Tag Archives: inflammation

Molecular Hydrogen CANCER treatment

Gas signaling molecules (GSMs), composed of oxygen, carbon monoxide, nitric oxide, hydrogen sulfide, etc., play critical roles in regulating signal transduction and cellular homeostasis. Interestingly, through various administrations, these molecules also exhibit potential in cancer treatment. Recently, hydrogen gas (formula: H2) emerges as another GSM which possesses multiple bioactivities, including anti-inflammation, anti-reactive oxygen species, and anti-cancer. Growing evidence has shown that hydrogen gas can either alleviate the side effects caused by conventional chemotherapeutics, or suppress the growth of cancer cells and xenograft tumor, suggesting its broad potent application in clinical therapy. In the current review, we summarize these studies and discuss the underlying mechanisms. The application of hydrogen gas in cancer treatment is still in its nascent stage, further mechanistic study and the development of portable instruments are warranted.


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 (56), ethylene (78), etc. These gaseous molecules possess multiple critical functions in regulating cell biology in vivo via signal transduction (9). More importantly, certain GSMs could serve as therapeutic agents in primary cancer, as well as in multidrug-resistant cancer treatment when used by directly or certain pharmaceutical formulations (913). In addition, some of these GSMs can be generated in body via different bacteria or enzymes, such as nitric oxide, hydrogen sulfide, indicating that they are more compatible molecules that may exhibit less adverse effects compared with conventional chemotherapeutics (91415). Recently, hydrogen gas has been recognized as another important GSM in biology, exhibiting appealing potential in health care for its role in preventing cell injury from various attacking (1619).

With the formula of H2, hydrogen gas is the lightest molecule in the nature which only accounts for about 0.5 parts per million (ppm) of all the gas. Naturally, hydrogen gas is a colorless, odorless, tasteless, non-toxic, highly combustible gas which may form explosive mixtures with air in concentrations from 4 to 74% that can be triggered by spark, heat, or sunlight. Hydrogen gas can be generated in small amount by hydrogenase of certain members of the human gastrointestinal tract microbiota from unabsorbed carbohydrates in the intestine through degradation and metabolism (2021), which then is partially diffused into blood flow and released and detected in exhaled breath (20), indicating its potential to serve as a biomarker.

As the lightest molecule in natural, hydrogen gas exhibits appealing penetration property, as it can rapidly diffuse through cell membranes (2223). Study in animal model showed that, after orally administration of hydrogen super-rich water (HSRW) and intra-peritoneal administration of hydrogen super-rich saline (HSRS), the hydrogen concentration reached the peak at 5 min; while it took 1 min by intravenous administration of HSRS (23). Another in vivo study tested the distribution of hydrogen in brain, liver, kidney, mesentery fat, and thigh muscle in rat upon inhalation of 3% hydrogen gas (24). The concentration order of hydrogen gas, when reached saturated status, was liver, brain, mesentery, muscle, kidney, indicating various distributions among organs in rats. Except the thigh muscle required a longer time to saturate, the other organs need 5–10 min to reach Cmax (maximum hydrogen concentration). Meanwhile, the liver had the highest Cmax (24). The information may direct the future clinical application of hydrogen gas.

Although hydrogen gas was studied as a therapy in a skin squamous carcinoma mouse model back in 1975 (25), its potential in medical application has not been vastly explored until 2007, when Oshawa et al. reported that hydrogen could ameliorate cerebral ischemia-reperfusion injury by selectively reducing cytotoxic reactive oxygen species (ROS), including hydroxyl radical (•OH) and peroxynitrite (ONOO-) (26), which then provoked a worldwide attention. Upon various administrative formulations, hydrogen gas has been served as a therapeutic agent for a variety of illnesses, such as Parkinson’s disease (2728), rheumatoid arthritis (29), brain injury (30), ischemic reperfusion injury (3132), and diabetes (3334), etc.

More importantly, hydrogen has been shown to improve clinical end-points and surrogate markers, from metabolic diseases to chronic systemic inflammatory disorders to cancer (17). A clinical study in 2016 showed that inhalation of hydrogen gas was safe in patients with post-cardiac arrest syndrome (35), its further therapeutic application in other diseases became even more appealing.

In the current review, we take a spot on its application in cancer treatment. Typically, hydrogen gas may exert its bio-functions via regulating ROS, inflammation and apoptosis events.

Hydrogen Gas Selectively Scavenges Hydroxyl Radical and Peroxynitrite, and Regulates Certain Antioxidant Enzymes

By far, many studies have indicated that hydrogen gas doesn’t target specific proteins, but regulate several key players in cancer, including ROS, and certain antioxidant enzymes (36).

ROS refers to a series of unstable molecules that contain oxygen, including singlet oxygen (O2•), hydrogen peroxide (H2O2), hydroxyl radical (•OH), superoxide (O2•O2-), nitric oxide (NO•), and peroxynitrite (ONOO), etc. (3738). Once generated in vivo, due to their high reactivity, ROS may attack proteins, DNA/RNA and lipids in cells, eliciting distinct damage that may lead to apoptosis. The presence of ROS can produce cellular stress and damage that may produce cell death, via a mechanism known as oxidative stress (3940). Normally, under physical condition, cells including cancer cells maintain a balance between generation and elimination of ROS, which is of paramount importance for their survival (4142). The over-produced ROS, resulted from imbalance regulatory system or outer chemical attack (including chemotherapy/radiotherapy), may initiate inner apoptosis cascade, causing severely toxic effects (4345).

