We present you a medical report published in m. August 2019, which summarizes research on the application of hydrogen gas (H2) in cancer treatment over the last 15 years. We have kept the structure of the report so that you can easily navigate when you open the text in English. Title of the report: 'Hydrogen gas in cancer treatment' Open the link to read the original text. /https://doi.org/10.3389/fonc.2019.00696/ Both in the official document and at the end of our article, you will find the reference clinical studies (the numbers in parentheses) referenced in the report. Note in "Table 1" after the references at the end of the paper how many of the studies were on patients taking hydrogen gas via H2-rich water/hydrogen water.
Gas signaling molecules (GSMs), composed of oxygen, carbon monoxide, nitric oxide, hydrogen sulfide, etc., play a critical role in regulating signal transmission between cells and cellular homeostasis. Interestingly, through various administrations, these molecules also show potential in cancer treatment. Recently, hydrogen gas (formula: H2) has emerged, as a novel HSM that possesses multiple bioactivities including anti-inflammatory, antioxidant and anticancer. A growing body of evidence shows that hydrogen gas alleviates the side effects caused by conventional chemotherapeutics and inhibits cancer cell and xenograft tumor growth, suggesting its widespread powerful application in clinical therapy. In this review, we summarize these studies and discuss the underlying mechanisms of action. The application of hydrogen gas in cancer treatment is still in its infancy, but further research and development of portable H2 therapy devices are encouraged.
Introduction
Gaseous signaling molecules (GSMs) refer to a group of gaseous molecules, such as oxygen (1), nitric oxide (2), carbon monoxide (3), hydrogen sulfide (4), sulfur dioxide (5, 6), ethylene (7 , 8), etc. These gaseous molecules have multiple critical functions in regulating cell biology "in vivo" through signaling (9). More importantly, some GSMs can serve as therapeutic agents in primary cancer as well as in the treatment of patients resistant to multiple drugs when used directly or certain pharmaceutical formulations (9-13). In addition, some of these GCMs can be generated in the body by various bacteria or enzymes, such as nitric oxide, hydrogen sulfide, indicating that they are body-compatible molecules that exhibit less adverse effects compared with conventional chemotherapeutics (9, 14, 15) . Recently, hydrogen gas has been recognized as another important GMM in biology, showing tremendous potential in health care to prevent cell damage of various nature (16-19).
With its molecular formula, hydrogen gas (H2) is the lightest molecule in nature, representing only about 0.5 parts per million (ppm) of the total gas. Naturally occurring, hydrogen gas is a colorless, odorless, tasteless, nontoxic, highly flammable gas that can form explosive mixtures with air in concentrations ranging from 4 to 74%, which can be triggered by a spark, heat, or sunlight. Hydrogen gas can be generated in small amounts by the hydrogenase of the microbiota of the human gastrointestinal tract, as well as from unabsorbed carbohydrates in the intestine by degradation and metabolism (20, 21). H2 is then partially diffused into the bloodstream and eliminated from the body on exhaled breath (20). This indicates its potential to serve, as a biomarker.
As the lightest molecule in nature, hydrogen gas exhibits deep penetration ability as it can diffuse rapidly across cell membranes (22, 23). A study showed that after oral administration of water enriched with hydrogen gas (hydrogen water) and intraperitoneal administration of super-hydrogen-rich saline (HSRS), the hydrogen concentration reached its peak in 5 min; or in 1 min by intraperitoneal administration of saline enriched with hydrogen gas (23). Another "in vivo" study tested the distribution of hydrogen in the brain, liver, kidney, mesenteric adipose tissue, and thigh muscles when 3% hydrogen gas was inhaled (24). The different concentration of hydrogen gas on reaching saturation status of the body by organ was as follows: liver, brain, mesentery, muscle, kidney, indicating different distributions among organs. Apart from the thigh muscle requiring a longer time to saturate, the other organs need 5-10 minutes to reach Cmax (maximum hydrogen concentration). Distinctively, the liver shows the highest Cmax (24). The information will aid and guide future clinical application of hydrogen gas.
