Category Archives: [:en]molecular hydrogen water [:ro]apa hidrogenata/apa hidrogenizata/apa cu hidrogen molecular

Molecular Hydrogen CANCER treatment

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

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

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

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

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

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

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

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

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

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

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

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

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

Hydrogen Gas Suppresses Inflammatory Cytokines

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

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

Hydrogen Gas Inhibits/Induces Apoptosis

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

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

Hydrogen Gas Exhibits Potential in Cancer Treatment

Hydrogen Gas Relieves the Adverse Effects Related to Chemotherapy/Radiotherapy

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

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

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

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

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

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

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

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

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

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

Hydrogen Gas Acts Synergistically With Thermal Therapy

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

Hydrogen Gas Suppresses Tumor Formation

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

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

Hydrogen Gas Suppresses Tumor Growth

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

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

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

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

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

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

TABLE 1

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

FIGURE 1

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

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

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

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

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].

https://water-ionizers.info/en/2017/09/05/modalities-of-molecular-hydrogen-administrationin-water-gas-or-saline-to-animals-humans-and-plants/

 

SEE ALL WATER IONIZERS – MOLECULAR HYDROGEN GENERATORS

REVIEW ARTICLE

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

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

Author Contributions

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

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.

References

1. De Bels D, Corazza F, Germonpre P, Balestra C. The normobaric oxygen paradox: a novel way to administer oxygen as an adjuvant treatment for cancer? Med Hypotheses. (2011) 76:467–70. doi: 10.1016/j.mehy.2010.11.022

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Oliveira C, Benfeito S, Fernandes C, Cagide F, Silva T, Borges F. NO and HNO donors, nitrones, and nitroxides: past, present, and future. Med Res Rev. (2018) 38:1159–87. doi: 10.1002/med.21461

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Vitek L, Gbelcova H, Muchova L, Vanova K, Zelenka J, Konickova R, et al. Antiproliferative effects of carbon monoxide on pancreatic cancer. Dig Liver Dis. (2014) 46:369–75. doi: 10.1016/j.dld.2013.12.007

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Flannigan KL, Wallace JL. Hydrogen sulfide-based anti-inflammatory and chemopreventive therapies: an experimental approach. Curr Pharm Des. (2015) 21:3012–22. doi: 10.2174/1381612821666150514105413

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Li Z, Huang Y, Du J, Liu AD, Tang C, Qi Y, et al. Endogenous sulfur dioxide inhibits vascular calcification in association with the TGF-beta/Smad signaling pathway. Int J Mol Sci. (2016) 17:266. doi: 10.3390/ijms17030266

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Jin H, Liu AD, Holmberg L, Zhao M, Chen S, Yang J, et al. The role of sulfur dioxide in the regulation of mitochondrion-related cardiomyocyte apoptosis in rats with isopropylarterenol-induced myocardial injury. Int J Mol Sci. (2013) 14:10465–82. doi: 10.3390/ijms140510465

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Jiroutova P, Oklestkova J, Strnad M. Crosstalk between brassinosteroids and ethylene during plant growth and under abiotic stress conditions. Int J Mol Sci. (2018) 19:3283. doi: 10.3390/ijms19103283

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Paardekooper LM, van den Bogaart G, Kox M, Dingjan I, Neerincx AH, Bendix MB, et al. Ethylene, an early marker of systemic inflammation in humans. Sci Rep. (2017) 7:6889. doi: 10.1038/s41598-017-05930-9

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Cui Q, Yang Y, Ji N, Wang JQ, Ren L, Yang DH, et al. Gaseous signaling molecules and their application in resistant cancer treatment: from invisible to visible. Future Med Chem. (2019) 11:323–6. doi: 10.4155/fmc-2018-0403

CrossRef Full Text | Google Scholar

10. Huang Z, Fu J, Zhang Y. Nitric oxide donor-based cancer therapy: advances and prospects. J Med Chem. (2017) 60:7617–35. doi: 10.1021/acs.jmedchem.6b01672

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Ma Y, Yan Z, Deng X, Guo J, Hu J, Yu Y, et al. Anticancer effect of exogenous hydrogen sulfide in cisplatinresistant A549/DDP cells. Oncol Rep. (2018) 39:2969–77. doi: 10.3892/or.2018.6362

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Zheng DW, Li B, Li CX, Xu L, Fan JX, Lei Q, et al. Photocatalyzing CO2 to CO for enhanced cancer therapy. Adv Mater. (2017) 29:1703822. doi: 10.1002/adma.201703822

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Chen J, Luo H, Liu Y, Zhang W, Li H, Luo T, et al. Oxygen-self-produced nanoplatform for relieving hypoxia and breaking resistance to sonodynamic treatment of pancreatic cancer. Acs Nano. (2017) 11:12849–62. doi: 10.1021/acsnano.7b08225

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Stuehr DJ, Vasquez-Vivar J. Nitric oxide synthases-from genes to function. Nitric Oxide. (2017) 63:29. doi: 10.1016/j.niox.2017.01.005

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Cao X, Ding L, Xie ZZ, Yang Y, Whiteman M, Moore PK, et al. A review of hydrogen sulfide synthesis, metabolism, and measurement: is modulation of hydrogen sulfide a novel therapeutic for cancer? Antioxid Redox Signal. (2018) 31:1–38. doi: 10.1089/ars.2017.7058

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Zhai X, Chen X, Ohta S, Sun X. Review and prospect of the biomedical effects of hydrogen. Med Gas Res. (2014) 4:19. doi: 10.1186/s13618-014-0019-6