Hydrogen gas may act as a ROS modulator. First, as shown in Ohsawa et al.’s study, hydrogen gas could selectively scavenge the most cytotoxic ROS, •OH, as tested in an acute rat model of cerebral ischemia and reperfusion (26). Another study also confirmed that hydrogen gas might reduce the oxygen toxicity resulted from hyperbaric oxygen via effectively reducing •OH (46).

Second, hydrogen may induce the expression of some antioxidant enzymes that can eliminate ROS, and it plays key roles in regulating redox homeostasis of cancer cells (4247). Studies have indicated that upon hydrogen gas treatment, the expression of superoxide dismutase (SOD) (48), heme oxyganase-1 (HO-1) (49), as well as nuclear factor erythroid 2-related factor 2 (Nrf2) (50), increased significantly, strengthening its potential in eliminating ROS.

By regulating ROS, hydrogen gas may act as an adjuvant regimen to reduce the adverse effects in cancer treatment while at the same time doesn’t abrogate the cytotoxicity of other therapy, such as radiotherapy and chemotherapy (4851). Interestingly, due the over-produced ROS in cancer cells (38), the administration of hydrogen gas may lower the ROS level at the beginning, but it provokes much more ROS production as a result of compensation effect, leading to the killing of cancer cells (52).

Hydrogen Gas Suppresses Inflammatory Cytokines

Inflammatory cytokines are a series of signal molecules that mediate the innate immune response, whose dys-regulation may contribute in many diseases, including cancer (5355). Typical inflammatory cytokines include interleukins (ILs) excreted by white blood cells, tumor necrosis factors (TNFs) excreted by macrophages, both of which have shown close linkage to cancer initiation and progression (5659), and both of ILs and TNFs can be suppressed by hydrogen gas (6061).

Inflammation induced by chemotherapy in cancer patients not only causes severely adverse effects (6263), but also leads to cancer metastasis, and treatment failure (6465). By regulating inflammation, hydrogen gas can prevent tumor formation, progression, as well as reduce the side effects caused by chemotherapy/radiotherapy (66).

Hydrogen Gas Inhibits/Induces Apoptosis

Apoptosis, also termed as programed cell death, can be triggered by extrinsic or intrinsic signals and executed by different molecular pathways, which serve as one efficient strategy for cancer treatment (6768). Generally, apoptosis can be induced by (1) provoking the death receptors of cell surface (such as Fas, TNF receptors, or TNF-related apoptosis-inducing ligand), (2) suppressing the survival signaling (such as epidermal growth factor receptor, mitogen-activated protein kinase, or phosphoinositide 3-kinases), and (3) activating the pro-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, or down-regulating anti-apoptosis proteins (such as X-linked inhibitor of apoptosis protein, surviving, and the inhibitor of apoptosis) (6970).

Hydrogen gas can regulate intracellular apoptosis by impacting the expression of apoptosis-related enzymes. At certain concentration, it can either serve as apoptosis-inhibiting agent via inhibiting the pro-apoptotic B-cell lymphoma-2-associated X protein (Bax), caspase-3, 8, 12, and enhancing the anti-apoptotic B-cell lymphoma-2 (Bcl-2) (71), or as apoptosis-inducing agent via the contrast mechanisms (72), suggesting its potential in protecting normal cells from anti-cancer drugs or in suppressing cancer cells.

Hydrogen Gas Exhibits Potential in Cancer Treatment

Hydrogen Gas Relieves the Adverse Effects Related to Chemotherapy/Radiotherapy

Chemotherapy and radiotherapy remain the leading strategies to treat cancer (7374). However, cancer patients receiving these treatments often experience fatigue and impaired quality of life (7577). The skyrocketed generation of ROS during the treatment is believed to contribute in the adverse effects, resulting in remarkable oxidative stress, and inflammation (414278). Therefore, benefited from its anti-oxidant and anti-inflammatory and other cell protective properties, hydrogen gas can be adopted as an adjuvant therapeutic regimen to suppress these adverse effects.

Under treatment of epidermal growth factor receptor inhibitor gefitinib, patients with non-small cell lung cancer often suffer with severe acute interstitial pneumonia (79). In a mice model treated with oral administration of gefitinib and intraperitoneal injection of naphthalene which induced severely lung injury due to oxidative stress, hydrogen-rich water treatment significantly reduced the inflammatory cytokines, such as IL-6 and TNFα in the bronchoalveolar lavage fluid, leading to a relieve of lung inflammation. More importantly, hydrogen-rich water didn’t impair the overall anti-tumor effects of gefitinib both in vitro and in vivo, while in contrast, it antagonized the weight loss induced by gefitinib and naphthalene, and enhanced the overall survival rate, suggesting hydrogen gas to be a promising adjuvant agent that has potential to be applied in clinical practice to improve quality of life of cancer patients (80).

