actively advocated for "dignified euthanasia." He recently planned to travel to Switzerland with his family to seek euthanasia. He had already received clearance for travel and planned to document the entire process on Facebook. He posted a photo of himself embracing his son, expressing mixed emotions about the impending farewell, saying, "It's hard to let go! It's hard not to let go! Tears cannot express the sorrow of that century-long farewell!" He revealed at the end that he "is going home" and would rush to create paintings of himself with his son for an exhibition in Taipei, urging everyone to support the euthanasia bill.

Taiwanese media reported:

Fu Da Ren appeared on a program with his son Fu Jun Hao, sitting beside him with his arm around his son's shoulder, gently asking, "Will you be okay when I'm gone?" His son, unable to speak for a long time, replied, "Dad, I love you!" Fu Da Ren was very emotional and responded, "Son, I love you."

Postponing the Trip to Switzerland

On January 27, 2018, Taiwanese media reported—

84-year-old famous sports broadcaster Fu Da Ren, suffering from advanced pancreatic cancer, sought euthanasia and had traveled to Switzerland, where he had received the "green light" to proceed. He originally planned to fly to Switzerland at the end of the month, even choosing to wear a bright red suit to welcome this "happy event." However, on the 26th, his son told him, "Dad! Yan Ru and I have decided to get married before the Spring Festival! Slow down!" He decided to postpone his trip, leaving behind trophies and photos with Taiwanese celebrities, all to support his son's wedding, exclaiming, "I am speechless!"

Fu Da Ren mentioned he has had 2.5 marriages. His first wife bore him a daughter and they divorced; she now lives in the U.S. His second wife was a widow of a Taiwanese Navy officer and a broadcaster. The "0.5 marriage" refers to Miss Chen, who is 36 years younger than him. Although they never formalized their engagement, she has always accompanied him and is considered a confidante. At 17, Miss Chen admired Fu Da Ren's talent and gave birth to a son, Jun Hao, who is now 26 years old, 180 cm tall, and handsome. As an elderly father, Fu Da Ren's love for his son is evident, and even his second wife views Jun Hao as her own. Jun Hao often says he is happy to have two loving mothers. Fu Da Ren decided to hold off on his trip to Switzerland until after his son's wedding.

Visiting Fu Da Ren

On March 6, 2018, the day after our group from the mainland arrived in Taipei for a "hydrogen" journey, we were driven by car through the Sun Yat-sen Memorial Hall, catching sight of Taiwan's largest media center, the Taiwan Television building, and walking through several old streets before stopping in front of a regular apartment building on Section 3 of Bade Road. Mr. Lin, familiar with the area, led us into a small elevator and up to the third floor, where a door stood open. A tall, thin elderly man was waiting at the door, shaking our hands tightly while saying, "I am Taiwan's Song Shi Xiong."

He was Fu Da Ren! With his tall and robust figure, flowing white hair, and dressed in black traditional attire with a white floral scarf, he still exuded the charisma of a media star despite his serious illness. We all sat down on the sofa in his modest living room, which made it hard to believe this was the home of a media giant. However, the countless certificates and awards adorning the walls showcased his profound cultural background and high social standing. A large photo of basketball star Jeremy Lin shooting a basket on the front wall indicated the owner's passion for basketball.

Standing face-to-face with me, Fu Da Ren spoke my many "titles" in one breath, smiling as he said, "I was so happy to hear you came from the mainland; I immediately did some 'homework' about you online. We are brothers sharing the same illness!" He took my hand and said, "I am planning my trip to Switzerland at the end of this month. Since you are here, you may be my last group of friends from the mainland!" He mentioned that he had completed two things: he had hosted his son's wedding and distributed his assets, leaving him with no attachments.

He took out a basketball signed by himself and Jeremy Lin, solemnly handing it to me, saying, "I am leaving soon, and I have nothing valuable left, only this basketball, which is my treasured possession, for you, 'the great one.'" He then picked up a recently published book, signed it, and posed for a photo with us.

He spoke passionately about his illness. He said he has pancreatic cancer and has suffered greatly. He does not want to cause pain to his family or consume social resources, so he resolutely seeks euthanasia.

"Actually, I am reluctant to leave my son and family. The happy thing is that after returning from Switzerland, I held a wedding for my son." Fu Da Ren laughed heartily. He added, "Strangely enough, aside from abdominal pain and diarrhea, everything else seems to be getting better."

I conducted a simple physical examination on him and found no enlargement of the liver or spleen, no ascites, and no palpable masses. There was deep tenderness in the abdomen. He mentioned that the doctor informed him of abdominal cavity metastasis. However, based on my experience, he has not yet reached a state of "terminal illness." This gave me confidence in treating him. Of course, I needed to understand his treatment history. He explained that the critical turning point occurred in the past two months.

I asked what treatments he had undergone since being diagnosed with pancreatic cancer. He told me that the tumor was located at the head of the pancreas, compressing the common bile duct, causing jaundice. The doctor placed a stent in the bile duct during an endoscopy; he took morphine tablets for pain relief but did not undergo any other special treatment.

He remarked, "Pancreatic cancer is too aggressive; surgery is not an option. The world-renowned tenor Pavarotti had pancreatic cancer, underwent surgery and chemotherapy in the U.S., and suffered greatly, yet he only lived for 13 months. I advocate for courage in youth and joy in old age. Therefore, I want to be the first person in Taiwan to experience euthanasia, also to tell others—death should be joyful!"

"But your current condition is stable," I found it hard to understand. Generally, pancreatic cancer progresses, and since it has been a year since the onset in May 2017, it seems inconsistent with the "norm."

He pondered for a moment, seemingly realizing something, and said, "I inhale hydrogen, hydrogen gas. Since October 17, 2017, I have been inhaling hydrogen for 6 hours a day." He looked at Mr. Lin, who was present, and said, "It was Mr. Lin who sent me the hydrogen inhalation device from the mainland; we have been friends for many years." He took Mr. Lin's hand and said, "Thank you."

Is Hydrogen Effective?

Mr. Lin stated, "Because Teacher Fu had no other options left. I have been researching the effects of hydrogen on the human body for seven years and found that when creating tumor animal models, if the animals inhale hydrogen simultaneously, the models cannot succeed. In cell cultures, it was also found that in a hydrogen-rich environment, the movement of tumor cells slows, and cell division decreases."

Recent research on "Chinese-style cancer control" has given me a mindset of "not giving up easily" when facing patients, or perhaps an impulse. Academician Tang Zhao You advocates for "control" rather than "fighting cancer." Cancer cells are not invading "foreign enemies" but are "internal rebellions," resulting from normal cells undergoing genetic mutations due to adverse environmental factors. For "external enemies," such as bacteria and viruses that cause diseases, we must "fight," meaning to eliminate them entirely. However, for the "internal rebellion" of cancer cells, we can only "control," which involves both extermination and transformation.

How to "control"? Academician Tang Zhao You explains the "cancer control" strategy using "The Art of War" by Sun Tzu. As Sun Tzu states in the chapter on "Force": "In war, engage with the regular and win with the extraordinary." "Regular" is the foundation, "extraordinary" is the soul. Simply following the routine is hard to breakthrough; the key is to win through surprise. In the chapter on "Form," it states, "The good defender hides beneath the nine layers of earth." If the tumor is fierce and cannot be eradicated, one must "keep a low profile," attack moderately, and enhance one's "stability" (immune capacity) to coexist peacefully with cancer cells.

Hydrogen is a selective neutralizer of toxic free radicals like ·OH and other reactive oxygen species. Reactive oxygen species have strong oxidative properties, damaging cellular nuclear DNA and mitochondrial DNA, leading to cellular mutations. Hydrogen can "transform" cancer cells and their microenvironment. Could Mr. Fu Da Ren's pancreatic cancer be controlled by this small natural substance H2?

I want to study Da Ren's treatment and understand "exactly!"

Furthermore, for a celebrity like Fu Da Ren, who embodies the spirit of the Chinese nation, an idea has emerged in my mind: save him!

I also thought that if we apply the "Chinese-style cancer control" strategy for further treatment, perhaps we could truly "engage with the regular and win with the extraordinary," saving him!

Inviting Him to Guangzhou

I invited him to the mainland, to Guangzhou. I said, "Brother Da Ren, it seems we are fated to meet; let’s go to Guangzhou, at least to enjoy the delicious food there."

Fu Da Ren immediately stood up, saying, "Really? I miss the mainland so much; there are so many friends there. Guangzhou has too much delicious food, and I can enjoy it well."

He held our hands and said, "To Guangzhou, let’s walk the path of survival!" A true media person, his every word and action radiated uniqueness.

Xu Ke Cheng

Commentary by Tang Zhao You

This touching text reminds me of the saying, "When the mountains are heavy and the waters are deep, doubts arise, but the willows are dark and the flowers bloom in another village." People cannot live forever, but they can extend their lives. Readers must ask: "Is it really the effect of inhaling hydrogen?" I think it is difficult for anyone to answer definitively, as the patient has undergone multiple treatments. The relief of late-stage pancreatic cancer is indeed a "coincidental" event, yet "inevitably resides within the coincidental." Inhaled hydrogen clearly does not belong to large-scale tumor extermination therapies, but on the basis of tumor extermination, it may achieve "small victories leading to great victories," hinting at the importance of "extermination and transformation in tandem."

Hydrogen and Pancreatic Cancer: The Miracle of Da Ren (Part 2)

"Rebirth" in Guangzhou

On the evening of April 5, 2018, at 7 PM, in a private room on the fifth floor of the Sunshine Hotel on Huangpu Avenue in Guangzhou, I treated Mr. Fu Da Ren to dinner, celebrating the results of a full gastrointestinal barium meal imaging he underwent all day, which found no evidence of "cancer metastasis" in the abdominal cavity. Mr. Fu was eating sea cucumbers heartily. The sea cucumbers were imported from Brazil by a friend of mine and are said to be "purely natural," "high in arginine," and "have anti-cancer effects." Suddenly, Mr. Fu's eyes turned red, and his hand holding the chopsticks trembled as he said, "If I hadn't come to Guangzhou, I would have left this world 48+8 hours ago." His voice was calm but tinged with bitterness.

Sitting to his right, his confidante Miss Chen also had tears in her eyes. She said, "The day before yesterday, April 3, was Mr. Fu's birthday, and it was originally his death day..."

Mr. Fu continued, "I have pancreatic cancer, and there are no treatment options in Taiwan. With the medical certificate from a Taiwanese hospital, my family and I went to Switzerland in November 2017. That is the only place in the world that allows foreigners to undergo euthanasia. After arranging my son's wedding, I had already purchased tickets for my family to return to Switzerland on March 26 of this year, scheduled for 11 AM on April 3, my birthday, to begin the death process: first, I would take a liquid orally, and three minutes later, I would fall asleep. Then, a lethal injection would be administered, and I would die in ten seconds."

He spoke slowly, as if recounting someone else's story.

My vision blurred with tears, and I suddenly grasped Mr. Fu's hand while Miss Chen came to stand behind us. Our three hands tightly held together, shaking. I said, "Let’s celebrate Brother Da Ren's rebirth!"

"Yes! I have passed my 'death day,'" Mr. Fu's voice suddenly rose, "Rebirth in Guangzhou! How joyful!"

Whether there is really "rebirth" is unclear; some say from a quantum perspective, perhaps life has "reincarnation." Buddhism believes in reincarnation. But Mr. Fu's life has indeed reversed over the strait.

"If it weren't for your visit to Taiwan on March 6, and if Mr. Lin hadn't brought me from Taiwan to Guangzhou on March 22, I would have flown to Switzerland; what a fate..."

Mr. Fu was excited and laughed heartily.

Arriving in Guangzhou

On March 22, 2018, at 6 PM, Fu Da Ren, under the escort of Mr. Lin, arrived in Guangzhou. Although he occasionally experienced abdominal pain and diarrhea, with watery stools, the freshness of being in Guangzhou after many years made him very excited.

Mr. Fu was admitted to my hospital's VIP ward 501, which is closest to my office on the sixth floor for easier care. Dr. Kong, the attending physician with over ten years of experience, was specifically responsible for his medical care, and the nutrition department manager prepared his meals. He quickly underwent a series of tests, including blood work, ultrasound, CT scans, X-rays, and barium meals.

Incredible Results

The test results came out, both expected and hard to believe. The CT scan showed that his pancreatic cancer still existed, with a tumor about seven to eight centimeters in the head of the pancreas, invading the bile duct, where a stent was placed; the pancreatic duct was dilated at the body and tail of the pancreas; there were multiple small lymph nodes surrounding the blood vessels. Compared to the PET-CT scan taken two months earlier at a major hospital in Taiwan, the differences were minimal. However, the incredible news was that the "shiny" metastatic lesion near the liver in the left lobe was gone.

The CT scan on March 25, 2018 (enhanced) showed a tumor in the head of the pancreas, similar to the tumor image from the previous PET-CT scan. Mr. Fu's pancreatic cancer had entered its ninth month. For patients with inoperable pancreatic cancer, the median survival time is six months. After six months, it is common for metastases to occur, especially in the liver, often leading to widespread liver metastases, as well as lung and abdominal cavity metastases. However, his lungs were clear, and after undergoing a gastrointestinal barium meal test, the radiology director spent over eight hours observing the barium as it moved from his esophagus to his rectum. Aside from discovering that his sigmoid colon was elongated (possibly congenital), the intestinal movement was good, with no signs of adhesions or metastatic tumors in the abdominal cavity.

More astonishingly, circulating tumor cells were only 1 per milliliter (within the normal range); various types of lymphocytes and cytokines reflecting immune function in his blood were "completely normal."

These tests indicated that Mr. Fu's pancreatic cancer was in a "stable" state. What "miraculous medicine" has made this fierce tumor seemingly "behave," at least slowing its progression?

Fu Ren also found it hard to believe the new test results, especially that the liver metastasis had vanished. The basis for the Taiwanese doctor's conclusion that he "needed no treatment" was the metastasis: liver and abdominal cavity metastases. He requested the radiology director to come to his room to explain whether the liver metastasis had truly disappeared.

The Role of Hydrogen

Fu Da Ren firmly believes: it is hydrogen that is saving him.

Indeed, if not hydrogen, then what? He has not undergone any "anti-cancer treatment," only had a bile duct stent placed, which was to relieve pressure from the pancreatic tumor and allow bile to drain, not having any anti-cancer effects.

On October 17, 2017, Mr. Lin sent him an oxygen nebulizer. As a Christian, he believes this is a gift from God. He believes that God provides oxygen for people to live and sends hydrogen for them to regain health.

Since Japanese scholar Professor Ohta first proposed that hydrogen has selective antioxidant effects in 2007, a large body of research has focused on the biological effects of hydrogen molecules, discovering that hydrogen, as a new type of antioxidant, has the following unique advantages—

First, it has selective antioxidant effects. Hydrogen's reducing ability is relatively weak and does not react directly with weakly oxidizing reactive oxygen species, but it can react with strongly oxidizing reactive oxygen species, such as hydroxyl radicals and nitrite anions. Second, hydrogen itself has a simple structure, and the products of its reactions with free radicals are also simple, leaving no residues and having no toxic side effects on the body. For example, it reacts with hydroxyl radicals to produce water, and excess hydrogen can be expelled through breathing. Third, hydrogen has a low molecular weight, allowing it to pass through the blood-brain barrier and diffuse freely into any part of the cell, including the nucleus and mitochondria.

Cancer cells are products of normal cells undergoing genetic mutations and changes under environmental influences, such as smoking, chemicals, radiation, infections, inflammation, negative emotions, and excessive exercise, all of which can promote the production of free radicals and facilitate genetic mutations in cells. Therefore, using hydrogen for antioxidant purposes to eliminate free radicals theoretically can suppress cancer cells and inhibit cancer progression. Of course, the effects of hydrogen molecules may extend beyond this, but existing experiments have undoubtedly shown that hydrogen has a suppressive effect on cancer cells.

Has Fu Da Ren's liver metastasis disappeared due to hydrogen? I hope to get further confirmation. However, from a clinical perspective, using hydrogen to "transform" cancer cells or their microenvironment, this simple, inexpensive, and non-toxic small molecule is certainly beneficial and harmless.

Enjoying Happiness

Fu Ren is ultimately a media person, knowledgeable and experienced. He wants to fully enjoy the happiness of being in Guangzhou. He said, "From now on, all the time for me is a gift from God."

I had considered using percutaneous cryoablation or irreversible electroporation (nanoknife) to ablate the pancreatic tumor, but for an 85-year-old, my biggest concern is safety, even though these are minimally invasive procedures...

I called in the best acupuncture doctor in my hospital and invited renowned pain specialists from Guangzhou to apply all available pain relief medications, intestinal function regulators, immune modulators, and traditional Chinese medicine...

Of course, I encouraged him to continue inhaling hydrogen. He is very experienced, inhaling for three hours each morning and before bed. He uses a mask instead of a nasal cannula and intentionally increases his breathing volume while inhaling. He said he knows that hydrogen molecules are very small and light, so he needs to exert some effort to drive them to the "ends of the earth" within his body.

As "The Art of War" by Sun Tzu states, "Defeating the enemy without fighting" is the way to victory. The body is a whole, and recovery from illness involves mindset, nutrition, exercise, and detoxification. "Toxins" refer to toxic reactive oxygen species, and hydrogen undertakes this task, but the force may not be enough; all aspects must work together to perhaps achieve "a little force can move a thousand pounds" and "win through surprise."

I kept my promise to let him enjoy the delicious food in Guangzhou. Besides the special diet prepared for him by the hospital, every few days, either I or my colleagues took him to various distinctive restaurants in Guangzhou to enjoy the food. We had Cantonese cuisine, Huaiyang cuisine, Chaozhou cuisine, and not only regular meals but also dim sum. He has a great appetite, and I often told him, "Brother, control yourself."

The earliest and most common symptom of pancreatic cancer patients is loss of appetite, so I was delighted that Mr. Fu could eat so well, as I had rarely seen a pancreatic cancer patient with such a good appetite. Yet, I was also worried because pancreatic cancer patients often have pancreatic insufficiency, and I was concerned he might not be able to digest.

His episodes of pain began to decrease, and his bowel movements reduced from over ten times a day to eight, six, and then three...

One time, I entered his room just as Miss Chen, whom he referred to as his "0.5 marriage," was nestled beside him, caressing his face and pinching his cheeks. Upon seeing me, she shyly smiled and said, "Director, look, he has gained weight. Since coming to Guangzhou, he has gained two kilograms."

Can a late-stage pancreatic cancer patient "gain weight"? What wonderful news!

One morning, as I walked into his room, Fu Da Ren suddenly stood up from the sofa, stood at attention, and saluted, saying, "Reporting to the director, today's stool is formed!"

He had become like an innocent child.

He took my hand and said earnestly, "Director, I am very worried." Just when I was both surprised and concerned, this old child burst into laughter, saying, "Now that the abdominal pain has lessened, if I return to Taiwan and don't have abdominal pain, how will I adjust?"

He truly is a big star and a well-known media personality from Taiwan!

"Triumphant" Return to Taiwan

Fu Da Ren was returning to Taiwan, and the nurse accompanied him to the site of the old Huangpu Military Academy and Beijiao. He cried, unable to speak for a long time...

On the morning of April 21, at 9:30 AM, Mr. Fu Da Ren, along with his confidante Miss Chen, boarded a China Southern Airlines flight, "triumphantly" returning to Taiwan.

After returning to Taiwan, Miss Chen sent a WeChat message: "… My husband walked from the door of death to the door of life; we are grateful for five generations..." At 7:14 PM, Mr. Fu sent a WeChat message: "… Being by your side for so many more days, so many blessings, it’s hard to forget! Whether I open my eyes or close them, it’s your smiling face… Little Qian (Lei Qian, Fu Da Ren's stepdaughter, chairwoman of the Taiwan Women's Association, former legislator of the Kuomintang) is very grateful..."

He later called, saying, "A month later, I will definitely go back to Guangzhou."

I happily replied, "I’ll be waiting for you to return, Brother Da Ren."

Xu Ke Cheng

Commentary by Tang Zhao You

This is Professor Xu's second article about Mr. Fu Da Ren, even more touching than the first. People cannot live forever, but they can extend their lives. However, even though cancer patients can extend their lives, they often suffer greatly. It is rare for late-stage pancreatic cancer patients to have a certain quality of life while extending their lives; I can't help but think of the role of "comprehensive treatment." I believe Mao Zedong's "On Protracted War" has three key points: First, view guerrilla warfare as strategically significant and do not underestimate "small skirmishes"; second, be flexible and mobile, advancing and retreating, not just advancing; third, emphasize "base construction." To combat cancer, one must "strengthen the body while combating the disease."

**Hydrogen and Pancreatic Cancer: The Miracle of Fu Daren (Part 3)**

**Shanghai Urgent Message**  

On the morning of June 1, 2018, as I arrived at the office, the phone rang urgently. Mr. Lin from Shanghai said, “Director, it’s urgent, Fu Daren has gone to Switzerland.”  

“What’s going on? Wasn’t he supposed to come to Guangzhou soon? We were all prepared!” I could hardly believe it. “He promised me he would cancel his trip to Switzerland!”  

“He was pressured by the media in Taiwan. The media and public opinion in Taiwan are fierce,” Mr. Lin’s voice was filled with anger and helplessness.  

For nearly half a year, Fu Daren had written several letters to Taiwan's leaders advocating for euthanasia to be implemented in Taiwan, wanting to be “the first case in Taiwan.” News about him appeared almost daily in Taiwanese newspapers and on television. Some articles were heartbreaking; one had a large headline reading, “What’s the progress of Fu Daren and Li Ao?” He solemnly called out to Li Ao, “Master Li, see you in heaven.”  

**Flying to Switzerland at Night: “Saving Lives Under the Knife”**  

A few minutes later, Mr. Lin called again, saying, “I’m checking for tickets and will fly to Switzerland immediately.” Just moments later, my son Xu Honghui called from Shanghai, saying, “I’m accompanying Mr. Lin, preparing to fly to Switzerland to represent you.”  

The next morning, Honghui sent a WeChat message:  

“We arrived in Zurich, Switzerland, at 2 PM on June 2. Earlier, Mr. Lin’s son had flown from Birmingham, UK, to meet us. We rented a car and reached the hotel by 4 PM. But in the vast Zurich, where can we find Daren? Mr. Lin called his immediate family, but all their phones were off. He inquired with friends and the Zurich Taiwanese Business Association, but no one knew where Fu Daren was staying. It was getting late, and we could only wait until the next day to find another way. The three of us had dinner in silence…”  

At 10:30 PM the next day, it was my usual bedtime, but I couldn’t sleep, my heart was always anxious. I sat in the study, checking my phone while browsing the internet for information on “euthanasia” in Switzerland, hoping to help Mr. Lin and his team from afar. Suddenly, the phone rang; it was Mr. Lin calling, saying, “We found Fu Daren; he is currently in ‘negotiations.’”  

