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.
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 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 (9–13). 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 (9, 14, 15). 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 (16–19).
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 (20, 21), 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 (22, 23). 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 (27, 28), rheumatoid arthritis (29), brain injury (30), ischemic reperfusion injury (31, 32), and diabetes (33, 34), 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 (∙O−2•O2-), nitric oxide (NO•), and peroxynitrite (ONOO−), etc. (37, 38). 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 (39, 40). 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 (41, 42). 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 (43–45).
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 (42, 47). 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 (48, 51). 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 (53–55). 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 (56–59), and both of ILs and TNFs can be suppressed by hydrogen gas (60, 61).
Inflammation induced by chemotherapy in cancer patients not only causes severely 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, 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 (67, 68). 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) (69, 70).
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 (73, 74). However, cancer patients receiving these treatments often experience fatigue and impaired quality of life (75–77). The skyrocketed generation of ROS during the treatment is believed to contribute in the adverse effects, resulting in remarkable oxidative stress, and inflammation (41, 42, 78). 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 (81, 82). 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 (83, 84).
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 (87, 88). 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 (48, 90).
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 (94, 95). 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).
Discussion
Hydrogen gas has been recognized as one medical gas that has potential in the treatment of cardiovascular disease, inflammatory disease, neurodegenerative disorders, and cancer (17, 60). 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).
Table 1. The Summary of various formulation, application, mechanisms of H2 in cancer treatment.
Figure 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.
NOTE:
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].
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Hydrogen Gas in Cancer Treatment
Sai Li1†, 
Rongrong Liao2†, Xiaoyan Sheng2†, Xiaojun Luo3, Xin Zhang1, Xiaomin Wen3, Jin 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.
Funding
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.
Acknowledgments
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
Effects of drinking molecular hydrogen water on the quality of life QOL of cancer patients treated with RADIATION therapy
Effects of drinking molecular hydrogen water on the quality of life of cancer patients treated with radiation therapy
This is the first report demonstrating the benefits of drinking molecular hydrogen water in liver cancer patients receiving radiation therapy for malignant tumors.
– Molecular hydrogen dissolved in water improved the QOL of (liver) cancer patients reciving radiotherapy
– Molecular hydrogen water mitigated oxidative stress marker during radiotherapy
– Molecular hydrogen water did NOT compromise the radiation cancer treatment efficacies
-Molecular hydrogen water treatment did NOT alter liver function or blood composition during radiotherapy
This study examined whether molecular hydrogen (dissolved in water ) treatment, improved QOL in patients receiving radiotherapy.
Cancer patients receiving radiotherapy often experience fatigue and impaired quality of life (QOL).
Most radiation-induced symptoms are believed to be associated with increased oxidative stress and inflammation, due to the generation of reactive oxygen species (ROS) during radiotherapy, and may significantly affect the patient’s quality of life (QOL) [2].
Molecular hydrogen (dissolve in water) can be administered as a therapeutic medical gas, has selective ANTIoxidant( molecular hydrogen ( water ) neutralizes only bad free radicals while supporting the beneficial ones) & ANTIinflammatory (molecular hydrogen( water )reduces inflammation in tisues) properties.
Drinking liquids(i.e. : water) with dissolved molecular hydrogen represents a novel method of molecular hydrogen gas delivery that is easily translatable into clinical practice, with beneficial effects for several medical conditions, including atherosclerosis, type 2 diabetes, metabolic syndrome, and cognitive impairment during aging and in Parkinson’s disease [7–11].
Methods
A randomized, placebo-controlled study was performed to evaluate the effects of drinking molecular hydrogen-rich water on 49 patients receiving radiotherapy for malignant liver tumors.
The subjects were randomly assigned to groups to either drink molecular hydrogen-rich water for 6 weeks (n = 25) or drink water containing a placebo (n = 24).
Subjects were provided with four 500 mL bottles of drinking molecular hydrogen water per day .
Molecular hydrogen rich water had final molecular hydrogen concentration; 0.55~0.65 mM.
The subjects were expected to consume 100-300 mL of molecular hydrogen-rich water more than 10 times per day for a total minimum consumption of 1500 mL (1.5 L) and a maximum consumption of 2000 mL (2.0 L).
Oral intake of molecular hydrogen water or placebo water started on the first day of radiotherapy and continued for 6 weeks.
All participants received 5040-6500 cGy of radiotherapy for 7-8 weeks using a 6 MV system (Cyber Knife, Fanuc, Yamanashi, Japan).
All the liver cancer patients survived through the 6 week follow-up period when the QOL questionnaire was administered.
The Korean version of the European Organization for Research and Treatment of Cancer’s QLQ-C30 instrument was used to evaluate global health status and QOL. The concentration of derivatives of reactive oxidative metabolites and biological antioxidant power in the peripheral blood were assessed.
Results & Conclusions
The consumption of molecular hydrogen-rich water for 6 weeks reduced reactive oxygen metabolites in the blood and maintained blood oxidation potential. QOL scores during radiotherapy were SIGNIFICANTLY IMPROVED in patients treated with molecular hydrogen-rich water compared to patients receiving placebo water.
There was no difference in tumor response to radiotherapy between the two groups( meaning drinking molecular hydrogen water did not interfere with the desired antitumor effects of radiation therapy ).
Daily consumption of molecular hydrogen-rich water is a potentially novel, therapeutic strategy for improving QOL after radiation exposure.
Consumption of hydrogen-rich water reduces the biological reaction to radiation-induced oxidative stress without compromising anti-tumor effects.
Molecular hydrogen dissolved in water improved the QOL of (liver) cancer patients receiving radiotherapy
The QOL of the liver cancer patients who were given placebo water deteriorated significantly within the first month of radiotherapy (Figure1A)
Gastrointestinal (GI) symptoms are one of the most common complaints of patients undergoing radiotherapy and are considered to have a high impact on the patient’s QOL after 6 weeks of radiotherapy.
The patients consuming molecular hydrogen water experienced significantly less appetite loss and fewer tasting disorders compared to the patients consuming placebo water.
Liver cancer patients experience GI symptoms and decreased QOL during radiotherapy. These symptoms usually occur as a result of the body repairing damage to healthy cells, are particularly common towards the end of a course of radiation treatment, and can last for some time. The symptoms and their impact on QOL can be worsened by having to travel to the hospital each day.
Drinking molecular hydrogen-rich water improved the QOL of the liver cancer patients receiving radiotherapy and did not require additional hospital visits.
There were no differences between the groups in the QOL subscales for fatigue, depression, or sleep. No significant difference was seen in the mean scores for vomiting or diarrhea (Figure1B).
Molecular hydrogen water mitigated oxidative stress marker during radiotherapy
Before treatment, there were no differences in total hydroperoxide levels, representative of total dROM levels, between the treatment groups.
Radiotherapy markedly increased total hydroperoxide levels in the patients consuming placebo water.
However, drinking molecular hydrogen water prevented this increase in total serum hydroperoxide, as determined by the dROM test (Figure2A), indicating DECREASED OXIDATIVE STRESS during radiotherapy in the liver cancer patients who consumed molecular hydrogen water.
Similarly, endogenous serum antioxidant activity significantly deteriorated during radiotherapy in the patients consuming placebo water, and biologic antioxidant activity was MAINTAINED in liver cancer patients who consumed molecular hydrogen-rich water, even after 6 weeks of radiotherapy (Figure2B).
Radiotherapy is associated with an increase in ROS, followed by damage to DNA, lipids, and proteins, and activation of transcription factors and signal transduction pathways. It has been estimated that 60-70% of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals [18].
Therefore, a number of trials with the goal of reducing adverse effects due to excess ROS production have been performed with antioxidants delivered during the course of radiotherapy. Supplementation with α-tocopherol improves the salivary flow rate and maintains salivary parameters [19]. Treatment with the antioxidant enzyme superoxide dismutase prevented radiotherapy-induced cystitis and rectitis in bladder cancer patients receiving radiotherapy [20]. In addition, the combined use of pentoxifylline and vitamin E reduced radiation-induced lung fibrosis in patients with lung cancer receiving radiotherapy [21].
Thus, in general, supplementation with antioxidants is likely to offer overall benefits in the treatment of adverse effects of radiotherapy.
However, not all antioxidants can afford radioprotection [22–24].
Furthermore, of significant concern is the finding that high doses of antioxidants administered as adjuvant therapy might compromise the efficacy of radiation treatment and increase of the risk of local recurrence of cancer [25,26].
Hence, the relatively lower toxicity associated with the use of these antioxidant agents is appealing, but not at the cost of poor tumor control.
In contrast, in this study, drinking molecular hydrogen-rich water did NOT affect radiotherapy’s anti-tumor effects.