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Ostojic SM. Molecular hydrogen: an inert gas turns clinically effective. Ann Med. (2015) 47:301–4. doi: 10.3109/07853890.2015.1034765

PubMed Abstract | CrossRef Full Text | Google Scholar

18. LeBaron TW, Laher I, Kura B, Slezak J. Hydrogen gas: from clinical medicine to an emerging ergogenic molecule for sports athletes. Can J Physiol Pharmacol. (2019) 10:1–11. doi: 10.1139/cjpp-2019-0067

CrossRef Full Text | Google Scholar

19. Guan P, Sun ZM, Luo LF, Zhao YS, Yang SC, Yu FY, et al. Hydrogen gas alleviates chronic intermittent hypoxia-induced renal injury through reducing iron overload. Molecules. (2019) 24: 24:E1184. doi: 10.3390/molecules24061184

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Sakai D, Hirooka Y, Kawashima H, Ohno E, Ishikawa T, Suhara H, et al. Increase in breath hydrogen concentration was correlated with the main pancreatic duct stenosis. J Breath Res. (2018) 12:36004. doi: 10.1088/1752-7163/aaaf77

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Smith NW, Shorten PR, Altermann EH, Roy NC, McNabb WC. Hydrogen cross-feeders of the human gastrointestinal tract. Gut Microbes. (2018) 10:1–9. doi: 10.1080/19490976.2018.1546522

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Fukuda K, Asoh S, Ishikawa M, Yamamoto Y, Ohsawa I, Ohta S. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem Biophys Res Commun. (2007) 361:670–4. doi: 10.1016/j.bbrc.2007.07.088

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Liu C, Kurokawa R, Fujino M, Hirano S, Sato B, Li XK. Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes. Sci Rep. (2014) 4:5485. doi: 10.1038/srep05485

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Yamamoto R, Homma K, Suzuki S, Sano M, Sasaki J. Hydrogen gas distribution in organs after inhalation: real-time monitoring of tissue hydrogen concentration in rat. Sci Rep. (2019) 9:1255. doi: 10.1038/s41598-018-38180-4

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science. (1975) 190:152–4. doi: 10.1126/science.1166304

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. (2007) 13:688–94. doi: 10.1038/nm1577

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Ostojic SM. Inadequate production of H2 by gut microbiota and Parkinson disease. Trends Endocrinol Metab. (2018) 29:286–8. doi: 10.1016/j.tem.2018.02.006

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Hirayama M, Ito M, Minato T, Yoritaka A, LeBaron TW, Ohno K. Inhalation of hydrogen gas elevates urinary 8-hydroxy-2′-deoxyguanine in Parkinson’s disease. Med Gas Res. (2018) 8:144–9. doi: 10.4103/2045-9912.248264

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Meng J, Yu P, Jiang H, Yuan T, Liu N, Tong J, et al. Molecular hydrogen decelerates rheumatoid arthritis progression through inhibition of oxidative stress. Am J Transl Res. (2016) 8:4472–7.

PubMed Abstract | Google Scholar

30. Shao A, Wu H, Hong Y, Tu S, Sun X, Wu Q, et al. Hydrogen-rich saline attenuated subarachnoid hemorrhage-induced early brain injury in rats by suppressing inflammatory response: possible involvement of NF-kappaB pathway and NLRP3 inflammasome. Mol Neurobiol. (2016) 53:3462–76. doi: 10.1007/s12035-015-9242-y

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Gao Y, Yang H, Chi J, Xu Q, Zhao L, Yang W, et al. Hydrogen gas attenuates myocardial ischemia reperfusion injury independent of postconditioning in rats by attenuating endoplasmic reticulum stress-induced autophagy. Cell Physiol Biochem. (2017) 43:1503–4. doi: 10.1159/000481974

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Dozen M, Enosawa S, Tada Y, Hirasawa K. Inhibition of hepatic ischemic reperfusion injury using saline exposed to electron discharge in a rat model. Cell Med. (2013) 5:83–7. doi: 10.3727/215517913X666486

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Fan M, Xu X, He X, Chen L, Qian L, Liu J, et al. Protective effects of hydrogen-rich saline against erectile dysfunction in a streptozotocin induced diabetic rat model. J Urol. (2013) 190:350–6. doi: 10.1016/j.juro.2012.12.001

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Zhang X, Liu J, Jin K, Xu H, Wang C, Zhang Z, et al. Subcutaneous injection of hydrogen gas is a novel effective treatment for type 2 diabetes. J Diabetes Investig. (2018) 9:83–90. doi: 10.1111/jdi.12674

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Tamura T, Hayashida K, Sano M, Suzuki M, Shibusawa T, Yoshizawa J, et al. Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome- first-in-human pilot study. Circ J. (2016) 80:1870–3. doi: 10.1253/circj.CJ-16-0127

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Ge L, Yang M, Yang NN, Yin XX, Song WG. Molecular hydrogen: a preventive and therapeutic medical gas for various diseases. Oncotarget. (2017) 8:102653–73. doi: 10.18632/oncotarget.21130

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. (2012) 24:981–90. doi: 10.1016/j.cellsig.2012.01.008

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Kumari S, Badana AK, G MM, G S, Malla R. Reactive oxygen species: a key constituent in cancer survival. Biomark Insights. (2018) 13:91914689. doi: 10.1177/1177271918755391

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Nita M, Grzybowski A. The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults. Oxid Med Cell Longev. (2016) 2016:3164734. doi: 10.1155/2016/3164734

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. (2004) 7:97–110. doi: 10.1016/j.drup.2004.01.004

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. (2010) 44:479–96. doi: 10.3109/10715761003667554