It turned out that the wise Mr. Lin had found Daren’s Facebook page online, which had a street view photo. Following the road signs in the picture, they discovered Fu Daren was staying at the Marriott Hotel right next to theirs. They went to the hotel front desk and found Daren’s son Junhao and his mother, Miss Chen. Upon hearing that Mr. Lin’s group had arrived, Fu Daren was shocked and cried uncontrollably…  

Mr. Lin said, “I’ll give you a brief report to help you sleep better.” He confidently said, “Don’t worry, Director, we are confident we can bring him back…”  

How could I sleep peacefully? I immediately sent a letter I had prepared for Fu Daren—  

“Brother Daren, we miss you! Come back soon.”  

Four years ago, I had similarly persuaded a late-stage pancreatic cancer patient. She was a beautiful 17-year-old girl named Xiaofeng, whose pancreatic tumor had spread to the surrounding area and to her liver, causing significant drops in various blood cell levels. She experienced pain, bleeding, and could not eat, having attempted suicide several times. Upon learning of her situation, I drove four hours with my colleagues one Sunday to persuade her to come to my hospital for treatment. Miraculously, her condition improved significantly. Although her tumor still exists, she now “coexists with cancer” and has almost no symptoms. Her name is Xiaofeng, and she now works at a company in Guangzhou…  

“Brother Daren, although you are older than Xiaofeng, you have even more people who love and care for you. You have many miracles: First, your pancreatic tumor has stabilized, showing no significant progression for ten months. More importantly, the ‘liver metastasis’ detected in Taiwan has disappeared, which is something that usually does not happen with pancreatic cancer. Second, your abdominal pain and diarrhea are not caused by the pancreatic tumor; they are due to functional abnormalities in the intestines, which can be controlled. In a sense, there is no pain that cannot be managed. Third, you have a good appetite, want to eat, and want to enjoy good food, which is an incredible sign; it’s rare for late-stage pancreatic cancer patients to “want to enjoy good food”…”  

“Brother Daren, come back to Guangzhou and Shanghai; we will do our utmost to treat you. You will survive and live happily and joyfully!”  

—Xu Kecheng, June 2, 2018, at 6 AM in Guangzhou  

I also sent an English letter to the compassionate euthanasia clinic in Switzerland, informing them that as Fu Daren’s attending physician, he had not yet reached the “euthanasia” criteria and that he could survive. I hoped they would “spare him.”  

**The Decision is Made**  

However, Fu Daren was resolute in his decision; he said he missed the mainland, missed his hometown in Shandong; he cherished his time in Guangzhou, especially that happiest month there. He knew that his pancreatic cancer would not kill him immediately, and he could survive, but he had promised society to be a model for “euthanasia.” He wanted to help those late-stage patients who rely on a few “tubes” to sustain their lives to leave their suffering as soon as possible…  

He posted his last message on Facebook, saying to friends from all walks of life, “If you have me in your heart, death is not a farewell,” and joked that he would continue to “argue” with Li Ao in heaven. He accepted a final interview with the media, saying, “This is my last stop; I’m getting off.”  

At 5:33 AM on June 7, I received a WeChat message from Fu Daren—  

“Dear brother, Director Xu Kecheng: You have done your best; your kindness to me moves me deeply, a debt of gratitude that cannot be repaid... According to destiny, everyone must die; sending you off a thousand miles, there will eventually be a parting. By God’s grace, I will extinguish my earthly toil and return to heaven, resting in the Lord’s embrace. Goodbye, my brother! I will bless you with lifelong peace, joy, health, and longevity! Take care.”  

Seeing this farewell message, I was filled with despair, imagining whether Fu Daren was crying, smiling, silent, or giving instructions. I imagined my son, representing me, following Mr. Lin to save someone thousands of miles away, only to return empty-handed, surely feeling guilt and regret…  

I subconsciously opened my phone and sent Fu Daren a WeChat message, wishing him, “Brother, safe travels, and joy in heaven.”  

**Farewell in Taiwan**  

On June 22, my secretary Tian Yu and I flew to Taipei, where we met with Mr. Lin, who had arrived earlier, and went directly to Fu Daren’s memorial hall, located not far from Taiwan Television. Fu Daren’s wife, Zheng Yi, led their son, daughter-in-law, and close friend Miss Chen to receive us. Zheng Yi, who had been a radio host, was over 80 but looked like a middle-aged woman in demeanor and speech. She solemnly conveyed Fu Daren’s last wishes: first, to thank the two benefactors he met in his final days—Mr. Lin and Dr. Xu Kecheng—for providing the miraculous substance “hydrogen” and their meticulous care; second, to ensure that Lin and Xu could watch the “farewell” video.  

This was a 15-minute video, the last family meeting before Fu Daren’s passing. In the video, Fu Daren first spoke about his tumultuous experiences, then vividly performed as a live NBA host, and finally asked his family members sitting around him to “sing a farewell song” together. He concluded with, “When young, we strive forward; when old, we joyfully say goodbye. Farewell! I love you, goodbye!”  

Ms. Zheng told us that before Fu Daren “left,” he showed no sadness, posting articles on Facebook daily and communicating with the media, filled with excitement, grateful to heaven for allowing him to “live for 86 years, 6 months, and 6 days,” expressing that the “extended match of life had honorably concluded,” and asking everyone to cooperate with him in hosting his final program: a peaceful end. Because Fu Daren’s father was a general who died fighting against Japan in World War II, he had originally planned to end his life on June 6—the day General MacArthur led the Allies to victory in Normandy—but due to reasons from the Swiss agency, it was delayed until the next day. On June 7 at 4:15 PM local time, Fu Daren entered the “peaceful end house,” reaching the natural, painless destination he had chosen in life.  

“Until the end of his life, he continued to comfort us. To alleviate our unbearable sorrow, that morning, he specifically accompanied us to the park,” Ms. Zheng said, her eyes reddening.  

Fu Daren’s ashes were placed in a Christian peace garden in Jinshan, a suburb of Taipei. The urn, gravestone, and burial site were all designed and chosen by Daren himself during his lifetime. Many cultural celebrities from Taiwan are buried here; he expressed a wish to remain with friends even after death, even if they argue, it would still be a joy.  

Ms. Zheng pulled me close as Fu Daren’s son solemnly placed his ashes in the grave. I suddenly felt a chilling sensation and a deep, ancient emotion. I recalled a scene from over two months ago, on April 5, at a banquet in the Sunshine Hotel in Guangzhou, when Fu Daren, after receiving a complete abdominal radiological evaluation showing “no evidence of metastasis,” was extremely excited, tears in his eyes, tightly holding my hand and saying, “It’s fate.”  

At the memorial, a band played somber songs, but in my ears, I still echoed the farewell song Fu Daren sang before “leaving” in Switzerland…  

“Parting sorrows gradually fade away, endlessly flowing like spring water.”  

A flock of birds suddenly flew overhead, not crows, but small yellow birds with red accents, chirping as if to remind everyone: Fu Daren, a great teacher, he will forever be the one singing.  

**Xu Kecheng**  

**Commentary by Tang Zhaoyou**  

It is truly regrettable that this pancreatic cancer patient actively applied for “euthanasia” because his pancreatic cancer had not progressed to the “final” stage. His pancreatic cancer was still stable, and the liver metastases were even undetectable on CT scans. I admire the patient’s fearlessness and courage in pursuing his “ideals.” His pancreatic cancer had lasted over 20 months since onset, during which he did not undergo any cancer treatment, only inhaled hydrogen. Whether the effects were due to hydrogen requires further research, but the tumor’s “stability” is certain.  

This is a typical case of “coexisting with cancer.” For cancer, complete “eradication” is certainly best, but it is practically impossible to completely eliminate cancer cells; thus, we should focus on “remodeling,” including remodeling cancer cells, the microenvironment, and the body. Given that pancreatic cancer is often inoperable once diagnosed, allowing patients to “coexist with cancer” should be the primary treatment strategy. Using hydrogen for rehabilitation can be a significant breakthrough.  

**Hydrogen “Protects” the Lungs: Safeguarding Health**  

**The “Miraculous Responder”**  

On March 5, 2018, at the Hydrogen Experience Center on the right side of Taipei’s National Taiwan University Hospital, I met Mr. Zeng, who was 84 years old. He was of medium build, slightly hunched, and his weathered face was covered with wrinkles, leaving deep marks of time. His deeply set eyes still seemed spirited. He sat silently in a chair. I approached and shook his hand; he looked at me, appearing a bit shy, and said, “I come here every day to inhale hydrogen; they treat me well!” He pointed to a service lady nearby.  

Accompanying Mr. Zeng was his son, who told us: his father had endured hardship, having worked as a coal miner for decades. The local coal mines had poor ventilation facilities, and although all the mines had closed in 2000, many miners were left with numerous diseases, almost all suffering from “pneumoconiosis.” Mr. Zeng’s pneumoconiosis was severe, and he had to be hospitalized several times every year.  

“In 2017, during one hospitalization, he nearly ‘left’ us,” Mr. Zeng’s son said. “After inhaling hydrogen, he has improved to today.” He excitedly took out Mr. Zeng’s chest X-ray.  

I examined Mr. Zeng’s chest X-ray. The quality was not very good, but it clearly showed patchy shadows of varying sizes in the upper, middle, and lower lung zones, with the right middle and lower lung zones being the most affected, graded at level 3 density, diagnosable as stage III pneumoconiosis. Mr. Zeng’s son said, “This is a recent film; the previous ones were much worse, both lungs were covered in patches, it was frightening!”  

When Mr. Zeng was hospitalized in 2017, he could hardly breathe, could not lie flat, his heart rate was 140-160 beats per minute, and his lips were purple. Even with high concentrations of oxygen, his blood oxygen saturation was only 90%. The doctor diagnosed him with “heart and lung failure” and issued a “critical illness notice.”  

“At that time, we family members had little hope left. It was heartbreaking that my father had suffered his whole life without enjoying any blessings; if he left just like that, it would be hard to accept,” Mr. Zeng’s son said.  

After all, they were of the same ethnicity, and the two sides had been separated for nearly 70 years, yet customs remained similar: elderly people hope to pass away at home. Mr. Zeng was taken out of the hospital by his family. Upon a friend’s recommendation, he went to the Hydrogen Experience Center to inhale hydrogen. In fact, he was not just inhaling hydrogen but also oxygen. Mr. Zeng used a hydrogen-oxygen nebulizer, which works by electrolyzing pure water with direct current and a small amount of food-grade catalyst, producing H2 and O2 molecules that are released from the cathode and anode. The inhaled gas consisted of 34% oxygen and 66% hydrogen.  

In clinical trials of drugs, there are often complete failures, but occasionally one or two miraculous effects are observed, earning the label of “miraculous responders.” Mr. Zeng is one such “miraculous responder.” His response was not to any specific drug but to the most ordinary hydrogen gas. After inhaling hydrogen and oxygen, his wheezing improved, his heart rate decreased, and the lung lesions stabilized.  

I was very pleased, both to see Mr. Zeng’s “miraculous response” and because it seemed to add another treatment weapon for us. In our hospital, we often see patients with chemotherapy-related lung damage, typically treated with steroids, but the effects are limited and side effects are particularly significant. Could hydrogen be used as an alternative treatment for these lung diseases?  

**The Painful Experience of an Indonesian Patient**  

In my book published a year ago, “Practicing Cancer Control in the Chinese Way,” I recorded the painful experience of an Indonesian patient—  

A 51-year-old male, diagnosed in August 2015 at a local hospital with right lung cancer and multiple metastases to both lungs and bones, pathologically adenocarcinoma, with an EGFR19 exon mutation. He underwent pemetrexed and carboplatin combination chemotherapy, every three weeks for a total of six cycles. The tumor progressed, and he switched to oral gefitinib treatment for three months, with no improvement, then switched to erlotinib for two months. The tumor continued to progress, and after stopping erlotinib, he began taking AZD9291 (osimertinib, a third-generation EGFR mutation inhibitor). On August 20, 2016, due to breathing difficulties, he was admitted to my hospital in an emergency. Examination revealed enlarged lymph nodes in the neck, compressing the trachea, necessitating a tracheostomy; CT showed bilateral diffuse ground-glass opacities with reticular nodules, likely due to interstitial pneumonia caused by the targeted drug, complicated by lung infection. He received symptomatic treatment with antibiotics and methylprednisolone, which slightly improved his symptoms, but he still could not be taken off the ventilator.  

The patient grasped my hand excitedly, asking the nurse to seal the tracheostomy tube with a cotton swab, holding his breath, and speaking slowly word by word, “Thank you. I want to live…” I forced a smile, seemingly the only thing I could do was offer a few words of “comfort”—the most painful helplessness for a physician.  

Cancer is difficult to treat primarily because the drugs used for systemic control, whether chemotherapy or today’s popular targeted therapies, have low efficacy for most cancers, with short-lived effects; secondly, they have significant side effects, killing cancer cells but also causing “secondary damage” to the body. This Indonesian patient received the most advanced third-generation targeted drug treatment but did not “respond”; instead, he developed interstitial pneumonia, a fatal lung damage.  

In cancer treatment, the incidence of lung damage caused by chemotherapy drugs ranges from 0.03% to 3%, and reports of lung damage induced by various anti-tumor drugs are almost ubiquitous in clinical trials and applications, such as the early use of bleomycin and alkylating agents for lung cancer, and more recent drugs like gemcitabine and paclitaxel. The incidence of lung injury caused by bleomycin is 6% to 10%. One study showed that among 141 Hodgkin lymphoma patients treated with a bleomycin-containing regimen, the incidence of lung damage reached 18%, with a 24% mortality rate.  

Targeted drugs can also cause lung damage. In a study of 1,976 patients with non-small cell lung cancer treated with gefitinib across 84 institutions, 70 patients (3.5%) developed interstitial pneumonia, with 31 (1.6%) dying; all patients had a history of chest radiotherapy. Men, those with a smoking history, and those with pre-existing interstitial pneumonia were more likely to develop it. Statistics show that among 92,821 patients treated with gefitinib outside Japan, the overall incidence of interstitial lung disease was about 0.28%, while in Japan, among 65,527 patients treated with gefitinib, the incidence was about 1.7%.  

Not only chemotherapy and molecular targeted drugs but also immune checkpoint inhibitors represented by PD-1/PD-L1, which are hailed as “milestone treatments,” can also cause lung damage.  

**Tears of an Old Man from Beijing**  

Some things in the world are just so coincidental. Recently, in the outpatient clinic, I saw a liver cancer patient after surgery who had metastases and was PD-L1 positive. Seeing that he had the financial means, I suggested he use Opdivo or Keytruda, but he refused, saying the side effects were too great. An hour later, an old man from Beijing hurriedly approached me, handing me a stack of CT films, saying he was seeking help for his son.  

His son, 40 years old, a PhD, had lung cancer and had received an injection of “K drug” (Keytruda) a week ago, leading to an “explosive worsening” of his condition and respiratory failure. I opened the CT films and saw diffuse patchy shadows in both lungs, typical of interstitial pneumonia.  

I recalled an article published in *The Lancet* titled “Increasing Reports of Immune Checkpoint Inhibitors Combined with Fatal Myocarditis,” warning that “there are currently no effective treatments, with a mortality rate as high as 46%.” Experts commenting on this article mentioned five serious complications associated with these drugs, including “immune pneumonia.”  

Acute interstitial pneumonia is one of the most severe complications of anti-cancer drugs, classified as a diffuse interstitial lung disease with a dire prognosis and a mortality rate of up to 72%. The aforementioned Indonesian patient ultimately died in the hospital, tragically not from lung cancer but from the complications of interstitial pneumonia caused by targeted drugs.  

The old man from Beijing tightly held my hand, tears streaming down his face, saying, “I only have one child! Please, whatever it takes, just save my son.” I looked at the copy of the medical advice from the Beijing hospital, which mainly prescribed antibiotics, dexamethasone, and prednisone at high doses. Moreover, his son was already on a ventilator.  

What miracle cure could I offer? I thought of Mr. Zeng, the old miner I had seen in Taiwan; although he did not have cancer, his pneumoconiosis that led to “heart and lung failure” was also an interstitial lung disease, and he had been revived thanks to inhaling hydrogen.  

The old man looked no older than me, but his disheveled white hair, deeply wrinkled face, and tired eyes filled with tears tugged at my heart. “We are all lost souls in this world; why must we have met before?” As a survivor who had endured cancer, in that brief encounter, I transcended my role as a doctor and saw him as a long-time friend. I held the old man’s hand and said, “Why not try inhaling hydrogen? Although I know this suggestion may not be feasible for his son far away in Beijing, I still couldn’t help but say it. I had my secretary first treat him to lunch, and then took him to my studio to experience inhaling hydrogen.”  

**Insights from Animal Experiments**  

The mechanisms of lung damage caused by chemotherapy and targeted drugs are unclear, possibly due to direct damage to alveolar type I and II epithelial cells, with the involvement of peroxide free radicals in this process.  

Free radicals can be produced endogenously and exogenously, with the latter induced by external factors such as smoking, toxins, pollution, excessive exercise, radiation, and drugs. Both chemotherapy and molecular targeted drugs can promote the production of peroxide free radicals in the body.  

Free radicals are generally quickly cleared from the body, but if they are produced in excess or if the antioxidant mechanisms are insufficient, they can chemically react with DNA, proteins, lipids, and carbohydrates, damaging vital molecules and causing cellular damage.  

Can hydrogen have a therapeutic effect on drug-induced lung damage? We looked at three animal experiments—  

**The first experiment:** Investigated the effects of inhaling hydrogen on experimental acute lung injury. Acute lung injury was induced by intratracheal instillation of lipopolysaccharide (LPS). Sixty-four mice were randomly divided into four groups. Hydrogen inhalation was performed at 1 and 6 hours after the experiment began, for a duration of one hour. All mice receiving LPS instillation developed acute lung injury. However, in the animal group receiving hydrogen inhalation, the lung injury was mild, characterized by reduced apoptosis of alveolar epithelial cells, decreased neutrophil accumulation in the lungs, and reduced inflammation; some pro-inflammatory cytokines such as tumor necrosis factor, macrophage inflammatory protein, and interleukins 1 and 6 were all reduced (the article was published in *Shock*, 2012, Volume 37).  

**The second experiment:** Studied the effects of hydrogen water on experimental lung damage. The experiment showed that in the PQ + hydrogen water group, lung damage was significantly less than in the PQ group, with less pleural effusion, lower protein content and cell counts in airway secretions, and histological changes in lung tissue that were also significantly milder than in the PQ group; the animals receiving hydrogen water had less lung edema, and indicators reflecting cellular lipid peroxidation and oxidative damage were significantly lower than in the experimental group not drinking hydrogen water. The authors also measured the apoptosis index and found that the hydrogen water group had significantly reduced lung epithelial apoptosis (the article appeared in *J Biomed Biotechnol*, 2011).  

**The third experiment:** Assessed the effects of hydrogen inhalation on a mouse model of chronic obstructive pulmonary disease (COPD) induced by smoking. The results showed that hydrogen inhalation significantly reduced the number of inflammatory cells in bronchoalveolar lavage fluid, as well as the expression of tumor necrosis factor, matrix metalloproteinase-12, elastase-3, caspase-8, and interleukins 6, 17, and 23, while increasing the tissue inhibitor of metalloproteinase-1. The experiment demonstrated that hydrogen inhalation could improve lung pathology, lung function, and cardiovascular function, reducing the right ventricular hypertrophy index. Inhalation of 22% and 41.6% hydrogen showed better results than inhalation of 2% hydrogen (the article appeared in *Int J Chron Obstruct Pulmon Dis*, 2017).  

**Conclusion**  

Mr. Zeng’s experience and the three experiments above strongly suggest that hydrogen can “protect” the lungs and has the effect of improving and preventing lung damage. The characteristics of hydrogen in lung protection include:  

1. Hydrogen has a small molecular weight, making it easy to pass through biological membranes and enter the cytoplasm, mitochondria, and cell nucleus. The lungs are the organs closest to the external environment, making it easier for hydrogen to enter.  

2. Hydrogen molecules can selectively react with hydroxyl free radicals and peroxynitrite without reducing other reactive oxygen species related to cellular signaling (such as HO), thus not affecting normal metabolic redox reactions in the body, nor the gas exchange function of the lungs themselves.  

3. Hydrogen molecules have higher tissue compatibility than other antioxidants, which is especially important for delicate tissues like the lungs.  

4. Hydrogen is particularly safe.  

5. The lungs have rich blood flow; whether inhaled or injected with hydrogen-containing solutions, hydrogen can quickly permeate lung tissue into the whole body, which is very helpful for improving the overall condition of the body.  

These effects of hydrogen suggest that it can eliminate or alleviate the side effects of chemotherapy and targeted drugs, providing “protection” for these mainstream treatments.  

**Xu Kecheng**  

**Commentary by Tang Zhaoyou**  

After reading “Hydrogen ‘Protects’ the Lungs,” I was reminded of my old partner from 20 years ago who practiced “Western learning in Chinese medicine.” She once treated a patient with early-stage breast cancer using traditional Chinese medicine with good results, but since it was not covered by insurance, the patient returned to the hospital for “standardized” chemotherapy. Three years later, I was shocked to hear that the patient had passed away, as it turned out she died from pulmonary fibrosis after chemotherapy. In 2016, an article in the *New England Journal of Medicine* was titled “Cardiotoxicity of Cancer Targeted Therapy,” which deeply affected my old partner who suffered from breast cancer. Chemotherapy needs to be divided, and targeted therapy is no exception. Seeing these negative issues with these therapies is not to tear them down but to complement them. “Hydrogen ‘Protects’ the Lungs” also provides us with clues on how to use “remodeling” methods to complement therapies.

Chapter 6

Seeing Hydrogen Cancer Control Through the "Third Eye"

Surprise! Her Cancer Relapsed with Multiple Metastases, and After One Month of Hydrogen Inhalation, All Her Indicators Returned to Normal

60-year-old Ms. Quan, a patient with recurrent ovarian cancer and multiple metastases, saw her tumor marker CA125 return to normal after stopping chemotherapy and continuing hydrogen inhalation for a month! On the afternoon of August 6, 2018, at a lecture on "Hydrogen Molecular Medicine and Health" hosted by the Xu Kecheng Care Health Studio in Guangdong Province, Ms. Quan shared her remarkable results with the audience. Her radiant and energetic demeanor left a deep impression on everyone present.