Molecular hydrogen water did NOT compromise the radiation cancer treatment efficacies
Tumor response to radiotherapy was similar between the cancer treatment groups, and 12 of 24 (50.0%) liver cancer patients in the placebo group and 12 of 25 (48%) patients in molecular hydrogen water group exhibited either a completed response (CR) or a partial response (PR). There were no patients in either group with progressive disease (PD) during the follow-up period (3 months). Thus, drinking molecular hydrogen water did NOT compromise the anti-tumor effects of radiotherapy.
Our results may suggest that hydrogen water functions not only as an antioxidant, but also plays a protective role by inducing radioprotective hormones or enzymes.
Molecular hydrogen water treatment did NOT alter liver function or blood composition during radiotherapy
There were no significant differences in aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase (γ-GTP) and total cholesterol levels at week 0 and week 6, regardless of the type of water consumed(Table2), indicating that molecular hydrogen water consumption did NOT alter liver function.
Similarly, there were no significant differences in red blood cell count, white blood cell count, or platelet count between patients consuming molecular hydrogen water and patients consuming placebo water (Table3).
This finding may provide the foundation for a clinically applicable, effective, and safe strategy for the delivery of molecular hydrogen gas (dissolved in water) to mitigate radiation-induced cellular injury.
Oral intake of daily molecular hydrogen-supplemented water might be a prophylactic strategy to improve QOL of the (liver cancer ) patients receiving radiotherapy.
Although the mechanisms underlying the beneficial effects of molecular hydrogen-rich water during radiotherapy have not been clearly elucidated, drinking molecular hydrogen dissolved in water reduced dROM levels and maintained BAP levels in the serum, suggesting molecular hydrogen-rich water exhibits potent systemic antioxidant activity.
The safety of molecular hydrogen-rich water has also been determined as well as the optimal concentration of molecular hydrogen dissolved in water;
Daily intake of molecular hydrogen-rich water may be a promising approach for counteracting radiation-induced impairments to QOL.
This therapeutic use of molecular hydrogen is also supported by the work of Qian et al., who demonstrated that treating human lymphocyte AHH-1 cells with molecular hydrogen (saline) before irradiation significantly inhibited ionizing irradiation-induced apoptosis and increased cell viability in vitro.
They also showed that injection of molecular hydrogen-rich saline could protect the gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde and intestinal 8-hydroxydeoxyguanosine levels, and increase plasma endogenous antioxidants in vivo [27].
Conclusions
In conclusion, our study demonstrated that drinking molecular hydrogen-rich water improved QOL and reduced oxidative markers in patients receiving radiotherapy for liver tumors.
This novel approach of oral intake of molecular hydrogen-rich water may be applicable to a wide range of radiation-related adverse symptoms.
Drinking solubilized molecular hydrogen (dissolved in water) on a daily basis is beneficial and would be quite easy to administer without complicating or changing a patient’s lifestyle
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Background
Radiotherapy is one of the major treatment options for malignant neoplasms. Nearly half of all newly diagnosed cancer patients will receive radiotherapy at some point during treatment and up to 25% may receive radiotherapy a second time [1]. Radiotherapy adversely affects the surrounding normal cells [2]. Acute radiation-associated side effects include fatigue, nausea, diarrhea, dry mouth, loss of appetite, hair loss, sore skin, and depression. Radiation increases the long-term risk of cancer, central nervous system disorders, cardiovascular disease, and cataracts. The likelihood of radiation-induced complications is related to the volume of the irradiated organ, the radiation dose delivered, the fractionation of the delivered dose, the delivery of radiation modifiers, and individual radiosensitivity [3]. Most radiation-induced symptoms are believed to be associated with increased oxidative stress and inflammation, due to the generation of reactive oxygen species (ROS) during radiotherapy, and may significantly affect the patient’s quality of life (QOL) [2].
4,5References
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- Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB. Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist. 2010;15(4):360–71. doi: 10.1634/theoncologist.2009-S104. [PMC free article] [PubMed] [Cross Ref]
- Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13(6):688–94. doi: 10.1038/nm1577. [PubMed] [Cross Ref]
- Buchholz BM, Kaczorowski DJ, Sugimoto R, Yang R, Wang Y, Billiar TR, McCurry KR, Bauer AJ, Nakao A. Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am J Transplant. 2008;8(10):2015–24. doi: 10.1111/j.1600-6143.2008.02359.x. [PubMed][Cross Ref]
- Huang C, Kawamura T, Toyoda Y, Nakao A. Recent Advances in Hydrogen Research as a Therapeutic Medical Gas. Free Rad Res. 2010;44(9):971–82. doi: 10.3109/10715762.2010.500328.[PubMed] [Cross Ref]
- Fujita K, Seike T, Yutsudo N, Ohno M, Yamada H, Yamaguchi H, Sakumi K, Yamakawa Y, Kido MA, Takaki A, Katafuchi T, Tanaka Y, Nakabeppu Y, Noda M. 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. doi: 10.1371/journal.pone.0007247.[PMC free article] [PubMed] [Cross Ref]
- Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N. Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr. 2010;46(2):140–9. doi: 10.3164/jcbn.09-100. [PMC free article] [PubMed][Cross Ref]
- Gu Y, Huang CS, Inoue T, Yamashita T, Ishida T, Kang KM, Nakao A. Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. J Clin Biochem Nutr. 2010;46(3):269–76. doi: 10.3164/jcbn.10-19. [PMC free article] [PubMed] [Cross Ref]
- Ohsawa I, Nishimaki K, Yamagata K, Ishikawa M, Ohta S. Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochem Biophys Res Commun. 2008;377(4):1195–8. doi: 10.1016/j.bbrc.2008.10.156. [PubMed] [Cross Ref]
- Kajiyama S, Hasegawa G, Asano M, Hosoda H, Fukui M, Nakamura N, Kitawaki J, Imai S, Nakano K, Ohta M, Adachi T, Obayashi H, Yoshikawa T. 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):137–43. doi: 10.1016/j.nutres.2008.01.008. [PubMed] [Cross Ref]
- Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC. et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–76. doi: 10.1093/jnci/85.5.365. [PubMed] [Cross Ref]
- Ezaki S, Suzuki K, Kurishima C, Miura M, Weilin W, Hoshi R, Tanitsu S, Tomita Y, Takayama C, Wada M, Kondo T, Tamura M. Resuscitation of preterm infants with reduced oxygen results in less oxidative stress than resuscitation with 100% oxygen. J Clin Biochem Nutr. 2009;44(1):111–8. doi: 10.3164/jcbn.08-221. [PMC free article] [PubMed] [Cross Ref]
- Kwon JH, Bae SH, Kim JY, Choi BO, Jang HS, Jang JW, Choi JY, Yoon SK, Chung KW. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. Stereotactic radiotherapy for liver cancer. BMC Cancer. 2010;10:475. doi: 10.1186/1471-2407-10-475. [PMC free article] [PubMed] [Cross Ref]
- Nakashima-Kamimura N, Mori T, Ohsawa I, Asoh S, Ohta S. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol. 2009;64(4):753–61. doi: 10.1007/s00280-008-0924-2.[PubMed] [Cross Ref]
- Sato Y, Kajiyama S, Amano A, Kondo Y, Sasaki T, Handa S, Takahashi R, Fukui M, Hasegawa G, Nakamura N, Fujinawa H, Mori T, Ohta M, Obayashi H, Maruyama N, Ishigami A. Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochem Biophys Res Commun. 2008;375(3):346–50. doi: 10.1016/j.bbrc.2008.08.020. [PubMed] [Cross Ref]
- Cardinal JS, Zhan J, Wang Y, Sugimoto R, Tsung A, McCurry KR, Billiar TR, Nakao A. Oral Administration Of Hydrogen Water Prevents Chronic Allograft Nephropathy In Rat Renal Transplantation. Kidney Int. 2009;77(2):101–9. [PubMed]
- Vijayalaxmi, Reiter RJ, Tan DX, Herman TS, Thomas CR Jr. Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys. 2004;59(3):639–53. doi: 10.1016/j.ijrobp.2004.02.006.[PubMed] [Cross Ref]
- Chitra S, Shyamala Devi CS. Effects of radiation and alpha-tocopherol on saliva flow rate, amylase activity, total protein and electrolyte levels in oral cavity cancer. Indian J Dent Res. 2008;19(3):213–8. doi: 10.4103/0970-9290.42953. [PubMed] [Cross Ref]
- Sanchiz F, Milla A, Artola N, Julia JC, Moya LM, Pedro A, Vila A. Prevention of radioinduced cystitis by orgotein: a randomized study. Anticancer Res. 1996;16(4A):2025–8. [PubMed]
- Misirlioglu CH, Demirkasimoglu T, Kucukplakci B, Sanri E, Altundag K. Pentoxifylline and alpha-tocopherol in prevention of radiation-induced lung toxicity in patients with lung cancer. Med Oncol. 2007;24(3):308–11. doi: 10.1007/s12032-007-0006-z. [PubMed] [Cross Ref]
- Xavier S, Yamada K, Samuni AM, Samuni A, DeGraff W, Krishna MC, Mitchell JB. Differential protection by nitroxides and hydroxylamines to radiation-induced and metal ion-catalyzed oxidative damage. Biochim Biophys Acta. 2002;1573(2):109–20. [PubMed]
- Prasad KN, Cole WC, Kumar B, Che Prasad K. Pros and cons of antioxidant use during radiation therapy. Cancer Treat Rev. 2002;28(2):79–91. doi: 10.1053/ctrv.2002.0260. [PubMed] [Cross Ref]
- Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM. Antioxidants and cancer therapy: a systematic review. J Clin Oncol. 2004;22(3):517–28. [PubMed]
- Bairati I, Meyer F, Gelinas M, Fortin A, Nabid A, Brochet F, Mercier JP, Tetu B, Harel F, Abdous B, Vigneault E, Vass S, Del Vecchio P, Roy J. Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J Clin Oncol. 2005;23(24):5805–13. doi: 10.1200/JCO.2005.05.514. [PubMed] [Cross Ref]
- Meyer F, Bairati I, Fortin A, Gelinas M, Nabid A, Brochet F, Tetu B. Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients. Int J Cancer. 2008;122(7):1679–83. [PubMed]
- Qian L, Cao F, Cui J, Huang Y, Zhou X, Liu S, Cai J. Radioprotective effect of hydrogen in cultured cells and mice. Free Radic Res. 2010;44(3):275–82. doi: 10.3109/10715760903468758. [PubMed][Cross Ref]
hydrogen-rich water protects LIVER function of colorectal CANCER patients during CHEMOTHERAPY
The study published in 2017 was conducted to investigate the protective effect of hydrogen-rich water on the liver function of colorectal cancer (CRC) patients treated with mFOLFOX6 chemotherapy.