Doxorubicin, an anthracycline antibiotic, is an effective anticancer agent in the treatment of various cancers, but its application is limited for the fatal dilated cardiomyopathy and hepatotoxicity (8182). One in vivo study showed that intraperitoneal injection of hydrogen-rich saline ameliorated the mortality, and cardiac dysfunction caused by doxorubicin. This treatment also attenuated histopathological changes in serum of rats, such as the serum brain natriuretic peptide (BNP), aspartate transaminase (AST), alanine transaminase (ALT), albumin and malondialdehyde (MDA) levels. Mechanistically, hydrogen-rich saline significantly lowered the ROS level, as well as inflammatory cytokines TNF-α, IL-1β, and IL-6 in cardiac and hepatic tissue. Hydrogen-rich saline also induced less expression of apoptotic Bax, cleaved caspase-3, and higher anti-apoptotic Bcl-2, resulting in less apoptosis in both tissues (71). This study suggested that hydrogen-rich saline treatment exerted its protective effects via inhibiting the inflammatory TNF-α/IL-6 pathway, increasing the cleaved C8 expression and Bcl-2/Bax ratio, and attenuating cell apoptosis in both heart and liver tissue (71).

Hydrogen-rich water also showed renal protective effect against cisplatin-induced nephrotoxicity in rats. In the studies, blood oxygenation level-dependent (BOLD) contrast magnetic resonance images (MRI) acquired in different treated group showed that the creatinine and blood urea nitrogen (BUN) levels, two parameters that related to nephrotoxicity, were significantly higher in cisplatin treated group than those in the control group. Hydrogen-rich water treatment could significantly reverse the toxic effects, and it showed much higher transverse relaxation rate by eliminating oxygen radicals (8384).

Another study showed that both inhaling hydrogen gas (1% hydrogen in air) and drinking hydrogen-rich water (0.8 mM hydrogen in water) could reverse the mortality, and body-weight loss caused by cisplatin via its anti-oxidant property. Both treatments improved the metamorphosis, accompanied with decreased apoptosis in the kidney, and nephrotoxicity as assessed by serum creatinine and BUN levels. More importantly, hydrogen didn’t impair the anti-tumor activity of cisplatin against cancer cell lines in vitro and in tumor-bearing mice (85). Similar results were also observed in Meng et al.’s study, as they showed that hydrogen-rich saline could attenuate the follicle-stimulating hormone release, elevate the level of estrogen, improve the development of follicles, and reduce the damage to the ovarian cortex induced by cisplatin. In the study, cisplatin treatment induced higher level of oxidation products, suppressed the antioxidant enzyme activity. The hydrogen-rich saline administration could reverse these toxic effects by reducing MDA and restoring the activity of superoxide dismutase (SOD), catalase (CAT), two important anti-oxidant enzymes. Furthermore, hydrogen-rich saline stimulated the Nrf2 pathway in rats with ovarian damage (86).

The mFOLFOX6 regimen, composed with folinic acid, 5-fluorouracil, and oxaliplatin, is used as first-line treatment for metastatic colorectal cancer, but it also confers toxic effects to liver, leading to bad quality of life of patient (8788). A clinical study was conducted in China by investing the protective effect of hydrogen-rich water on hepatic function of colorectal cancer patients (144 patients were enrolled and 136 of them were include in the final analysis) treated with mFOLFOX6 chemotherapy. The results showed that the placebo group exhibited damaging effects caused by mFOLFOX6 chemotherapy as measured by the elevated levels of ALT, AST and indirect bilirubin (IBIL), while the hydrogen-rich water combinational treatment group exhibited no differences in liver function during the treatment, probably due to its antioxidant activity, indicating it a promising protective agent to alleviate the mFOLFOX6-related liver injury (51).

Most of the ionizing radiation-induced adverse effects to normal cells are induced by hydroxyl radicals. The combination of radiotherapy with certain forms of hydrogen gas may be beneficial to alleviate these side effects (89). Indeed, several studies found that hydrogen could protect cells and mice from radiation (4890).

As tested in a rat model of skin damage established by using a 44 Gy electronic beam, the treated group by hydrogen-rich water exhibited higher lever of SOD activity and lower MDA and IL-6 in the wounded tissues than the control group and the distilled water group. Furthermore, hydrogen-rich water shortened the healing time and increased the healing rate of skin injury (48).

Gastrointestinal toxicity is a common side effect induced by radiotherapy, which impairs the life quality of cancer patients (91). As shown in Xiao et al.’s study in mice model, hydrogen-water administration via oral gavage increased the survival rate and body weight of mice which were exposed to total abdominal irradiation, accompanied with an improvement in gastrointestinal tract function and the epithelial integrity of the small intestine. Further microarray analysis revealed that hydrogen-water treatment up-regulated miR-1968-5p, which then up-regulated its target myeloid differentiation primary response gene 88 (MyD88, a mediator in immunopathology, and gut microbiota dynamics of certain intestinal diseases involving toll-like receptors 9) expression in the small intestine after total abdominal irradiation (92).

Another study conducted in clinical patients with malignant liver tumors showed that the consumption of hydrogen-rich water for 6 weeks reduced the level of reactive oxygen metabolite, hydroperoxide, and maintained the biologic antioxidant activity in the blood. Importantly, scores of quality of life during radiotherapy were significantly improved in hydrogen-rich water group compared to the placebo water group. Both groups exhibited similar tumor response to radiotherapy, indicating that the consumption of hydrogen-rich water reduced the radiation-induced oxidative stress while at the same time didn’t compromise anti-tumor effect of radiotherapy (93).