Ms. Quan has a lot of free time—her children are successfully studying in the UK and have settled there, leaving her happily alone in China. She also has a busy schedule—in addition to her daily visits to the Xu Kecheng Care Health Studio to inhale hydrogen, she tirelessly shares her experiences and insights with various participants. She has become a "hydrogen ambassador" at the studio, spreading the message of hydrogen and health, and lives a fulfilling and happy life. But she still feels a lingering fear when she recalls the onset of her illness five years ago: In October 2013, Teacher Quan experienced bloating, abdominal distension, general weakness, shortness of breath when walking, and a distended belly. She went to the hospital for a routine checkup, but no cause was found. "The doctor said I might have gained weight and told me to exercise more to lose weight."

After a while, her condition showed no improvement. Her belly grew larger day by day, almost as large as a woman in her seventh or eighth month of pregnancy. Feeling uneasy, she returned to the hospital for another checkup, which revealed a large amount of fluid in her abdominal cavity and a high tumor marker, CA125, which doubled, reaching around 2000.

Diagnosed with stage IIIc ovarian cancer with metastasis, Teacher Quan tossed and turned in bed, lamenting the injustice of her fate. Two days later, she gradually came to terms with the situation, stopped worrying, and began actively pursuing treatment.

Four courses of chemotherapy awaited her. After surviving chemotherapy, she underwent a complete hysterectomy, ovarian removal, and fallopian tube removal. Follow-up examinations three months later showed normal results. By early 2017, her CA125 began to rise again, and her lower back began to ache. A CT scan confirmed a recurrence, with her abdominal cavity riddled with tumors.

Teacher Quan underwent two rounds of cytoreductive surgery and then began chemotherapy. "I underwent five rounds of chemotherapy, and with each one, my white blood cell count dropped to around 1, my neutrophil count to 0, and my platelet count to around 20. In other words, each chemotherapy session was a close call with death."

Chemotherapy failed to effectively control Teacher Quan's condition; her CA125 didn't drop significantly during the first five rounds. Furthermore, due to the weakened immune system caused by chemotherapy, she also developed shingles.

"The doctor said I was resistant to the chemotherapy drugs and needed to switch to a different one." Around that time, I heard that Xu Kecheng's Care for Health Studio offered free hydrogen inhalation. Hydrogen's selective antioxidant properties can eliminate excess and harmful free radicals, helping to control cancer. So, Teacher Quan began hydrogen inhalation on June 30, 2018. After five days, she had a blood test to check her tumor markers. The results showed a decrease of over 70 points, almost 50%.

Teacher Quan was overjoyed and made a bold decision: to stop chemotherapy and continue hydrogen inhalation for a month to see if it would achieve cancer control.

On August 6, Teacher Quan woke up early and rushed to the hospital for a blood test. Her CA125 level had dropped by over 50 points, bringing it back to normal! She was so excited that she immediately shared the good news with the studio's hydrogen inhalation service group. The group was abuzz with excitement, and everyone was sincerely happy for her.

"Hydrogen inhalation has given me a huge surprise. I used to feel exhausted after walking even a dozen meters, but after hydrogen inhalation, I felt better every day. After two weeks of inhalation, I could walk several kilometers without feeling tired." I recently traveled to the UK for my son's graduation. After a long-haul flight of over ten hours, I wasn't tired at all!

Since then, Teacher Quan has continued to inhale hydrogen and tirelessly shares her experiences with numerous cancer patients, sharing the miraculous cancer-control benefits of hydrogen molecules. She has become a special volunteer at the Xu Kecheng Care for Health Studio.

Teacher Quan: This is the best gift I've received on Teacher's Day.

Teacher Quan, a stage IIIc ovarian cancer patient, experienced a relapse of her cancer. After five days of hydrogen inhalation, her CA125 (a tumor marker) level dropped by almost 50%. After a month of inhalation, the CA125 level returned to a normal level of 29.41. On September 10, 2018, even better news arrived: after two months of hydrogen inhalation, Teacher Quan's CA125 level had dropped to 17.22, the lowest level in her five years of illness. This was the best gift she received on this Teacher's Day! On September 10, 2018, Teacher Quan shared this good news with everyone in the hydrogen inhalation experience group. She shared all the test results before and after hydrogen inhalation (see Figures 2-5) and wrote the following self-narrative:

I am a patient with stage IIIC ovarian cancer. The five-year survival rate for patients with stage 3 and 4 ovarian cancer is 20%-30%. When I was first diagnosed in December 2013, I already had ascites that had metastasized throughout the abdominal cavity, and the peritoneum was covered with sesame-sized tumors. The normal CA125 value is 35, but my CA125 tumor index was as high as 2252. I underwent the first exploratory surgery on December 25, 2013, followed by four rounds of chemotherapy. In June 2014, I underwent another debulking surgery, followed by four rounds of chemotherapy. In January 2015, my CA125 index returned to normal. But two years later, in early 2017, I started feeling unwell. My tumor markers kept climbing every three months, so I underwent a CT scan, which revealed metastases in the S7 segment of the liver and the abdominal cavity, with tumors of varying sizes. This continued until December 27, 2017, when I underwent another laparotomy, a complete debulking surgery, exactly four years after my first exploratory surgery.

Why was each surgery called a debulking surgery? Because my tumor had spread throughout my entire abdominal cavity, the doctors could only remove what was visible to the naked eye; they couldn't completely eliminate what was invisible. After another debulking surgery, I continued with chemotherapy. Because I had already undergone eight previous rounds of chemotherapy, which had already taken a heavy toll on my body, the subsequent chemotherapy was too much for me to handle. After each round of chemotherapy, my white blood cell count dropped to just over 1, my neutrophil count plummeted to zero, and my platelet count dropped to over 20. This meant my immune function was almost nonexistent, and even the slightest infection could be fatal. If my platelet count drops below 10, I'll bleed profusely and die. So, every chemotherapy session was a close call. After surgery, on June 4, 2018, I underwent my fifth chemotherapy session. Unfortunately, due to my weakened immune system, I contracted shingles.

Under these circumstances, I had developed a deep fear of chemotherapy. Coincidentally, I heard that Xu Kecheng's Care for Health Studio was offering a free hydrogen inhalation trial, so I visited the studio on June 30, 2018. After five days of inhalation, I had my tumor markers checked, and the results were astonishing—my CA125 had dropped by over 70 points, almost 50% from my original level! This gave me great hope. My tumor markers hadn't dropped as expected with each previous chemotherapy session, and I suspected drug resistance. Combined with my fear of chemotherapy, I made a decision: I would stop chemotherapy and continue hydrogen inhalation for a month to see how effective it was. On August 6th, a month after I started inhaling hydrogen, I went to the hospital early in the morning with a trepidation. The results came back around noon: my CA125 tumor marker had dropped by over 50 points, returning to normal! The effects of hydrogen inhalation were truly miraculous.

After another month of inhaling hydrogen, my follow-up test on September 7th revealed that my CA125 tumor marker (normal value is 35) had dropped further from 29.41 to 17.22, the lowest level in my five years of illness. This drop in markers further demonstrated the miraculous effects of hydrogen inhalation.

Since starting hydrogen inhalation, I've felt better and better. I used to feel physically exhausted. Every time I saw the doctor, they'd ask me what was ailing me, and I'd always reply, "I just don't have the energy. I can't even walk or go up and down stairs." Now I can walk faster than even young people, almost jogging without getting out of breath.

As I mentioned earlier, the five-year survival rate for patients with stage 3 or 4 ovarian cancer is only 20% to 30%. December 2018 was the month I was diagnosed with cancer. Five years? Can I make it through that five-year mark? I'm inhaling hydrogen every day. It all depends on whether it can help me overcome this barrier and show its miraculous effects again! Wish me good luck!

Professor Sun Xuejun's Comments

I've also seen Professor Quan, and it certainly doesn't resemble the situation after multiple rounds of chemotherapy for cancer. Judging by her CA125 level, there's a strong correlation between her condition and this level. It was at 2000 before surgery, returned to normal after resection, and then rose again after the tumor recurred. Despite multiple rounds of chemotherapy, it hasn't returned to normal. After a short period of hydrogen inhalation, this elevated level has miraculously dropped rapidly. This is truly a testament to the magical power of hydrogen.

There's no definitive conclusion yet on hydrogen's ability to control tumors, and it's difficult to rigorously and accurately analyze this effect. Based on my understanding of hydrogen's biological effects and this patient's condition, I personally believe that hydrogen did have an effect on her. However, at this stage, this effect is short-term, and the long-term effects still need to be observed. Of course, I hope she recovers. Restoring health. Hydrogen's effects are most likely due to the antioxidant and anti-inflammatory properties of hydrogen, which, after inhaling large amounts, partially restored her immune system, which had been weakened by chemotherapy and cancer. This enhanced immune system effectively attacked tumor cells, allowing her to regain relative health. A direct role for hydrogen in its anti-tumor effects cannot be ruled out. Of course, this requires further research to verify.

"Hydrogen Inhaler Sister" Effortlessly Controls Cancer, Walking 20,000 Steps a Day Without Feeling Tired

Teacher Quan, who had ovarian cancer recurrence and metastasis after surgery, began hydrogen inhalation at the end of June 2018. One month later, her cancer markers were completely normal. Two months after hydrogen inhalation, her tumor markers dropped again, which was encouraging. Her story has become a legend among cancer patients, and she has become known as the "Hydrogen Inhaler Sister."

Five months have passed. How is Teacher Quan's condition? Are her markers still normal? On December 1, 2018, a radiant Teacher Quan made a grand appearance in Wuyishan, joining a gathering of cancer survivors from across the country. Not only did she complete the 2.5-kilometer "1,000-Person Walk," she also pushed herself to the limit, walking nearly 20,000 steps that day, demonstrating to everyone who cared about her that she was doing well!

A Stylish Walk in Wuyi

On the afternoon of November 30, 2018, Teacher Quan's flight arrived at Wuyishan Airport. Stepping out of the plane, she was greeted by a clear blue sky and lush green mountains. A refreshing breeze blew in her face, making her feel like she had entered a springtime scene filled with birdsong and fragrant flowers. "'Natural Oxygen Bar,' it truly lives up to its reputation!" she excitedly posed for a photo in front of the airport terminal. Teacher Quan explained that in mid-November, after returning from a visit to her family in the UK, she went to the hospital for a checkup, had blood drawn, and underwent an MRI. The results showed that her tumor markers remained within normal range. This time, she also had a surprise. An MRI in July had revealed a suspected metastatic lesion in her liver, but this time, the suspected lesion had disappeared.

Teacher Quan felt particularly relaxed and at ease during her trip to Wuyishan. She credited hydrogen with her good mood and well-being.

On December 1st, Wuyishan Square was bustling with activity. The opening ceremony of the inaugural China Wuyishan Health and Fitness Tourism Season, "I Exercise, I Am Healthy, Meet at the 2022 Beijing Winter Olympics," was held there. Nearly a thousand members of cancer rehabilitation associations from across the country gathered.

Teacher Quan was busy running around, greeting old friends and making new ones, enjoying herself. "So you're the hydrogen inhalation sister!" Many people had already heard of Teacher Quan's hydrogen inhalation recovery efforts, and upon meeting her, they were particularly enthusiastic. Following the opening ceremony, the "Thousand-Person Walk" event took place. Xu Kecheng The professor took Teacher Quan's hand, and the two of them, full of energy, strode forward with great strides.

They also happened to meet Ms. Miaoxuan from the Shenzhen branch of "Light of Life." Ms. Miaoxuan was diagnosed with cholangiocarcinoma seven years ago and underwent three surgeries. Her pain was excruciating, with each subsequent relapse, and each subsequent chemotherapy treatment. Under the guidance of Professor Xu Kecheng, she underwent a series of rehabilitation treatments. "Over the past two years, my cancer markers have been within normal range, and my disease is under excellent control!"

Professor Xu Kecheng said that both Teacher Quan and Ms. Miao have benefited from China's approach to cancer control, and he was deeply pleased to see them doing so well.

As everyone chatted and laughed, the 2.5-kilometer journey slipped by unnoticed. Still eager to get more done, Teacher Quan added another step to her walk through Wuyi. Breathing the fresh air, she admired Wuyi's unique natural beauty and sampled the region's famous black tea and delicacies. She walked nearly 20,000 steps that day, crediting hydrogen inhalation with maintaining her excellent stamina.

She was a dazzling star both inside and outside the venue.

On December 2, 2018, at the High-Level Micro-Forum on Cancer Prevention, Treatment, and Rehabilitation, Professor Xu Kecheng delivered a speech titled "Practicing 'Chinese-Style Cancer Control.'"

Renowned oncologist Academician Tang Zhaoyou proposed the "Chinese-Style Cancer Control" concept of combining "elimination" and "transformation." As a student of Academician Tang Zhaoyou, Professor Xu Kecheng has been practicing this concept in the clinical field.

"Teacher Quan is a beneficiary of the 'Chinese-style cancer control.' Teacher Quan, please stand up and show us!" Professor Xu Kecheng pointed to the audience and described how Teacher Quan's chemotherapy tortured her to death, yet her tumor markers showed no significant decrease. However, after hydrogen inhalation, their markers remained normal.

The radiant Teacher Quan stood up, waved, and introduced herself, prompting enthusiastic applause from the audience.

The audience was so fascinated by Teacher Quan's experience with hydrogen cancer control that even before the forum ended, many cancer patients had already approached Teacher Quan, peppering her with questions and even asking to add her on WeChat. Teacher Quan patiently answered each question and even created a hydrogen inhalation WeChat group on the spot. That evening, another enthusiastic "fan" took a taxi to the hotel to ask Teacher Quan for advice on cancer control. Teacher Quan was incredibly busy.

Teacher Quan revealed that her filial daughter, who was on annual leave in December, insisted on taking her on a trip to Thailand. This generous invitation put her in a difficult position: on the one hand, her condition was under good control, and on the other, she was in good physical condition. Going out for some fun was understandable, but on the other hand, she wanted to inhale hydrogen; she couldn't live without it!

Lin Hong

Luck or Qi? Another ovarian cancer patient's test results returned to normal after hydrogen inhalation.

On October 8, 2018, receiving the test results from the hospital was perhaps the happiest moment in Pan Xkun's more than seven years of cancer battle. Over those seven years, she had endured three recurrences, two major surgeries, and 24 chemotherapy sessions.

Tumor markers were like a roller coaster—they immediately dropped after chemotherapy, only to rise rapidly. At her wit's end, she found hydrogen. After two months of hydrogen inhalation, her cancer markers returned to normal and have remained stable.

One day in December 2010, Pan Xkun received a call from her neighborhood committee: "It's the end of the year. Did you have your gynecological exam this year?" "I forgot. I'll make up for it tomorrow!"

The next day, Pan Xkun hurried to the Haizhu District Maternal and Child Health Hospital for an ultrasound. "Maybe because it was the weekend, there were fewer people getting checked, so the doctor was extra thorough." Suddenly, she said seriously, "Something's not right. There's a tumor on your ovary. You need further testing."

Ovarian cancer, stage III! This all came as a complete surprise. Pan Xkun She was completely unprepared. In January 2011, she underwent surgery to completely remove her ovaries and underwent six rounds of chemotherapy. She then had regular annual checkups and lived peacefully for four years.

In January 2015, she felt a sticky sensation in her vagina while going to the bathroom. A test revealed elevated tumor markers, prompting further examination at a cancer hospital, which confirmed a recurrence of ovarian cancer. This was followed by six cycles of chemotherapy over six months. In July 2016, a year after completing chemotherapy, the cancer returned, requiring another six rounds of chemotherapy. In August 2017, about a year after completing chemotherapy, the cancer returned for the third time. This time, the doctor recommended three rounds of chemotherapy, with the goal of pursuing surgery once the tumor shrank. On March 12, 2018, after completing three rounds of chemotherapy, Pan X underwent another surgery and three rounds of post-operative chemotherapy.

Over seven years, three recurrences, two major surgeries, and 24 rounds of chemotherapy—the recurrence of cancer left her physically and mentally devastated and excruciatingly painful. Speaking of her bloody battle against cancer, Pan Xkun was overcome with emotion. (The following appears to be unrelated and likely a separate topic:)

But the restless cancer cells in her body didn't let this cancer warrior go. In April of this year, a follow-up examination revealed that her cancer marker CA153 had risen to 28.23 (normal range is 0-25), indicating the presence of cancer or precancerous lesions—a bad sign.

Continue chemotherapy? Pan Xkun had endured the pain of chemotherapy over the years. But besides continuing chemotherapy, what else could she do? She was at a loss.

"Go to Professor Xu Kecheng's health studio and try hydrogen!" suggested Teacher Quan, an ovarian cancer patient who had received a free trial there. Teacher Quan, a patient with recurrent ovarian cancer after surgery, experienced complete normalization of her cancer markers after a month of hydrogen inhalation at Xu Kecheng's Care Health Studio. She continued to inhale hydrogen, and her markers continued to decline.

Determined to give it a try, Pan Xkun began inhaling hydrogen daily at the studio on July 22, 2018. On September 7, she went to the hospital for a follow-up examination. The tumor index CA153 dropped to 25.39, almost reaching the normal level. In the past month, she has not received any treatment except for hydrogen inhalation. Is it luck or the effect of hydrogen? She decided to continue to inhale hydrogen for a month to see if hydrogen is really so magical. On October 8, she got the latest test results: 21.38! Finally normal, she was overjoyed! Pan Xkun said that in addition to the "gold standard" of blood tests, hydrogen has also brought her many pleasant changes: (1) good sleep, sleeping through the night; (2) good appetite, everything tastes good; (3) good physical strength, can walk 10,000 steps every day. She said that now she does not feel tired after walking for an hour and a half in Xiaogang Park every day.

"True Qi" has a miraculous effect on ovarian cancer?

Ovarian malignant tumors are one of the common malignant tumors of the female reproductive organs. Due to the hidden location of the onset and the lack of obvious early symptoms, patients are often in the late stage when they seek medical treatment. Despite significant progress in the treatment of ovarian cancer in recent years, the overall cure rate remains only around 30%, making the development of effective therapeutic drugs urgent. In July 2018, Professor Ma Xuemei's research group at Beijing University of Technology published an article titled "Therapeutic Potential of Molecular Hydrogen in Ovarian Cancer" in the journal Translational Cancer Research. The article reported that in an ovarian cancer mouse model, continuous hydrogen breathing for six weeks significantly reduced tumor volume (32.3%) and significantly decreased Ki67 (30.0%) and CD34 (74.0%) expression. In vitro cell experiments demonstrated that hydrogen significantly inhibited the proliferation, invasion, migration, and colony formation of ovarian cancer cells and reduced the ability of tumor spheres to form. These results suggest that hydrogen could be a potential anti-cancer drug molecule for the treatment of ovarian cancer.

 Lin Hong

How to Improve Radiotherapy Sequelae? A Nasopharyngeal Cancer Patient Tells You—Hydrogen Inhalation!

Radiotherapy is currently the most effective treatment for nasopharyngeal cancer. However, alongside effective treatment, varying degrees of sequelae often arise. In severe cases, the quality of life can be significantly compromised, leading to immense suffering, as experienced by Zhou Ximei.

At 64 years old, Zhou Ximei was an employee at a medical device company in Guangdong Province before her retirement. One day in December 2001, she noticed her nose was bleeding. Coincidentally, she had to visit the Guangdong Provincial Hospital of Traditional Chinese Medicine for work, and a colleague kindly reminded her, "You should get it checked while you're there."

Soon, this "quick check" yielded results—stage I nasopharyngeal cancer. Zhou Ximei was admitted to the hospital and underwent three courses of a total of 36 radiotherapy sessions. Following annual check-ups, the tumor did not recur, and she lived normally, gradually shedding the shadow of cancer.

However, ten years after her diagnosis, an unexpected issue arose. Zhou Ximei began to suffer from rotten teeth, followed by gradual atrophy of her tongue, leading to unclear speech, hearing loss, difficulty swallowing, and problems with her sense of smell. Doctors informed her that these were sequelae of radiotherapy for nasopharyngeal cancer, and there was no particularly effective treatment available—only methods like massage and rehabilitation exercises to "control the progression of the condition."

"The suffering after radiotherapy is far more tormenting than the cancer itself," Zhou Ximei recounted, tears streaming down her face. Despite her commitment to rehabilitation exercises, her symptoms did not improve. Due to her speech difficulties, she became classified as a level one disabled person. Her ear problems also worsened, with her left ear frequently discharging pus and her hearing diminishing until she could hear nothing at all.

Fortunately, the illness did not destroy Zhou Ximei's will. She has a passion for calligraphy and painting, enduring her pain to perform at nursing homes and teaching painting to children in remote schools for free. As the head of the nasopharyngeal cancer rehabilitation work at the Guangdong Life Light Cancer Rehabilitation Association, she actively organized and participated in various association activities, helping and encouraging fellow patients.

To outsiders, Zhou Ximei appears strong and optimistic, a vibrant advocate for public welfare. What others do not know is that the sequelae of her radiotherapy have not diminished due to her strength. She has been seeking effective treatments, trying acupuncture, physical therapy, and traditional Chinese medicine, but unfortunately with little effect.

On October 18, 2018, she visited Xu Kecheng's Health Care Studio to experience hydrogen inhalation for free, inhaling for four consecutive days. A miraculous change occurred! "In the past, when the weather changed and there was a temperature difference, I would have nasal congestion and tinnitus. After inhaling hydrogen for a few days, I walked into an air-conditioned room from outside and found a significant improvement. Additionally, the pus discharge from my ear decreased."

Thus, she canceled all social activities and devoted herself entirely to inhaling hydrogen at the studio. After a month of inhalation, she reported that the pus in her ear was gone, her nasal breathing was smooth, and her quality of life had greatly improved. Recently, she specially delivered her calligraphy and painting works to the studio to express her gratitude to Professor Xu Kecheng and the studio staff. She said, "Professor Xu Kecheng is the president of our Life Light Association. Under his compassionate guidance, I have learned to face life correctly. The hydrogen therapy he promotes has benefited me greatly, and I am truly grateful to him!"

Clinical Research on Hydrogen's Role in Reducing Radiotherapy Side Effects

Professor Xu Kecheng often states that rehabilitation is a complement to the "mainstream" treatment of cancer. The goal of cancer treatment is not only to help patients survive but also to ensure they live well and maintain quality of life. For example, the complications Zhou Ximei faced after radiotherapy caused her immense suffering. However, these late-onset complications are not due to human error; they are inherent characteristics of radiotherapy, which patients cannot "blame on fate" and must endure helplessly.