A controlled, randomized, single-blind clinical trial was designed.
A total of 152 patients with colorectal cancer were recruited by the Department of Oncology of Taishan Hospital (Taian, China) between June 2010 and February 2016, among whom 146 met the inclusion criteria. Subsequently, 144 patients were randomized into the treatment with hydrogen water(n=80) and placebo (n=64) groups. At the end of the study, 76 patients in the hydrogen water treatment group and 60 patients in the placebo group were included in the final analysis.
The 80 patients group started drinking hydrogen-rich water 1 day prior to chemotherapy until the end of the cycle, for a total of 4 days, with a total intake of 1,000 ml hydrogen-rich water per day in 4 doses (250 ml hydrogen-rich water each). Hydrogen-rich water was consumed 0.5 h after a meal and before bedtime.
The patients did not discontinue consuming hydrogen-rich water during the entire course of chemotherapy.
The other 64 placebo patients consumed distilled water, with a daily intake of 1,000 ml in 4 doses (250 ml each).
The changes in liver function after the chemotherapy, such as altered levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase, indirect bilirubin (IBIL) and direct bilirubin, were observed. The damaging effects of the mFOLFOX6 chemotherapy on liver function were mainly represented by increased ALT, AST and IBIL levels. The hydrogen-rich water group exhibited no significant differences in liver function before and after treatment, whereas the placebo group exhibited significantly elevated levels of ALT, AST and IBIL. Thus, hydrogen-rich water appeared to alleviate the mFOLFOX6-related liver injury
-
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- PMID:29142752
- PMCID:PMC5666661
- DOI:10.3892/mco.2017.1409
Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy.
Author information
- 1
- Department of Oncology, Shandong Provincial Taishan Hospital, Taian, Shandong 271000, P.R. China.
- 2
- Department of Pathology, Taishan Medical University, Taian, Shandong 271000, P.R. China.
- 3
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China.
Molecular hydrogen (water) in the treatment of acute and chronic neurological conditions(Alzheimer’s, Parkinson’s,etc): mechanisms of protection and routes of administration
Molecular hydrogen (water) in the treatment of acute and chronic neurological conditions(i.e Alzheimer’s, Parkinson’s, etc. ): mechanisms of protection and routes of administration
Molecular hydrogen water & Parkinson’s disease (PD)
Parkinson’s disease PD is a disorder that presents with extrapyramidal symptoms caused by the degeneration and loss of dopamine-producing cells in substantia nigra. Oxidative stress is known to be involved in the clinical condition of PD.(7) Moreover, the involvement of mitochondrial dysfunction in PD has been reported.(45)
The effects of molecular hydrogen H2 on Parkinson’s disease PD have been reported in animal models of PD as well as in clinical studies.(46–48)
In 2009, Fujita et al.(47) and Fu et al.(48) reported that consuming molecular hydrogen H2-rich water inhibits oxidative stress on the nigrostriatal pathway and prevents the loss of dopamine cells in a PD animal model. With the consumption of molecular hydrogen H2-rich-water-drinking, oxidative stress in the nigrostriatal pathway was inhibited and loss of dopamine cells was decreased. These results suggest that consuming molecular hydrogen H2-rich water could affect the onset of Parkinson’s Disease PD.
In recent years, the results of a clinical trial on the effects of consuming molecular hydrogen H2-rich water for Parkinson’s Disease PD have been reported.(49) A randomized double-blind study showed that consuming molecular hydrogen H2-rich water (1,000 ml/day) for 48 weeks significantly improved the total Unified Parkinson’s Disease Rating Scale (UPDRS) score of Parkinson’s disease PD patients treated with levodopa. A double-blind multi-center trial of molecular hydrogen H2 water is currently underway (Table 1).(50)
Molecular hydrogen water & Alzheimer’s disease (AD)
Alzheimer Disease AD, an age-related neurodegenerative disease, is the most common cause of dementia.(1,51) Pathologically, it is characterized by the deposition of Aβ protein outside nerve cells and the accumulation of phosphorylated tau protein inside nerve cells. There is also a marked loss of nervous cells in the cerebral cortex.(52) In recent years, oxidative stress and neuroinflammation have been reported to be involved in Alzheimer’s disease AD.(1,5) To date, reports have centered on the involvement of oxidative stress in brain parenchyma.(1,51,53)The accumulation of Aβ protein is strongly associated with the failure of Aβ clearance that is closely related to the pathogenesis of Alzheimer’s Disease AD.(5) It is known that low-density lipoprotein receptor-related protein 1 (LRP1) is involved in Aβ protein elimination. LRP dysfunction caused by oxidative stress and neuroinflammation is involved in the onset of Alzheimer’s Disease AD.(5) The regulation of oxidative stress and neuroinflammation may prevent the onset or progression of Alzheimer’s Disease AD. A number of reports have investigated the effects of molecular hydrogen H2 for the prevention of Alzheimer’s Disease AD onset.(51,53)
In a rat Alzheimer’s Disease AD model, it has been reported that the administration of molecular H2-rich saline (5 ml/kg, i.p., daily) inhibited oxidative stress, cytokine production, and nuclear factor-κB (NF-κB) production in the hippocampus and cerebral cortex, and improved impaired memory.(51,53)
It has been reported that consuming molecular hydrogen H2-rich water inhibits age-related brain alterations and spatial memory decline.(54)
The therapeutic effect of molecular hydrogen H2-rich water following Traumatic brain injury (TBI) and in posttraumatic onset of Alzheimer’s disease (AD) was investigated by Dohi et al. in 2014,(18) who investigated whether the consumption of molecular hydrogen H2-rich water 24 h prior to trauma can inhibit neuronal damage in a controlled cortical injury model using mice. The authors found that the expression of the phosphorylated tau proteins AT8 and Alz50 in the hippocampus and cortex was blocked in mice that consumed molecular hydrogen H2-rich water. Moreover, the activity of astrocytes and microglia were inhibited in mice Traumatic Brain Injury model consuming molecular hydrogen H2-rich water. The expression of genes induced by Traumatic Brain Injury, particularly those that are involved in oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, and adenosine triphosphate (ATP) and nucleotide binding, was inhibited by consuming molecular hydrogen H2-rich water.
Dohi et al.(18) specifically reviewed the role of molecular hydrogen H2-rich water in neuroinflammation following brain trauma. The consumption of molecular hydrogen H2-rich water influenced the production of cytokines and chemokines in the damaged brain and inhibited the production of hypoxia inducible factor-1 (HIF-1), MMP-9, and cyclophilin A. However,molecular hydrogen H2-rich water did not affect the production of amyloid precursor protein (APP), Aβ-40, or Aβ-42. They also investigated the relationship between molecular hydrogen H2 and ATP production and reported that molecular hydrogen H2 increased basal respiration, reserve capacity, and nonmitochondrial respiration but did not increase aerobic ATP production. It has thus been demonstrated that the inhibitory effects of molecular hydrogen H2 on nerve damage are not solely due to its simple function as a free radical scavenger (Fig. 1 and and22).
Oxidative stress caused by reactive oxygen species is considered a major mediator of tissue and cell injuries in various neuronal conditions, including neurological emergencies and neurodegenerative diseases.