Hydrogen Gas Acts Synergistically With Thermal Therapy

Recently, one study found that hydrogen might enhance the effect of photothermal therapy. Zhao et al. designed the hydrogenated Pd nanocrystals (named as PdH0.2) as multifunctional hydrogen carrier to allow the tumor-targeted delivery (due to 30 nm cubic Pd nanocrystal) and controlled release of bio-reductive hydrogen (due to the hydrogen incorporated into the lattice of Pd). As shown in this study, hydrogen release could be adjusted by the power and duration of near-infrared (NIR) irradiation. Treatment of PdH0.2 nanocrystals plus NIR irradiation lead to higher initial ROS loss in cancer cells, and the subsequent ROS rebound was also much higher than that in normal cells, resulting in more apoptosis, and severely mitochondrial metabolism inhibition in cancer cells but not in normal cells. The combination of PdH0.2 nanocrystals with NIR irradiation significantly enhanced the anticancer efficacies of thermal therapy, achieving a synergetic anticancer effect. In vivo safety evaluation showed that the injection dose of 10 mg kg−1 PdH0.2 nanocrystals caused no death, no changes of several blood indicators, and no affected functions of liver and kidney. In 4T1 murine breast cancer tumor model and B16-F10 melanoma tumor model, the combined PdH0.2 nanocrystals and NIR irradiation therapy exhibited a synergetic anticancer effect, leading to remarkable tumor inhibition when compared with thermal therapy. Meanwhile, the combination group showed no visible damage to heart, liver, spleen, lung, and kidney, indicating suitable tissue safety and compatibility (52).

Hydrogen Gas Suppresses Tumor Formation

Li et al. reported that the consumption of hydrogen-rich water alleviated renal injury caused by Ferric nitrilotriacetate (Fe-NTA) in rats, evidenced by decreased levels of serum creatinine and BUN. Hydrogen-rich water suppressed the Fe-NTA-induced oxidative stress by lowering lipid peroxidation, ONOO, and inhibiting the activities of NADPH oxidase and xanthine oxidase, as well as by up-regulating antioxidant catalase, and restoring mitochondrial function in kidneys. Consequently, Fe-NTA-induced inflammatory cytokines, such as NF-κB, IL-6, and monocyte chemoattractant protein-1 were significantly alleviated by hydrogen treatment. More importantly, hydrogen-rich water consumption inhibited several cancer-related proteins expression, including vascular endothelial growth factor (VEGF), signal transducer and activator of transcription 3 (STAT3) phosphorylation, and proliferating cell nuclear antigen (PCNA) in rats, resulting in lower incidence of renal cell carcinoma and the suppression of tumor growth. This work suggested that hydrogen-rich water was a promising regimen to attenuate Fe-NTA-induced renal injury and suppress early tumor events (66).

Non-alcoholic steatohepatitis (NASH) due to oxidative stress induced by various stimuli, is one of the reasons that cause hepatocarcinogenesis (9495). In a mouse model, hydrogen-rich water administration lowered the hepatic cholesterol, peroxisome proliferator-activated receptor-α (PPARα) expression, and increased the anti-oxidative effects in the liver when compared with control and pioglitazone treated group (96). Hydrogen-rich water exhibited strong inhibitory effects to inflammatory cytokines TNF-α and IL-6, oxidative stress and apoptosis biomarker. As shown in NASH-related hepatocarcinogenesis model, in the group of hydrogen-rich water treatment, tumor incidence was lower and the tumor volumes were smaller than control and pioglitazone treated group. The above findings indicated that hydrogen-rich water had potential in liver protection and liver cancer treatment (96).

Hydrogen Gas Suppresses Tumor Growth

Not only working as an adjuvant therapy, hydrogen gas can also suppress tumor and tumor cells growth.

As shown in Wang et al.’s study, on lung cancer cell lines A549 and H1975 cells, hydrogen gas inhibited the cell proliferation, migration, and invasion, and induced remarkable apoptosis as tested by CCK-8, wound healing, transwell assays and flow cytometry. Hydrogen gas arrested the cell cycle at G2/M stage on both cell lines via inhibiting the expression of several cell cycle regulating proteins, including Cyclin D1, CDK4, and CDK6. Chromosomes 3 (SMC3), a complex required for chromosome cohesion during the cell cycle (97), was suppressed by hydrogen gas via ubiquitinating effects. Importantly, in vivo study showed that under hydrogen gas treatment, tumor growth was significantly inhibited, as well as the expression of Ki-67, VEGF and SMC3. These data suggested that hydrogen gas could serve as a new method for the treatment of lung cancer (98).

Due to its physicochemical characteristics, the use of hydrogen gas has been strictly limited in hospital and medical facilities and laboratories. Li et al. designed a solidified hydrogen-occluding-silica (H2-silica) that could stably release molecular hydrogen into cell culture medium. H2-silica could concentration-dependently inhibit the cell viability of human esophageal squamous cell carcinoma (KYSE-70) cells, while it need higher dose to suppress normal human esophageal epithelial cells (HEEpiCs), indicating its selective profile. This effect was further confirmed by apoptosis and cell migration assay in these two cell lines. Mechanistic study revealed that H2-silica exerted its anticancer via inducing H2O2 accumulation, cell cycle arrest, and apoptosis induction mediated by mitochondrial apoptotic pathways (72).

Recently, hydrogen gas was found to inhibit cancer stem cells (CSCs). Hydrogen gas reduced the colony formation and sphere formation of human ovarian cancer cell lines Hs38.T and PA-1 cells via inhibiting the proliferation marker Ki67, stem cell markers CD34, and angiogenesis. Hydrogen gas treatment significantly inhibited the proliferation, invasion, migration of both Hs38.T and PA-1 cells. More important, inhalation of hydrogen gas inhibited the tumor volume significantly as shown in the Hs38.T xenografted BALB/c nude mice model (99).