In fact, despite many achievements in modern medical research, there is generally little that can be done for these seemingly simple complications beyond symptomatic treatment and temporary relief. Zhou Ximei's severe complications from radiotherapy and her remarkable improvement after hydrogen inhalation may have been unexpected for her and us alike.

There have been clinical studies on hydrogen's ability to reduce radiotherapy side effects. In 2011, a clinical study from the University of Pittsburgh provided evidence. Liver cancer patients undergoing radiotherapy who also received hydrogen for six weeks showed significantly higher quality of life scores during treatment compared to those who received a placebo. There was no difference in treatment efficacy between the two groups, but the hydrogen group had lower levels of reactive oxygen species in their blood.

Research by Professor Sun Xuejun from Shanghai Second Military Medical University found that hydrogen can reduce mortality in animals exposed to radiation. In a study where mice were exposed to a lethal dose of radiation, 90% died after two weeks, while only 20% of the animals receiving hydrogen died, indicating a significant difference. The authors believe that hydrogen protects against overall damage caused by radiation.

Professor Xu Kecheng believes that the improvement in Zhou Ximei's radiotherapy complications after hydrogen inhalation can be theoretically explained. The mechanism of radiation therapy for cancer involves: first, the direct action of radiation on DNA molecular chains, causing single and double-strand breaks; second, the indirect action, where radiation ionizes water molecules, producing reactive oxygen free radicals. These free radicals then interact with biological macromolecules (RH) and subsequently with DNA chains. In other words, free radicals can kill cancer cells. However, radiotherapy does not exclusively target cancerous tissues; it almost always damages adjacent normal tissues. This is especially true in nasopharyngeal cancer, where the local structure is complex, leading to collateral damage.

Zhou Ximei experienced rotten teeth, tongue atrophy, loss of smell, unclear speech, and ear pus discharge ten years after radiotherapy—these are the consequences of such collateral damage. The large amounts of toxic reactive oxygen species generated by radiation persist in the area, causing chronic inflammation and tissue destruction, which in turn promotes the production of reactive oxygen species, creating a vicious cycle. The persistence of Zhou Ximei's complications is due to this reason.

Hydrogen can selectively neutralize toxic reactive oxygen species. Hydrogen inhalation rehabilitation is a gift sent to Zhou Ximei. She is so strong, enthusiastic, and caring that she deserves this reward.

Best wishes to Zhou Ximei!

Lin Hong

His Metastatic Tumor Shrunk, He Says Thanks to Hydrogen

On Wednesday, November 14, 2018, it was a consultation day for Professor Xu Kecheng. Near the end of the workday, a couple hurried in. Upon seeing Xu Kecheng, they were overwhelmed with excitement. The wife explained that they had come not only to seek treatment for her husband, Mr. Tan (whose jawbone was necrotic due to medication) but also to express their gratitude to Professor Xu.

Thanks to hydrogen, her husband's lung metastasis had significantly improved, "The doctor even thought he had undergone surgery," they joyfully shared.

Mr. Tan, 64, worked at a school in Guangzhou before his retirement. In early 2011, during a routine health check at work, he was unexpectedly diagnosed with kidney cancer. In March of the same year, he underwent a radical right nephrectomy, and post-operative pathology indicated grade I clear cell carcinoma, with invasion of the renal capsule.

In the following years, check-ups showed no abnormalities. However, in early 2017, Mr. Tan began experiencing pain in his right knee joint and weakness in his lower limbs. After hospitalization, PET-CT scans and biopsies confirmed lung and bone metastasis from kidney cancer, leading him to start medication to control the disease.

In February 2018, he began to feel increasing pain in his lower front teeth and had to visit a dental hospital for extraction. However, after the extraction, the pain did not subside, and he exhibited signs of jaw necrosis, causing him immense suffering. After several medical consultations, it was discovered that this was a side effect of long-term use of Zeta, a medication used to treat solid tumor bone metastases, which can also cause varying degrees of adverse reactions. Mr. Tan humorously remarked, "I hit the jackpot," and reluctantly stopped taking the medication.

While enduring these severe side effects, his lung metastasis situation was also concerning. At this time, a fellow patient from the Guangdong Life Light Cancer Rehabilitation Association informed him that the association's president, renowned cancer treatment expert Professor Xu Kecheng, was using hydrogen to control cancer, benefiting many cancer patients.

In June 2018, on Professor Xu's recommendation, Mr. Tan began using a hydrogen-oxygen nebulizer at home for rehabilitation, inhaling for about five hours daily.

He mentioned that he didn't feel much during inhalation, but the results of his hospital check-up on August 31, two months later, surprised him greatly.

"When the doctor held up my scans, he said, 'Your scans are much better now, of course, (lung metastasis) after surgery!'" Mr. Tan was taken aback and replied, "Doctor, I haven't had surgery!" "How is that possible?" the doctor found it hard to believe. "It's true! I've been inhaling hydrogen at home for over two months." Mr. Tan was overjoyed, thinking, "Inhaling hydrogen actually achieved the effect of surgery—it's unimaginable!"

This visit to Professor Xu was both for treatment and to share good news. After listening to their story, Professor Xu laughed heartily: "The joy of patients benefiting is the greatest happiness for doctors!" Since starting hydrogen therapy, he has been filled with joy every day.

Lin Hong

Xu Kecheng's Commentary: Discussing Cancer Control Through Immune Regulation

CD8+ cytotoxic T cells are important immune effector cells that play a significant role in immune control of tumors, but their immune function is closely related to cell surface molecules.

Programmed death-1 (PD-1) is a key immune inhibitory molecule expressed during T cell activation. It binds to its ligand, programmed cell death ligand-1 (PD-L1), through TCR and CD28. Under continuous stimulation by tumor antigens, PD-1 on CD8+ T cells binds to PD-L1 on cancer cells, leading to T cell exhaustion, cessation of proliferation, and loss of cytokine production and immune activation capacity, meaning they cannot attack cancer cells. PD-1 is a marker for exhausted T cells, expressed abundantly in the circulation of cancer patients' CD8+ T cells and tumor-infiltrating lymphocytes, and is associated with poor prognosis in various cancers (including breast cancer, pancreatic cancer, and gastric cancer).

Japanese researchers Akagi J and Baba H found that the levels of PD-1+CD8+ T cells in peripheral blood correlate with progression-free survival (PFS) and overall survival (OS) in cancer patients. A total of 55 patients with stage IV colorectal cancer were examined. Patients inhaled hydrogen for three hours, three months in total. CD8+ T cells were isolated from peripheral blood and analyzed for their phenotype using flow cytometry.

The results showed that patients with high levels of exhausted PD-1+CD8+ T cells in peripheral blood had shorter PFS and OS. After inhaling hydrogen, the number of exhausted PD-1+CD8+ T cells decreased, while active PD-1-CD8+ T cells increased, extending PFS and OS accordingly. These results suggest that hydrogen restores the function of exhausted late-stage PD-1+CD8+ T cells, converting them into active late-stage PD-1-CD8+ T cells, thus achieving a balance between PD-1+ and PD-1-CD8+ T cells, improving the patients' anti-tumor immune function and consequently their prognosis.

The mechanisms by which hydrogen restores the function of exhausted T cells remain unclear. It is known that exhausted tumor-infiltrating and circulating CD8+ T cells are characterized by metabolic insufficiency, accompanied by mitochondrial dysfunction and quality decline, as well as loss of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1a). PGC-1a is a positive regulatory factor in mitochondrial metabolism that enhances insulin sensitivity, increases mitochondrial respiration, and promotes mitochondrial biogenesis and fatty acid beta-oxidation. It is believed that inactivation of PGC-1a leads to mitochondrial dysfunction, causing CD8+ T cell exhaustion and loss of immune capability. Hydrogen molecules activate PGC-1a, rescuing CD8+ T cells that have become exhausted due to mitochondrial dysfunction, thus restoring their immune activity.

A 23-Year Cancer Warrior Finds a New Treasure for Cancer Control

If Huang Xueqiong did not mention it herself, no one would guess that she is a breast cancer patient with 23 years of cancer history. This cancer warrior's journey has been fraught with challenges—several years ago, her breast cancer recurred, and then glassy nodules appeared in her left lung. Recently, she discovered hydrogen inhalation as a new tool for cancer control. After inhaling hydrogen, her breast cancer stabilized, her sleep improved, and the glassy nodules in her lung shrank.

64-year-old Aunt Huang is slightly plump, friendly, and talkative, always wearing a cheerful expression. She appears completely normal, and no one would suspect she has been battling breast cancer for 23 years.

One day in October 1995, while taking a shower, Aunt Huang noticed discharge from her right nipple. Sensitive to her body, she realized the seriousness of the situation and immediately went to the hospital for examination, where she was diagnosed with ductal papilloma.

She quickly underwent a right mastectomy, without chemotherapy, and took endocrine medication for over half a year.

For the next five, ten, and fifteen years, Aunt Huang lived like a normal person, with the shadow of breast cancer long gone. However, in the 19th year, at the end of March 2014, she noticed a hard lump at the site of the surgical scar. Remembering that she had been frequently ill with fevers during that time, she felt a pang of dread: Could it be cancer returning?

"From the scans, it looked like it might not be good. Following the doctor's advice, she underwent surgery for removal. Three days later, the pathology results confirmed the doctor's suspicions—Aunt Huang's breast cancer had recurred.

Aunt Huang could hardly believe that cancer could return nearly 20 years later. But the harsh reality was clear, and she quickly accepted it, adjusting her mindset and undergoing six rounds of chemotherapy while continuing to take endocrine medication.

In 2015, a follow-up revealed a glassy nodule in her left lower lung measuring approximately 7.5×6(mm). Could it be lung cancer? Aunt Huang was at a loss. Since glassy nodules could be benign or precancerous lesions or early lung cancer, the doctor suggested continued observation and regular follow-ups.

A year later, the nodule grew to 9mm. The doctor recommended surgery, but she decided to wait and began hyperthermia treatment at a nearby hospital. After six months, a follow-up showed the nodule had shrunk to 8mm. "In the past two years, I continued with hyperthermia, but the nodule remained at 8mm and did not shrink further," Aunt Huang felt somewhat helpless.

In October 2018, as a member of the Guangdong Life Light Cancer Rehabilitation Association, Aunt Huang, with the association's help, visited Xu Kecheng's Health Care Studio to experience hydrogen inhalation. After inhaling for about half a month, she noticed significant improvements in her sleep; previously, she could only sleep five to six hours a night, but now she could sleep for eight hours.

Even more surprising followed. A month after starting hydrogen inhalation, her CT report indicated no recurrence of breast cancer, and the glassy nodule in her lung had shrunk from 8x6(mm) to 5×6(mm). With hydrogen as her new treasure for cancer control, Aunt Huang was overjoyed. "Now I've stopped hyperthermia and focused entirely on inhaling hydrogen at the studio!"

Commentary

Glassy nodules in the lungs appear as shadows or hazy areas on CT scans. Various causes can lead to glassy changes, such as inflammation, fibrosis, atypical adenomatous hyperplasia, in situ adenocarcinoma, and pulmonary hemorrhage. Advanced age, a history of smoking, a history of malignant tumors in the chest for over five years, spiculated edges of the nodule, larger nodule diameter, and location in the upper lung lobe are all risk factors for malignancy.

The larger the nodule, the greater the likelihood of malignancy. When the nodule diameter exceeds 8mm or continues to grow, the probability of malignant transformation significantly increases, and surgical resection or ablation is generally recommended. Aunt Huang's lung glassy nodule reached 8mm, and given her history of breast cancer, standard practice would typically call for surgery or ablation. However, she chose to inhale hydrogen first, and after a month, the nodule shrank. This could indicate two possibilities: the nodule is a non-cancerous lesion, such as inflammation, and hydrogen has anti-inflammatory effects; or the nodule is early-stage cancer, and hydrogen inhibits cancer cell growth.

Lin Hong

The Power of Hydrogen? Miraculous Disappearance of Brain Metastases...

When He Xihua received her latest brain MRI report, she could hardly believe her eyes: the metastatic lesion in her left parietal lobe had disappeared! For a patient with stage IV breast cancer with multiple bone and brain metastases, such a result is enough to bring tears of joy. She wondered: what caused her brain metastasis to vanish? Perhaps it was hydrogen!

In May 2017, He Xihua went to the hospital due to a lump in her right breast, only to be diagnosed with stage IV breast cancer with multiple bone metastases. After seven rounds of chemotherapy and treatment with lapatinib, she underwent modified radical mastectomy in November of the same year and completed her eighth round of chemotherapy on December 8. On February 7, 2018, she began 25 sessions of radiotherapy, and in July of the same year, she started taking Xeloda.

Despite actively undergoing treatment, He Xihua's condition continued to progress. An enhanced MRI of the head on July 27, 2018, revealed abnormal signals in the left occipital lobe and leptomeninges, with clear boundaries and regular shape, measuring approximately 8×5(mm). The diagnosis was intracranial metastasis.

For the brain metastasis, the doctors suggested either neurosurgery or brain radiotherapy, alongside continuing Xeloda. Considering the effects and side effects, she hesitated. At that moment, she heard about the hydrogen inhalation experience offered at Xu Kecheng's Health Care Studio, which might help with cancer control. She decided against surgery or radiotherapy and began consistently inhaling hydrogen for over three months starting in August, while continuing to take Xeloda. On November 8, her enhanced MRI results were unexpectedly ideal—no abnormal signals were seen in the brain, the gray-white matter boundaries were clear, and no abnormal enhancement was noted... The original lesion in the left occipital lobe had disappeared.

He Xihua reflected that since her diagnosis of brain metastasis on June 20, aside from continuing her chemotherapy with Xeloda, she had not undergone any other treatment. However, to her knowledge, Xeloda was not particularly effective against brain metastases. Could it really be that hydrogen worked wonders? She was overjoyed!

Sharing her joy was her husband, He Xizong, who was also battling cancer. He Xizong was diagnosed with nasopharyngeal cancer in 2013 and underwent 32 sessions of radiotherapy. He described how, after radiotherapy, he often experienced nasal congestion and a strong feeling of blockage, severely affecting his sleep and causing him to frequently suffer from insomnia. "I had headaches, neck pain, and felt terrible!" He had tried various nutritional supplements, but they had little effect.

"Before, I would sleep but still feel tired; now, sometimes I can sleep for ten hours!" Since he started inhaling hydrogen with his wife, he said, "My nasal passages have cleared up, my energy is better than before I got sick, I enjoy eating, I sleep well, and I've gained weight! I'm now 62 kg, and my goal is 65 kg; I'm almost there!"

Commentary

A review published in July 2018 in the Journal of Clinical Oncology noted that most cytotoxic drugs cannot cross the blood-brain barrier, and almost all large clinical trials have excluded patients with brain metastases. Therefore, whether chemotherapy can be applied to treat brain metastases remains controversial, and there is no standard systemic treatment plan for breast cancer brain metastases. In recent years, studies have found that some chemotherapy drugs can cross the blood-brain barrier, achieving effective concentrations in brain metastases to kill tumor cells. The National Comprehensive Cancer Network (NCCN) guidelines recommend capecitabine (note: Xeloda), high-dose methotrexate, cisplatin combined with etoposide, and temozolomide monotherapy for breast cancer brain metastases (recommendation level: 2A).

However, there is no evidence that capecitabine alone is effective for treating brain metastases. He Xihua's brain metastasis disappeared after three months of hydrogen inhalation, which may indicate that hydrogen played a role, or perhaps hydrogen worked synergistically with the chemotherapy drug she was taking.

Lin Hong

Because of Hydrogen, She Walked into Her First Rehabilitation Sports Event

On October 30, 2018, a special sports event was held at the Liwan Sports Center in Guangzhou. The athletes participating in the event came from different places, each with unique life experiences and professional backgrounds, ranging from elderly individuals to young teenagers. They all belonged to a common family—the Guangdong Life Light Cancer Rehabilitation Association.

This was the sixth sports event organized by the association, and it was also the first event attended by Cao Xijun since joining the association. She appeared particularly excited. Over the past few years, she had suffered greatly from severe side effects of chemotherapy—numbness in her hands and feet, unstable walking, and frequent dizziness. Thanks to hydrogen inhalation, her knee pain significantly improved, allowing her to walk into the sports event venue for the first time.

In 2012, Aunt Cao was unfortunately diagnosed with invasive ductal carcinoma of the breast, which was triple-negative, meaning that endocrine therapy and targeted therapy for Her-2 would not work for her. That same year, she underwent a right mastectomy and eight rounds of chemotherapy.

Chemotherapy caused damage to her peripheral nerves, resulting in a painful, needle-like sensation in her hands and feet. Additionally, due to severe knee pain, she could not stand for long and had to hold onto walls for support when going up and down stairs.

"I've been a member of the Life Light 'Wuyang' station for several years, but I've never participated in a sports event before. This year, I finally could participate, not only walking in the opening ceremony but also standing for nearly an hour!" Aunt Cao exclaimed excitedly, saying that such an experience was something she had never dared to imagine before.

Why such a significant change? She attributed it to hydrogen inhalation, which alleviated her knee pain.

In mid-September 2018, she heard that hydrogen could improve side effects from chemotherapy and aid in cancer rehabilitation. The renowned cancer treatment expert and president of Life Light, Professor Xu Kecheng, had opened an inhalation experience area in his public service studio, providing free access for everyone. She then invited her husband Jiang Xinxin to join her for the experience.

Aunt Cao shared that her husband had been suffering from chronic nephritis for over 25 years and had been taking medications like Bailing capsules and Uremia Clearing to manage his condition. After she fell ill, her husband devoted himself to taking care of her, which was particularly challenging. In 2013, she discovered that her husband had excessive bubbles in his urine, compelling him to go to the hospital for a check-up, where it was found that his white blood cell count was very high. The doctor was concerned that his kidneys could not handle it and did not prescribe any anti-inflammatory medication. He subsequently underwent check-ups every six months, with consistently elevated white blood cell counts.

During the Spring Festival in February 2018, Jiang Xinxin suddenly experienced severe chest pain and was urgently hospitalized, diagnosed with acute exudative pleuritis and multiple lung infections. After half a month of hospitalization, his condition stabilized, and he was discharged. "The doctor specifically called me into the office and said, 'His pleural effusion is cloudy and difficult to absorb.'"

After discharge, Jiang Xinxin continued taking anti-inflammatory medication for over a month, but follow-up results in May and August 2018 still showed elevated white blood cell counts. Hearing that hydrogen could reduce inflammation, Aunt Cao encouraged her husband to give it a try. "At first, he was hesitant and reluctant to come. But after his first inhalation on September 22, he felt much easier to breathe and more relaxed, so he continued inhaling hydrogen."

After inhaling for half a month, the couple visited their son's house to take care of their grandchild. "Previously, he would be out of breath after climbing two flights of stairs, but now he could go up to the sixth floor in one breath and still have the energy to carry the grandchild. They were overjoyed.

The difficult-to-absorb pleural effusion had also mostly been absorbed. In November 2018, Aunt Cao accompanied her husband for a follow-up check-up. The results were even more surprising: Jiang Xinxin's long-abnormal white blood cell count finally returned to normal for the first time, and the doctor acknowledged, "His legs are good, and he doesn't get breathless!" Inhaling hydrogen has benefited both of them, and now they frequently walk at Haizhu Lake, covering thousands of steps easily and comfortably.

Commentary

Hydrogen can indeed alleviate arthritis. In Lourdes, France, it is said that on February 11, 1852, the Virgin Mary appeared to a 14-year-old shepherd girl, instructing her to drink water from the Bernadette River. Subsequently, people discovered that this spring water could heal, especially for paralysis. Many patients came seeking healing, and after recovery, they discarded their wheelchairs and crutches, which have since become a unique sight in the area.

In a 30-meter-long tunnel in the Nordenau mine in Germany, spring water flows from the rock wall of an area approximately 100 square meters. By 2003, over two million people from around the world had visited to experience it, with various healed cases including 18 types, the most common being joint pain, along with bronchopneumonia, kidney disease, and more.

Given hydrogen molecules' antioxidant and anti-inflammatory effects, hydrogen has been used in sports medicine, proving to significantly improve rheumatoid, traumatic, and gouty arthritis (Ostojic SM Int J Sports Med, 2015).

Lin Hong

A Nearly Revolutionary Discovery! Late-stage Gallbladder Cancer Patients “Come Back to Life,” and the Reason is a Small “Hydrogen”

Gallbladder cancer, a malignancy comparable to pancreatic cancer. A large literature review published in October 2018 in the European Journal of Surgical Oncology collected data from 474 patients. For patients with advanced gallbladder cancer that cannot be surgically removed, the median survival time is only 5 to 10.8 months; for metastatic late-stage patients, the survival time is even shorter.

This is just a case, but it is real and undeniable!

This is a late-stage gallbladder cancer patient—

A massive gallbladder cancer tumor invading the duodenum, causing intestinal obstruction...

Huge multiple liver metastases occupying at least half of the liver...

Severe anemia, with hemoglobin at only 4 grams...

Rheumatic heart disease, having undergone mitral valve replacement, with heart failure...

Aged 72, hospitalized six times in three years, exhausting her body...

All of these conditions concentrated in one person. Any one of them could lead to death!

What method could possibly “reverse” all this, bringing her back to life?

Surgery? Absolutely impossible!

Chemotherapy? Unbearable!

Targeted therapy? No evidence!

Immunotherapy? No evidence!

Waiting, only waiting...

But, there is always a way out!

Persistence, wisdom, innovation... surprisingly, a “revolutionary” miracle occurred in this strong elderly woman!

Medical History

Aunt Pan, 72 years old, from Fujian, has late-stage gallbladder adenocarcinoma, multiple lymph node metastases in the hepatic hilum and head of the pancreas, severe anemia, heart failure, type 2 diabetes, and rheumatic heart disease after mitral valve replacement. The tumor presses on the duodenum, causing obstruction and preventing her from eating, and she had a feeding tube for 51 days...

Each of these factors, if mishandled, could lead to her rapid death. Surgery was impossible; chemotherapy was intolerable; the currently popular and expensive immune “miracle drug” had severe side effects, forcing her to give up... Other than symptomatic treatment, it seemed there was nothing more to be done. Just such a dying cancer patient ultimately experienced a major turnaround—her gallbladder tumor shrank by 2/3, liver metastases decreased, tumor markers returned to normal, vital signs stabilized, she could eat, walk, and was in good spirits, recently discharged from the hospital, a true “medical miracle.”

What caused her to “come back to life” and turn danger into safety? Currently, all evidence seems to point to—hydrogen. If it is indeed the work of hydrogen, it could be considered a disruptive discovery in the medical field, shocking and inspiring!