Oxidative stress caused by reactive oxygen species (ROS) is a major mediator of tissue and cellular injuries in various neuronal conditions, including neurological emergencies and neurodegenerative diseases.(1–7)
Control of oxidative stress is a major therapeutic strategy for various neuronal conditions.(6,8,9) There are many methods for controlling oxidative stress with the use of free radical scavengers being the most common approach.(6,8) Evidence from animal experiments support the notion that free radical scavengers and antioxidants dramatically reduce cerebral damage.(9) Edaravone (MCI-186), a novel free radical scavenger, was developed to prevent lipid peroxidation in pathological neurological conditions.(8,9)Edaravone is currently the only antioxidant drug approved for treating cerebral infarction that improves the functional outcome of ischemic stroke.(8) Brain hypothermia therapy (targeted temperature management) can also effectively control oxidative stress. Brain hypothermia therapy is effective in patients with various acute neuronal diseases.(6,10,11)
In 2007, Ohsawa et al.(12) reported that molecular hydrogen (H2) can act as an antioxidant to prevent and treat middle cerebral artery occlusion–reperfusion injury in rats. This effect has been supported by additional reports. Recently, the beneficial effect of molecular H2 has been reported in many other organs, including the brain.(13–17) The first major therapeutic effect of molecular hydrogen H2 was that of an antioxidant, combining with hydroxyl ions to produce water.(12) Recently, other biological mechanisms of molecular hydrogen H2 (anti-inflammatory, anti-apoptosis, anti-cytokine, DNA expression, and energy metabolism) have been proposed (Fig. 1 and and22).(18)Therefore, the biology of molecular hydrogen H2 is not simple. In this review, we discuss the role of molecular H2 in various neuronal conditions.
Method and Route of Administration in Molecular hydrogen H2 Therapy
As a small (2 Da), uncharged molecule of hydrogen H2, would be expected to readily distribute throughout the body, including being able to easily penetrate cell membranes, However we are unable to determine the distribution of moleclar hydrogen H2 among organs and its concentrations in each organ and serum based on the administration methods and dosage. This problem was investigated in 2014.(55) A comparative review was conducted on the consumption of molecular hydrogen H2-rich water, i.p. or intravenous administration of molecular hydrogen H2-rich saline, and inhalation of molecular hydrogen H2 gas. The results showed that the highest concentrations are reached 1 min after intravenous administration and 5 min after oral administration. The highest concentration was reached 30 min after the inhalation of molecular hydrogen H2 gas and was maintained for some time. Although molecular hydrogen H2 concentrations in the brain tend to be high after either intravenous administration or inhalation, no significant differences have been observed in comparison with the concentrations after the consumption of molecular hydrogen H2-rich water and i.p. administration of molecular hydrogen H2-rich saline. Thus, although there have been variations based on the administration method, all methods have been found to result in the presence of molecular hydrogen H2 in the serum and brain tissue. Liu et al.(39) measured molecular hydrogen H2 levels in the arteries, veins, and brain tissues after the inhalation of 2% molecular hydrogen H2 gas. They found that arterial molecular hydrogen H2 peaked at 30 min after administration, whereas venous and brain tissue molecular hydrogen H2 peaked at 45 min after administration. They reported that molecular hydrogen H2 levels were similar in arteries and brain tissues.
This demonstrated that molecular hydrogen H2 migrates to the brain tissue regardless of the method of administration(Thus, the studies below might as well have been performed using molecular hydrogen water instead of molecular hydrogen gas or molecular hydrogen saline).
These results suggest that the consumption of molecular hydrogen H2-rich water prevents neurodegenerative disease and that molecular hydrogen H2-rich drinking water could be used to treat acute brain disorders (Fig. 1 and and22).
Molecular Hydrogen & Neurological Diseases
Molecular hydrogen & Ischemic brain injury
It has been reported that molecular hydrogen H2 prevents ischemic brain damage in animal experiments.(12,19–21) Ohsawa et al.(12) reported that inhalation of 2% molecular hydrogen H2 gas strongly suppressed infarct volume after middle cerebral artery ischemia–reperfusion in rats. In an electron spin resonance (ESR) study, they showed that molecular hydrogen H2 had hydroxyl radical scavenging activity. Hydroxynonenal (HNE) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) immunoreactivity was suppressed in the damaged brain after treatment with 2% molecular hydrogen H2. molecular hydrogen H2 inhalation reduced ischemic damage and hemorrhagic volume after transient middle crebral artery occlusion (MCAO) ischemia.(19) Free radical generation after ischemia induces matrix metalloproteinase (MMP) expression.(19,20) MMP-9 promotes hemorrhagic infarction by disrupting cerebral vessels.(20) molecular hydrogen H2 inhalation has been found to reduce MMP-9 expression in an MCAO rat model. molecular hydrogen H2 also has a neuroprotective effect against global ischemia. Ji et al.(21) reported that molecular hydrogen H2-rich saline injection [5 ml/kg intra-peritoneal (i.p.) administration] after global ischemia reduced neuronal cell death in hippocampal Cornet d’Ammon 1 (CA1) lesions in rats. Cerebral hypoxia–ischemia and neonatal asphyxia are major causes of brain damage in neonates. molecular hydrogen H2 gas inhalation and molecular hydrogen H2-rich saline injection provide early neuroprotection from neonatal neurological damage.(22) Nagatani et al.(23) reported that that an molecular hydrogen H2-enriched intravenous solution is safe for patients with acute cerebral infarction, including patients treated with tissue plasminogen activator (t-PA) therapy.
Metabolic syndrome is a strong risk factor of stroke. It has been reported that molecular hydrogen H2 therapy can improve metabolic syndrome in basic and clinical settings.(24–27) molecular hydrogen H2 therapy may reduce stroke in patients with metabolic syndrome involving diabetes mellitus.
Molecular hydrogen & Hemorrhagic stroke
Hemorrhagic stroke involving intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) is a critical neuronal condition, and the mortality rate of hemorrhagic stroke is still high.(28–30) Manaenko et al.(28) reported a neuroprotective effect of molecular hydrogen H2 gas inhalation using an experimental ICH animal model.molecular hydrogen H2 gas inhalation suppresses redox stress and blood brain barrier (BBB) disruption by reducing mast cell activation and degranulation. Brain edema and neurological deficits were also suppressed. In SAH, there are several studies demonstrating the neuroprotective effect of molecular hydrogen H2 treatment.(29–31) A clinical trial has started in patients with SAH (Table 1).(32)
Molecular hydrogen & Traumatic brain injury (TBI)
The efficacy of molecular hydrogen H2 for treating TBI has been investigated in several studies.(18,33,34) Ji et al.(33) reported that in a rat TBI model,molecular hydrogen H2 gas inhalation has been found to protect BBB permeability and regulate posttraumatic brain edema, thereby inhibiting brain damage. molecular hydrogen H2 gas inhalation also inhibits the decrease in superoxide dismutase (SOD) activity and catalase (CAT) activity. These are antioxidant enzymes in posttraumatic brains that inhibit the production of malondialdehyde (MDA) and 8-iso-prostaglandin F2α (8-iso-PGF2α). Eckermann et al.(34) reported that in a surgical trauma mouse model involving right frontal lobectomy, molecular hydrogen H2 gas inhalation has been found to inhibit postoperative brain edema and improve the postoperative neurobehavioral score. The same report also showed that lipid peroxidation and the production of oxidative stress substances were not inhibited by molecular hydrogen H2 gas inhalation.(34)
Molecular Hydrogen & Spinal cord injury
Chen et al.(35) reviewed the effects of molecular hydrogen H2-rich saline administration (i.p.) in a rat traumatic spinal cord injury model. They found that posttraumatic neurological symptoms were improved by molecular hydrogen H2-rich saline treatment. Furthermore, molecular hydrogen H2-rich saline treatment has been found to reduce inflammatory cell infiltration, TdT-mediated dUTP nick and labeling (TUNEL)-positive cells, and hemorrhage. In addition, oxidative stress was inhibited and the expression of brain derived neurotrophic factor (BDNF) was increased.
The effects of molecular hydrogen H2 administration on spinal cord ischemia have also been reported.(36,37) Huang et al.(36)investigated the effects of molecular hydrogen H2 gas inhalation in a rabbit spinal cord ischemia–reperfusion model. They reviewed the effects of molecular hydrogen H2 inhalation with different concentrations (1, 2, and 4%) and reported that molecular hydrogen H2 gas inhalation at concentrations of 2% and 4% inhibited neuronal death. However, they did not observe significant differences between the two groups in terms of effects with 2% and 4% being equally effective.(36) It has been reported that the inhalation of 2% molecular hydrogen H2 gas inhibits apoptosis following spinal cord injury caused by ischemia–reperfusion. In addition, molecular hydrogen H2 gas inhalation regulates caspase-3 activity, the production of inflammatory cytokines, oxidative stress, and the decrease in endogenous antioxidant substances. Zhou et al.(37) also reported that molecular hydrogen H2-rich saline administration (i.p.) has beneficial effects on spinal cord ischemia–reperfusion injury in rabbits.