As the lightest molecule in nature, hydrogen gas exhibits the ability to penetrate deeply because it can diffuse rapidly across cell membranes (22, 23). A study showed that after oral administration of water enriched with hydrogen gas (hydrogen water) and intraperitoneal administration of super-hydrogen-rich saline (HSRS), the hydrogen concentration reached its peak in 5 min; or in 1 min by intraperitoneal administration of saline enriched with hydrogen gas (23). Another "in vivo" study tested the distribution of hydrogen in the brain, liver, kidney, mesenteric adipose tissue, and thigh muscles when 3% hydrogen gas was inhaled (24). The different concentration of hydrogen gas on reaching saturation status of the body by organ was as follows: liver, brain, mesentery, muscle, kidney, indicating different distributions among organs. Apart from the thigh muscle requiring a longer time to saturate, the other organs need 5-10 minutes to reach Cmax (maximum hydrogen concentration). Distinctively, the liver shows the highest Cmax (24). The information will aid and guide future clinical application of hydrogen gas.
Although hydrogen gas was investigated as a therapy in a mouse model of flat skin cancer in 1975 (25), its potential in medical application was not significantly explored until 2007, when Oshawa et al. reported that hydrogen could ameliorate cerebral ischemia-reperfusion injury by selectively reducing cytotoxic free radicals (ROS), including hydroxyl radical (- OH) and peroxynitrite (ONOO-) (26). This has caused a worldwide sensation. Under various administrative prescriptions, hydrogen gas has been used as a therapeutic agent for various diseases, such as Parkinson's disease (27, 28), rheumatoid arthritis (29), brain injury (30), ischemic reperfusion (31, 32), diabetes (33, 34), etc.
The most valuable action of hydrogen is that it improves clinical endpoints and surrogate markers, from metabolic diseases to chronic systemic inflammatory disorders and cancer (17). A clinical study in 2016 showed that hydrogen gas intake is safe in patients with post-heart attack syndrome (35), its further therapeutic application in other diseases is becoming increasingly popular.
In this review, we focus on its application in cancer treatment. Most commonly, hydrogen gas exerts its biofunctions by regulating oxidative stress, inflammation, and apoptosis.
Hydrogen gas selectively eliminates the hydroxyl radical and peroxynitrite, and regulates some antioxidant enzymes.
So far, many studies have shown that hydrogen gas does not target specific proteins but regulates several key players in cancer, including dangerous free radicals (ROS) and some antioxidant enzymes (36).
ROS are unstable molecules that contain oxygen, including singlet oxygen (O2 -), hydrogen peroxide (H2O2), hydroxyl radical ( OH), superoxide (O - 2), nitric oxide (NO -), and peroxynitrite (ONOO-), among others (37, 38). Once generated "in vivo", due to their high reactivity, ROS can attack proteins, DNA/RNA and lipids in cells, causing distinct damage that can lead to apoptosis. The presence of ROS can cause cellular stress and damage, which can lead to cell death, through a mechanism known as oxidative stress (39, 40). Normally, in a physical state, cells, including cancer cells, maintain a balance between ROS generation and elimination, which is essential for their survival (41, 42). Excessively produced ROS, resulting from a regulatory system imbalance or external chemical attack (including chemotherapy/radiation), can cascade to intrinsic apoptosis, causing highly toxic effects (43-45).
Hydrogen gas acts, as a ROS modulator. First, as shown in the study by Ohsawa et al. hydrogen gas can selectively scavenge the most cytotoxic ROS, - OH, as tested in an acute model of cerebral ischemia and reperfusion (26). Another study also confirmed that hydrogen gas can reduce oxygen toxicity resulting from hyperbaric oxygenation by effectively reducing - OH (46).
Second, hydrogen can induce the expression of some antioxidant enzymes that can eliminate ROS, and it plays a key role in regulating redox homeostasis of cancer cells (42, 47). Studies have shown that upon treatment with hydrogen gas, the expression of superoxide dismutase (SOD) (48), heme oxygenase-1 (HO-1) (49), and nuclear factor erythroid 2-related factor 2 (Nrf2) (50 ) is significantly increased, enhancing its ROS scavenging potential.