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Cui Q, Wang JQ, Assaraf YG, Ren L, Gupta P, Wei L, et al. Modulating ROS to overcome multidrug resistance in cancer. Drug Resist Updat. (2018) 41:1–25. doi: 10.1016/j.drup.2018.11.001

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Zhao Y, Hu X, Liu Y, Dong S, Wen Z, He W, et al. ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway. Mol Cancer. (2017) 16:79. doi: 10.1186/s12943-017-0648-1

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Zha J, Chen F, Dong H, Shi P, Yao Y, Zhang Y, et al. Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition. J Transl Med. (2014) 12:163. doi: 10.1186/1479-5876-12-163

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. (2013) 12:931–47. doi: 10.1038/nrd4002

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Yu J, Yu Q, Liu Y, Zhang R, Xue L. Hydrogen gas alleviates oxygen toxicity by reducing hydroxyl radical levels in PC12 cells. PLoS ONE. (2017) 12:e173645. doi: 10.1371/journal.pone.0173645

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Li Y, Li Q, Chen H, Wang T, Liu L, Wang G, et al. Hydrogen gas alleviates the intestinal injury caused by severe sepsis in mice by increasing the expression of heme oxygenase-1. Shock. (2015) 44:90–8. doi: 10.1097/SHK.0000000000000382

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Zhou P, Lin B, Wang P, Pan T, Wang S, Chen W, et al. The healing effect of hydrogen-rich water on acute radiation-induced skin injury in rats. J Radiat Res. (2019) 60:17–22. doi: 10.1093/jrr/rry074

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Iketani M, Ohshiro J, Urushibara T, Takahashi M, Arai T, Kawaguchi H, et al. Preadministration of hydrogen-rich water protects against lipopolysaccharide-induced sepsis and attenuates liver injury. Shock. (2017) 48:85–93. doi: 10.1097/SHK.0000000000000810

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Dong A, Yu Y, Wang Y, Li C, Chen H, Bian Y, et al. Protective effects of hydrogen gas against sepsis-induced acute lung injury via regulation of mitochondrial function and dynamics. Int Immunopharmacol. (2018) 65:366–72. doi: 10.1016/j.intimp.2018.10.012

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Yang Q, Ji G, Pan R, Zhao Y, Yan P. Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy. Mol Clin Oncol. (2017) 7:891–6. doi: 10.3892/mco.2017.1409

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Zhao P, Jin Z, Chen Q, Yang T, Chen D, Meng J, et al. Local generation of hydrogen for enhanced photothermal therapy. Nat Commun. (2018) 9:4241. doi: 10.1038/s41467-018-06630-2

PubMed Abstract | CrossRef Full Text | Google Scholar

53. Antonioli L, Blandizzi C, Pacher P, Hasko G. Immunity, inflammation and cancer: a leading role for adenosine. Nat Rev Cancer. (2013) 13:842–57. doi: 10.1038/nrc3613

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Dermond O, Ruegg C. Inhibition of tumor angiogenesis by non-steroidal anti-inflammatory drugs: emerging mechanisms and therapeutic perspectives. Drug Resist Updat. (2001) 4:314–21. doi: 10.1054/drup.2001.0219

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Shakola F, Suri P, Ruggiu M. Splicing regulation of pro-inflammatory cytokines and chemokines: at the interface of the neuroendocrine and immune systems. Biomolecules. (2015) 5:2073–100. doi: 10.3390/biom5032073

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Bottazzi B, Riboli E, Mantovani A. Aging, inflammation, and cancer. Semin Immunol. (2018) 40:74–82. doi: 10.1016/j.smim.2018.10.011

PubMed Abstract | CrossRef Full Text | Google Scholar

57. Zitvogel L, Pietrocola F, Kroemer G. Nutrition, inflammation, and cancer. Nat Immunol. (2017) 18:843–50. doi: 10.1038/ni.3754

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Liu K, Lu X, Zhu YS, Le N, Kim H, Poh CF. Plasma-derived inflammatory proteins predict oral squamous cell carcinoma. Front Oncol. (2018) 8:585. doi: 10.3389/fonc.2018.00585

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Mager LF, Wasmer MH, Rau TT, Krebs P. Cytokine-induced modulation of colorectal cancer. Front Oncol. (2016) 6:96. doi: 10.3389/fonc.2016.00096

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Ning K, Liu WW, Huang JL, Lu HT, Sun XJ. Effects of hydrogen on polarization of macrophages and microglia in a stroke model. Med Gas Res. (2018) 8:154–9. doi: 10.4103/2045-9912.248266

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Zhang N, Deng C, Zhang X, Zhang J, Bai C. Inhalation of hydrogen gas attenuates airway inflammation and oxidative stress in allergic asthmatic mice. Asthma Res Pract. (2018) 4:3. doi: 10.1186/s40733-018-0040-y

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Wardill HR, Mander KA, Van Sebille YZ, Gibson RJ, Logan RM, Bowen JM, et al. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. Int J Cancer. (2016) 139:2635–45. doi: 10.1002/ijc.30252

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Cheung YT, Ng T, Shwe M, Ho HK, Foo KM, Cham MT, et al. Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study. Ann Oncol. (2015) 26:1446–51. doi: 10.1093/annonc/mdv206

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Vyas D, Laput G, Vyas AK. Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis. Onco Targets Ther. (2014) 7:1015–23. doi: 10.2147/OTT.S60114

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Padoan A, Plebani M, Basso D. Inflammation and pancreatic cancer: focus on metabolism, cytokines, and immunity. Int J Mol Sci. (2019) 20:E676. doi: 10.3390/ijms20030676