Other acute neurological conditions
In recent years, research has shown that there is a high incidence of comorbid central nervous system symptoms in sepsis cases.(38) Using a mice cecal ligation and puncture (CLP) model, Liu et al.(39) reported that molecular hydrogen H2 gas inhalation improves septic encephalopathy. They reported that 2%molecular hydrogen H2 gas inhalation inhibited post-CLP apoptosis, brain edema, BBB permeability, cytokine production, and oxidative stress in the CA1 hippocampus region as well as improves cognitive function. Nakano et al.(40) reported that maternal administration of molecular hydrogen H2 has a suppressive effect on fetal brain injury caused by intrauterine inflammation with maternal intraperitoneal injection of lipopolysaccharide (LPS).
The treatment of carbon monoxide (CO) poisoning encephalopathy, which is a common gas poisoning, is yet to be established.(41,42) Sun et al.(42) and Shen et al.(41) investigated the effects of molecular hydrogen H2-rich saline. They reported that in a CO poisoning model, the administration of molecular hydrogen H2-rich saline decreased glial activation, cytokine production, oxidative stress, and caspase 3 and 9 production as well as inhibited nerve cell death.
It is known that oxidative stress causes nerve cell impairments.(43) The consumption of molecular hydrogen H2-rich water inhibits oxidative stress and thereby inhibits the onset of stress-induced brain damage.(43)
Hypoxic brain injury caused by asphyxiation, hypoxic ischemic encephalopathy, neonatal asphyxia, and other similar hypoxia-mediated event is a common clinical condition in medical emergencies. Molecular hydrogen H2 treatment has been found to inhibit cell death in an in vitro hypoxia/reoxygenation model using immortalized mouse hippocampal (HT-22) cells. Molecular hydrogen H2 treatment increased phosphorylated Akt (p-Akt) and B-cell leukemia/lymphoma-2 (BCL-2), while it decreased Bax and cleaved caspase-3.(44) In recent years, it has been found that the microRNA-200 (miR-200) family regulates oxidative stress.(44) The inhibition of miR-200 suppresses H/R-induced cell death, reducing ROS production and MMP. Molecular hydrogen H2 treatment suppressed H/R-induced expression of miR-200. In Japan, a double blind randomized controlled trial for post cardiac arrest syndrome has started from 2017 (Table 1).
-
-
diatomic molecular hydrogen H2 dissolved in Alkaline Ionized Water Products (you could drink around 4 liters per day as an adult )
-
AlkaViva Vesta H2 water ionizer AlkaViva Vesta H2 water ionizer – 9 Plate
Enjoy the H2 Advantage Here -
AlkaViva-DELPHI-H2-water-ionizer-purifier-and-hydrogen-water-generator -
AlkaViva Athena H2 Water Ionizer purifier - Enjoy molecular hydrogen water from an entry level price top quality water ionizer
-
Melody-II-H2-water-ionizer-purifier-AlkaViva - Enjoy neutral pH water rich in molecular Hydrogen form AlkaViva IonPia H2 hydrogen water ionizer
molecular hydrogen water generator AlkaViva IonPia H2 668300
-
abbreviations
| AD | Alzheimer’s disease |
| APP | amyloid precursor protein |
| ATP | adenosine triphosphate |
| BBB | blood brain barrier |
| CA1 | Cornet d’Armon 1 |
| CLP | cecal ligation and puncture |
| CO | carbon monoxide |
| ICH | intracerebral hemorrhage |
| LRP | lipoprotein receptor-related protein |
| MCAO | middle cerebral artery occlusion |
| miR-200 | microRNA-200 |
| MMP | matrix metalloproteinase |
| PD | Parkinson’s disease |
| ROS | reactive oxygen species |
| SAH | subarachnoid hemorrhage |
| TBI | traumatic brain injury |
References
Molecular Hydrogen as an Emerging Therapeutic Medical Gas for NEURODEGENERATIVE and Other Diseases
Abstract
Effects of molecular hydrogen (water ) on various diseases have been documented for 63 disease models and human diseases in the past four and a half years(by 2012(. Most studies have been performed on rodents including two models of Parkinson’s disease and three models of Alzheimer’s disease. Prominent effects are observed especially in oxidative stress-mediated diseases including neonatal cerebral hypoxia; Parkinson’s disease; ischemia/reperfusion of spinal cord, heart, lung, liver, kidney, and intestine; transplantation of lung, heart, kidney, and intestine. Six human diseases have been studied to date: diabetes mellitus type 2, metabolic syndrome, hemodialysis, inflammatory and mitochondrial myopathies, brain stem infarction, and radiation-induced adverse effects.
Two enigmas, however, remain to be solved. First, no dose-response effect is observed. Rodents and humans are able to take a small amount of hydrogen by drinking hydrogen-rich water, but marked effects are observed. Second, intestinal bacteria in humans and rodents produce a large amount of hydrogen, but an addition of a small amount of hydrogen exhibits marked effects. Further studies are required to elucidate molecular bases of prominent hydrogen (water ) effects and to determine the optimal frequency, amount, and method of hydrogen administration for each human disease
1. Introduction
Molecular hydrogen (H2) is the smallest gas molecule made of two protons and two electrons. Hydrogen is combustible when the concentration is 4–75%. Hydrogen, however, is a stable gas that can react only with oxide radical ion (•O−) and hydroxyl radical (•OH) in water with low reaction rate constants [1]:
The reaction rate constants of •O− and •OH with other molecules are mostly in the orders of 109 to 1010 M−1·s−1, whereas those with H2 are in the order of 107 M−1·s−1. Hydrogen, however, is a small molecule that can easily dissipate throughout the body and cells, and the collision rates of hydrogen with other molecules are expected to be very high, which is likely to be able to overcome the low reaction rate constants [2]. Hydrogen is not easily dissolved in water, and 100%-saturated hydrogen water contains 1.6 ppm or 0.8 mM hydrogen at room temperature( our note: see AlkaViva Vesta H2 water ionizer performance below)
In 1995, hydrogen was first applied to human to overcome high-pressure nervous syndrome in deep sea diving [3]. Hydrogen was used to reduce nitrogen (N2) toxicity and to reduce breathing resistance in the deep sea. In 2001, being prompted by the radical-scavenging activity of hydrogen, Gharib and colleagues examined an effect of molecular hydrogen on a mouse model of schistosomiasis-associated chronic liver inflammation [4]. Mice were placed in a chamber with 70% hydrogen gas for two weeks. The mice exhibited decreased fibrosis, improvement of hemodynamics, increased nitric oxide synthase (NOS) II activity, increased antioxidant enzyme activity, decreased lipid peroxide levels, and decreased circulating tumor-necrosis-factor-(TNF-) α levels. Although helium gas also exerted some protective effects in their model, the effect of helium gas was not recapitulated in a mouse model of ischemia/reperfusion injury of the liver [5].
2. Effects of Hydrogen (water ) Have Been Reported in 63 Disease Models and Human Diseases
A major breakthrough in hydrogen research occurred after Ohsawa and colleagues reported a prominent effect of molecular hydrogen on a rat model of cerebral infarction in June 2007 [6]. Rats were subjected to left middle cerebral artery occlusion. Rats placed in 2–4% hydrogen gas chamber showed significantly smaller infarction volumes compared to controls. They attributed the hydrogen effect to the specific scavenging activity of hydroxyl radical (•OH). They also demonstrated that hydrogen scavenges peroxynitrite (ONOO−) but to a lesser extent.
As have been previously reviewed [7, 8], effects of molecular hydrogen on various diseases have been reported since then. The total number of disease models and human diseases for which molecular hydrogen has been proven to be effective has reached 63 (by 2012)(Table 1). The number of papers is increasing each year (Figure 1). Among the 87 papers cited in Table 1, 21 papers showed an effect with inhalation of hydrogen gas, 23 with drinking hydrogen-rich water, 27 with intraperitoneal administration or drip infusion of hydrogen-rich saline, 10 with hydrogen-rich medium for cell or tissue culture, and 6 with the other administration methods including instillation and dialysis solution. In addition, among the 87 papers, 67 papers showed an effect in rodents, 7 in humans, 1 in rabbits, 1 in pigs, and 11 in cultured cells or cultured tissues.