Another recent study also confirmed the effects of hydrogen gas in suppressing glioblastoma (GBM), the most common malignant brain tumor. In vitro study indicated that hydrogen gas inhibited several markers involved in stemness, resulting in the suppression of sphere formation, cell migration, invasion, and colony formation of glioma cells. By inhaling hydrogen gas (67%) 1 h, 2 times per day, the GBM growth was significantly inhibited, and the survival rate was improved in a rat orthotopic glioma model, suggesting that hydrogen might be a promising agent in the treatment of GBM (100).


Hydrogen gas has been recognized as one medical gas that has potential in the treatment of cardiovascular disease, inflammatory disease, neurodegenerative disorders, and cancer (1760). As a hydroxyl radical and peroxynitrite scavenger, and due to its anti-inflammatory effects, hydrogen gas may work to prevent/relieve the adverse effects caused by chemotherapy and radiotherapy without compromise their anti-cancer potential (as summarized in Table 1 and Figure 1). Hydrogen gas may also work alone or synergistically with other therapy to suppress tumor growth via inducing apoptosis, inhibiting CSCs-related and cell cycle-related factors, etc. (summarized in Table 1).


www.frontiersin.orgTable 1. The Summary of various formulation, application, mechanisms of H2 in cancer treatment.


www.frontiersin.orgFigure 1. Hydrogen in cancer treatment.

More importantly, in most of the research, hydrogen gas has demonstrated safety profile and certain selectivity property to cancer cells over normal cells, which is quite pivotal to clinical trials. One clinical trials (NCT03818347) is now undergoing to study the hydrogen gas in cancer rehabilitation in China.

By far, several delivery methods have proved to be available and convenient, including inhalation, drinking hydrogen-dissolved water, injection with hydrogen-saturated saline and taking a hydrogen bath (101). Hydrogen-rich water is non-toxic, inexpensive, easily administered, and can readily diffuse into tissues and cells (102), cross the blood-brain barrier (103), suggesting its potential in the treatment of brain tumor. Further portable devices that are well-designed and safe enough will be needed.

However, regarding its medicinal properties, such as dosage and administration, or possible adverse reactions and use in specific populations, less information is available. Its mechanism, target, indications are also not clear, further study are warranted.


Molecular hydrogen-rich water generally shows a more prominent effect than molecular hydrogen gas, although the amount of hydrogen taken up by hydrogen water is ~100 times less than that given by hydrogen gas [11].

We have showed that drinking molecular hydrogen water, but not continuous molecular hydrogen gas exposure, prevented development of 6-hydorxydopamine-induced Parkinson’s disease in rats [11].





Front. Oncol., 06 August 2019 | https://doi.org/10.3389/fonc.2019.00696

Hydrogen Gas in Cancer Treatment
Sai Li1Rongrong Liao2Xiaoyan Sheng2Xiaojun Luo3Xin Zhang1Xiaomin Wen3Jin Zhou2* and Kang Peng1,3*
  • 1Department of Pharmacy, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
  • 2Nursing Department, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
  • 3The Centre of Preventive Treatment of Disease, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China

Author Contributions

SL, XW, JZ, and KP: conceptualization. SL, RL, XS, XL, XZ, JZ, and KP: writing. SL, RL, and XS: revising.


This work was supported in part by grants from the Natural Science Foundation of Guangdong Province (2018A030313987) and Traditional Chinese Medicine Bureau of Guangdong Province (20164015 and 20183009) and Science and Technology Planning Project of Guangdong Province (2016ZC0059).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We thank Miss Ryma Iftikhar, Dhiviya Samuel, Mahnoor Shamsi (St. John’s University), and Mr. Muaz Sadeia for editing and revising the manuscript.


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Citation: Li S, Liao R, Sheng X, Luo X, Zhang X, Wen X, Zhou J and Peng K (2019) Hydrogen Gas in Cancer Treatment. Front. Oncol. 9:696. doi: 10.3389/fonc.2019.00696

Received: 02 May 2019; Accepted: 15 July 2019;
Published: 06 August 2019.

Edited by:

Nelson Shu-Sang Yee, Penn State Milton S. Hershey Medical Center, United States

Reviewed by:

Leo E. Otterbein, Beth Israelv Deaconess Medical Center and Harvard Medical School, United States
Paolo Armando Gagliardi, University of Bern, Switzerland

Copyright © 2019 Li, Liao, Sheng, Luo, Zhang, Wen, Zhou and Peng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jin Zhou, zhou-jin-2008@163.com; Kang Peng, kds978@163.com

These authors share co-first authorship

Studies and observations on the HEALTH effects of drinking electrolyzed-reduced alkaline water ( ionized)

B. Rubik Institute for Frontier Science, Oakland, California, USA


Studies and observations on the health effects of drinking electrolyzed-reduced alkaline(ionized ) water Municipal drinking water, prefiltered and treated by partial electrolysis, followed by collecting the cathodic water that is alkaline (pH 8.5 to 9.5), shows a high negative oxidative reductive potential (ORP) (-150 to -250 mV) compared to untreated tap water (+150 mV) as well as smaller molecular clusters.