Persistence

“Save her! No matter how difficult, no matter how much it costs! We will do everything we can to save Mom!” On September 21, 2018, perhaps the most difficult and painful day for the Huang family of five brothers, but everyone remained resolute and united in their intentions.

Since Aunt Pan fell ill, she has been hospitalized six times. The five sons took turns caring for her, contributing both money and effort, without complaint. On September 21, Aunt Pan was hospitalized for the sixth time, and the next day was critically ill and admitted to the ICU. The doctors repeatedly informed the family: “The time may not be long; you need to be mentally prepared.”

Upon her sixth admission, Aunt Pan had severe anemia, with hemoglobin at only 37g/L, total serum protein at 53.3g/L, albumin at 25.6g/L, red blood cells at 1.49x10^2/L, hematocrit at 0.14%, CA199 at 88.18U/ml, AFP at 14.11IU/ml, CEA at 39.68ng/ml, heart failure, and the tumor pressing on the duodenum causing a fistula, with the liver occupied by metastases. The situation was extremely critical, but the five brothers were still unwilling to give up, even if there was only a glimmer of hope, “because Mom is the only one we have!”

In the hearts of the five sons, “Mom has suffered her whole life.” Aunt Pan worked as a farmer in her early years, then moved to Hong Kong to work as a textile worker, doing the most basic and hardest jobs. Fortunately, her children have all been successful; the eldest, second, third, and fourth sons are all savvy businesspeople, while the youngest son is exceptionally talented, working for a large company in Hong Kong after graduation. The sons always compete to honor their mother, one saying, “Mom, I’ve made soup at home, hurry over!” and another calling, “Mom, I’ve prepared good dishes, come to my house tomorrow!”

Aunt Pan’s happy times abruptly ended in 2017. In November 2017, she went to the hospital due to pain and swelling in her upper right abdomen, highly suspecting gallbladder cancer, with metastases to the liver, hepatic hilum, and surrounding head of the pancreas. A month later, a hospital biopsy confirmed it was stage III moderately differentiated adenocarcinoma of the gallbladder. She underwent nano-knife ablation treatment and later took oral tegafur, but the effect was poor, and she experienced recurrent anemia, requiring multiple hospital visits.

Each time Aunt Pan returned to the hospital, one or two of the Huang brothers would stay close to care for her, while the others would rush to Guangzhou to visit whenever they had time. The filial piety and persistence of the Huang brothers deeply moved Qian Wei, the director of the inpatient department at the Affiliated Cancer Hospital of Jinan University, and the attending physician, Pan Zhongbao: “We will do our utmost to alleviate the patient’s symptoms and extend her life!” After Aunt Pan was transferred to the ICU and a feeding tube was inserted, the medical staff worked tirelessly to maintain her nutrition and manage her symptoms, all with extreme caution. However, everyone knew that unless a miracle occurred, Aunt Pan would inevitably face death soon.

Miracle

While the medical staff worked hard to save her, the Huang brothers were also searching for methods, trying to “turn decay into magic” to keep their beloved mother with them. In early October 2018, the fifth brother in Hong Kong happened to see a news report online about “Professor Xu Kecheng using hydrogen to control cancer.” He quickly contacted Shanghai Meiyiliao and obtained a hydrogen-oxygen nebulizer. With Aunt Pan’s knowledge, he had her inhale hydrogen-oxygen gas daily. Starting with 2 hours a day, then increasing to 4 hours, 8 hours... “Inhale for 2 hours, rest for half an hour, then inhale for another 2 hours, maintaining 8 hours a day.”

Aunt Pan’s spirits improved day by day; on the 51st day of hospitalization, she finally had her feeding tube removed, could eat, and could walk! The five brothers were overjoyed! To seek another hope, they decided to try PD-1 inhibitor drugs on their mother. However, after just one injection, Aunt Pan experienced severe side effects, including fatigue, abdominal pain, skin itching, and low potassium, forcing them to abandon the treatment.

“Other than symptomatic treatment, there’s only hydrogen inhalation,” the Huang brothers never imagined that this seemingly desperate decision would bring their mother hope for life! On January 8, 2019, blood tests showed that red blood cells, hemoglobin, and albumin were gradually rising and returning to normal. More importantly, three cancer markers returned to normal.

Even more exciting, the CT re-examination results on January 12, 2019, showed that compared to the examination on November 27, 2018, her gallbladder tumor had shrunk by 2/3, and the liver metastases had all decreased.

“It’s simply a miracle!” “I can’t believe it!” On January 17, upon hearing the news of the elderly lady’s recovery, Professor Xu Kecheng, accompanied by Director Qian Wei, excitedly went to visit Aunt Pan.

Professor Xu couldn’t believe that just a few months earlier, this elderly lady from Fujian, who had received multiple “critical condition notices” from the ward, now looked rosy, energetic, and robust. “She can eat, walk, and goes to the café every day!” Upon seeing Director Xu, Aunt Pan stopped inhaling hydrogen, immediately got out of bed, and walked to the café with Professor Xu and Director Qian.

As the saying goes, “Liver and gallbladder reflect each other.” Gallbladder cancer, like liver cancer, is highly malignant, prone to recurrence, and has a poor prognosis, making people “dread it.” An October 2018 literature review in the European Journal of Surgical Oncology included eight articles on the chemotherapy results for 474 cases of advanced gallbladder cancer, concluding that only 1/3 of advanced patients benefit from chemotherapy, and patients who cannot undergo radical surgery have a median survival time of 5 to 10.8 months. Existing literature has also found no evidence that PD-1 inhibitors benefit gallbladder cancer patients.

Professor Xu Kecheng expressed his heartfelt gratitude, tightly holding the patient’s son’s hand, saying, “Thank you, thank you to the five brothers; it is due to your persistence and wisdom that your mother came back to life!”

He continued, “Hydrogen control of cancer has abundant experimental evidence, but for such a severe cancer case like this elderly lady’s, achieving such results solely through hydrogen inhalation (hydrogen-oxygen mixture) is almost revolutionary!”

Professor Xu emphasized that this is a case, encouraging and giving us hope...

Professor Shi Jianguo, a doctoral supervisor and oncology expert at the Air Force Medical University (formerly the Fourth Military Medical University), expressed that after reviewing this patient’s medical records, it is indeed encouraging, hoping that more cases can be replicated.

Lin Hong

Hydrogen inhalation brings many surprises; she said this “treasure” is priceless.

“If I had a large villa now and the only hydrogen-oxygen nebulizer, I would definitely choose the machine!” This is the heartfelt sentiment of Ms. Yang, a breast cancer patient from Jining, after a month of hydrogen inhalation. Her cancer markers have returned to normal, and in addition, hydrogen inhalation has brought her many delightful changes, making her ecstatic.

August 22, 2018, was an unforgettable day for Ms. Yang. Just the day before, she flew from Shandong to Guangzhou with her 8-year-old daughter, feeling anxious. On the morning of the 22nd, she left her daughter sleeping in the hotel and arrived at the outpatient clinic of Professor Xu Kecheng at the Affiliated Cancer Hospital of Jinan University as scheduled.

Ms. Yang is a well-known lactation consultant in Jining, usually helping others clear their milk ducts. One day in 2016, she had the sudden thought to “try it on herself,” and when she squeezed her right breast, yellow fluid appeared. Realizing something was wrong, she rushed to the hospital, where she was diagnosed with a benign papilloma and underwent surgery. She recalls that on the day of the surgery, a hard lump appeared at the site. When she asked the doctor, she was told, “It will disappear soon; it should take about three months.”

Three months passed, then six months, then a year, and the lump remained. In November 2017, Ms. Yang underwent a mammogram and was diagnosed with breast cancer. The pathology results indicated stage 0 ductal carcinoma in situ. In December 2017, Ms. Yang underwent a total mastectomy of the right breast at a major hospital in Beijing.

On August 19, 2018, during a follow-up, she discovered that her cancer antigen CA125 had risen to 75.39 (normal value 0-35). What to do? “Just observe.” The local doctors didn’t provide her with better advice.

At this time, she happened to see a news report about “Professor Xu Kecheng using hydrogen to treat cancer,” and she immediately looked up the Affiliated Cancer Hospital of Jinan University to make an appointment with him. “Using hydrogen to treat disease? Are you crazy? How is that possible!” Friends and family advised her against it. Fortunately, her husband fully supported her, giving her reassurance.

On the 22nd, leaving her daughter at the hotel, she took a taxi to the cancer hospital to see Professor Xu Kecheng. Professor Xu patiently listened to her description and, after carefully reviewing her pathology data, said, “An elevated CA125 indicates the presence of cancer or precancerous changes. We can observe for a while.”

“Our doctors said the same, but I’m worried! What if the cancer spreads?” Ms. Yang became anxious, feeling disappointed: many praised Professor Xu for daring to challenge the most difficult cancers, but today he wasn’t challenging for her.

She fell silent, studying the kind old doctor, “He must have a way to help me!” Her confidence was restored.

Sure enough, Professor Xu spoke up: “You should try inhaling hydrogen. We have a member in our cancer recovery association with ovarian cancer, and her CA125 decreased after inhaling hydrogen.”

As soon as Professor Xu finished speaking, she stood up, moved to his side, grabbed his hand excitedly, and said, “Professor, I came here specifically for your hydrogen treatment! I’ve been a fan of yours for a long time and wanted to buy your book but couldn’t find it!”

Professor Xu smiled, stood up, and handed her a signed copy of his new book, Practicing Chinese-style Cancer Control. “I didn’t expect such a famous expert to be so approachable!” Ms. Yang was very grateful.

After leaving the hospital, she rushed to Xu Kecheng’s Health Care Studio for an hour and a half of hydrogen inhalation experience. The gas from the hydrogen-oxygen nebulizer continuously flowed into her body through a nasal cannula. After inhaling, she returned to the hotel, feeling unprecedented fatigue and slept very soundly that night. The next day, she returned to the studio for another experience, and this time she felt much lighter, with her previously dull complexion brightening. However, the studio was a thousand miles away from her home, making it impossible to go every day, so Ms. Yang chose to return to Jining to inhale hydrogen at home, inhaling for 4 to 6 hours daily. “As soon as I get home, I turn on the machine, watch TV while inhaling, and even inhale while sleeping.”

She noticed significant changes in her body:

Years of adenomyosis led to heavy menstrual flow, painful periods, and irregular cycles. After a month of hydrogen inhalation, she experienced no discomfort during her menstrual period, and both flow and duration normalized.

Previously, she had many dark spots on her skin and had tried various products and methods to remove them without success. Since inhaling hydrogen, the dark spots on her face have faded, large spots have shrunk, and small spots have disappeared. Her face has become fuller, her complexion rosy, and her skin smooth.

In the past, during dry autumn mornings, she would often wake up with a dry mouth and bitter taste, but now that has disappeared.

During the National Day holiday in 2018, Ms. Yang went for a follow-up examination, and her liver cyst had shrunk, with tumor marker CA125 dropping to 24.62, returning to normal. She was overjoyed!

Her joy was shared by her in-laws. During the holiday, her mother-in-law stayed at Ms. Yang’s home and also tried hydrogen inhalation. “My mother-in-law has arthritis and was in pain, needing painkillers, but after a few days of inhaling hydrogen, she said the pain was much less, and she didn’t need to take medicine anymore. My father-in-law had a cerebral thrombosis, and after inhaling, he no longer felt dizzy and had a better appetite.”

She concluded that hydrogen inhalation has a dose effect; the longer the inhalation time, the more pronounced the effect. “Now I can’t live without this ‘treasure’ (the hydrogen-oxygen nebulizer) for a day, and I take it with me wherever I go! Every weekend, Ms. Yang drives back to the county from Jining with her youngest daughter to reunite with her husband and eldest daughter, and she always brings this precious hydrogen-oxygen nebulizer. “My mother-in-law is afraid of damaging my machine, so she specially covers it with cloth.”

Ms. Yang reflected, “I feel my greatest fortune is having embraced this new thing. If I had a large villa now and the only hydrogen-oxygen nebulizer, I would definitely choose the machine!”

Ms. Yang also shared her insights on cancer resistance.

Both of my parents passed away from cancer; my father had colon cancer, and my mother had bladder cancer. A little over a year after my mother’s death, I was also diagnosed with cancer. I think my illness may be greatly related to emotional distress.

Although my condition isn’t severe, I have seen my loved ones leave because of cancer, and many young friends around me are also battling cancer. I deeply feel that fighting cancer is not easy, and I am very willing to share my experience with hydrogen inhalation to help more cancer warriors still suffering.

Additionally, Academician Tang Zhaoyou and Professor Xu mentioned swimming in Chinese-style Cancer Control (Tang Zhaoyou: moderate swimming increases dopamine secretion, which can inhibit tumors). Now I swim 1000 meters almost every day. Swimming has enhanced my resistance, and hydrogen inhalation has improved my body’s internal environment. I believe that combining the two will yield better results. Every cancer patient should have confidence in themselves.

Lin Hong

At the Moment She Received the Test Report, She Couldn’t Believe Her Eyes

On October 25, 2018, during Professor Xu Kecheng’s outpatient day, He Xian brought her freshly released test results to see him. Although the lab report clearly showed that the two most important tumor markers, CEA and CA19-9, had returned to normal, she still couldn’t believe her eyes and needed to confirm with an authoritative expert.

“Your results are excellent, congratulations!” Professor Xu’s confirmation brought great joy to He Xian, who thanked him repeatedly.

“What treatments have you undergone during this time?” Professor Xu asked with concern.

“A month ago, you suggested I try hydrogen inhalation, do you remember?”

“Besides inhaling hydrogen, have you undergone any other treatments?” Dr. Wen Weifeng and the nurse asked in unison.

“No, really none!” Ms. He raised her voice to confirm her statement.

66-year-old He Xian is a retired teacher from a university. In March 2015, after feeling discomfort in her stomach, she went to the hospital for an endoscopy, which revealed abnormalities, leading to a further diagnosis of poorly differentiated gastric adenocarcinoma stage I (including signet-ring cell type). During her hospitalization for gastric cancer treatment, a 0.3 cm ground-glass nodule was incidentally found in her left lung.

A CT re-examination in January 2018 showed that the ground-glass nodule in her left lung had grown to 0.8 cm, with some solid tissue. Upon the doctor’s recommendation, she underwent surgical removal, and the biopsy results confirmed stage I lung adenocarcinoma, with no need for chemotherapy. Further genetic testing revealed a mutation in her 19th gene, making targeted therapy possible.

In March, all check results were normal, but in July, the two most important tumor markers, CEA and CA19-9, suddenly rose to 17.64 (normal value 0-5) and 36.7 (normal value 0-35). The elevation of these markers indicated a recurrence or impending recurrence of the tumor, yet CT and endoscopy found no lesions. This was undoubtedly a “time bomb” buried inside her! She was advised to undergo chemotherapy or take targeted drugs.

Was there a better option? He Xian was at a loss. She made an appointment with Professor Xu Kecheng. Professor Xu also suggested chemotherapy, at least taking targeted drugs. She refused, hoping Professor Xu would provide some recovery measures, especially hydrogen inhalation.

On September 17, 2018, Ms. He began experiencing hydrogen inhalation at Xu Kecheng’s Health Care Studio. On October 15, less than a month after starting hydrogen inhalation, she went for a follow-up at Sun Yat-sen University Cancer Center. When she received the test results, she could hardly believe her eyes—CEA was 3.71, and CA19-9 was 32.77, both returning to normal!

In addition to the visible decrease in the indicators, she also experienced other significant changes: previously, she had difficulty falling asleep and would wake up regularly at 4 a.m., but now she sleeps through the night with high-quality rest; her stools, which were previously loose and unformed, have improved, and her digestive function is normal. She was so happy that she continued to inhale hydrogen to maintain the effects.

Lin Hong

Xu Kecheng’s Commentary

CEA and CA19-9 are tumor markers, and their elevation can be found in many cancers. For Ms. He, both markers were elevated; which cancer did they originate from—gastric or lung cancer? It could be either!

The tumor markers for gastric or lung cancer can be abnormal in one or several markers simultaneously. Although not every patient will show elevated markers, once they do, especially for patients who have previously had cancer, they should be highly vigilant about the possibility of recurrence, even if endoscopy, ultrasound, and CT scans fail to detect tumors, as there can be several months or even years between the elevation of markers and the discovery of tumors. We can refer to this period as “pre-disease.”

Facing such “pre-disease,” it is a difficult choice for both patients and doctors. Generally, chemotherapy is required, but chemotherapy has side effects, which patients often find hard to accept. Ms. He was precisely concerned about this.

I am an old doctor trained in traditional medicine and part of the “circle,” so I must speak the language of the “circle,” yet as a cancer survivor, I may understand better than most what patients are thinking.

“The best doctor treats the pre-disease.” We must be “the best doctors!”

If chemotherapy is the “right path” for treating this “pre-disease,” then hydrogen may be the “bent path” or “side path.” We can “overtake on a bend” or “change lanes to overtake.” Many studies have proven that hydrogen molecules can transform the microenvironment.

Other studies suggest that the biological effects of hydrogen molecules are positively correlated with the concentration of hydrogen in tissues.

Hydrogen molecules can inhibit cancer cells, generally believed to be due to their antioxidant and anti-inflammatory effects. The most powerful and toxic oxidants in the body are OH and ONOO2, which can act on nucleic acids, lipids, and proteins, causing DNA damage, lipid peroxidation, and protein denaturation. Smoking, air pollution, chemicals, and mental stress can trigger these oxidants, leading to cell mutations and the generation of cancer cells. Hydrogen molecules are specific scavengers of these two oxidants. Recent research shows that hydrogen molecules can also exert control over cancer by maintaining mitochondria and regulating immunity.

Because of Hydrogen, He Excitedly Walked on Stage and Deeply Bowed to Xu Kecheng

On October 22, 2018, a lecture on "Hydrogen Molecules and Health" was held at the Sunshine Hotel, featuring renowned cancer treatment expert Professor Xu Kecheng. For nearly a year, he had been focused on one thing—researching hydrogen therapy for cancer. He reviewed a large amount of literature, embarked on a "hydrogen journey," and set up a hydrogen inhalation experience area in his studio.

During the sharing session after the lecture, several participants who had experienced significant benefits from hydrogen inhalation shared their feelings. At the end, an elderly man suddenly walked onto the stage and deeply bowed to Professor Xu, then bowed to the volunteers in the studio. The old man's actions surprised everyone.

Who was he? Why was he so emotional?

Mr. Sun, the one bowing, is a villager from "China’s Happiest Village." On August 6, 2018, under the leadership of the "village chief," he came to attend a lecture by Professor Xu and Professor Sun Xuejun about hydrogen medicine. At the venue, several hydrogen-oxygen nebulizers were set up for free public use. Throughout the lecture, Mr. Sun diligently inhaled hydrogen and listened attentively. Over two hours later, when the lecture concluded, Mr. Shen, sitting next to him, suddenly said, "Wow, your face has become rosy!"

"Oh? Is it really that magical? I’ll have to come back to try it again!" But he thought to himself that with so many people coming to Professor Xu's studio for hydrogen inhalation, he probably wouldn’t be able to get an appointment, so he didn’t take the initiative to return.

On September 15, "China’s Happiest Village" held a celebration at the Sunshine Hotel, where Mr. Sun met volunteer Deng Yingzi from the studio again. With her assistance, he began to consistently visit the studio daily for hydrogen inhalation starting on the 16th.

It turns out that Mr. Sun had been a heavy smoker for over 30 years. "When I was in the Air Force, I was more disciplined, but I started smoking when I went to college in 1975, smoking two packs a day." In 2010, Mr. Sun started experiencing severe shortness of breath. Upon examination, he was diagnosed with chronic obstructive pulmonary disease (COPD), stage three.

The airflow obstruction in COPD worsens over time, affecting not only the respiratory system but also the skeletal muscles, heart, and other organs, leading to cor pulmonale and ultimately resulting in respiratory failure and multi-organ failure. The doctor ordered him to quit smoking immediately, or he would "be in big trouble soon." Realizing the dangers of COPD, the military-born Mr. Sun decisively quit smoking within a week.

However, there is currently no effective cure for COPD. The disease frequently leads to acute exacerbations requiring hospitalization, with each exacerbation being a significant blow to Mr. Sun's respiratory function. "All I can do is slow its progression."

"I didn't even have the strength to lift a bottle of mineral water; I would be out of breath after a few steps up the stairs, and I couldn’t sleep at night due to shortness of breath." The impact of COPD on Mr. Sun's life was evident, and the fluctuating nature of his condition caused him immense suffering.

By chance, after attending the medical lecture on August 6, he became interested in hydrogen and, with the thoughtful arrangements of the studio volunteers, persisted in the experience for a month.

"Incredible! Hydrogen is truly amazing!" His stomach improved, he enjoyed eating; his sleep improved, wanting to sleep by 10 PM; he had energy to go to the market and could drag home carts loaded with dozens of pounds of goods; even the spots on his body faded...

Hydrogen significantly improved Mr. Sun's COPD symptoms, and he was filled with gratitude for Professor Xu and the studio volunteers, which led to his emotional moment on stage bowing.

Scientific Evidence for Hydrogen's Lung Protection

COPD has "four highs" characteristics in China: high prevalence, high disability rate, high mortality rate, and high disease burden, making it a serious public health issue. Smoking is the most common risk factor for COPD, with a strong correlation between smoking amount, oxidative stress, and COPD symptoms.

In May 2017, Professor Sun Wuzhuang from Hebei Medical University and others published a medical paper in the International Journal of COPD titled "Hydrogen coadministration slows the development of COPD-like lung disease in a cigarette smoke-induced rat model." The article studied the beneficial effects of different hydrogen concentrations on COPD and potential mechanisms. It was found that hydrogen inhalation slowed the onset of lung disease induced by cigarette smoke in rat models, with 22% and 41.6% hydrogen inhalation yielding better results than 2% hydrogen.

The researchers established a rat COPD model using smoke exposure and intervened with different concentrations of hydrogen inhalation via a hydrogen-oxygen nebulizer, observing the rats' daily living conditions and weight changes, evaluating lung function and right ventricular hypertrophy index, and assessing leukocytes in bronchoalveolar lavage fluid. They analyzed lung tissue pathological changes using light and electron microscopy and observed cardiovascular structures and pulmonary arterial pressure changes through ultrasound. They applied immunohistochemistry, Western blot, real-time PCR, and measured tumor necrosis factor, interleukins IL-6, IL-17, IL-23, matrix metalloproteinase-12, tissue inhibitors of metalloproteinases-1 (TIMP-1), caspase-3, caspase-8 proteins, and lung tissue mRNA levels.