Table 1
Sixty-three disease models and human diseases for which beneficial effects of hydrogen have been documented.
| Diseases | Species | Administration |
|---|---|---|
| Brain | ||
| Cerebral infarction [6, 30, 55, 56] | Rodent, human | Gas, saline |
| Cerebral superoxide production [75] | Rodent | Water |
| Restraint-induced dementia [22] | Rodent | Water |
| Alzheimer’s disease [23, 24] | Rodent | Saline |
| Senile dementia in senescence-accelerated mice [25] | Rodent | Water |
| Parkinson’s disease [18, 19] | Rodent | Water |
| Hemorrhagic infarction [34] | Rodent | Gas |
| Brain trauma [76] | Rodent | Gas |
| Carbon monoxide intoxication [52] | Rodent | Saline |
| Transient global cerebral ischemia [66] | Rodent | Gas |
| Deep hypothermic circulatory arrest-induced brain damage [57] | Rodent | Saline |
| Surgically induced brain injury [77] | Rodent | Gas |
| Spinal Cord | ||
| Spinal cord injury [78] | Rodent | Saline |
| Spinal cord ischemia/reperfusion [51] | Rabbit | Gas |
| Eye | ||
| Glaucoma [79] | Rodent | Instillation |
| Corneal alkali-burn [61] | Rodent | Instillation |
| Ear | ||
| Hearing loss [80–82] | Tissue, rodent | Medium, water |
| Lung | ||
| Oxygen-induced lung injury [53, 60, 83, 84] | Rodent | Saline |
| Lung transplantation [85] | Rodent | Gas |
| Paraquat-induced lung injury [86] | Rodent | Saline |
| Radiation-induced lung injury [87–89] | Rodent | Water |
| Burn-induced lung injury [90] | Rodent | Saline |
| Intestinal ischemia/reperfusion-induced lung injury [44] | Rodent | Saline |
| Heart | ||
| Acute myocardial infarction [36, 65, 91] | Rodent | Gas, saline |
| Cardiac transplantation [46] | Rodent | Gas |
| Sleep apnea-induced cardiac hypoxia [48] | Rodent | Gas |
| Liver | ||
| Schistosomiasis-associated chronic liver inflammation [4] | Rodent | Gas |
| Liver ischemia/reperfusion [5] | Rodent | Gas |
| Hepatitis [43] | Rodent | Intestinal gas |
| Obstructive jaundice [47] | Rodent | Saline |
| Carbon tetrachloride-induced hepatopathy [62] | Rodent | Saline |
| Radiation-induced adverse effects for liver tumors [31] | Human | Water |
| Kidney | ||
| Cisplatin-induced nephropathy [92–94] | Rodent | Gas, water |
| Hemodialysis [20, 28] | Human | Dialysis solution |
| Kidney transplantation [95] | Rodent | Water |
| Renal ischemia/reperfusion [54] | Rodent | Saline |
| Melamine-induced urinary stone [96] | Rodent | Water |
| Chronic kidney disease [37] | Rodent | Water |
| Pancreas | ||
| Acute pancreatitis [97] | Rodent | Saline |
| Intestine | ||
| Intestinal transplantation [41, 45, 59] | Rodent | Gas, medium, saline |
| Ulcerative colitis [42] | Rodent | Gas |
| Intestinal ischemia/reperfusion [63] | Rodent | Saline |
| Blood vessel | ||
| Atherosclerosis [98] | Rodent | Water |
| Muscle | ||
| Inflammatory and mitochondrial myopathies [29] | Human | Water |
| Cartilage | ||
| NO-induced cartilage toxicity [38] | Cells | Medium |
| Metabolism | ||
| Diabetes mellitus type I [32] | Rodent | Water |
| Diabetes mellitus type II [26] | Human | Water |
| Metabolic syndrome [27, 99] | Human, rodent | Water |
| Diabetes/obesity [33] | Rodent | Water |
| Perinatal disorders | ||
| Neonatal cerebral hypoxia [10–12] | Rodent, pig | Gas, saline |
| Preeclampsia [58] | Rodent | Saline |
| Inflammation/allergy | ||
| Type I allergy [64] | Rodent | Water |
| Sepsis [100] | Rodent | Gas |
| Zymosan-induced inflammation [101] | Rodent | Gas |
| LPS/IFNγ-induced NO production [67] | Cells | Gas |
| Cancer | ||
| Growth of tongue carcinoma cells [14] | Cells | Medium |
| Lung cancer cells [15] | Cells | Medium |
| Radiation-induced thymic lymphoma [16] | Rodent | Saline |
| Others | ||
| UVB-induced skin injury [49] | Rodent | Bathing |
| Decompression sickness [102] | Rodent | Saline |
| Viability of pluripotent stromal cells [103] | Cells | Gas |
| Radiation-induced cell damage [104, 105] | Cells | Medium |
| Oxidized low density lipoprotein-induced cell toxicity [50] | Cells | Medium |
| High glucose-induced oxidative stress [35] | Cells | Medium |
Two papers, however, showed that hydrogen was ineffective for two disease models (Table 2). One such disease was moderate to severe neonatal brain hypoxia [9], although marked effects of hydrogen gas [10, 11] and intraperitoneal administration of hydrogen-rich saline [12] on neonatal brain hypoxia have been reported in rats [10, 12] and pigs [11]. We frequently observe that therapeutic intervention that is effective for mild cases has little or no effect on severe cases, and hydrogen is unlikely to be an exception. Another disease is muscle disuse atrophy [13]. Although oxidative stress is involved in the development of muscle disuse atrophy, oxidative stress may not be a major driving factor causing atrophy and thus attenuation of oxidative stress by hydrogen may not be able to exhibit a beneficial effect.
Table 2
Two disease models for which hydrogen has no effect.
Effects of molecular hydrogen have been observed essentially in all the tissues and disease states including the brain, spinal cord, eye, ear, lung, heart, liver, kidney, pancreas, intestine, blood vessel, muscle, cartilage, metabolism, perinatal disorders, and inflammation/allergy. Among them, marked effects are observed in ischemia/reperfusion disorders as well as in inflammatory disorders. It is interesting to note, however, that only three papers addressed effects on cancers. First, molecular hydrogen caused growth inhibition of human tongue carcinoma cells HSC-4 and human fibrosarcoma cells HT-1080 but did not compromise growth of normal human tongue epithelial-like cells DOK [14]. Second, hydrogen suppressed the expression of vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis, in human lung adenocarcinoma cells A549, which was mediated by downregulation of extracellular signal-regulated kinase (ERK) [15]. Third, hydrogen protected BALB/c mice from developing radiation-induced thymic lymphoma [16]. Elimination of radical oxygen species by hydrogen should reduce a probability of introducing somatic mutations. Unlike other disease models, cancer studies were performed only with cells in two of the three papers. Hydrogen is likely to have a beneficial effect on cancer development by suppressing somatic mutations, but an effect on cancer growth and invasion needs to be analyzed further in detail.
3. Effects of Molecular Hydrogen on Rodent Models of Neurodegenerative Diseases
Parkinson’s disease is caused by death of dopaminergic neurons at the substantia nigra pars compact of the midbrain and is the second most common neurodegenerative disease after Alzheimer’s disease. Parkinson’s disease is caused by two mechanisms: excessive oxidative stress and abnormal ubiquitin-proteasome system [17]. The neurotransmitter, dopamine, is a prooxidant by itself and dopaminergic cells are destined to be exposed to high concentrations of radical oxygen species. An abnormal ubiquitin-proteasome system also causes aggregation of insoluble α-synuclein in the neuronal cell body that leads to neuronal cell death. We made a rat model of hemi-Parkinson’s disease by stereotactically injecting catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in the right striatum [18]. Ad libitum administration of hydrogen-rich water starting one week before surgery completely abolished the development of hemi-Parkinson’s symptoms. The number of dopaminergic neurons on the toxin-injected side was reduced to 40.2% of that on the control side, whereas hydrogen treatment improved the reduction to 83.0%. We also started giving hydrogen-rich water three days after surgery, and hemi-Parkinson’s symptoms were again suppressed, but not as much as those observed in pretreated rats. The number of dopaminergic neurons on the toxin-injected side was 76.3% of that on the control side. Pretreated rats were also sacrificed 48 hrs after toxin injection, and the tyrosine hydroxylase activity at the striatum, where dopaminergic neurons terminate, was decreased in both hydrogen and control groups. This indicated that hydrogen did not directly detoxicate 6-OHDA but exerted a delayed protective effect for dopaminergic cells. Fujita and colleagues also demonstrated a similar prominent effect of hydrogen-rich water on an MPTP-(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-) induced mouse model of Parkinson’s disease [19]. MPTP is a neurotoxin that blocks complex I of the mitochondrial electron transport system and causes Parkinson’s disease in mice and humans. It is interesting to note that the concentration of hydrogen that they used for the MPTP mice was only 0.08 ppm (5% saturation), which is the second lowest among all the trials published to date for rodents and humans. The lowest hydrogen concentration ever tested is 0.048 ppm in the dialysis solution for patients receiving hemodialysis [20].