A growing body of literature indicates beneficial effects from drinking this electrolyszed (ionized) alkaline water by patients with diabetes and kidney disease, with improved outcomes and fewer medical complications. Additional studies suggest that this water increases the activity of a key detoxifying enzyme in the body, superoxide dismutase, which is central to protecting against free radical damage both in aging and chronic degenerative disease. Recent published studies on the health benefits of this drinking (alkaline ionized/electrolyzed reduced ) water are summarized. Evidence from live blood analysis from a case study suggests that drinking reduced alkaline water reduces blood cell stickiness, aggregation, and early clotting. Results suggest that long term consumption of this water slows the effects of aging and may improve the peripheral circulation; serve as an adjunct therapy for diabetes and kidney disorders; and help prevent cardiovascular and other chronic diseases.

1 Introduction

Water, which constitutes over 70% of the human body, is involved in virtually every function of life. It is an essential but often underrated necessity that is involved in most biochemical reactions; a constituent of the bodily fluids – blood, lymph, cerebrospinal fluid, saliva and other digestive fluids; joint lubrication; detoxification; and maintaining the blood pressure. Yet it is far more than just a constituent. A new science of water is emerging in which the structure and dynamics of water is much more complex than was previously thought. Water is a complex dynamic liquid sensitive and responsive to its environment. We are now in the midst of a paradigm shift in which liquid water is seen as an active agent rather than a passive constituent or universal solvent of life. For example, water and living systems are equally sensitive to a single quantum of magnetic flux [1]. Water shows long-range ordering features around cell membranes, where is it more like an epitaxial liquid crystal with distinct properties in those regions that radically distinguish it from bulk water [2] while chemically still remaining H2O. It used to be thought that water was passive, “dancing to the tune of biomolecules”, but now, water is considered the “matrix of life.” The greatest physiological change with aging is not within our biomolecules, but in the loss of water from the body. The body of a young infant consists of over 80% water, but that of a person over 70 years old is typically comprised of less than 60% water. There are many concerns about drinking water quality worldwide today. Many people choose to drink commercially bottled water for various reasons, but its healthfulness is questionable. Some device manufacturers claim that water treated by a vortex, electromagnetic fields, or other physical means to “energize” it, is more healthful than untreated waters and may also slow the aging process. In this paper, we review published evidence for the impact on health of drinking a particular type of water called “electrolyzed-reduced”(ionized alkaline) water and show observations from the blood.

2 Background and literature review

Alkaline mineral water with a relatively high negative oxidative reductive potential (ORP = -150 to -300 millivolts) and a pH over 8.0 is characteristic of natural mountain streams and certain deep wells. Aside from these natural sources, where can one find water with these properties? If this natural water were to be bottled, it would lose its high negative ORP and may react with plastic bottles that contain phthalates, toxic carcinogens. Nonetheless, one can generate water with these properties at point-of-use by using a device called a water ionizer. This is a commercially available water treatment system for the home that first filters the water through a multi-stage water filter to remove chlorine, chloramine, and other contaminants, and then performs partial electrolysis of the filtered water over platinum-coated titanium electrodes with a DC electric field. This yields 2 fractions: oxidized acidic water from the anode, and reduced alkaline water from the cathode. The reduced alkaline water appears to match most closely natural mountain spring water at the source in its physical properties and taste. This water is the subject of this paper. It has been called by various names: reduced, electrolyzed-reduced, and alkaline ionized water, to name a few. In this paper, we refer to it as ERW, “electrolyzed-reduced water.” The ERW fraction retains the alkaline ionic minerals from the tap water, including calcium and magnesium, which are important minerals for health, has a high negative ORP, an alkaline pH, a low level of dissolved oxygen, and is microstructured, with 5 to 6 molecules of water per cluster. It also has a lower surface tension than the starting tap water, which makes it a better solvent and may improve hydration.

Most of the studies on ERW have been conducted in Japan, Korea, and China. Not all of the research reports have been translated into English. Peer-reviewed studies from various laboratories worldwide show that ERW “electrolyzed-reduced” water aka (ionized alkaline) water , with its high negative ORP, scavenges free radical chemical species, protecting from oxidative damage. This, along with its alkalinity and microstructure, yield numerous health benefits. In addition, clinical reports, with or without controlled studies supporting them, further suggest that ERW produces declines in blood sugar levels in diabetic patients; improvements in peripheral circulation in diabetic gangrene; improvements in intestinal flora; declines in uric acid levels in patients with gout; improvements in liver function tests in hepatic disorders; improvements in gastroduodenal ulcer with prevention of recurrences; improved hydration and fluid replacement; and improvements in blood pressure in the case of either hypertension or hypotension. Here we summarize some of the key findings from the peer-reviewed literature on humans and other biological systems.

2.1 Active reducing agent and protection against oxidative stress

Shirahata et al. studied the properties of ERW “electrolyzed-reduced” water aka (ionized alkaline) water and reported that it showed a superoxide dismutase-like activity in protecting against oxidative damage, alleviating oxidative damage of DNA molecules and other species in vitro [3]. This antioxidant effect of ERW “electrolyzed-reduced” water aka (ionized alkaline) water has been verified [4]. The nature of the reducing species (antioxidant) in ERW “electrolyzed-reduced” water aka (ionized alkaline) water has been proposed to be active hydrogen and/or molecular hydrogen, but it is NOT the same as ordinary hydrogen gas and remains unresolved [5, 6]. One group reports that ERW contains both atomic and molecular hydrogen [7]. ERW “electrolyzed-reduced” water aka (ionized alkaline) water prevented oxidative cleavage of proteins and also stimulated the activity of free radical scavenger, ascorbic acid(vitamin C) [8]. Rats, upon drinking ERW “electrolyzed-reduced” water aka (ionized alkaline) water for just one week, showed significantly reduced amounts of peroxidized lipid in their urine, suggesting reduced oxidative stress in the rats [9]. These studies document that ERW has strong antioxidant activity. Antioxidant activity is important to protect cells and biomolecules from the toxic effects of oxidative damage associated with reactive oxygen species such as superoxide radicals that are associated with the biochemistry of inflammation and implicated as underlying factors in chronic disease.