PubMed Abstract | CrossRef Full Text | Google Scholar

66. Li FY, Zhu SX, Wang ZP, Wang H, Zhao Y, Chen GP. Consumption of hydrogen-rich water protects against ferric nitrilotriacetate-induced nephrotoxicity and early tumor promotional events in rats. Food Chem Toxicol. (2013) 61:248–54. doi: 10.1016/j.fct.2013.10.004

PubMed Abstract | CrossRef Full Text | Google Scholar

67. Huang D, Ichikawa K. Drug discovery targeting apoptosis. Nat Rev Drug Discov. (2008) 7:1041. doi: 10.1038/nrd2765

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Pfeffer CM, Singh A. Apoptosis: a target for anticancer therapy. Int J Mol Sci. (2018) 19:E448. doi: 10.3390/ijms19020448

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Qiao L, Wong BC. Targeting apoptosis as an approach for gastrointestinal cancer therapy. Drug Resist Updat. (2009) 12:55–64. doi: 10.1016/j.drup.2009.02.002

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Kumar S. Caspase 2 in apoptosis, the DNA damage response and tumour suppression: enigma no more? Nat Rev Cancer. (2009) 9:897–903. doi: 10.1038/nrc2745

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Gao Y, Yang H, Fan Y, Li L, Fang J, Yang W. Hydrogen-rich saline attenuates cardiac and hepatic injury in doxorubicin rat model by inhibiting inflammation and apoptosis. Mediators Inflamm. (2016) 2016:1320365. doi: 10.1155/2016/1320365

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Li Q, Tanaka Y, Miwa N. Influence of hydrogen-occluding-silica on migration and apoptosis in human esophageal cells in vitroMed Gas Res. (2017) 7:76–85. doi: 10.4103/2045-9912.208510

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Wang FH, Shen L, Li J, Zhou ZW, Liang H, Zhang XT, et al. The chinese society of clinical oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer. Cancer Commun. (2019) 39:10. doi: 10.1186/s40880-019-0349-9

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Verheij M, Vens C, van Triest B. Novel therapeutics in combination with radiotherapy to improve cancer treatment: rationale, mechanisms of action and clinical perspective. Drug Resist Updat. (2010) 13:29–43. doi: 10.1016/j.drup.2010.01.002

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Sun YJ, Hu YJ, Jin D, Li JW, Yu B. Health-related quality of life after treatment for malignant bone tumors: a follow-up study in China. Asian Pac J Cancer Prev. (2012) 13:3099–102. doi: 10.7314/APJCP.2012.13.7.3099

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Susanne K, Michael F, Thomas S, Peter E, Andreas H. Predictors of fatigue in cancer patients: a longitudinal study. Support Care Cancer. (2019) 120:425–32. doi: 10.1007/s00520-019-4660-4

CrossRef Full Text | Google Scholar

77. Razzaghdoust A, Mofid B, Peyghambarlou P. Predictors of chemotherapy-induced severe anemia in cancer patients receiving chemotherapy. Support Care Cancer. (2019). doi: 10.1007/s00520-019-04780-7. [Epub ahead of print].

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Schumacker PT. Reactive oxygen species in cancer cells: live by the sword, die by the sword. Cancer Cell. (2006) 10:175–6. doi: 10.1016/j.ccr.2006.08.015

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Inoue A, Saijo Y, Maemondo M, Gomi K, Tokue Y, Kimura Y, et al. Severe acute interstitial pneumonia and gefitinib. Lancet. (2003) 361:137–9. doi: 10.1016/S0140-6736(03)12190-3

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Terasaki Y, Suzuki T, Tonaki K, Terasaki M, Kuwahara N, Ohsiro J, et al. Molecular hydrogen attenuates gefitinib-induced exacerbation of naphthalene-evoked acute lung injury through a reduction in oxidative stress and inflammation. Lab Invest. (2019) 99:793–806. doi: 10.1038/s41374-019-0187-z

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Luo W, Wen G, Yang L, Tang J, Wang J, Wang J, et al. Dual-targeted and pH-sensitive doxorubicin prodrug-microbubble complex with ultrasound for tumor treatment. Theranostics. (2017) 7:452–65. doi: 10.7150/thno.16677

PubMed Abstract | CrossRef Full Text | Google Scholar

82. Shen BY, Chen C, Xu YF, Shen JJ, Guo HM, Li HF, et al. Is the combinational administration of doxorubicin and glutathione a reasonable proposal? Acta Pharmacol Sin. (2019) 40:699–709. doi: 10.1038/s41401-018-0158-8

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Matsushita T, Kusakabe Y, Kitamura A, Okada S, Murase K. Investigation of protective effect of hydrogen-rich water against cisplatin-induced nephrotoxicity in rats using blood oxygenation level-dependent magnetic resonance imaging. Jpn J Radiol. (2011) 29:503–12. doi: 10.1007/s11604-011-0588-4

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Kitamura A, Kobayashi S, Matsushita T, Fujinawa H, Murase K. Experimental verification of protective effect of hydrogen-rich water against cisplatin-induced nephrotoxicity in rats using dynamic contrast-enhanced CT. Br J Radiol. (2010) 83:509–14. doi: 10.1259/bjr/25604811

PubMed Abstract | CrossRef Full Text | Google Scholar

85. 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) 64:753–61. doi: 10.1007/s00280-008-0924-2

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Meng X, Chen H, Wang G, Yu Y, Xie K. Hydrogen-rich saline attenuates chemotherapy-induced ovarian injury via regulation of oxidative stress. Exp Ther Med. (2015) 10:2277–82. doi: 10.3892/etm.2015.2787