Experimental results indicated that hydrogen inhalation significantly reduced the number of inflammatory cells in bronchoalveolar lavage fluid, as well as the mRNA and protein expression levels of tumor necrosis factor TNF-a, IL-6, IL-17, IL-23, metalloproteinase-12, caspase-3, and caspase-8, while increasing the mRNA and protein expression levels of metalloproteinase-1 tissue inhibitor (TIMP-1). Additionally, hydrogen inhalation improved lung pathology, lung function, and cardiovascular function, lowering the right ventricular hypertrophy index.

In May 2018, a research paper published by Professor Zheng Zeguang's team at the Respiratory Disease Institute of Guangzhou Medical University in J Thorac Dis pointed out that inhaling high concentrations of hydrogen improved lung emphysema, chronic bronchitis, small airway remodeling, and lung function decline caused by smoking in mice. This protective effect is attributed to hydrogen's anti-inflammatory and antioxidant properties. The inhibition of the ERK1/2 and NF-kB signaling pathways may be related to hydrogen's anti-inflammatory effects.

Lin Hong

She Was Overjoyed Just Because She Smelled a Bad Odor

"Do you believe it? I lost my sense of smell for over 20 years, and after inhaling hydrogen for just an hour and a half, it miraculously returned!" American Chinese Zhang Ming'en was ecstatic and wanted to share her story as a "miraculous responder" to hydrogen.

Ms. Zhang was born in Hong Kong and immigrated with her family to Washington, USA, during her youth. Living in Washington, known for its distinct seasons and abundant flora, was not a joyful experience for her. She began a long battle with pollen allergies. During the spring and summer pollen seasons, as well as the late summer to late autumn when reeds flourished, sneezing, runny nose, and watery eyes became her norm. Many people with pollen allergies experience nasal discharge forward, but hers flowed backward. To make matters worse, she suffered from bronchial pneumonia four times in one year, nearly losing her life.

To control her condition, she had to repeatedly take steroid medications and antibiotics. However, the side effects of the medications were immediate: due to the burden on her regulatory mechanisms, her originally precise endocrine system was disrupted, her gut microbiota became imbalanced, liver and kidney functions deteriorated, and her immune function weakened, leading to edema and weight gain, causing her immense suffering!

While being tormented by illness, her sense of smell gradually disappeared. "Around the age of 20, I realized I had lost my precious sense of smell when the vibrant roses no longer smelled fragrant, and places piled with garbage no longer stank."

Ten years ago, Ms. Zhang received some Brazilian green propolis from a friend. Taking it morning and night helped her control her pollen allergy effectively, but her sense of smell still did not return, leaving her feeling regretful yet helpless.

In early 2018, she accompanied her friend Amy, who was suffering from breast cancer, to a follow-up at the Fuda Cancer Hospital. Thanks to the help of Professor Xu and other experts, Amy's condition was effectively controlled. Ms. Zhang brought a personal album as a gift for Professor Xu to show her gratitude.

On July 9, 2018, Professor Xu invited renowned Hong Kong writer Mr. Zhong Zimei and Amy to visit his health care studio located in Room 708 of the Sunshine Hotel in Guangzhou, and Ms. Zhang accompanied them as Amy's close friend.

Professor Xu introduced that more than 200 diseases in the human body are related to free radicals, and hydrogen is an ideal selective scavenger of free radicals, capable of treating various diseases and positively protecting and regulating many bodily functions. He also warmly invited them to experience hydrogen inhalation.

"Can hydrogen really be used for health and treatment?" Ms. Zhang found it a bit unbelievable. "Isn’t hydrogen flammable and explosive? Could it be dangerous?" She expressed her concerns. The studio volunteers explained that hydrogen only poses a risk of combustion or explosion in environments with excessive pressure or high temperatures; in a well-ventilated, normal temperature environment, the small amount of hydrogen produced by the machine would not cause an explosion. Additionally, the hydrogen-oxygen nebulizer used in the studio, provided by Meiyiliao Technology, does not have a hydrogen storage chamber; the hydrogen-oxygen mixture generated by electrolysis is delivered directly into the body via a tube, making it very safe.

With her doubts alleviated, Ms. Zhang began to read popular science literature about hydrogen while following the breathing techniques taught by the volunteers to relax and enjoy inhaling hydrogen.

An hour and a half passed quickly, and she and her companions took the elevator to leave. In the elevator, she suddenly smelled a burnt odor. "How can there be a smoke smell?" she murmured. Just a second after she spoke, she suddenly realized, her sense of smell, which had been "frozen" for over 20 years, had miraculously returned!

"I need to go back!" She was overjoyed and immediately returned to Professor Xu’s health care studio, excitedly shaking the volunteer's hand and thanking them repeatedly.

She felt that every blood vessel and cell in her nose was slowly awakening, like plants gradually sprouting in early spring, bursting with vitality; this experience was truly magical!

Even more surprisingly, her restored sense of smell was not fleeting. Every day thereafter, she could perceive the world through her nose, making her feel happier.

On July 30, Ms. Zhang got up early and rushed from Hong Kong to Professor Xu’s health care studio to experience hydrogen inhalation again. To do this, she specially changed her flight back to the United States from August 1 to August 2. Before leaving, she thoughtfully bought mango-flavored cake and several bags of handmade cookies from a well-known store in Hong Kong to personally deliver to Professor Xu. "I can smell the mango flavor of this cake; it’s so fragrant!" Her words were full of gratitude.

Lin Hong

Professor Wei Youzhen's Commentary

Apart from light, the biosphere's air layer is filled with gas molecules, which guide organisms to "discover," undoubtedly serving as a gaseous "navigation" for life. After billions of years of evolution, many animal partners of humanity, although their sense of taste has degenerated, still retain a keen sense of smell, relying on it to discern "benefits and harms," such as dogs and eagles. However, humans, due to the high development of the neocortex, have overshadowed the olfactory bulb of the old brain, generating "intelligence" while degenerating their sense of smell, becoming "olfactory dull" animals. Nevertheless, for humans, the sense of smell remains a "basic ability" to "discover" the world; we rely on it not only for identification but also to influence higher emotions in the brain: fragrant aromas!

Yet, there are some people in the real world who "cannot distinguish between fragrance and odor," simply because the olfactory cells in their nasal mucosa have been "snowed in," either due to allergies or inflammation. Hydrogen can "clear the clouds," allowing olfactory cells to see the light again and re-accept the "stimuli" that permeate the air—whether fragrant or pungent; these stimuli will be transmitted to the brain through the olfactory bulb and tract, preventing the brain from being "lonely" and thus avoiding dementia.

Hydrogen Has Magical Powers? After an Accidental Experience, She Went from Weak to Refreshed

In Professor Xu Kecheng's health care studio, there is a male and female "regular couple" who have been loving partners for over 30 years. The wife is a stomach cancer patient, and the husband has high blood pressure and sleep issues. After a chance hydrogen inhalation experience, the wife had a "miraculous response" and has since persisted, with significant improvements in her symptoms. The husband, who accompanied her, also achieved delightful results from inhaling hydrogen.

Describing Ms. Chen, who had undergone eight chemotherapy sessions, before her hydrogen experience, as "light as a willow, weak and unable to withstand the wind" is quite accurate. She began experiencing pain in her upper abdomen in July 2017 while visiting relatives in Canada but didn’t think much of it at the time. It wasn’t until she returned to China in September for a check-up that she was diagnosed with gastric antrum cancer. After surgery to remove most of her stomach in October, she began chemotherapy.

Eight rounds of chemotherapy were excruciating for her: her sleep quality was extremely poor, going to bed at 9 PM but often not falling asleep until after midnight, waking up once or twice an hour; she lost weight rapidly, her complexion darkened, and she spoke weakly; she often felt dizzy and was too weak to get out of bed, relying on her husband for everything. Her husband, Huang Xsheng, cooked and bought groceries every day without complaint. When Ms. Chen was in a bad mood, he patiently comforted her and helped her cope with her negative emotions. He was both her caregiver and her emotional support in fighting cancer.

One day in early August 2018, in a WeChat group for cancer patients seeking support, Ms. Chen saw a message that caught her attention: on August 6, there would be a lecture on hydrogen and cancer recovery at Professor Xu Kecheng's health care studio at the Sunshine Hotel. Hydrogen can also treat cancer recovery? Despite her doubts, she decided to attend, following Professor Xu's name.

For Ms. Chen, who was extremely weak, going out was a luxury—she would be out of breath after just a few steps, and her husband had to carry a small stool with him to support her.

The short distance from home to the bus station and then to the Sunshine Hotel was exhausting for Ms. Chen; she had to stop and rest on the stool every few steps before finally making it into the venue.

Not long after the lecture began, Ms. Chen felt her strength waning. She barely held on until Professor Xu began speaking, but she felt dizzy and nearly fainted. With the support of her husband, Huang Xsheng, she left the venue. Volunteer Deng Yingzi helped her into the adjacent Room 708, where Professor Xu's health care studio is located, and turned on a hydrogen-oxygen nebulizer for her to try inhaling. Following Deng Yingzi's breathing techniques, she experienced the sensation of hydrogen and oxygen flowing continuously into her body. An hour and a half later, her strength gradually returned, and she felt somewhat lighter.

The truly "magical" change occurred after she returned home and went to sleep: she sweated profusely in the first half of the night, so much that her clothes were soaked through; in the second half, she slept soundly, waking up refreshed in the morning. Why did this happen? She thought it might be "detoxification."

The surprising detoxification effect prompted Ms. Chen to return to Professor Xu's health care studio, where volunteer Peng Ximei welcomed her and added her to the hydrogen inhalation service group. Since then, she has consistently visited the studio for hydrogen inhalation, accompanied by her husband, regardless of the weather.

The changes that hydrogen inhalation brought to Ms. Chen were evident. Three days after starting hydrogen inhalation, she went from struggling to walk to being able to leave her stool behind and walk a little distance, and her face gradually regained color. After half a month, she could return home alone without her husband’s accompaniment, and her sleep quality significantly improved, often sleeping through the night.

Ms. Chen's husband also benefited from hydrogen inhalation. He had high blood pressure and sleep issues, and after inhaling hydrogen, he could "sleep until the birds sang," with his blood pressure stabilizing. They both said they were most aware of the changes in their bodies. Now, they felt good mentally, physically strong, and in a better mood.

Regarding Ms. Chen's experience, I specifically consulted professionals.

Interviewer: Why did Ms. Chen recover her strength so quickly after just an hour and a half of hydrogen inhalation?

Dr. Kong Xiaofeng: Based on our observed cases, those who had symptoms, especially severe ones, showed rapid improvement after hydrogen inhalation. This may relate to what Ms. Chen mentioned about having "toxins" in her body. These toxins are reactive oxygen species, primarily hydroxyl radicals (·OH).

She is a stomach cancer patient who has undergone surgery and chemotherapy. The formation, progression, and invasion of cancer cells are all related to reactive oxygen species, but cancer cells themselves are also sites of reactive oxygen species production. Surgical trauma, especially from chemotherapy, promotes a large production of reactive oxygen species in the body. These reactive oxygen species can damage mitochondrial function. Mitochondria are the energy factories in our bodies. Walking, moving, and thinking all require energy. When energy is insufficient, it naturally becomes difficult to walk, leading to fatigue, making one feel "light as a willow, weak and unable to withstand the wind." Hydrogen selectively neutralizes toxic reactive oxygen species, and this effect occurs rapidly. Additionally, hydrogen protects mitochondria. Therefore, it is understandable that Ms. Chen felt energetic after inhaling hydrogen.

Interviewer: What about Ms. Chen sweating profusely after her first hydrogen inhalation? Hydrogen is known to be very safe, and our intestines naturally produce hydrogen. Is this a side effect of hydrogen inhalation?

Professor Wei Youzhen: Profuse sweating in the middle of the night is akin to "night sweats" in tuberculosis, indicating that the immune function of the body is at play. This suggests that hydrogen may stimulate the immune function of the body.

Sweat glands are skin glands that secrete sweat and are regulated by the autonomic nervous system (vegetative nervous system). Under normal circumstances, through feedback and central nervous system influence, they perform secretion and excretion functions. For example, in high environmental temperatures, sweating occurs naturally to lower body temperature, aiding in self-protection; during heightened emotions or stress, the vegetative nervous system regulates sweating. If the function of the vegetative nervous system is disrupted or affected by toxins, sweat gland secretion and excretion become disturbed, and “sweating” becomes a “symptom.” Conditions such as hyperthyroidism, diabetes mellitus sequelae, tuberculosis, and menopause can cause excessive, involuntary sweating—"night sweats."

In this patient, due to the disturbance of illness, the immune system was suppressed and metabolism lowered. After hydrogen inhalation, it may have triggered the body's immune system to recalibrate, allowing it to reach a level capable of "sweating," which should be a good sign.

Lin Hong

Beijing Professor with Allergic Rhinitis Shares Her Experience

The winter in Beijing has passed, and the north wind blows cold. The arrival of friends from the south brings a different warmth to the northern winter.

From November 16 to 18, 2018, Professor Xu Kecheng visited Beijing to participate in the second annual academic conference of the Chinese Rehabilitation Medicine Society. Additionally, he had an important activity: to meet his long-cherished old friend and former patient, Sister Wang.

Sister Wang had been a leader in a large organization, a department-level official. Her husband had once been a prominent leader in a province and later served in a central government position, and everyone habitually called him "Old Secretary."

Sister Wang suffers from right renal pelvis and ureter cancer. Her left kidney had undergone atrophy years ago due to other reasons and had poor function; if her right kidney were removed, she would need lifelong dialysis. She refused the kidney removal surgery and, two years ago, accompanied by the Old Secretary, traveled south to Guangzhou's Fuda Cancer Hospital for minimally invasive ablation and other treatments, successfully preserving her right kidney and controlling the tumor. However, the problem was that Sister Wang often felt fatigued, especially after undergoing a complex ablation treatment in December 2017, feeling weak all over, unwilling to talk, and reluctant to move, as she described, lifting her arms and legs felt like they were filled with lead.

Fatigue may seem trivial, but "cancer fatigue" in cancer patients is quite troublesome. Professor Xu considered many solutions for Sister Wang, including stopping certain medications, improving nutrition, increasing caloric intake, infusing "energy medications," providing psychological support, taking traditional Chinese herbal formulas to strengthen the spleen and kidneys, and orally administering a ginseng "essence" product that was being reported to the FDA in the United States specifically for "cancer fatigue," but there was no significant improvement.

Professor Xu managed to obtain a small hydrogen-oxygen nebulizer for her, allowing her to inhale a hydrogen-oxygen mixture of 66.6% hydrogen and 33.4% oxygen for 2 to 4 hours daily. When she returned to Beijing, he encouraged her to bring the machine with her. In June 2018, when Professor Xu visited Beijing, he found Sister Wang full of energy and enjoying her meals. Was it the effect of hydrogen? He once asked her to think carefully about which method was most effective in treating her fatigue. Sister Wang smiled and said, "To be honest, it’s that hydrogen you recommended. I've been inhaling it ever since, and it really works; it’s a good thing."

Sister Wang was very happy; she wanted to return to the northwest, where she had worked hard for half her life, to share the achievements of reform and opening up. However, being an elderly person, the change in environment caused her to develop dermatomyositis, leading to severe muscle weakness and difficulty moving, which was extremely distressing. Upon returning to Beijing, she was immediately hospitalized and treated with steroids, which controlled her condition.

On the afternoon of November 17, 2018, Professor Xu specially invited Professor Ge from Beijing and his wife to drive and visit their mutual friend, Sister Wang.

Professor Ge is a cardiovascular expert who has engaged in clinical research at a military hospital for nearly 40 years and is also from the same hometown as Professor Xu, so they have a lot to discuss. During the drive, they naturally talked about Beijing’s air quality, traffic, and also about hydrogen.

"Old Xu, that hydrogen of yours is indeed a bit magical! A few months ago, Professor Xu sent him a hydrogen-oxygen nebulizer, partly because he works in cardiology and wanted to test hydrogen's effects on cardiovascular diseases, as there have been many reports from Japan, and China should not lag behind. Professor Xu hoped he would become his 'hydrogen partner.' Additionally, he is getting older, and hydrogen could help him with 'health care.'

However, this fellow from the same hometown did not take the machine seriously and left it unused. A month later, when Professor Xu saw him, he asked how the hydrogen was working, and Professor Ge smiled and vaguely responded. Hydrogen medicine is still young; even doctors who do not care will not understand it, let alone the simplicity of hydrogen molecules and whether they truly help health. Although Professor Xu felt somewhat helpless, he hoped that time would provide the answer. Now, the fellow finally "expressed his stance," and Professor Xu felt a surge of joy.

"Last month, I tried it by chance and found that my nose wasn’t so blocked anymore. I continued for over ten days, and my nasal congestion improved significantly; I hardly sneezed anymore. Professor Xu, you’re right," Professor Ge said earnestly, "I apologize for not taking it seriously before."

"Previously, he would always apply dexamethasone and various oils, such as salad oil and sesame oil, before going to bed," Mrs. Ge interjected, "Now, my husband’s nose is clear, and he doesn’t sneeze anymore; he tells everyone that hydrogen is good."

During rush hour, the roads were congested, and after two hours, they arrived at a purple-red building, which is referred to by locals as the "Minister's Courtyard." On the surface, it looked like an ordinary residential building, except that there were soldiers on guard. Sister Wang's husband, who had been waiting, came forward to greet them.

The "Old Secretary" was simply dressed, humble, and polite, warmly greeting the visitors as he led them inside.

With friends from the south visiting, Sister Wang, who had difficulty moving, specifically transferred from her bed to a wheelchair to meet everyone in the living room. There was a noticeable improvement in the swelling of her face and arms. Professor Xu carefully reviewed her medical records and believed her condition was stable, attributing some of the improvement to hydrogen. However, the side effects of steroids were also evident. Professor Ge stood beside Sister Wang and said, "Sister, you must keep inhaling hydrogen; it can eliminate these side effects. Look at me; my allergic rhinitis has disappeared." He shared his own experience of how hydrogen had produced "magical" effects on him with Sister Wang.

In the evening, while dining at a restaurant near the "Old Secretary's" home, they again discussed hydrogen. Professor Ge particularly enjoyed this meal, not only because friends had come from afar but also because the hydrogen brought him physical comfort.

Professor Xu was also very happy; Professor Ge had finally become his "hydrogen partner." Professor Xu opened his laptop and showed him a paper on hydrogen treatment for rhinitis. This article, written by Chinese scholars, was published in Experimental and Therapeutic Medicine.

The study used ovalbumin (OVA) to sensitized female BALB/c mice and established an animal model of allergic rhinitis (AR) through intranasal ovalbumin stimulation, exposing them to hydrogen and inert gas helium at different frequencies and durations. The frequency of sneezing/scratching and weight changes in the mice were recorded. Histological analysis and various cytokine analysis methods were employed to evaluate hydrogen's effects on ovalbumin-induced acute rhinitis. The results showed that the hydrogen inhalation group (AR+H2) had significantly fewer instances of nasal itching and sneezing compared to the control group and the helium inhalation group. The mice in the hydrogen inhalation group had the most significant decrease in sneezing and scratching, and the longer and more frequently they inhaled hydrogen, the more pronounced the improvement.

Interestingly, the nasal mucosal structure also changed after hydrogen inhalation, showing a significant reduction in inflammatory cell infiltration.

Seeing the above experiment, Professor Ge smiled and said, "It’s a pity that if I had taken a nasal mucosal biopsy before inhaling hydrogen and now took another one, I could be a little white mouse."

Lin Hong

A person in sub-health wrote these words excitedly after inhaling hydrogen for 30 days.

What is sub-health?

According to Western medicine, sub-health refers to a state between health and disease, where modern medical examinations do not show significant changes in disease indicators, but the body's vitality declines, and various adaptive abilities decrease to varying degrees. The individual also reports some uncomfortable physiological states. Traditional Chinese medicine proposed the concept of "treating the unillness" in the "Huangdi Neijing" thousands of years ago. This "unillness" indicates that the body has certain degrees of yin-yang imbalance, abnormal qi and blood flow, and dysfunction of organs, but has not yet entered a pathological state of disease, thus existing between illness and non-illness.

The best time for disease treatment or intervention is when it has not formed or has just formed, as stated in the "Book of the Later Han: Biography of Ding Hong": "If you can stop the problem before it starts, the evil will dissipate, and harm will be removed, leading to good fortune."

Many studies have proven that hydrogen molecules, which have anti-inflammatory and selective antioxidant effects, can transform the body's microenvironment and effectively treat "unillness." Mr. Shen, who has suffered from rhinitis for many years and often feels discomfort in his liver, is a typical sub-healthy individual. After experiencing a 30-day hydrogen-oxygen nebulizer session at Xu Kecheng's Health Care Studio, his physical condition improved significantly. He was so excited that he meticulously recorded the changes and insights from these 30 days.

By chance, I attended a lecture on "Hydrogen and Health" hosted by Xu Kecheng's Health Care Studio. I remember during the lecture, an elderly man slowly walked over to sit next to me in the hall, looking pale and lethargic. He placed the nasal cannula on and slumped in his seat. I thought he was just a patient and continued to listen to the lecture. As the two-hour lecture was about to end, I turned to look at the elderly man beside me and was amazed to find that his complexion had turned rosy and his eyes were much brighter. What was happening? It was so miraculous! I couldn't help but want to experience it myself. With the help of Teacher Deng at the studio, I successfully obtained a 30-day experience opportunity with the beautiful hydrogen-oxygen nebulizer, embarking on a wonderful journey to health.

Before attending Professor Xu Kecheng's hydrogen inhalation lecture, I felt that my physical condition was very poor. I had noticeable discomfort in my liver, felt heavy when walking, and experienced slight dizziness. As for rhinitis, it had been a long-standing issue. Since inhaling hydrogen is safe, I decided to give it a try.

After inhaling for 1.5 hours daily for just two days, I already felt my steps becoming much lighter, and my energy began to surge. After learning about my rhinitis, the staff kindly reminded me to increase the mist to enhance the therapeutic effect. By the fifth day of inhaling hydrogen, the discomfort in my liver had significantly diminished. Interestingly, it seemed that my long-standing smoking addiction also weakened, as I no longer felt the urge to smoke aimlessly.

By the 15th day, my mental state had completely returned to normal, and the rhinitis that had been bothering me seemed to have disappeared due to the improvement in nasal airflow. I then increased my intake of selenium-rich foods in my daily diet, insisting on eating at least one selenium-rich egg and trying to drink selenium-rich tea. By the 20th day of inhaling hydrogen, the discomfort in my liver had nearly vanished. Oh, I must mention an unexpected surprise: I had previously discovered floaters in my vision after long hours of looking at my phone, but after inhaling hydrogen for over 20 days, the floaters had also improved, which was truly delightful.