2.2 Prolonged lifespan in nematodes and mice

It is well accepted that oxidative damaged mice compared to control mice fed tap water [10]. Landis and Tower showed that enhanced activity of superoxide dismutase, as has been demonstrated by various investigators using ERW, can reduce oxidative damage and extend life span [11]. A study on ERW used in the aqueous medium of the nematode (worm), C. Elegans in laboratory cultures showed that it significantly extended its lifespan, which has been interpreted to be at least in part due to the reactive oxygen species (ROS)-scavenging action of ERW [12].

2.3 Studies on kidney disease and use of hemodialysis

In end-stage kidney-diseased patients on dialysis, ERW “electrolyzed-reduced” water aka (ionized alkaline) water appears to have a beneficial effect on reduction of hemodialysis-induced oxidative stress. Huang et al. studied the reactive oxygen species in the plasma of these patients and found that ERW “electrolyzed-reduced” water aka (ionized alkaline) water diminished hemodialysis-enhanced peroxide levels, and minimized oxidized and inflammatory markers (C-reactive protein and interleukin-6) after 1 month of drinking ERW “electrolyzed-reduced” water aka (ionized alkaline) water . These findings suggest that cardiovascular complications (stroke and heart attack) in these kidney dialysis patients might be prevented by ERW [13].

Another study investigated use of ERW directly in the hemodialysis process of 8 kidney patients, and found that the viability of patients’ polymorphonuclear leukocytes was better preserved [14].

2.4 Studies on diabetes and blood glucose levels

Reactive oxygen species (ROS), such as superoxide and other free radical oxygen species, are known to cause reduction of glucose update by inhibiting the insulin-signaling pathway in cultured cells. Therefore, the scavenging of ROS is important to the control of diabetes. ERW scavenged intracellular ROS and stimulated glucose uptake in the presence or absence of insulin in rat L6 skeletal muscle cells and mouse 3T3/L1 adipocytes. This insulin-like activity of ERW was inhibited by wortmannin, a specific inhibitor of PI-3 kinase, a key molecule in insulin signalling pathways. ERW protected insulin responsive cells from sugar toxicity and improved the damaged sugar tolerance of type II diabetes model mice. This suggests that ERW may improve the status of those with insulin-independent diabetes mellitus [15]. Oxidative stress is produced under diabetic conditions and involved in progression of pancreatic beta-cell dysfunction. ERW in diabetic mice improved islet beta-cell function, resulting in increased release of circulating insulin and improved insulin sensitivity in both type I and type II diabetes [16, 17]. In a study on Otsuka Long-Evans Tokushima Fatty (OLETF) rats, ERW given to one group showed significantly lower blood glucose levels than controls given tap water. Moreover, blood levels of triglycerides and total cholesterol also decreased in the rats fed ERW [18].

A study on 411 type II diabetes patients whose average age was 71.5 years, who drank natural reduced water from the Nordenau Spring in Germany, up to 2 liters per day over 6 days, showed that 186 (45%) responded positively, with reduced blood glucose, improved cholesterol, LDL, HDL, and serum creatinine levels. 70.6% of a random sample of 136 of the patients also showed a decrease in blood ROS [19].

Recent bioelectrical impedance analysis studies showed that diabetics have a lower ratio of intracellular water (ICW) to extracellular water (ECW).

336 type II diabetics were recruited in a randomized, double-blind trial. The subjects received 250 ml of ERW or distilled water twice daily for 4 weeks. Results show that ERW consumption improved cell water distribution (ICW/ECW), basal metabolism rate, and cell capacitance during the 4-week period. The authors speculate that the relatively small size of the water molecule clusters in ERW may underlie the beneficial findings of improved cell structure and function [20].

2.5 Stimulation of anaerobic microflora in the human gut

The high negative ORP of ERW favors the growth of key anaerobic bacteria in the human gut that are important for normal intestinal microflora, health of the colon, and optimum nutrition [21]. 2.6 Lack of toxicity in microbes, cells, and animals ERW used up to a concentration of 100% in the Ames Test with Salmonella typhimurium did not show any bacterial mutations, either in the presence or absence of rat liver for exogenous metabolic activation. Similarly, ERW did not induce any chromosome aberrations in Chinese hamster lung fibroblast cells with or without rat liver, for up to 24 hours. Rats administered ERW at a dose of 20 mL/kg/day for 28 days via intragastric infusion did not show any clinical symptoms or toxic changes. These results demonstrate the expected safety for a 60 kg human to drink at least 1.2L/day of ERW [22]. Developing animals are the most sensitive to biological agents and are often used in studies to investigate toxicity. Thus, ERW was given to pregnant and also lactating rats to look for any effects. Development of rat fetuses and offspring were normal, and ERW increased the weight of the animals over controls. ERW was also found to have positive biological effects on postnatal growth. Moreover, postnatal morphological development was also accelerated [23]. No significant difference in milk yield or suckled milk volume was noted. It is suspected that the water-hydrated calcium cations transferred to the fetus through the placenta and to the offspring through the milk, might be the cause of the increased body weight, since calcium plays a key role in skeletal formation [24].