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Marco MR, Zhou L, Patil S, Marcet JE, Varma MG, Oommen S, et al. Consolidation mFOLFOX6 chemotherapy after chemoradiotherapy improves survival in patients with locally advanced rectal cancer: final results of a multicenter phase II trial. Dis Colon Rectum. (2018) 61:1146–55. doi: 10.1097/DCR.0000000000001207

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Horimatsu T, Nakayama N, Moriwaki T, Hirashima Y, Fujita M, Asayama M, et al. A phase II study of 5-fluorouracil/L-leucovorin/oxaliplatin. (mFOLFOX6) in Japanese patients with metastatic or unresectable small bowel adenocarcinoma. Int J Clin Oncol. (2017) 22:905–12. doi: 10.1007/s10147-017-1138-6

CrossRef Full Text | Google Scholar

89. Chuai Y, Zhao L, Ni J, Sun D, Cui J, Li B, et al. A possible prevention strategy of radiation pneumonitis: combine radiotherapy with aerosol inhalation of hydrogen-rich solution. Med Sci Monit. (2011) 17:Y1–4. doi: 10.12659/MSM.881698

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Mei K, Zhao S, Qian L, Li B, Ni J, Cai J. Hydrogen protects rats from dermatitis caused by local radiation. J Dermatolog Treat. (2014) 25:182–8. doi: 10.3109/09546634.2012.762639

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Rodriguez ML, Martin MM, Padellano LC, Palomo AM, Puebla YI. Gastrointestinal toxicity associated to radiation therapy. Clin Transl Oncol. (2010) 12:554–61. doi: 10.1007/s12094-010-0553-1

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Xiao HW, Li Y, Luo D, Dong JL, Zhou LX, Zhao SY, et al. Hydrogen-water ameliorates radiation-induced gastrointestinal toxicity via MyD88’s effects on the gut microbiota. Exp Mol Med. (2018) 50:e433. doi: 10.1038/emm.2017.246

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Kang KM, Kang YN, Choi IB, Gu Y, Kawamura T, Toyoda Y, et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Med Gas Res. (2011) 1:11. doi: 10.1186/2045-9912-1-11

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Phan J, Ng V, Sheinbaum A, French S, Choi G, El KM, et al. Hyperlipidemia and nonalcoholic steatohepatitis predispose to hepatocellular carcinoma development without cirrhosis. J Clin Gastroenterol. (2019) 53:309–13. doi: 10.1097/MCG.0000000000001062

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Ma C, Zhang Q, Greten TF. Non-alcoholic fatty liver disease promotes hepatocellular carcinoma through direct and indirect effects on hepatocytes. Febs J. (2018) 285:752–62. doi: 10.1111/febs.14209

CrossRef Full Text | Google Scholar

96. Kawai D, Takaki A, Nakatsuka A, Wada J, Tamaki N, Yasunaka T, et al. Hydrogen-rich water prevents progression of non-alcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. Hepatology. (2012) 56:912–21. doi: 10.1002/hep.25782

CrossRef Full Text | Google Scholar

97. Kissebah AH, Sonnenberg GE, Myklebust J, Goldstein M, Broman K, James RG, et al. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc Natl Acad Sci USA. (2000) 97:14478–83. doi: 10.1073/pnas.97.26.14478

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Wang D, Wang L, Zhang Y, Zhao Y, Chen G. Hydrogen gas inhibits lung cancer progression through targeting SMC3. Biomed Pharmacother. (2018) 104:788–97. doi: 10.1016/j.biopha.2018.05.055

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Shang L, Xie F, Li J, Zhang Y, Liu M, Zhao P, et al. Therapeutic potential of molecular hydrogen in ovarian cancer. Transl Cancer Res. (2018) 7:988–95. doi: 10.21037/tcr.2018.07.09

CrossRef Full Text | Google Scholar

100. Liu MY, Xie F, Zhang Y, Wang TT, Ma SN, Zhao PX, et al. Molecular hydrogen suppresses glioblastoma growth via inducing the glioma stem-like cell differentiation. Stem Cell Res Ther. (2019) 10:145. doi: 10.1186/s13287-019-1241-x

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Zhang JY, Liu C, Zhou L, Qu K, Wang R, Tai MH, et al. A review of hydrogen as a new medical therapy. Hepatogastroenterology. (2012) 59:1026–32. doi: 10.5754/hge11883

PubMed Abstract | CrossRef Full Text | Google Scholar

102. Ohta S. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des. (2011) 17:2241–52. doi: 10.2174/138161211797052664

PubMed Abstract | CrossRef Full Text | Google Scholar

103. Dixon BJ, Tang J, Zhang JH. The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance. Med Gas Res. (2013) 3:10. doi: 10.1186/2045-9912-3-10

PubMed Abstract | CrossRef Full Text | Google Scholar

 

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) [].

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 [].

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).

Table 1

Patient Characteristics

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).

Figure 1

Placebo water and molecular hydrogen water improved the QOL of patients receiving radiotherapy. A. Weekly assessment of the patients’ QOL. B. Scoring system of GI symptoms after 6 weeks of radiotherapy with or without molecular hydrogen water.

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).

Figure 2

Molecular hydrogen water mitigated oxidative stress marker during radiotherapy. Antioxidative effects in patients with placebo water (n = 24) and molecular hydrogen rich water (n = 25). The dROM level (A) represents the total level of peroxide metabolities, and BAP (B) reflects ...
Previous experimental studies have linked daily consumption of molecular hydrogen-rich water with improvement of a number of conditions in rodent models, including reducing atherosclerosis in apolipoprotein E knockout mice [], alleviating cisplatin(chemotherapy)-induced nephrotoxicity [], reducing vitamin C deficiency-induced brain injury [], preventing chronic allograft nephropathy after renal transplantation [], and ameliorating cognitive defects in senescence-accelerated mice [] and a Parkinson’s disease model []. In human studies, consumption of molecular hydrogen-rich water prevented adult-onset diabetes and insulin resistance [], as well as oxidative stress in potential metabolic syndrome [].

