Safety & Health Benefits of Hydrogen Water – Nobel Prize Nominee, Dr. GARTH NICOLSON


Safety & Health Benefits of Hydrogen Water – Nobel Prize Nominee, Dr. GARTH NICOLSON

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

AlkaViva EmcoTech/Jupiter alkaline ionized water as cancer treatment -clinical case , integrative oncology

AlkaViva EmcoTech/Jupiter alkaline ionized water as cancer treatment -clinical case , integrative oncology

Abstract

The present article describes the ongoing (partial) remission of a female patient (41 years old) from estrogen receptor (ER)-positive/progesterone receptor (PR)-negative metastatic breast cancer in response to a combination treatment directed towards the revitalization of the mitochondrial respiratory chain (oxidative phosphorylation), the suppression of NF-kappaB as a factor triggering the inflammatory response, and chemotherapy with capecitabine. The reduction of tumor mass was evidenced by a continuing decline of CA15-3 and CEA tumor marker serum levels and 18FDG-PET-CT plus magnetic resonance (MR) imaging. It is concluded that such combination treatment might be a useful option for treating already formed metastases and for providing protection against the formation of metastases in ER positive breast cancer. The findings need to be corroborated by clinical trials. Whether similar results can be expected for other malignant tumor phenotypes relying on glycolysis as the main energy source remains to be elucidated.

1. Introduction

Since Richard Nixon declared war on cancer about 30 years ago, much efforts have been made in order to overcome this dreadful disease. Enormous financial resources have been invested in cancer research in the last three decades, yet most metastasized solid malignant tumors are still considered incurable. Chemotherapy has been shown to be a potent (long lasting) treatment option against only a few solid cancers including testis cancer. The overall contribution of curative and adjuvant cytotoxic chemotherapy was assessed to be 2.3% in Australia and 2.1% in the United States of America with a five-year survival in adults based on data for 1998 []. Under chemotherapy, cancer cells can gradually develop drug resistance that is acquired, for instance, by overexpression of transporter proteins (e.g., those belonging to the ATP-binding cassette type) [,] and fractionation of the cancerous stem cells [] (which are less sensitive to exposure to cytostatics than more differentiated cancer cells), plus AKT [,] and NF-kappaB [,] overexpression as a compensatory response to administered cytotoxic drugs. Likewise, induced hypoxia may act as protective shield against tumor eradication by chemotherapeutics and radiation due to alterations of gene expression profiles related to hypoxia, which result in the inhibition of apoptosis [].

On the other hand, a plethora of “alternative” cancer therapies have been developed and applied in the past. Here, we report on a combination treatment, including chemotherapy, bisphosphonates, and complementary measures, aiming at the normalization of the cellular metabolism, vascular angiogenesis, cell life cycle, and cell proliferation activity.

2. Experimental

2.1. Chemicals/Dietary Supplements

Super Ubiquinol CoQ10, Life Extension, article nr. 01426, USA: www.lefeurope.com

Vitamin B2, tablets, 10 mg, Jenapharm®, Mibe GmbH, Germany

Vitamin B3, capsules, 54 mg, Allpharm, Germany, PZN 6605862

5-Loxin®capsules, 75 mg, (std. for acetyl-11-keto-β-boswellic acid (AKBA), minimum 30% on dry basis), Life Extension, article nr. 00939, USA, www.lefeurope.com

Linseed oil, Linosan Leinöl, Heirler Cenovis GmbH, D-78303 Radolfzell, Germany

Bio-Kefir, Andechser Natur, 1,5% fat, containing L(+) dextrorotatory lactic acid, Andechser Molkerei Scheitz GmbH, D-82346 Andechs, Germany, www.andechser-molkerei.de

Bio-Yoghurt, Andechser Natur, 0,1% fat, containing L. acidophilus and B. bifidus, Andechser Molkerei Scheitz GmbH, D-82346 Andechs, Germany, www.andechser-molkerei.de

Flaxseed, freshly ground

EPA/DHA: Mega EPA/DHA, capsules, Life Extension, article nr. 00625

Sodium selenite, Selenase®200 XXL, 200 μg selenium, biosyn Arzneimittel GmbH, D-70734 Fellbach, Germany

L-Carnitine: Multinorm® L-Carnitin aktiv, 250 mg L-carnitin plus 3 μg Vitamin B12, Sankt Pirmin® Naturprodukte GmbH, D-55218 Ingelheim, Germany

L-Carnitine, 300 mg capsules: Altapharma, Germany

Zinc, Unizink® 50, 50 mg zinc-bis(hydrogen-DL-aspartat), Kohler Pharma GmbH, D-64665 Alsbach-Hähnlein, Germany, PZN-3441621

Ibandronat Bondronat®, 6 mg/6 mL concentrate, Roche Pharma AG, D-79639 Grenzach-Wyhlen, Germany

Capecitabine, Xeloda®, Roche Pharma AG, D-79639 Grenzach-Wyhlen, Germany

Drinking water ion exchanger and filter, pHresh, EMCO TECH Co. Ltd., Korea

Vitamin D and vitamin A were sporadically taken.