2.7 Inhibition of cancer but not normal cells

It is known that tumor cells produce ROS more abundantly than normal cells. It is also well known that antioxidants can inhibit tumor cell proliferation, which indicates an important role of ROS in mediating the loss of growth control. Human tongue carcinoma cells were shown to be significantly inhibited for either colony formation or colony sizes by ERW in cell cultures without inhibition to normal human tongue epithelial cells. ERW also caused growth inhibition, cell degeneration, and inhibition of invasion to human fibrosarcoma cells HT-1080. These studies suggest that ERW may help prevent tumor progression and invasion [25]. In vitro examination of leukemia cells (HL-60) treated with ERW showed enhanced mitochondrial damage and cell apoptosis. However, normal peripheral blood mononuclear cells showed no cytotoxic effect from ERW [26]. ERW also suppressed the growth rate of cancer cells transplanted into mice, demonstrating anti-cancer effects in vivo.

2.8 Protection of liver from toxic agents

Mice with carbon tetrachloride-induced liver damage given ERW showed significantly lowered serum levels of hepatic enzyme markers and increased activities of superoxide dismutase and other key detoxifying enzymes. The effects of ERW were similar to silymarin, an extract from milk thistle well known for its hepato-protective properties. Results suggest that ERW may be used to protect the liver against toxins that induce oxidative damage [27].

2.9 Conclusions from the literature review

These studies show impressive health benefits in humans and other biological systems from consumption of ERW over a very short time, and without any toxic effects observed. Clearly, ERW is a useful adjunct for treating ROS-associated diseases, including diabetes, kidney disease, cancer, and cardiovascular disease. In addition, due to its anti-aging effects in scavenging oxygen free radicals, ERW appears to be an excellent choice for regular water consumption, although its antioxidant activity is unstable upon storage. Nonetheless, it is easily produced from tap water at point-of-use.

3 Observations from live blood analysis

The blood is the most easily monitored tissue that can show rapid changes that correlate with health and disease. We have observed that persons drinking ERW show exceptionally clean biological terrains as monitored by live blood analysis. Live blood analysis is the visual examination of a small droplet of fresh capillary blood typically taken from the fingertip, put onto a glass slide, and immediately observed under a high-powered light microscope equipped with a dark-field condenser. This method offers a visual perspective of the blood cells and plasma at high magnification enhanced by modern optical techniques. It provides an assessment of the ecology of the blood, the “biological terrain”. Live blood analysis is used clinically to look for the malaria and Lyme disease parasites. Here we discuss it as a tool to assess blood cell stickiness, clumping, and coagulation and clotting processes, which are related to the activation of the inflammatory cascade.

A microphotograph from live blood analysis is shown in Figure 1. This is a photograph of normal healthy blood of a fasted female, age 37. The red blood cells (RBCs) are seen as single, free, round cells. Only a few platelet aggregates are seen in the plasma as grey areas. No RBC stickiness and no other clotting factors are found throughout the blood sample.

Figure 1: Normal healthy blood from female, age 37.

By contrast, Figure 2 shows the blood of a male, 65 years old. This blood is also typical of that found in many elderly persons. The RBCs are sticky and tightly clumped together in rouleau (rolls of coins seen on edge). Fibrin (white threads) is present, indicating that blood coagulation and clotting have been activated. This is the picture of systemic inflammation. Peripheral circulation was also impaired for this subject, because only single RBC can move freely through the smallest capillaries. Poor circulation in the extremities is a common complaint of the elderly.

Figure 2: Unhealthy blood from male, 65, showing blood congestion and clotting.

Following this test, the subject, M, age 65, drank 1 to 1.5 liters/day of ERW from a water ionizer for 6 months but made no other changes in diet or lifestyle. Figure 3 shows the blood from the same person after 6 months. The RBC stickiness, aggregation, and clotting factors are no longer present. It is particularly striking to see this change in an older person’s blood. Although this is a single case presented here, numerous other cases have been observed as well.

4 Conclusions

Chronic inflammation is considered to be one of the main underlying factors of virtually all of the chronic degenerative diseases, including cancer, cardiovascular, and autoimmune diseases. From observing changes in the biological terrain apparently due to consumption of ERW, it appears that ERW may be a useful intervention to mitigate activation of the clotting and inflammatory pathways. Long-term consumption of ERW may improve the blood circulation and possibly help prevent the chronic diseases of our times. Acid-alkaline balance is another key to health and wellness [28]. Metabolism of food leads to acid wastes, yet the biological terrain needs to be alkaline, pH 7.2-7.4. Drinking alkaline water such as ERW can contribute to neutralizing acid waste and maintaining proper pH balance in the body. In conclusion, a growing body of scientific and clinical literature shows increasing support for ERW as a “functional” drinking water that scavenges free radicals, diminishes systemic inflammation, and is a useful adjunct for treating ROS-associated diseases, including diabetes, kidney disease, cancer, and cardiovascular disease. From observations of the blood, it appears to mitigate early blood clotting and systemic inflammation seen as sticky, aggregated RBCs and fibrin. Collectively, this evidence points to ERW alkaline ionized water as a healthy drinking water


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