Alzheimer’s disease is the most common neurodegenerative disease and is characterized by abnormal aggregation of β-amyloid (Aβ) and tau, the large aggregates of which are recognizable as senile plaques and neurofibrillary tangles, respectively [21]. Effects of molecular hydrogen on Alzheimer’s disease have been studied in three rodent models. First, Nagata and colleagues made a mouse model of dementia by restricting movement of mice for 10 hrs a day [22]. They analyzed cognitive functions through passive avoidance learning, object recognition tasks, and the Morris water maze and demonstrated that ad libitum administration of hydrogen-rich water efficiently ameliorated cognitive impairment. They also showed that neural proliferation in the dentate gyrus was restored by hydrogen water . Second, Li and colleagues made a rat model of Alzheimer’s disease by intracerebroventricular injection of Aβ1-42 [23]. They analyzed cognitive functions by the Morris water maze open field tasks, and electrophysiological measurement of long-term potentiation (LTP) and found that intraperitoneal injection of hydrogen-rich saline for 14 days efficiently ameliorated cognitive decline and preserved LTP. The same team later reported that the protective effects were mediated by suppression of abnormal activation of IL1β, JNK, and NFκB [24]. Third, Gu and colleagues used a senescence-accelerated mouse strain (SAMP8) that exhibits early aging syndromes including impairment in learning ability and memory [25]. Ad libitum administration of hydrogen-rich water for 30 days prevented cognitive decline, which was examined by the Morris water maze. Additionally, ad libitum drinking of hydrogen water for 18 weeks showed efficient amelioration of hippocampal neurodegeneration.
Cerebrovascular diseases are the most frequently reported neurological diseases for which hydrogen (water )has prominent effects. As stated in Section 2, current hydrogen (water ) research has broken out after Ohsawa reported a prominent effect of 2–4% hydrogen for a rat model of left cerebral artery occlusion in 2007 [6].
In addition to neurodegenerative disorders of Parkinson’s disease and Alzheimer’s disease, effects of molecular hydrogen (water ) have been reported in eight other brain diseases listed under the categories of “brain” and “perinatal disorders” in Table 1. The brain consumes a large amount of oxygen and is predisposed to be exposed to a large amount of radical oxygen species especially under pathological conditions. Molecular hydrogen is thus likely to exert a prominent beneficial effect on brain diseases.
4. Molecular Hydrogen Is Effective for Six Human Diseases(known by 2012)
As in other therapeutic modalities, effects of molecular hydrogen have been tested mostly on rodents but have also been studied in six human diseases( by 2012). The reported human diseases include diabetes mellitus type II [26], metabolic syndrome [27], hemodialysis [20, 28], inflammatory and mitochondrial myopathies [29], brain stem infarction [30], and radiation-induced adverse effects for liver tumor [31]. These studies are reviewed in detail here. In addition, a therapeutic trial for Parkinson’s disease is currently in progress and exhibits favorable responses as far as we know, but the details are not yet disclosed.
First, Kajiyama and colleagues performed a randomized, double-blind, placebo-controlled, crossover study in 30 patients with diabetes mellitus type II and 6 patients with impaired glucose tolerance [26]. The patients consumed either 900 mL of hydrogen-rich water or placebo water for 8 weeks, with a 12-week washout period. They measured 13 biomarkers to estimate lipid and glucose metabolisms at baseline and at 8 weeks after hydrogen water treatment. All the biomarkers were favorably changed with hydrogen, but statistical significance was observed only in improvement of electronegative charge-modified low-density lipoprotein-(LDL-) cholesterol, small dense LDL, and urinary 8-isoprostanes. In four of six patients with impaired glucose tolerance, hydrogen normalized the oral glucose tolerance test. Lack of statistical significance in their studies was likely due to the small number of patients and the short observation period. Lack of statistical significance, however, may also suggest a less prominent effect in human diabetes mellitus compared to rodent models [32, 33].
Second, Nakao and colleagues performed an open-label trial in 20 subjects with potential metabolic syndrome [27]. Hydrogen-rich water was produced by placing a metallic magnesium stick in water, which yielded 0.55–0.65 mM hydrogen water (70–80% saturation). The participants consumed 1.5–2.0 liters of hydrogen water per day for 8 weeks and showed a 39% increase in urinary superoxide dismutase (SOD), an enzyme that catalyzes superoxide anion (O2−); a 43% decrease in urinary thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation; an 8% increase in high-density-lipoprotein-(HDL-) cholesterol; a 13% decrease in total cholesterol/HDL-cholesterol. The aspartate aminotransferase (AST) and alanine transaminase (ALT) levels remained unchanged, whereas the gamma glutamyl transferase (GGT) level was increased by 24% but was still within a normal range. Although the study was not double blinded and placebo controlled, improvements in biomarkers were much more than those in other hydrogen water studies in humans. As this study used a large amount of hydrogen water, the amount of hydrogen might have been a critical determinant. Alternatively, excessive hydration might have prevented the participants from excessive food intake.
Third, Nakayama and colleagues performed an open-label placebo-controlled crossover trial of 12 sessions of hemodialysis in eight patients [28] and an open-label trial of 78 sessions of hemodialysis in 21 patients [20]. In both studies, continuous sessions of hemodialysis with hydrogen-rich dialysis solution decreased systolic blood pressure before and after dialysis. In the short-term study, plasma methylguanidine was significantly decreased. In the long-term study, plasma monocyte chemoattractant protein 1 and myeloperoxidase were significantly decreased.
Fourth, we performed an open-label trial of 1.0 liter of hydrogen water per day for 12 weeks in 14 patients with muscular diseases including muscular dystrophies, polymyositis/dermatomyositis, and mitochondrial myopathies, as well as a randomized, double-blind, placebo-controlled, crossover trial of 0.5 liter of hydrogen water or dehydrogenized water per day for 8 weeks in 22 patients with dermatomyositis and mitochondrial myopathies [29]. In the open-label trial, significant improvements were observed in lactate-to-pyruvate ratio, fasting blood glucose, serum matrix metalloproteinase-3 (MMP3), and triglycerides. Especially, the lactate-to-pyruvate ratio, which is a sensitive biomarker for the compromised mitochondrial electron transport system, was decreased by 28% in mitochondrial myopathies. In addition, MMP3, which represents the activity of inflammation, was decreased by 27% in dermatomyositis. In the double-blind trial, a statistically significant improvement was observed only in serum lactate in mitochondrial myopathies, but lactate-to-pyruvate ratio in mitochondrial myopathies and MMP3 in dermatomyositis were also decreased. Lack of statistical significance with the double-blind study was likely due to the shorter observation period and the lower amount of hydrogen compared to those of the open-label trial.
Fifth, Kang and colleagues performed a randomized placebo-controlled study of 1.5–2.0 liters of 0.55–0.65 mM hydrogen water per day for 6 weeks in 49 patients receiving radiation therapy for malignant liver tumors. Hydrogen water suppressed the elevation of total hydroperoxide levels, maintained serum antioxidant capacity, and improved the quality of life (QOL) scores. In particular, hydrogen water efficiently prevented loss of appetite. Although the patients were randomly assigned to the hydrogen and placebo groups, the study could not be completely blinded because hydrogen water was produced with a metallic magnesium stick, which generated hydrogen bubbles.
Sixth, Ono and colleagues intravenously administered hydrogen along with Edaravone, a clinically approved radical scavenger, in 8 patients with acute brain stem infarction and compared MRI indices of 26 patients who received Edaravone alone [30]. The relative diffusion-weighted images (rDWIs), regional apparent diffusion coefficients (rADCs), and pseudonormalization time of rDWI and rADC were all improved with the combined infusion of Edaravone and hydrogen.
No adverse effect of hydrogen has been documented in the six human diseases described above. Among the six diseases, the most prominent effect was observed in subjects with metabolic syndrome, who consumed 1.5–2.0 liters of hydrogen water per day [27].
The amount of hydrogen water may be a critical parameter that determines clinical outcome.
It is also interesting to note that lipid and glucose metabolisms were analyzed in three studies and all showed favorable responses to hydrogen [26, 27, 29].
Update : since 2012 more clinical trials have been performed.
Acarbose/MOLECULAR HYDROGEN TREATMENT AND THE RISK OF CARDIOVASCULAR DISEASE AND HYPERTENSION IN PATIENTS WITH IMPAIRED GLUCOSE TOLERANCE: THE STOP-NIDDM TRIAL Molecular Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. Molecular 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 MOLECULAR HYDROGEN WATER FOR PATIENTS WITH PRESSURE ULCER – EFFECTS ON NORMAL HUMAN SKIN WOUNDS MOLECULAR HYDROGEN WATER FOR PATIENTS WITH RHEUMATOID ARTHRITIS: AN OPEN-LABEL PILOT STUDY EFFECTIVENESS OF ORAL AND TOPICAL MOLECULAR HYDROGEN FOR SPORTS-RELATED SOFT TISSUE INJURIES MOLECULAR HYDROGEN WATER BENEFITS FOR ATHLETES, EXERCISE, MUSCLE FATIGUE MOLECULAR HYDROGEN WATER FOR VASCULAR ENDOTELIAL FUNCTION MOLECULAR HYDROGEN WATER- PERIODONTITIS TREATMENT
Please see this section:Hydrogen water
5. Molecular Bases of Hydrogen Effects
Effects of hydrogen on various diseases have been attributed to four major molecular mechanisms: a specific scavenging activity of hydroxyl radical, a scavenging activity of peroxynitrite, alterations of gene expressions, and signal-modulating activities. The four mechanisms are not mutually exclusive and some of them may be causally associated with other mechanisms.