2.2. Procedure

The mentioned chemicals/dietary supplements have been taken as follows:

Alkalized drinking water was prepared ad lib by using water ion exchanger and filter. The filtered water was boiled prior to use.

Capecitabine was taken orally at 3.65 g Xeloda®/70 kg body weight per day. Two weeks of treatment were followed by one week of therapy pause per cycle.

“Budwig diet”: the following items were mixed for preparing a full batch using a blender: 1 kg Bio-Yoghurt, 0.1% fat, 0.25 kg Bio-Kefir, 1.5% fat, 6 table spoons of linseed oil, 4 table spoons of linseed, to be freshly milled: A part of this full batch may be prepared daily (the daily dose per person was about 250 grams).

Taken together around noon: 400 mg of Ubiquinol CoQ10 (4 capsules à 100 mg), 10 mg vitamin B2 (Riboflavin), 50 mg vitamin B3 (Niacin)

Taken three times daily: 2 softgels of MEGA EPA/DHA (eicosapentaenoic acid/docosahexaenoic acid), including 720 mg of EPA and 480 mg of DHA per 2 capsules.

One capsule of 5-Loxin®, one dose of Multinorm® L-Carnitin aktiv (taken only during chemotherapy pause; during the chemotherapy 300 mg pure L-carnitine not containing vitamin B12 was ingested), one tablet of Unizink® 50, and one tablet of Selenase®200 XXL were taken daily. EPA/DHA are COX-2 inhibitors. Therefore, the heart and vascular functions should be checked by a physician on a regular basis (it has been found that members of synthetic COX-2 inhibitors have been found to increase thrombosis, stroke, and heart attack risk under certain conditions). Moreover, Q10/B2/B3 were not taken in combination with radiation (the antioxidant Q10 potentially quenches the oxidative damage caused by radiation). EPA and DHA have potentially blood thinning effect.

3. Results

3.1. Applied Methodology and Methods

It has been hypothesized by the author that a multi-factorial approach towards breast cancer treatment would result in a synergetic response and reduced likelihood of development of resistance to treatment. Accordingly, it was sought to combine complementary, non-antagonistic treatments, which have the theoretical potential to suppress tumorigenesis and proliferation, with a “conventional” treatment. The envisaged therapy modules were Budwig diet and normalization of the fatty acid dietary balance, alkaline therapy, suppression of the inflammatory signaling chain, revitalization of the mitochondrial respiratory chain, bone protection against osteoclast-effected resorption by bisphosphonates and AKBA, and finally chemotherapy in the form of the prodrug capecitabine as 5-fluorouracil precursor []. The latter has been the recommended treatment by the medical tumor board in charge.

The described efforts have concretely been undertaken for suppressing refractory breast cancer stage IV in a female patient (body mass index 24–26, 41 years old), having developed a ductal carcinoma in situ in 2007. After biopsy revealed an estrogen receptor positive and progesterone receptor negative breast cancer, followed by surgical resection of the invaded sentinel lymph nodes, a neoadjuvant chemotherapy (four cycles Epirubicin/Cyclophosphamide, followed by four cycles of Taxotere®) was applied. However, the tumor showed little response (the tumor regression grade according to Sinn was only 1). Thus, the first and second axillary lymph node levels were resected in the following, and the affected breast was ablated. No suspicious tumor marker levels have been observed after ablation. The resection area was furthermore treated with radiation (gamma rays). The post-operational therapy included firstly tamoxifen, clodronate (a bisphosphonate), and a GNRH analogue (Enantone-Gyn®).

However, in September 2008, the patient – alerted by pain in the spinal cord – underwent MRI imaging, which revealed multiple bone metastases, including in the spinal cord.