By upregulating ROS, hydrogen gas can act as an adjuvant regimen to reduce the adverse effects of cancer treatment, while at the same time not overriding the cytotoxicity of other therapy, such as radiotherapy and chemotherapy (48, 51). Interestingly, due to the overproduction of ROS in cancer cells (38), the administration of hydrogen gas lowers the level of ROS initially, but this provokes a compensatory effect and increased ROS production in cancer cells, leading to their death.
Hydrogen gas suppresses inflammatory cytokines
Inflammatory cytokines are a series of signaling molecules that mediate the innate immune response, dys-regulation of which can contribute to the onset and development of many diseases, including cancer (53-55). Typical inflammatory cytokines include interleukins (ILs) secreted by white blood cells, tumor necrosis factors (TNFs) secreted by macrophages, both of which have shown a close association with cancer initiation and progression (56-59), and both ILs and TNFs can be suppressed by hydrogen gas intake (60, 61).
Chemotherapy-induced inflammation in cancer patients not only causes serious adverse effects (62, 63) but also leads to cancer metastasis and treatment failure (64, 65). By regulating inflammation, hydrogen gas can prevent tumor formation, progression, and reduce the side effects caused by chemotherapy/radiotherapy (66).
Hydrogen gas inhibits/induces apoptosis
Apoptosis, also called programmed cell death, can be induced by external or internal signals and executed by various molecular pathways that serve as one effective strategy for cancer treatment (67, 68). In general, apoptosis can be induced by (1) provoking death receptors on the cell surface (such as Fas, TNF receptors, or TNF-related apoptosis-inducing ligand), (2) suppressing the survival signal (such as epidermal growth factor receptor, mitogen-activated protein kinase, or phosphoinositide 3-kinases), and (3) activation of pro-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins or down-regulating anti-apoptotic proteins (such as X-linked) apoptosis inhibitor protein, survivin, and apoptosis inhibitor) (69, 70).
Hydrogen gas regulates intracellular apoptosis by affecting the expression of apoptosis-related enzymes. At a certain concentration, it can serve as a means to inhibit apoptosis by inhibiting pro-apoptotic B-cell lymphoma-2associated X protein (Bax), caspase-3, 8, 12 and enhancing anti-apoptotic B-cell lymphoma-2 (Bcl-2) (71). Hydrogen gas also serves as a means to induce apoptosis via contrast mechanisms (72), suggesting its potential to protect healthy cells from anticancer drugs or to suppress cancer cells.
H2MEDICAL TEAM: The following are the final points of the report, and in order to keep the article more concise we will only translate their titles and conclusion:
Hydrogen Gas Exhibits Potential in Cancer Treatment
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Hydrogen Gas Relieves the Adverse Effects Related to Chemotherapy/Radiotherapy
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Hydrogen Gas Acts Synergistically With Thermal Therapy
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Hydrogen Gas Suppresses Tumor Formation
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Hydrogen Gas Suppresses Tumor Growth
Discussion / Conclusion
Hydrogen gas is recognized as a medical gas that has the potential to treat cardiovascular disease, inflammatory diseases, neurodegenerative disorders, and cancer (17, 60). By eliminating hydroxyl radicals and peroxynitrites, as well as through its anti-inflammatory effects, hydrogen gas can assist in preventing/mitigating the adverse effects caused by chemotherapy and radiotherapy without compromising their anticancer potential. Hydrogen gas can also work alone or synergistically with other therapy to suppress tumor growth by inducing apoptosis, inhibiting CSCs-linkage, cell cycle-related factors, etc. Look at "Table 1" and "Chart 1" at the end of the article after the references.
The H2MEDICAL team is truly committed to educating the public as well as contributing to a better quality of life for everyone. Our devices are medically certified and feature maximum therapeutic effect as well as the highest safety class. /see the devices/. Note in "Table 1" after the references at the end of the article, how much of the research was on patients taking hydrogen gas via H2-rich water.
Find out which are the Hydrogen Tolerant Diseases in the menu Hydrogen Medicine.
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