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 [].

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 []. Treatment with the antioxidant enzyme superoxide dismutase prevented radiotherapy-induced cystitis and rectitis in bladder cancer patients receiving radiotherapy []. In addition, the combined use of pentoxifylline and vitamin E reduced radiation-induced lung fibrosis in patients with lung cancer receiving radiotherapy [].

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 [].

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 [,].

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).

Table 2

Changes in liver function tests

Table 3

Peripheral blood cell counts

 

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 [].

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

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 []. Radiotherapy adversely affects the surrounding normal cells []. 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 []. 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) [].

original article:
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3231938/

References

  • Ringborg U, Bergqvist D, Brorsson B, Cavallin-Stahl E, Ceberg J, Einhorn N, Frodin JE, Jarhult J, Lamnevik G, Lindholm C, Littbrand B, Norlund A, Nylen U, Rosen M, Svensson H, Moller TR. The Swedish Council on Technology Assessment in Health Care (SBU) systematic overview of radiotherapy for cancer including a prospective survey of radiotherapy practice in Sweden 2001–summary and conclusions. Acta Oncol. 2003;42(5-6):357–65. doi: 10.1080/02841860310010826.[PubMed] [Cross Ref]
  • Zhao W, Robbins ME. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem. 2009;16(2):130–43. doi: 10.2174/092986709787002790. [PubMed] [Cross Ref]
  • 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

 

 

PMID:29142752
PMCID:PMC5666661
DOI:10.3892/mco.2017.1409
 2017 Nov;7(5):891-896. doi: 10.3892/mco.2017.1409. Epub 2017 Sep 1.
Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy.
Yang Q1Ji G1Pan R1Zhao Y2Yan P3.

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

 
 
We review the effects of molecular hydrogen water therapy in acute neuronal conditions and neurodegenerative diseases.
Molecular hydrogen water therapy /drinking water with dissolved molecular hydrogen may be useful for the prevention of neurodegenerative diseases and for reducing the symptoms of acute neuronal conditions.
 
Recently, the neuroprotective effects of treatment with molecular hydrogen (water) have been reported in both basic and clinical settings-as you will see below, we have examined the effects of molecular hydrogen H2  (water) treatment on acute central nervous system diseases and on chronic neurodegenerative diseases. We have also examined the various mechanism by which molecular hydrogen H2 exerts its neuroprotective effects .
Molecular hydrogen  H2 acts as a scavenger for OH and ONOO, affects neuroinflammation, preserves mitochondrial energy production, and possesses neuroprotective properties.
 
Unlike more conventional drugs, molecular hydrogen  H2 treatment, particularly the consumption of  molecular hydrogen  H2-rich water, has no known serious side effects and is effective for preventing the onset of neurodegenerative disease and aggravation of acute neuronal conditions – i.e.:
 

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.() Moreover, the involvement of mitochondrial dysfunction in PD has been reported.()

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.()

In 2009, Fujita et al.() and Fu et al.() 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.() 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).()

 

Molecular hydrogen water &  Alzheimer’s disease (AD)

Alzheimer Disease AD, an age-related neurodegenerative disease, is the most common cause of dementia.(,) 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.() In recent years, oxidative stress and neuroinflammation have been reported to be involved in Alzheimer’s disease AD.(,) To date, reports have centered on the involvement of oxidative stress in brain parenchyma.(,,)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.() 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.() 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.(,)

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.(,)

It has  been reported that consuming molecular hydrogen H2-rich water inhibits age-related brain alterations and spatial memory decline.()

 

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,() 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.() 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).

 
Molecular hydrogen is well characterized as a selective scavenger of hydroxyl radicals and peroxynitrite.

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.()

Control of oxidative stress is a major therapeutic strategy for various neuronal conditions.(,,) There are many methods for controlling oxidative stress with the use of free radical scavengers being the most common approach.(,) Evidence from animal experiments support the notion that free radical scavengers and antioxidants dramatically reduce cerebral damage.() Edaravone (MCI-186), a novel free radical scavenger, was developed to prevent lipid peroxidation in pathological neurological conditions.(,)Edaravone is currently the only antioxidant drug approved for treating cerebral infarction that improves the functional outcome of ischemic stroke.() Brain hypothermia therapy (targeted temperature management) can also effectively control oxidative stress. Brain hypothermia therapy is effective in patients with various acute neuronal diseases.(,,)

In 2007, Ohsawa et al.() 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.() The first major therapeutic effect of molecular hydrogen H2 was that of an antioxidant, combining with hydroxyl ions to produce water.() 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).()Therefore, the biology of molecular hydrogen H2 is not simple. In this review, we discuss the role of molecular H2 in various neuronal conditions.

Fig. 1

Beneficial effects of molecular hydrogen in pathophysiology of various acute neuronal conditions. ATP, adenosine triphosphate; miR-200, microRNA-200; ROS, reactive oxygen species.

Fig. 2

Effect of consumption of molecular hydrogen-rich water as functional water in pathophysiology of neurodegenerative diseases. ATP, adenosine triphosphate; miR-200, microRNA-200; ROS, reactive oxygen species.