Reflecting on my nearly 30 days of inhaling hydrogen, I gradually gained comfort in my body while also acquiring some small tips on hydrogen inhalation that I would like to share with everyone:

1. **Posture**: Relax your whole body, keep your back parallel to the back of the hydrogen inhalation chair, place your legs on the chair's extension board, and rest your hands naturally on the armrests. Close or slightly close your eyes.

2. **Breathing**: Keep your mouth closed and inhale through your nostrils, ensuring that your inhalation is even and prolonged. Then slightly open your mouth to exhale gently.

3. **Duration recommendation**: Hydrogen inhalation should be continuous; maintaining over one hour of high-quality inhalation daily is ideal. First-time users should persist for 7 to 15 consecutive days, using noticeable improvement in bodily sensations as a signal to pause for one to two days before resuming the previous cycle. Those with conditions can inhale long-term.

4. **Combination recommendation**: Hydrogen inhalation should be part of the body's conditioning, so medications should still be taken when necessary. Sub-healthy individuals should also adjust their diet, lifestyle habits, and appropriately increase their intake of suitable trace elements.

5. **Others**: Ensure adequate water intake before and during hydrogen inhalation.

Finally, I want to thank Professor Xu Kecheng and his Health Care Studio, Teacher Deng for their voluntary and enthusiastic help, and the two female staff members at the studio for their meticulous work, allowing our bodies to regain health. Of course, I also want to thank the company for introducing the hydrogen-oxygen nebulizer, as high-concentration medical-grade hydrogen is our guarantee for rapid recovery.

Targeted conditioning along with appropriate medication is our guarantee for health. I wish all hydrogen inhalation partners better health! Professor Xu Kecheng describes health in very simple terms: "good complexion, abundant energy, able to eat well, can gain weight, smooth bowel movements, and unobstructed urination," otherwise, it is "sub-health." Professor Xu believes that sub-health is essentially a problem with the body's energy metabolism.

Nobel Prize-winning physicist and one of the founders of quantum mechanics, Professor Erwin Schrödinger, pointed out that life is an energy system with "orderliness and regularity" mechanisms. All life activities in the human body require energy, just as machines need energy to operate, but the efficiency of energy utilization in the human body is far greater than that of existing artificial machines. Mitochondria are the power plants in human cells that generate energy, burning food to produce energy-carrying ATP, thus constructing the "orderliness" of living organisms and maintaining the structure and function of the body. If mitochondrial function is impaired, energy supply and consumption become insufficient, leading to "disorder" in living organisms, which can result in various "discomforts" or minor ailments, i.e., sub-health, which may not be detectable in clinical examinations but can severely impact quality of life.

Mitochondrial damage is associated with the excessive generation of toxic reactive oxygen species in the body. Hydrogen molecules can selectively eliminate toxic reactive oxygen species like hydroxyl radicals, maintaining mitochondrial function and correcting abnormal energy metabolism. This may be the primary mechanism through which inhaling hydrogen improves sub-health.

Chapter Seven

Selected Media Reports

Can hydrogen also treat diseases? Yes! Cancer experts in Guangzhou use "hydrogen" to control cancer.

On the afternoon of August 6, 2018, a lecture on "Molecular Hydrogen and Health" was held at the Sunshine Hotel in Tianhe District, Guangzhou. The conference hall, temporarily converted by Xu Kecheng's Health Care Studio, was bustling with people. Among the many attendees, 60-year-old retired teacher Ms. Quan stood out as particularly lively. As a cancer patient with recurrent ovarian cancer and multiple metastases, her specific tumor markers normalized after stopping chemotherapy and consistently inhaling hydrogen daily.

The remarkable changes observed in Ms. Quan delighted Professor Xu Kecheng, the honorary director of the Ruida Cancer Hospital affiliated with Jinan University. Engaged in research on hydrogen for cancer control, he has been closely monitoring every patient's subtle changes and has collected over 60 cases of verified effective patient data.

"People say that understanding comes naturally, and the path to simplicity is straightforward. As we delve deeper into hydrogen therapy for diseases, perhaps this simple substance, ranked first in the periodic table, can indeed play a more significant role in human health," said Xu Kecheng.

Recurrent cancer patient: "After inhaling hydrogen for a month and a half, my tumor markers decreased.

Ms. Quan, now 60, has been battling cancer for three years. In 2015, she underwent surgery and multiple rounds of chemotherapy for ovarian cancer. However, by the end of 2017, the tumor recurred and metastasized, filling her abdomen with cancerous masses. After undergoing two tumor debulking surgeries, she entered a cycle of chemotherapy. "After five rounds of chemotherapy, my white blood cell count dropped to around 1, my absolute neutrophil count fell to 0, and my platelet count dropped to about 20. Each chemotherapy session felt like a brush with death."

The effects of the initial surgeries and high-dose chemotherapy only became apparent after the fifth round. Test reports showed that only one of her three tumor markers had decreased. Chemotherapy failed to help Ms. Quan effectively control her condition, and her CA125 levels did not significantly drop after the first five treatments. Additionally, due to the immunosuppressive effects of chemotherapy, she developed shingles.

"The doctor said I was resistant to the chemotherapy drugs and needed to switch medications. At that time, I heard that Director Xu Kecheng's health studio offered free hydrogen inhalation. The selective antioxidant properties of hydrogen can eliminate excess and harmful free radicals, which may help control cancer." Thus, Ms. Quan began inhaling hydrogen on June 30, 2018. After five days, she had her tumor markers checked again, and the results showed a decrease of over 70 points, nearly a 50% reduction. She stopped chemotherapy and continued inhaling hydrogen for a month to see if it could help control her cancer.

Before sharing her experience on stage, Ms. Quan had her blood tested again, and her markers had dropped by another 50 points, now within the normal range. "Inhaling hydrogen was a huge surprise for me. Previously, I would be exhausted after walking just a few meters, but after inhaling hydrogen, I felt better every day. After half a month, I could walk several kilometers without getting tired. I even went to the UK to attend my child's graduation ceremony, which made me feel incredibly happy."

The hydrogen Ms. Quan inhaled was produced by a device called a "hydrogen-oxygen nebulizer." The device contains special electrodes that can decompose pure water, generating colorless and odorless hydrogen and oxygen. The machine automatically controls the gas flow, typically set at 3 liters per minute when inhaled through a nasal cannula. Ms. Quan insisted on inhaling hydrogen for at least two hours every day.

History of Hydrogen Research: Studies from the 1970s Show Hydrogen Can Treat Diseases

Hydrogen, as the first element in the periodic table, exists in molecular form as the lightest and least dense gas in nature, accounting for only 9.5% of all elements in the human body. However, it provides chemical energy essential for life and is a crucial substance for health.

The understanding of hydrogen has been a long process. From the 16th century when chemists first recorded it as a flammable gas to accurately describing its properties and preparation methods, it took several centuries. Chemists discovered that under the influence of electric current, hydrogen could combine with oxygen to form water, leading to its naming as "hydrogen," meaning "water-forming element." Due to its weight being only 1/11 of air, hydrogen was initially used as a primary material for producing airships. In recent years, molecular hydrogen (H) has gained increasing attention as a useful and unique medical gas, with more reports and scientific literature documenting its therapeutic effects.

In 2007, Dr. Shigeo Ohta and his research team at Tokyo Medical University published a paper in "Nature Medicine," reporting astonishing therapeutic effects of molecular hydrogen on rat models of cerebral infarction. The article showed that inhaling hydrogen at concentrations of 1% to 4% significantly reduced the size of cerebral infarctions in rats. They also indicated that hydrogen specifically scavenges free radicals and peroxynitrite without affecting hydrogen peroxide or superoxide. This paper sparked interest in the role of molecular hydrogen in various diseases.

Before the Japanese scientists published their findings, biological effects of hydrogen had already been studied in limited scopes. In 1975, Dole and his colleagues at Baylor University and Texas A&M reported the hydrogen effect in "Science," observing significant tumor reduction in nude mice with squamous cell carcinoma placed in a chamber containing 2.5% oxygen and 97.5% hydrogen at 8 atmospheres.

In 1978, reports indicated similar effects of high-pressure hydrogen on leukemia. A gas mixture containing 49% hydrogen, 50% helium, and 1% oxygen effectively prevented decompression sickness and nitrogen narcosis in divers working below 500 meters sea level.

In 2001, French scientists reported that high-pressure hydrogen had anti-inflammatory effects on mouse models of schistosomiasis-related chronic hepatitis. While high-pressure hydrogen may be effective for certain diseases, only a few studies have been published, and comparisons between high-pressure and normal-pressure hydrogen have yet to be made.

Did Hydrogen Medicine Start in China? Grassroots Enthusiasts Observed Hydrogen Atoms in Animals

The article published by Dr. Shigeo Ohta in "Nature Medicine" has long been regarded as a benchmark in the field of hydrogen medicine and is considered the beginning of molecular hydrogen research. However, Professor Xu Kecheng discovered in interviews that this "beginning" actually occurred in China. A grassroots scientific enthusiast began studying the medical value of hydrogen as early as the 1990s. This enthusiast even purchased radioactive hydrogen isotope tritium to inject into small mice to observe the behavior of hydrogen in animals.

In 1991, Du Yuanwei, a biology teacher at the Fourth Middle School in Zibo, Shandong Province, became fascinated by hydrogen's miraculous effects after a chance discovery. After approximately five years of experiments and discussions, Du wrote numerous academic papers. However, since he was not a "medical professional," his articles were not recognized by formal scientific or medical journals. He published his papers in local science newspapers and industry magazines, explaining that hydrogen gas can be used as energy in the body.

From this grassroots scientist's perspective, inhaling hydrogen can enhance health, cure diseases, and prolong life. Hydrogen can be administered directly and used for disease treatment, as well as for sports rehabilitation.

This biology teacher began conducting hydrogen experiments on plants in the 1990s, discovering that plants grown in hydrogen-rich environments had significantly extended flowering periods. He injected hydrogen from purchased cylinders directly into rats, rabbits, and other animals, observing enhanced resistance to anesthesia and hunger in these animals.

"This was essentially a toxicity test for hydrogen, and the results not only confirmed that hydrogen did not harm the animals but also demonstrated a certain degree of anti-toxicity (anesthetic) capability," the biology teacher stated in an interview with Southern Metropolis Daily, adding that he even injected hydrogen into himself to verify the results.

In 1997, Du Yuanwei submitted an article titled "The Huge Effects of Hydrogen on Living Organisms" to the Third International Academic Exchange Conference on Environmental Engineering and Chemical Engineering, proposing that hydrogen, as a strong reducing agent, could combat cancer, aging, and chronic diseases caused by environmental pollution, and boldly suggested that hydrogen acts as a "cleaner" in the body. He stated that hydrogen molecules directly reacting with hydroxyl radicals are the basis for treating inflammatory damage, proposing that "hydrogen can promote vitality through an unknown mechanism."

In 1999, Du published an article in the "Journal of Shandong Normal University," reiterating that hydrogen has reducing properties in animals and can act as an antioxidant. In his exploration of the significance of hydrogen in life activities, he proposed that "the accumulation of excessive peroxides during metabolic processes leads to many diseases and aging, indicating that the body must have mechanisms to combat these peroxides. Hydrogen, as a strong reducing agent, naturally and without side effects eliminates peroxides, achieving a balance in terms of oxidation and reduction."

"If judging by the publication of results in formal academic journals, Du Yuanwei's viewpoints align closely with today's understanding of hydrogen molecular biology. His discoveries predated the 2001 findings of French diving medicine experts demonstrating the anti-inflammatory effects of breathing high-pressure hydrogen at 8 atmospheres by two years and the Japanese discovery of the specific scavenging effects of hydrogen molecules on free radicals by eight years," Xu Kecheng remarked.

In the experimental reports provided by Du Yuanwei, there is a report utilizing radioactive hydrogen to trace the pathways of hydrogen in animals. "It is challenging to observe how ordinary hydrogen atoms move within animals using laboratory methods. Therefore, I specifically purchased small bottles of the radioactive isotope tritium (3H) and entrusted a university laboratory to conduct the experiments." He told Southern Metropolis Daily that after electrolyzing water to produce tritium gas and allowing mice to inhale it, the presence of tritium was detected in various tissues and organs of the mice.

"This indicates that hydrogen moves comprehensively within the body once inhaled," Du Yuanwei stated, adding that this experiment also proved that once the safety, non-toxicity, and clear therapeutic mechanisms of hydrogen are established, its medical value will play a significant role in treating various diseases across multiple organs.

Xu Kecheng highly appreciates Du Yuanwei's research findings. Currently, the medical community generally considers the 2007 article in "Nature Medicine" about the antioxidant effects of molecular hydrogen as the beginning of "hydrogen medicine." However, Xu Kecheng proudly states, "This 'beginning' seems to have originated in China."

Why Can Hydrogen Treat Diseases? Experts Claim Hydrogen is the Nemesis of Overoxidation and Free Radicals

If Du Yuanwei's research represents grassroots spontaneous validation, then Sun Xuejun from the Second Military Medical University brings a strong academic background to hydrogen medicine. He was one of the first experts to introduce Dr. Ohta's research findings to China, and since then, many medical professionals and experts have participated in research related to hydrogen medicine.

Sun Xuejun has long been engaged in marine medicine research and was the first in China to promote the study of the biological effects of hydrogen. He also introduced the research findings of Japanese scientists to China.

"Currently, the mainstream view regarding the pathophysiological mechanisms of hydrogen therapy for diseases is that hydrogen acts as a selective antioxidant," Sun Xuejun explained. The macromolecules that make up cells contain paired electrons, which provide stability. If an electron is lost, the molecule becomes an unstable "free radical." In biology, free radicals refer to free molecules, atoms, or atom groups that contain one or more unpaired electrons. Free radicals are highly reactive, seeking to regain stability by "stealing" electrons from other molecules, leading to what is known as "oxidative stress reactions." Not all free radicals are harmful. A certain amount of free radicals is produced during metabolism, referred to as endogenous free radicals, which participate in information transmission and are essential active signaling factors for the body. The body has an automatic antioxidant system that can promptly eliminate excess free radicals. Both must be in a balanced state. If harmful and excessively produced free radicals are not cleared in time, they can damage vital substances, including DNA, proteins, and lipids, causing harm to the body.

"It can be said that free radicals are the root of all diseases." Currently, hydrogen molecules exhibit antioxidant properties superior to all known antioxidants, such as vitamin C, carotene, and lecithin, providing powerful prevention and treatment for various symptoms caused by free radicals, including allergic dermatitis, constipation, hypertension, diabetes, cancer, and atherosclerosis. "A notable characteristic of hydrogen is its strong penetrability, allowing it to easily enter cells, including the nucleus and mitochondria, whereas many other antioxidants struggle to reach these areas quickly and fail to achieve optimal antioxidant effects," he stated.

Academician Team Support: Research Shows Hydrogen is Beneficial for Treating Chronic Obstructive Pulmonary Disease

Sun Xuejun also stated that according to the latest medical research, chronic inflammation can lead to severe issues, with a chronic inflammatory response present in conditions like arteriosclerosis, hypertension, and diabetes. There are also situations where the body incorrectly triggers inflammatory signals without any injury, leading to autoimmune diseases, where the immune system erroneously attacks its tissues.

While research has proven that chronic inflammation is a key pathogenic factor, no ideal drugs have been found to effectively combat chronic inflammation. For example, corticosteroids like prednisone have excellent anti-inflammatory effects, but their long-term use can result in numerous side effects, which can be as harmful as or even worse than many chronic diseases. "Hydrogen has been proven to be an anti-inflammatory substance, and since it is a very safe gas that can be used long-term, it may play a role in the pathological basis of many chronic diseases caused by chronic inflammation. Many people have found that drinking hydrogen water can lower blood sugar, blood pressure, and bad cholesterol, possibly due to hydrogen's anti-inflammatory effects," Sun Xuejun said.

In 2011, Academician Wu Mengchao, a pioneer in liver surgery, and his team first discovered the protective effects of hydrogen against liver damage in mouse experiments. The research findings were eventually published in the "Journal of Hepatology" in the United States.

Experts in respiratory diseases, including Academician Zhong Nanshan of the Chinese Academy of Engineering, have also been paying attention to the medical value of hydrogen. Under his advocacy and participation, in 2014, six multi-center randomized double-blind studies on hydrogen therapy were conducted in more than 30 hospitals in China. These studies included hydrogen-assisted treatment for allergic rhinitis and focused on chronic obstructive pulmonary disease and asthma, which were of particular interest to the academician himself. Nearly 800 cases were enrolled in this research, with two studies completed and others ongoing. Preliminary findings indicated that hydrogen played a significant role in assisting treatment for allergic rhinitis and chronic obstructive pulmonary disease.

In public interviews, Academician Zhong Nanshan stated that the clinical application of hydrogen could push forward the basic treatment of many diseases, serving as a means of "treating the unillness." He also predicted that further research in hydrogen medicine could potentially change the current medical landscape.

The Future of Hydrogen Medicine: "The Application of Hydrogen in Cancer Prevention and Control Holds Great Promise"

Cancer treatment expert Professor Xu Kecheng began to focus on the role of hydrogen medicine in cancer treatment a year ago. He visited numerous patients who controlled their cancer conditions through hydrogen inhalation and found that the vast majority of patients showed improvement, with some even experiencing miraculous effects. Through experiments, he discovered that it was difficult to create tumor animal models in a hydrogen-rich environment.

"In a regular environment, injecting cancer cells into an animal body quickly leads to a cancer diagnosis. However, in a hydrogen environment, achieving a similar diagnosis becomes challenging, providing reverse validation of hydrogen's effectiveness in inhibiting tumor formation." Laboratory observations revealed that in a hydrogen environment, cancer cells slowed their movement, reduced division, and increased apoptosis, with many cancer cells forming vacuoles.

These cases and laboratory data convinced him to conduct in-depth research on using hydrogen to control and combat cancer. "Currently, the prospects for applying hydrogen in cancer prevention and control are vast," he stated. For example, it can serve as an auxiliary treatment before and after surgeries and chemotherapy to enhance efficacy and reduce side effects; additionally, it can be introduced during recovery after effective cancer treatment to prevent recurrence and metastasis. Furthermore, for cases of chemotherapy failure or drug resistance, hydrogen inhalation therapy may yield results. "Given that hydrogen therapy acts on multiple targets, its anti-cancer and cancer control functions will continue to emerge in the overall treatment of cancer."

As research into hydrogen medicine deepens, hydrogen inhalation also has positive implications for preventing cancer in high-risk populations. "Individuals infected with hepatitis B and HPV have a significantly increased probability of developing liver cancer and cervical cancer; inhaling hydrogen may help prevent cancer formation. Similarly, smokers, those exposed to high-risk environments, and individuals with a family history of tumors may also benefit from hydrogen inhalation for preventive purposes."

Academician Tang Zhaoyou, a leader in tumor surgery in China, has shown great interest in using hydrogen to control and combat cancer. As the originator of the "Chinese-style cancer control" concept, Academician Tang has reviewed over 50 "investigation reports" written by Xu Kecheng after his visits. He noted that hydrogen inhalation is not a large-scale method for eliminating tumors but may achieve cumulative victories akin to guerrilla warfare on the foundation of tumor elimination. He agrees that "hydrogen therapy may have its roles in pre-treatment, in-treatment, and post-treatment, serving as new auxiliary treatment, comprehensive treatment, and supportive therapy."

As a student of Tang Zhaoyou, Xu Kecheng has conducted extensive research and practice in implementing Chinese-style cancer control. He believes that the main strategy of Chinese-style cancer control is a combination of "elimination" and "transformation," allowing patients to coexist with cancer and live long-term. "Transformation" includes transforming cancer cells, the microenvironment, and the overall environment (the entire body). Hydrogen will play an important role in this "transformation."

Fortunately, an increasing number of medical institutions are beginning to engage in medical research, and more companies are producing medical-related products. "Hydrogen medicine products range from hydrogen inhalation to hydrogen water cups and hydrogen chambers," Xu Kecheng stated. The growing attention to hydrogen medicine is positive, but research into hydrogen medicine is ongoing, and many blind, hasty projects in hydrogen medicine are not advisable. "While the 'naturalness' of hydrogen suggests its immense safety, it is still a flammable and explosive gas; if concentration is not properly controlled, hydrogen can easily catch fire and explode."

The explosive limit of hydrogen is 4.0% to 75.6% (by volume concentration), meaning that if the volume concentration of hydrogen in the air is between 4.0% and 75.6%, it will explode upon encountering a flame. However, if the hydrogen concentration is below 4.0% or above 75.6%, it will not explode, even in the presence of a flame. The explosion at the nuclear power plant during the 2011 Japan earthquake was ultimately determined to be a hydrogen explosion.

Reported by Wang Daobin, Southern Metropolis Daily

Intern Huang Feiyue, Correspondent Wang Pulinhong

Can Inhaling Hydrogen Really Cure All Diseases?

Hypertension, depression, insomnia... even cancer. If someone tells you that a therapy called "hydrogen inhalation" can treat these conditions, would you believe it? Hydrogen is a flammable gas; can inhaling it really have such "magical" effects? What are the scientific principles behind it? Is hydrogen inhalation effective for treating diseases, or is it merely a psychological effect?

Recently, during interviews, reporters learned that this "hydrogen therapy" is gradually gaining attention in the medical community, and the selective antioxidant properties of hydrogen are key to its so-called ability to "cure all diseases."

Why Do People Get Sick? The Main Cause is Imbalance in Oxidation-Reduction

To understand why hydrogen can treat diseases, we first need to discuss why people get sick. The human body is constantly in a dynamic balance with its surrounding environment. Under the influence of pathogenic factors such as bacteria and radiation, this balance can be disrupted, leading to damage to the body and pathological changes in organ function, metabolism, and mental structure, which then manifest as clinical symptoms and signs.

When cells in the body undergo oxidation, oxidative damage occurs. Medically speaking, this is due to both internal and external factors causing a massive outbreak of free radicals in the body, a phenomenon known as oxidative stress. Free radicals are atoms, atomic groups, or molecules that contain unpaired electrons, and they are essential for maintaining normal life. The reactions involving free radicals are fundamental to energy metabolism. When a person inhales oxygen and consumes food, energy substrates and substances that promote energy transformation undergo oxidation in the body, producing a large number of free radicals. Free radicals continuously generate and are also constantly cleared, maintaining a normal physiological level. An excess or deficiency of free radicals can have adverse effects or even harm the body.