The first molecular mechanism identified for hydrogen was its specific scavenging activity of hydroxyl radical [6]. Indeed, oxidative stress markers like 8-OHdG, 4-hydroxyl-2-nonenal (4-HNE), malondialdehyde (MDA), and thiobarbituric acid reactive substances (TBARSs) are decreased in all the examined patients and rodents. As hydrogen can easily dissipate in exhalation, hydrogen in drinking water is able to stay in human and rodent bodies in less than 10 min (unpublished data). Hydrogen, however, can bind to glycogen, and the dwell time of hydrogen is prolonged in rat liver after food intake [33]. A question still remains if mice and humans can take a sufficient amount of hydrogen that efficiently scavenges hydroxyl radicals that are continuously generated in normal and disease states.
Another molecular mechanism of hydrogen effect is its peroxynitrite-(ONOO−-) scavenging activity [6]. Although hydrogen cannot eliminate peroxynitrite as efficiently as hydroxyl radical in vitro [6], hydrogen can efficiently reduce nitric-oxide-(NO-) induced production of nitrotyrosine in rodents [34–38]. NO is a gaseous molecule that also exerts therapeutic effects including relaxation of blood vessels and inhibition of platelet aggregation [39]. NO, however, is also toxic at higher concentrations because NO leads to ONOO−-mediated production of nitrotyrosine, which compromises protein functions. A part of hydrogen effects may thus be attributed to the reduced production of nitrotyrosine.
Expression profiling of rat liver demonstrated that hydrogen has a minimal effect on expression levels of individual genes in normal rats [40]. Gene ontology analysis, however, revealed that oxidoreduction-related genes were upregulated. In disease models of rodents, expression of individual genes and proteins is analyzed. In many disease models, hydrogen downregulated proinflammatory cytokines including tumor necrosis-factor-(TNF-) α, interleukin-(IL-) 1β, IL-6, IL-12, interferon-(IFN-) γ, and high mobility group box 1 (HMGB1) [4, 23, 24, 36, 41–59]. Hydrogen also downregulated nuclear factors including nuclear factor kappa B (NFκB), JNK, and proliferation cell nuclear antigen (PCNA) [24, 44, 50, 55, 60–63]. Caspases were also downregulated [10, 55–57, 62, 64, 65]. Other interesting molecules studied to date include vascular endothelial growth factor (VEGF) [15]; MMP2 and MMP9 [34]; brain natriuretic peptide [48]; intercellular-adhesion-molecule-1 (ICAM-1) and myeloperoxidase [36]; B-cell lymphoma 2 (Bcl2) and Bcl2-associated X protein (Bax) [60]; MMP3 and MMP13 [38]; cyclooxygenase 2 (COX-2), neuronal nitric oxide synthase (nNOS), and connexins 30 and 43 [66]; ionized calcium binding adaptor molecule 1 (Iba1) [52]; fibroblast growth factor 21 (FGF21) [33]. Most molecules, however, are probably passengers that are secondarily changed by hydrogen administration, and some are potentially direct targets of hydrogen effects, which need to be identified in the future.
Using rat RBL-2H3 mast cells, we demonstrated that hydrogen attenuates phosphorylation of FcεRI-associated Lyn and its downstream signaling molecules [64]. As phosphorylation of Lyn is again regulated by the downstream signaling molecules and makes a loop of signal transduction pathways, we could not identify the exact target of hydrogen. Our study also demonstrated that hydrogen ameliorates an immediate-type allergic reaction not by radical-scavenging activity but by direct modulation of signaling pathway(s). In addition, using murine RAW264 macrophage cells, we demonstrated that hydrogen reduces LPS/IFNγ-induced NO production [67]. We found that hydrogen inhibits phosphorylation of ASK1 and its downstream signaling molecules, p38 MAP kinase, JNK, and IκBα without affecting ROS production by NADPH oxidase. Both studies point to a notion that hydrogen is a gaseous signal modulator. More animal and cells models are expected to be explored to confirm that hydrogen exerts its beneficial effect as a signal modulator.
Two enigmas remain to be solved for hydrogen effects. First, no dose-response effect of hydrogen has been observed. Hydrogen has been administered to animals and humans in the forms of hydrogen gas, hydrogen-rich water, hydrogen-rich saline, instillation, and dialysis solution (Table 1). Supposing that a 60-kg person drinks 1000 mL of saturated hydrogen-rich water (1.6 ppm or 0.8 mM) per day, 0.8 mmoles of hydrogen is consumed by the body each day, which is predicted to give rise to a hydrogen concentration of 0.8 mmoles/(60 kg × 60%) = 0.022 mM (2.8% saturation = 0.022 mM/0.8 mM). As hydrogen mostly disappears in 10 min by dissipation in exhalation (unpublished data), an individual is exposed to 2.8% hydrogen only for 10 min. On the other hand, when a person is placed in a 2% hydrogen environment for 24 hrs, body water is predicted to become 2% saturation (0.016 mM). Even if we suppose that the hydrogen concentration after drinking hydrogen water remains the same for 10 min, areas under the curves of hydrogen water and 2% hydrogen gas are 0.022 mM × 1/6 hrs and 0.016 mM × 24 hrs, respectively. Thus, the amount of hydrogen given by 2% hydrogen gas should be 104 or more times higher than that given by drinking hydrogen water. In addition, animals and patients are usually not able to drink 100%-saturated hydrogen water. If the hydrogen concentration is 72% of the saturation level, the peak concentrations achieved by drinking hydrogen water and 2% hydrogen gas should be identical (0.022 mM × 72% = 0.016 mM). Nevertheless, hydrogen water is as effective as, or sometimes more effective than, hydrogen gas.
In addition, orally taken hydrogen can be readily distributed in the stomach, intestine, liver, heart, and lung but is mostly lost in exhalation. Thus, hydrogen concentrations in the arteries are predicted to be very low. Nevertheless, marked hydrogen effects are observed in the brain, spinal cord, kidney, pancreas muscle, and cartilage, where hydrogen is carried via arteries.
The second enigma is intestinal production of hydrogen gas in rodents and humans. Although no mammalian cells can produce hydrogen endogenously, hydrogen is produced by intestinal bacteria carrying hydrogenase in both rodents and humans. We humans are able to make a maximum of 12 liters of hydrogen in our intestines [68, 69]. Specific-pathogen-free (SPF) animals are different from aseptic animals and carry intestinal bacteria that produce hydrogen. The amount of hydrogen taken by water or gas is much less than that produced by intestinal bacteria, but the exogenously administered hydrogen demonstrates a prominent effect.
In a mouse model of Concanavalin A-induced hepatitis, Kajiya and colleagues killed intestinal bacteria by prescribing a cocktail of antibiotics [43]. Elimination of intestinal hydrogen worsened hepatitis. Restitution of a hydrogenase-negative strain of E. coli had no effects, whereas that of a hydrogenase-positive strain of E. coli ameliorated hepatitis. This is the only report that addressed a beneficial effect of intestinal bacteria, and no human study has been reported to date. Kajiya and colleagues also demonstrated that drinking hydrogen-rich water was more effective than the restitution of hydrogenase-positive bacteria. If intestinal hydrogen is as effective as the other hydrogen administration methods, we can easily increase hydrogen concentrations in our bodies by an α-glucosidase inhibitor, acarbose [70], an ingredient of curry, turmeric [71], or a nonabsorbable synthetic disaccharide, lactulose [68, 72, 73]. The enigma of intestinal bacteria thus needs to be solved in the future.
7. Summary and Conclusions
Effects of hydrogen have been reported in 63 disease models and human diseases (Table 1). Only two diseases of cerebral infarction and metabolic syndrome have been analyzed in both rodents and humans.
Lack of any adverse effects of hydrogen enabled clinical studies even in the absence of animal studies. Some other human studies including Parkinson’s disease are currently in progress, and promising effects of hydrogen are expected to emerge for many other human diseases. We also have to elucidate molecular bases of hydrogen effects in detail.
8. Added Note in Proof
We recently reported a line of evidence that molecular hydrogen has no dose-response effect in a rat model of Parkinson’s disease [74].
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Acknowledgments
Works performed in the authors’ laboratories were supported by Grants-in-Aid from the MEXT and MHLW of Japan and from the Priority Research Project of Aichi.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377272/
References
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