As a consequence, the medication was altered as follows by the medical board in charge: Letrozol (aromatase inhibitor, 2.5 mg/d) and Ibandronat (6 mg intravenous infusion per month) as bisphosphonate. However, the disease progressed and a staging (18FDG-PET-CT and MRI) in March 2009 revealed the formation of various liver metastases. Therefore, the medication was changed to capecitabine chemotherapy instead of anti-hormonal therapy, accompanied by continuation of administration of Ibandronat.

Together with this therapy change, the author recommended the complimentary ingestion of the following substances: “Budwig diet” (linseed oil, flaxseed, and yoghurt), EPA/DHA concentrate in the form of distilled fish oil, ubiquinol (Q10 in reduced form), and vitamins B2 and B3, later on also 5-Loxin®(AKBA). See above for further dosage and substance specifications.

3.2. Results

After about three months (June 2009) of continued intake of the above mentioned substances (besides 5-Loxin®), PET-CT showed no metabolic activity of the liver metastases any longer and reduced activity of the bone metastases under 18F-deoxyglucose as tracer in the PET. Concurrently, a decline of the tumor markers’ (CA 15-3 and CEA) serum concentration was observed.

At this time, as a further element, 5-Loxin® (AKBA) was introduced into the supplementation scheme for the reasons mentioned.

Nine months later, the MRI showed that three out of six initial liver metastases could no longer be imaged, and that the largest lesion had decreased from about 15 mm to about 7 mm. A further small liver metastasis remained unchanged in size. This situation is depicted in Figure 1. Again, no metabolic activity in 18FDG-PET-CT was detected for any of the liver metastases.

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Diffusion-weighted MRI of the liver showing two metastases in the right lobe in (a) June 2009, and (b) February 2010. One metastasis (arrow) decreased from 15 mm in diameter to 7 mm, while the other remained unchanged (courtesy of Prof. Dr. E. Rummeny, Klinikum Rechts der Isar, Technische Universität München, Technical University of Munich, Germany).

Moreover, the PET-CT (18F-deoxyglucose as PET tracer) showed, in addition, a reduction of the size and metabolic activity of bone metastases, accompanied by re-calcification of the lesions. The response to treatment correlated with markedly decreased tumor marker serum levels, with CEA concentration being close to the significance threshold of 4 ng/mL. The development of the tumor marker levels over time is displayed in Table 1 below. The decline of tumor marker concentrations has been found to correlate with cancer remission in clinical studies on breast cancer patients [,]. In addition, the initial concentration of CEA has been associated with the clinical disease outcome in breast cancer patients.

Table 1.

Development of the CEA and CA 15-3 serum concentrations over time; cut-off values were 4 ng/mL for CEA and 27 U/mL for CA15-3.

Date/Months after Therapy Start CA 15-3 (U/mL) Excess over Cut-off Value [%] CEA (ng/mL) Excess over Cut-off Value [%]
29 June 2009/3 49.3 82.6 31.4 684
13 September 2009/7 46.2 71.1 8.4 110
11 January 2010/10 37 37.0 4.1 2.5
19 April 2010/13 38.3 41.9 3.6 -10.8
12 July 2010/16 35.7 32.3 4.1 1.5

The latest 18FDG-PET-CT of August 2010 showed ongoing sclerosis of at least some of the bone lesions and stable disease.

4. Discussion and Conclusions

A plethora of complementary cancer treatments have been reported. Firstly, the intake of polysaccharides and proteoglucans, such as mushroom and yeast glucans [  ,  ], mistletoe lectins [,] and nerium oleander extracts, the latter also in combination with sutherlandia frutescens extracts [,], have been described. The activation of the immune system against cancer cells has been ascribed to all of these compounds.

Another approach employed against the proliferation of cancer is alkaline therapy, which addresses the cellular acid-base balance. It has been found that extracellular/interstitial cancer tissue is more acidic than healthy tissue due to excessive production of lactic acid stemming from the glycolysis of glucose []. Otto Warburg already suggested in the last century that (as a consequence of hypoxia often encountered in tumor tissues) cancer cells undergo excessive glycolysis instead of relying on the energetically by far more effective oxidative phosphorylation [,], a fact which could recently also be verified by biopsy analysis in breast cancer patients, revealing a marked decrease in β-F1-ATPase/HSP60 expression ratio during disease progression []. Lately, it has been suggested that the initiation of glycolysis could be triggered by AKT activation during tumor development [] and that the resulting acidification of the extra-cellular cancer tissue brings about survival advantages for cancer cells [,]. It has been found recently that T-cell development is markedly suppressed in acidified cancer tissue []. Alternative alkaline therapies applied for cancer treatment included the intake of sodium bicarbonate [], cesium chloride [], or alkaline diet, which is based on fruit and vegetables having high potassium content. A further approach was the ingestion of alkaline drinking water obtained from ion exchangers.