When the level of oxidation in cells exceeds their antioxidant capacity to clear oxidants, an imbalance occurs between the oxidative system and the antioxidant system, known as redox imbalance. Excess free radicals, particularly toxic reactive oxygen species, begin to attack biological macromolecules, causing damage to tissue cells. Therefore, oxidative damage is the fundamental cause of various diseases and aging in the body. For example, in the treatment of inflammation in the human body, it is generally believed that eliminating oxygen free radicals is the most fundamental method to alleviate inflammatory responses.

The Principle of Treatment: Hydrogen Can Eliminate Toxic Free Radicals in the Body

Xu Kecheng, a domestic oncology expert and honorary president of the Affiliated Fuda Cancer Hospital of Jinan University, told reporters from Yangcheng Evening News that "hydrogen therapy" is a new treatment gradually gaining attention in the medical field. Questions about how many diseases hydrogen inhalation can effectively treat, to what extent it is effective, and whether there are side effects are being researched more and more in the medical community.

Xu explained that regardless of the disease a person has, there is a common factor: the presence of toxic free radicals in the body. Free radicals (reactive oxygen species) can be good or bad. Japanese scientists have discovered that hydrogen can specifically eliminate harmful free radicals. This is because one of hydrogen's most typical and important chemical properties is its reductive nature, allowing it to selectively neutralize toxic free radicals. Analyzing the mechanisms of disease occurrence, oxidative damage is almost the most basic pathological and physiological process of all diseases. Therefore, since hydrogen is a selective antioxidant, it is very likely to have therapeutic effects on most human diseases.

Why does hydrogen have selective antioxidant properties? It turns out that hydrogen's reductive ability is very weak compared to various reductants in cellular metabolism. According to the principle of redox priority: when multiple reductants are present for the same oxidant, the strongest reductant usually reacts first. Thus, in normal cellular metabolic processes, hydrogen essentially has no effect. However, in abnormal cells, the situation is different. For instance, in tumor tissue cells, a large number of free radicals are produced, preventing normal metabolic reactions, leading to a deficiency of other reductants, which gives hydrogen the opportunity to react chemically with free radicals. The result is that it neutralizes the unpaired electrons in free radicals—most of which come from oxygen atoms—allowing them to react and form water, a stable substance, while the free radicals that lost oxygen atoms also become stable substances in the process.

Minimal Side Effects Due to Hydrogen's Inactive Nature

At Xu Kecheng's health care studio in Guangdong Province, reporters observed that all 15 "hydrogen inhalation machines" set up there were filled with people inhaling hydrogen through tubes in their noses. Staff informed the reporters that these machines only require pure or distilled water to electrolyze it into a mixed gas containing 66% hydrogen and 33% oxygen. Patients only need to take deep breaths to inhale the gas, completing a treatment session that lasts at least one and a half hours. A 62-year-old woman named Chen shared that she was diagnosed with stomach cancer years ago and became very weak after a series of chemotherapy treatments. Since she started inhaling hydrogen in early August 2018, she has noticed significant improvements in her health. "After the first inhalation, I went home and sweated profusely; after three sessions, I found that my sleep, which used to wake me up every hour, had improved, and my previously pale complexion also improved, and my strength gradually returned. Now I can walk in the community every day."

Another man reported that he was diagnosed with liver cancer four years ago, underwent surgery, but unfortunately had a recurrence last year. After being recommended to inhale hydrogen, the most noticeable change has been improved sleep and a significant boost in energy.

In terms of tumor treatment, tumor cell walls produce more reactive oxygen species than normal cells, affecting cell proliferation, DNA synthesis, and angiogenesis. Reactive oxygen species also play a crucial role as "second messengers" in intracellular signal transduction, inducing and maintaining the carcinogenic capabilities of cancer cells. At this time, hydrogen, as an antioxidant, shows potential for treating tumor diseases. Moreover, scientists have found that compared to other antioxidants, hydrogen can easily pass through cell membranes and organelle membranes to reach the necessary sites for reduction reactions, selectively eliminating reactive oxygen species. Due to hydrogen's inactive nature, it does not cause damage to the body's physiological functions or metabolic disorders.

Rapid Progress, But Biological Safety Needs Verification

The role of hydrogen in human health can be traced back to 1975. At that time, a paper was published in *Science* magazine stating that continuous inhalation of 97.5% hydrogen gas at 8 atmospheres for 14 days could effectively treat malignant skin tumors in animals, attributing this effect to its antioxidant properties.

In addition, in 2001, a French diving medical scientist proved that inhaling high-pressure hydrogen at 8 atmospheres could also treat inflammatory responses caused by Schistosoma mansoni infections, marking the first demonstration of hydrogen's anti-inflammatory effects and proposing that direct reactions between hydrogen and hydroxyl radicals are the basis for treating inflammatory damage.

However, these studies did not receive widespread attention, primarily because high-pressure hydrogen is difficult to use as a general clinical treatment. It wasn't until 2007 that Professor Ota Naruo from Japan Medical University successfully used 2% hydrogen to treat animal models of cerebral ischemia and published the results in *Nature Medicine*, finally drawing global attention to "hydrogen therapy." Consequently, 2007 is recognized as the inaugural year of "hydrogen medicine."

Since then, research on hydrogen biology has surged, with the United States, Japan, and China currently being the countries with the most research on the biological effects of hydrogen medicine, involving dozens of research institutions in each country. In China, Professor Sun Xuejun from the Second Military Medical University is considered one of the first to introduce hydrogen therapy and is known as "the first person in Chinese hydrogen medicine." Professor Sun has been engaged in gas effect research for a long time, but it was only after seeing Professor Ota's research results in 2007 that he began studying the medical effects of hydrogen, gradually discovering the usefulness of this therapy.

Today, the medical community in China is continuously accumulating research results on hydrogen biology. For example, the number of studies involving "hydrogen medicine" indexed by the China National Knowledge Infrastructure (CNKI) shows that in 2007, topics related to "hydrogen" were primarily energy-related, while after 2007, numerous papers on the medical effects of "hydrogen" on various diseases, including mental illnesses, heart diseases, and cancers, began to emerge.

Some academicians have also begun researching "hydrogen medicine." Among them, Wang Hongyang, an academician of the Chinese Academy of Engineering and director of the National Liver Cancer Science Center, led a research group to complete the study "Hydrogen Therapy for Liver Injury," which was published in the internationally renowned journal *Journal of Hepatology*.

In 2014, Chinese Academy of Engineering academician Zhong Nanshan found hydrogen to be effective for chronic obstructive pulmonary disease (COPD). During his speech at the World Conference on Chest Diseases, he pointed out that "hydrogen molecules mainly target chronic diseases, fundamentally enhancing antioxidant stress, rather than purely repairing effects, which is beneficial for the body's recovery; the concept is to treat the cause rather than the symptoms."

In March 2014, the Hydrogen Molecular Biomedical Professional Committee of the China Medical Care International Exchange Promotion Association was also established. However, at present, "hydrogen medicine" remains in the basic and clinical research stage. Xu Kecheng told reporters that he hopes to collect as many clinical cases as possible through his public welfare studio. Experts have pointed out that although hydrogen has been found effective for many diseases, the biological mechanisms of this effect still require further research, and its clinical effects need sufficient evidence support. For instance, researchers from the Zhejiang Provincial Academy of Medical Sciences, Dong Wenbin and Zheng Gaoli, have stated that the biological safety of hydrogen cannot yet be fully proven, and many issues regarding hydrogen therapy still need further investigation.

Important Reminder: Do Not Attempt "Hydrogen Therapy" on Your Own

Up to this point, one thing is particularly worth noting: using hydrogen for medical treatment should be done under the guidance of professional doctors and should never be used casually. For example, hydrogen used in everyday balloons is not recommended for medical treatment. In this regard, Lin Xinyong, president of Shanghai Meiyiliao Technology Co., stated that gases intended for human inhalation must pass safety tests for toxicity and biocompatibility. Even if hydrogen is produced through water electrolysis, if the relevant equipment parts are not medical-grade, risks may still exist.

Professor Wei Zhen from Tongji University’s affiliated Dongfang Hospital also stated that hydrogen used in balloons is generally industrial hydrogen, and its source may not necessarily be generated from water electrolysis; it may be mixed with other gases, making it unsuitable for human inhalation.

Revealing: Chinese Biology Teacher Published "Hydrogen Medicine" Paper Eight Years Earlier Than Japan

Currently, the medical community generally believes that it was the Japanese team led by Ota Naruo that pioneered "hydrogen medicine." However, as early as 1996, a middle school biology teacher from Linzi, Shandong, began publishing articles explaining the medical effects of hydrogen as an antioxidant and its ability to eliminate free radicals.

Professor Xu Kecheng specifically traveled to Shandong to find this biology teacher, Du Yuanwei. Xu believes that "hydrogen medicine" is a significant discovery that could reach the level of a Nobel Prize. If hydrogen medicine can be recognized by the academic community, then it should be awarded to a Chinese person.

Du Yuanwei graduated from the Biology Department of Shandong Normal University and began teaching biology at a middle school in Linzi, Shandong, after graduation. In an interview with reporters from Yangcheng Evening News, he stated that he enjoys conducting biological research in his spare time and is also fond of traditional Chinese medicine and practicing tai chi. Therefore, he often ponders what "qi" in traditional Chinese culture actually refers to. Through a process of elimination, he discovered that among gaseous elements in the periodic table, only hydrogen possesses energy and is chemically characterized as flammable. Oxygen only supports combustion and does not possess energy.

The process of human energy metabolism, along with the release of energy from glucose and other energy substances, generates water and releases a large amount of energy. Water and oxygen are indispensable substances for life, indicating that the relationships among hydrogen, oxygen, and water are inseparable. Thus, hydrogen should also play an important role in human life.

To verify his ideas, he conducted a series of experiments in his spare time and discussed them in a paper titled "Experimental Confirmation of the Role of Hydrogen in Life Activities," where he described how he produced tritium gas (one of hydrogen's isotopes, also known as "heavy hydrogen") through the electrolysis of heavy water and introduced it into the living environment of mice. He ultimately detected the presence of tritium in various tissues and organs of the mice, proving that tritium participates in biological life activities and transforms into tritium ions commonly found in living organisms. This experiment indirectly demonstrated that hydrogen gas in the air is both a constituent and an energy substance for life.

In 1999, the journal of Shandong Normal University published Du Yuanwei's article "A New Scientific Topic—An Exploration of the Significance of Hydrogen in Life Activities," which clearly stated: "During metabolic processes, humans produce excessive peroxides, and many diseases and aging are caused by these peroxides. The human body must have a certain life mechanism to combat these peroxides. Hydrogen is a strong reductant that naturally eliminates peroxides without side effects, achieving a balance in the sense of oxidation-reduction."

This article is arguably the earliest to expound on the antioxidant effects of hydrogen, distinct from the concept of "high-pressure hydrogen therapy," and its publication predates Ota Naruo's research by eight years.

Appendix: From Water to Hydrogen: Principles, Technologies, and Innovations in Water Electrolysis for Hydrogen Production

Water Electrolysis

Starting around 1970, Japanese households began installing water electrolysis machines with oxidation-reduction potential (ORP) functions in their kitchens. Through a micro electric field separation, alkaline water with negatively charged hydrogen ions flows out from the negative electrode, reportedly benefiting the intestinal environment, while acidic water with positively charged oxygen ions flows out from the positive electrode, said to be detrimental to health and only suitable for cleaning dishes or the environment. While this might waste water resources, health-conscious Japanese people are enthusiastic about it. Interestingly, decades later, it was discovered that the "waste gas" expelled from a vent in these devices was actually the hydrogen molecules that humans would later cherish.

Why hasn't negatively charged water been widely applied internationally? The primary reason is that water electrolysis machines require very high water quality, necessitating the use of filtered water; otherwise, the alloy electrodes in the device can easily become damaged and fail. As is well known, after World War II, Japan completely replaced all drinking water pipes with stainless steel 316 material during public facility reconstruction, ensuring that the water purified at treatment plants had minimal chances of secondary contamination before reaching households, making it generally safe for drinking. This certainly provided an important condition for the promotion of water electrolysis machines. However, most countries, including China, do not have such conditions, so if households wish to install water electrolysis machines, they must add a water purification system, complicating the application of purification systems due to varying water quality across regions.

After Japanese scientists confirmed in 2007 that hydrogen possesses selective antioxidant effects, there was significant interest in directly applying hydrogen in the health field. By using high pressure to dissolve hydrogen directly into drinking water, it was found to have more advantages than drinking electrolyzed water. Consequently, various hydrogen water products flooded the market, including hydrogen-rich water, hydrogen juice, hydrogen coffee, hydrogen cups, and hydrogen machines packaged in aluminum, cans, or bags.

The main issue with hydrogen water is that hydrogen molecules are not easily soluble in water; even if one drinks thousands of milliliters of water, the amount of hydrogen that enters the body is limited. Therefore, producing clean, inexpensive hydrogen gas from water that can be safely inhaled by humans has become an important research topic and innovative direction in hydrogen medicine.

Traditional Hydrogen Production via Electrolysis

Traditionally, water (H2O) can be separated into H2 (hydrogen) and O2 (oxygen) at room temperature using low voltage and high current. There are two methods: one involves adding conductive substances (hydrogen-oxygen mixture) to an electrolysis cell between alloy electrodes, and the other involves applying a solid electrolyte coated on a proton/ion exchange membrane (hydrogen-oxygen separation).

These two technologies are widely used in industry, such as in hydrogen fuel cells, laboratory gas chromatography, industrial combustion furnaces, and carbon removal in automotive engines.

**Electrolyte Electrolysis Cell Method:** As shown in the diagrams, the electrolyte is added to the electrolysis tank, and power is supplied to the positive and negative electrodes in the tank. Chemical reactions occur between the water molecules at both electrodes, generating oxygen at the anode and hydrogen at the cathode. The two gases mix in the electrolysis tank, producing hydrogen-oxygen mixed gas for output. This traditional electrolysis cell structure is relatively simple and does not require high purity of the water added, but it often suffers from decreased electrolysis efficiency due to excessive resistance between the two electrodes. Additionally, heat energy is easily released during electrolysis, preventing the electrolysis tank from running continuously for long periods, necessitating intermittent cooling. Moreover, the fixed concentration ratio (5%-15%) of the electrolyte gradually depletes as hot gases flow out, requiring replenishment after a certain operational period. The most concerning issue is that the electrolyte may be inhaled along with the gas, which could be harmful to health.

Polymer Membrane Electrolysis Cell Method:** As shown in the diagrams, this method uses a polymer membrane (ion or proton exchange membrane) instead of a conventional electrolyte solution, with a solid platinum material coated on the membrane for conductivity, preventing it from dispersing with the gas. The working principle centers on the exchange membrane, supplying power to the positive and negative electrodes on either side, generating oxygen at the anode and hydrogen ions (H+) at the cathode, which pass through the pores of the exchange membrane to the cathode chamber and combine with electrons to form hydrogen gas, achieving separate outputs for hydrogen and oxygen. Due to the extremely fine pore size of the exchange membrane, excessive impurities in the water can clog the pores and lead to failure, so deionized water is generally required. (Pure water has larger oxygen atom volumes, which can easily affect the fine pores, often causing role reversals between O2 and O3, leading to the so-called unstable ozone phenomenon. Impure oxygen is detrimental to human health and must be expelled, making it unsuitable for inhalation. Therefore, hydrogen machines on the market typically claim to produce high-concentration pure hydrogen (99.999%). It is important to note that common fully sulfonated proton exchange membranes contain perfluorosulfonic acid, which can irritate the eyes, respiratory system, and skin.

Improved Water Electrolysis for Hydrogen Production

Both of the aforementioned electrolysis methods have their pros and cons but are not suitable for human inhalation and should not be used for medical or health purposes. The National Medical Products Administration (NMPA) of China has classified hydrogen inhalation as a third-class medical device, subject to the strictest standards for home and medical use (this classification has also been adopted by the United States, European Union, and Japan), meaning that hydrogen inhalation is a medical action involving life safety, and the devices used must comply with third-class medical device safety standards.

Whether as medical devices or for home health use, hydrogen inhalation devices must meet the following conditions:

- The output therapeutic gas must meet the standards for medical breathing gases.

- It must be capable of operating continuously without downtime, ensuring an uninterrupted gas supply for patients with breathing difficulties and meeting dosage requirements for chronic patients.

- The output therapeutic gas must be filtered, temperature-controlled, and humidified.

- The employed electronic control system must comply with electromagnetic compatibility standards YY0505/GB4343.

- Information must be effectively and accurately recorded for intelligent management of patient history.

- If pure hydrogen is output, the flow rate should not exceed 1 liter per minute to avoid diluting the oxygen concentration in the air and causing hypoxia.

- The output hydrogen must have a sufficiently high concentration. If a hydrogen-oxygen mixture is used, the oxygen concentration must be maintained between 20%-40%, with a total flow that should not exceed the static breathing ventilation of 6 liters per minute to avoid discomfort and safety hazards.

- All gas/liquid pipeline materials must comply with biocompatibility standards for toxicity testing.

- The conductive electrolytes and platinum catalysts used must meet food and drug safety standards.

For future applications and promotion in households, hydrogen inhalation devices must also achieve the following key factors:

- Lightweight, compact, and low power consumption while producing a large volume of gas.

- Low cost, minimal maintenance, and long service life.

- No need to add electrolytes or replace exchange membranes.

- Compliance with electromagnetic radiation protection standards.

- Aesthetic design and quiet operation, with noise levels not exceeding 40 decibels.

- Hydrogen concentration detection and warning functions.

- Ability to prevent static electricity and combustion explosions.

- Integration with wearable external diagnostic technologies for comprehensive health management.

To meet these requirements, we have made bold improvements to traditional hydrogen production processes. The main innovations and their patent numbers in the hydrogen-oxygen gas atomization device are as follows:

- Multi-chamber integration, achieving zero gas chamber and zero explosion risk to meet safety requirements (CN105624724B and CN103789784B).

- Electrolyte retention system without loss or leakage, achieving green treatment requirements (CN106435633B).

- Modular integration for lightweight, efficient, and durable design, compliant with environmental standards (CN105624723B).

- Systematic integration of external components, with intelligent automation to suit various user scenarios (CN103785091B, CN105498065B).

- Water isolation oscillation function, ensuring that the agent is not contaminated, utilizing the small molecular weight of hydrogen to carry therapeutic agents while also providing humidification (CN103800979B).

- Smart cloud system, integrated with wearable detection devices, occasionally connecting to medical institutions' HES systems to meet comprehensive health management needs (CN103794003B).

In March 2017, the hydrogen-oxygen gas atomization device received "Innovative Medical Device" green channel qualification from the National Medical Products Administration.

Postscript

The work of editing "Hydrogen Control of Cancer: Theory and Practice" has concluded, and I can't help but feel a bit anxious as I casually flip through the chapters of the manuscript on my computer: What kind of doubts and criticisms will arise after this book is published?

I mentally hypothesize various potential doubts and criticisms while striving to convince myself first—"Are these cases real? Is such a simple hydrogen molecule really so magical?"

Truth is the soul of this book. We have personally visited all the cases, including visiting their homes; we have accurately recorded various treatments; and we have pathologic, imaging, and biochemical evidence for the reactions to diseases and their treatments. Moreover, we have documented patients' names, addresses, phone numbers, WeChat or email addresses, as well as hospitalization times and numbers, and copies of various examinations, inviting scrutiny.

"Are these 'case studies' not of high evidence level in evidence-based medicine?"

Case studies are also evidence! The core idea of evidence-based medicine is that medical decisions should be based on objective evidence as much as possible, rather than merely following "guidelines." Connecting individual "cases" together forms the basis of evidence.

I see patients from all over the country almost every day, most of whom have exhausted various treatment methods and come to our hospital as a last resort. For their treatment, my heart is often "suspended," not worrying about "finding evidence," but rather whether I can help them experience a "miracle" and relieve my "heart." Perhaps this is the essence of humanity, the "original intention" of being human.

In fact, the United States, which proposed evidence-based medicine, has never overlooked "miraculous" cases. In 2015, former U.S. President Carter was diagnosed with melanoma with brain metastasis and received a certain drug treatment. Four months later, MRI scans showed that the brain metastases had miraculously disappeared. The "case" of the president greatly propelled the evidence-based research and application of this "miracle drug."

Whether it is a case study or "evidence," the premise is patient benefit. The hard truth of cancer treatment is that patients must survive and live with quality. "Doctors are like parents, and angels of the medical field." The purpose of any treatment is not merely to gather "evidence," but more importantly, to achieve the "hard truth." If a patient, especially those with late-stage cancer who have been ineffective under evidence-based medicine "guidelines," experiences "miraculous" effects after receiving simple, inexpensive, and painless treatment, why shouldn't it be taken seriously and researched?

The sanctity of medicine lies in creating "miracles" while safeguarding life.

Decades ago, my good friend Professor Wang Jiyao was the first to translate "Evidence-based Medicine" into Chinese twenty years ago. She pointed out that emphasizing the importance of evidence alone is not the original intention of evidence-based medicine; evidence is important, but it is not sufficient for making clinical decisions. She proposed that "when making treatment decisions for patients, doctors must combine evidence with the patient's values and wishes, considering different environmental conditions, which is called shared decision making (SDM)." From Professor Wang's description, it is clear that evidence-based medicine and the maintenance of individual life are highly unified.

"Is this a declaration of a certain device?"

Research cannot be separated from tools and devices. Hydrogen medicine research has spurred the development of the hydrogen industry. In China, dozens to hundreds of companies engaged in hydrogen health products have emerged, providing many instruments and facilities that promote the progress of hydrogen medicine. The case results documented in this book all stem from a specific model of machine, but starting from this point, there will surely be comparisons, collaborations, and competition among different devices in the future, leading to mutual development and co-creation within China's hydrogen industry.

"Are there many foreign reports on hydrogen control of cancer? Is 'domestic' reliable?"

The importance of technology and products, whether imported or domestically produced, is significant. We advocate learning from global research achievements and promoting "foreign use for domestic purposes," but we must not "self-negate" and also encourage "domestic use for foreign purposes." As early as 1924, Professor Yan Fuqing, the founder of Shanghai Medical University, advocated that "Western medicine must be popularized and localized in China."

The essence of theoretical confidence, path confidence, and cultural confidence is the confidence that a Chinese person should possess, representing the ideological essence of the development and strengthening of the Chinese nation. This is also the original intention that drives my enthusiasm for "hydrogen control of cancer."

With China's rise, the development of Chinese medicine will undoubtedly witness many "miracles." Once again reviewing the entire manuscript of "Hydrogen Control of Cancer: Theory and Practice," I feel gratified, believing I have accomplished something very meaningful. Hydrogen medicine is still young, and its contribution to humanity has just begun! Researching hydrogen medicine is a long and important journey!

Xu Kecheng  

May 2019