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.() 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.() 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.(,) Ohsawa et al.() 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.() Free radical generation after ischemia induces matrix metalloproteinase (MMP) expression.(,) MMP-9 promotes hemorrhagic infarction by disrupting cerebral vessels.() 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.() 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.() Nagatani et al.() 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.() 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.() Manaenko et al.() 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.() A clinical trial has started in patients with SAH (Table 1).()

Table 1

Clinical trials of molecular hydrogen in central nervous system (CNS) diseases

Molecular hydrogen & Traumatic brain injury (TBI)

The efficacy of molecular hydrogen H2 for treating TBI has been investigated in several studies.(,,) Ji et al.() 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.() 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.() 

Molecular Hydrogen & Spinal cord injury

Chen et al.() 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.(,) Huang et al.()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.() 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.() 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.() Using a mice cecal ligation and puncture (CLP) model, Liu et al.() 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.() 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.(,) Sun et al.() and Shen et al.() 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.() The consumption of molecular hydrogen H2-rich water inhibits oxidative stress and thereby inhibits the onset of stress-induced brain damage.()

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.() In recent years, it has been found that the microRNA-200 (miR-200) family regulates oxidative stress.() 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).

 

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
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525017/

References

1. Huang WJ, Zhang X, Chen WW. Role of oxidative stress in Alzheimer’s disease. Biomed Rep. 2016;4:519–522. [PMC free article] [PubMed]
2. Dohi K, Ohtaki H, Nakamachi T, et al. Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury. J Neuroinflammation. 2010;7:41. [PMC free article] [PubMed]
3. Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury. J Neurotrauma. 2000;17:871–890.[PubMed]
4. Gaetani P, Pasqualin A, Rodriguez y Baena R, Borasio E, Marzatico F. Oxidative stress in the human brain after subarachnoid hemorrhage. J Neurosurg. 1998;89:748–754. [PubMed]
5. Erickson MA, Dohi K, Banks WA. Neuroinflammation: a common pathway in CNS diseases as mediated at the blood-brain barrier. Neuroimmunomodulation. 2012;19:121–130. [PMC free article][PubMed]
6. Dohi K, Miyamoto K, Fukuda K, et al. Status of systemic oxidative stress during therapeutic hypothermia in patients with post-cardiac arrest syndrome. Oxid Med Cell Longev. 2013;2013:562429.[PMC free article] [PubMed]
7. Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y. Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci U S A. 1996;93:2696–2701.[PMC free article] [PubMed]
8. Dohi K, Satoh K, Mihara Y, et al. Alkoxyl radical-scavenging activity of edaravone in patients with traumatic brain injury. J Neurotrauma. 2006;23:1591–1599. [PubMed]
9. Dohi K, Satoh K, Nakamachi T, et al. Does edaravone (MCI-186) act as an antioxidant and a neuroprotector in experimental traumatic brain injury? Antioxid Redox Signal. 2007;9:281–287. [PubMed]
10. Kaneko T, Kasaoka S, Nakahara T, et al. Effectiveness of lower target temperature therapeutic hypothermia in post-cardiac arrest syndrome patients with a resuscitation interval of ≤30 min. J Intensive Care. 2015;3:28. [PMC free article] [PubMed]
11. Silveira RC, Procianoy RS. Hypothermia therapy for newborns with hypoxic ischemic encephalopathy. J Pediatr (Rio J) 2015;91 (6 Suppl 1):S78–S83. [PubMed]
12. Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–694. [PubMed]
13. Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther. 2014;144:1–11. [PubMed]
14. Terasaki Y, Ohsawa I, Terasaki M, et al. Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. Am J Physiol Lung Cell Mol Physiol. 2011;301:L415–L426. [PubMed]
15. Yang Y, Li B, Liu C, et al. Hydrogen-rich saline protects immunocytes from radiation-induced apoptosis. Med Sci Monit. 2012;18:BR144–BR148. [PMC free article] [PubMed]
16. Zeng K, Huang H, Jiang XQ, Chen XJ, Huang W. Protective effects of hydrogen on renal ischemia/reperfusion injury in rats. Sichuan Da Xue Xue Bao Yi Xue Ban. 2014;45:39–42. (in Chinese)[PubMed]
17. Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K. Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles. Med Gas Res. 2015;5:12. [PMC free article] [PubMed]
18. Dohi K, Kraemer BC, Erickson MA, et al. Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS One. 2014;9:e108034.[PMC free article] [PubMed]
19. Chen CH, Manaenko A, Zhan Y, et al. Hydrogen gas reduced acute hyperglycemia-enhanced hemorrhagic transformation in a focal ischemia rat model. Neuroscience. 2010;169:402–414.[PMC free article] [PubMed]
20. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27:697–709. [PubMed]
21. Ji Q, Hui K, Zhang L, Sun X, Li W, Duan M. The effect of hydrogen-rich saline on the brain of rats with transient ischemia. J Surg Res. 2011;168:e95–e101. [PubMed]
22. Domoki F, Oláh O, Zimmermann A, et al. Hydrogen is neuroprotective and preserves cerebrovascular reactivity in asphyxiated newborn pigs. Pediatr Res. 2010;68:387–392. [PubMed]
23. Nagatani K, Nawashiro H, Takeuchi S, et al. Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: initial clinical studies. Med Gas Res. 2013;3:13.[PMC free article] [PubMed]
24. Song G, Li M, Sang H, et al. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome. J Lipid Res. 2013;54:1884–1893.[PMC free article] [PubMed]
25. Kajiyama S, Hasegawa G, Asano M, et al. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res. 2008;28:137–143. [PubMed]
26. 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;46:140–149. [PMC free article] [PubMed]
27. Hashimoto M, Katakura M, Nabika T, et al. Effects of hydrogen-rich water on abnormalities in a SHR.Cg-Leprcp/NDmcr rat – a metabolic syndrome rat model. Med Gas Res. 2011;1:26. [PMC free article][PubMed]
28. Manaenko A, Lekic T, Ma Q, Zhang JH, Tang J. Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice. Crit Care Med. 2013;41:1266–1275. [PMC free article][PubMed]
29. Zhuang Z, Zhou ML, You WC, et al. Hydrogen-rich saline alleviates early brain injury via reducing oxidative stress and brain edema following experimental subarachnoid hemorrhage in rabbits. BMC Neurosci. 2012;13:47. [PMC free article] [PubMed]
30. Zhuang Z, Sun XJ, Zhang X, et al. Nuclear factor-κB/Bcl-XL pathway is involved in the protective effect of hydrogen-rich saline on the brain following experimental subarachnoid hemorrhage in rabbits. J Neurosci Res. 2013;91:1599–1608. [PubMed]
31. Hong Y, Shao A, Wang J, et al. Neuroprotective effect of hydrogen-rich saline against neurologic damage and apoptosis in early brain injury following subarachnoid hemorrhage: possible role of the Akt/GSK3β signaling pathway. PLoS One. 2014;9:e96212. [PMC free article] [PubMed]
32. Takeuchi S, Mori K, Arimoto H, et al. Effects of intravenous infusion of hydrogen-rich fluid combined with intra-cisternal infusion of magnesium sulfate in severe aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial. BMC Neurol. 2014;14:176. [PMC free article] [PubMed]
33. Ji X, Liu W, Xie K, et al. Beneficial effects of hydrogen gas in a rat model of traumatic brain injury via reducing oxidative stress. Brain Res. 2010;1354:196–205. [PubMed]
34. Eckermann JM, Chen W, Jadhav V, et al. Hydrogen is neuroprotective against surgically induced brain injury. Med Gas Res. 2011;1:7. [PMC free article] [PubMed]
35. Chen C, Chen Q, Mao Y, et al. Hydrogen-rich saline protects against spinal cord injury in rats. Neurochem Res. 2010;35:1111–1118. [PubMed]
36. Huang Y, Xie K, Li J, et al. Beneficial effects of hydrogen gas against spinal cord ischemia-reperfusion injury in rabbits. Brain Res. 2011;1378:125–136. [PubMed]
37. Zhou L, Wang X, Xue W, et al. Beneficial effects of hydrogen-rich saline against spinal cord ischemia-reperfusion injury in rabbits. Brain Res. 2013;1517:150–160. [PubMed]
38. Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol. 2012;8:557–566. [PubMed]
39. Liu L, Xie K, Chen H, et al. Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis. Brain Res. 2014;1589:78–92. [PubMed]
40. Nakano T, Kotani T, Mano Y, et al. Maternal molecular hydrogen administration on lipopolysaccharide-induced mouse fetal brain injury. J Clin Biochem Nutr. 2015;57:178–182. [PMC free article] [PubMed]
41. Shen MH, Cai JM, Sun Q, et al. Neuroprotective effect of hydrogen-rich saline in acute carbon monoxide poisoning. CNS Neurosci Ther. 2013;19:361–363. [PubMed]
42. Sun Q, Cai J, Zhou J, et al. Molecular Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity. Crit Care Med. 2011;39:765–769. [PubMed]
43. Nagata K, Nakashima-Kamimura N, Mikami T, Ohsawa I, Ohta S. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice.  Neuropsychopharmacology. 2009;34:501–508. [PubMed]
44. Wei R, Zhang R, Xie Y, Shen L, Chen F. MOLECULAR hydrogen suppresses hypoxia/reoxygenation-induced cell death in hippocampal neurons through reducing oxidative stress. Cell Physiol Biochem. 2015;36:585–598.[PubMed]
45. Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 2008;7:97–109. [PubMed]
46. Ito M, Hirayama M, Yamai K, et al. Drinking molecular hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Med Gas Res. 2012;2:15. [PMC free article] [PubMed]
47. Fujita K, Seike T, Yutsudo N, et al. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. PLoS One. 2009;4:e7247. [PMC free article] [PubMed]
48. Fu Y, Ito M, Fujita Y, et al. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson’s disease. Neurosci Lett. 2009;453:81–85. [PubMed]
49. Yoritaka A, Takanashi M, Hirayama M, Nakahara T, Ohta S, Hattori N. Pilot study of molecular hydrogen H2 therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial. Mov Disord. 2013;28:836–839.[PubMed]
50. Yoritaka A, Abe T, Ohtsuka C, et al. A randomized double-blind multi-center trial of molecular hydrogen water for Parkinson’s disease: protocol and baseline characteristics. BMC Neurol. 2016;16:66. [PMC free article][PubMed]
51. Wang C, Li J, Liu Q, et al. Molecular hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer’s disease. Neurosci Lett. 2011;491:127–132. [PubMed]
52. Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol. 2011;70:532–540. [PMC free article] [PubMed]
53. Li J, Wang C, Zhang JH, Cai JM, Cao YP, Sun XJ. Molecular hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Res. 2010;1328:152–161. [PubMed]
54. Gu Y, Huang CS, Inoue T, et al. Drinking  molecular hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. J Clin Biochem Nutr. 2010;46:269–276. [PMC free article] [PubMed]
55. Liu C, Kurokawa R, Fujino M, Hirano S, Sato B, Li XK. Estimation of the molecular hydrogen concentration in rat tissue using an airtight tube following the administration of molecular hydrogen via various routes. Sci Rep. 2014;4:5485. [PMC free article] [PubMed]