Another avenue towards cancer suppression has been established by the supplementation of (essential) polyunsaturated fatty acids, aiming at re-establishing cellular membrane functionality [] and fluidity []. In addition, the polyunsaturated omega-3 fatty acids eicosapentaenoic (EPA) and docosapentaenoic acid (DHA) have been found to have a direct bearing on gene expression level by e.g., deactivation of NF-kappaB and AKT by EPA and DHA in a mouse model []. Polyunsaturated omega-3 fatty acids have also been shown to possess anti-inflammatory properties, for instance. by suppression of NF-KappaB and cyclooxygenases [], or caused by the reduction of prostaglandin E2 biosynthesis via arachidonic acid due to a shift in the omega-6 fatty acid/omega-3 FA level towards omega-3 species (omega-6 fatty acids form the pool for the endogenous biosynthesis of E2 prostaglandin) [,].

In addition, a direct positive correlation between cytotoxic drug efficacy and DHA level in breast adipose tissue of patients has been observed [  ]. Also, recent clinical studies suggested that EPA/DHA supplementation may suppress cancer-related cachexia []. Whereas severe side effects have been reported for the prolonged administration of some synthetic COX-II inhibitors, including increased thrombosis, stroke, and heart attack risk, to our best knowledge no comparably grave effects have been reported for the prolonged intake of EPA/DHA (e.g. in the form of fish oil) in clinical studies. The side effects of fish oil therapy, including blood thinning, have recently been discussed, e.g., by Farooqui et al.[].

Likewise, Johanna Budwig established a cancer diet (the so-called “Budwig diet”), which includes inter alia the daily intake of linseed oil as a potent source of alpha-linolenic acid as essential omega-3 fatty acid []. Anecdotal cases of complete cancer remissions after continued Budwig diet have been reported []. To our best knowledge, no randomized clinical trials exploring the efficacy of the Budwig diet have been launched to date. The consequence of a continued Budwig diet is said to be an optimization of the dietary balance of omega-6/omega-3 fatty acids and reconstitution of physiologically intact cellular membrane composition by enhanced administration of polyunsaturated fatty acids as a substitute for peroxidized and saturated fatty acids in cellular membranes, thus increasing membrane fluidity. Furthermore, it has been hypothesized that polyunsaturated fatty acids may act as oxygen carriers []. The present-day Western diet results in an adverse ratio of about 15:1 of omega-6/omega-3 fatty acids, whereas a ratio of about 1:1 has been reported as paleolithic reference value for humans []. As a consequence, the endogenous high level of omega-6 fatty acids in humans fosters the increased biosynthesis of pro-inflammatory arachidonic acid from e.g., linoleic acid. Moreover, it has been hypothesized that cottage cheese, quark or yoghurt as second constituent of the Budwig diet refills the pool of sulfhydryl amino acids (which are essential for glutathione biosynthesis).

Warburg considered the glycolytic switch as being a final event in cancer formation, accompanied by irreversible genetic changes and the inactivation of the mitochondrial respiratory chain in cells, giving rise to their dedifferentiation []. However, recent studies suggest that this may not be the case: Dichloroacetate has been shown to be a potent inhibitor of pyruvate dehydrogenase kinase, thereby suppressing, as other agents, the glycolytic switch and thus fostering oxidative phosphorylation [,,]. As a consequence of such an apparent normalization of the cellular energy production, cancer remissions in animal trials and anecdotal reports of healing of malignant tumors in human patients have been reported lately [].

Moreover, investigations involving the administration of coenzyme Q10 directed towards the revitalization of the mitochondrial respiratory chain suggest that, indeed, the inhibition of the respiratory chain (Q10 is present in various complexes thereof) can be reversed or at least be halted: Folkers et al. reported that breast cancer patients taking 90 mg per day Q10 stayed in a state of constant disease, and did not develop new metastases. No patient in the group died, although about 20% (6/32) deaths were statistically expected in the observation period. When the dose of Q10 was augmented to 390 mg daily, five patients who already showed remission under 90 mg of Q10 per day went into apparently complete remission, including the eradication of liver metastases [,]. Cases of complete remission in response to high doses of Q10 for other cancer types, such as small cell bronchogenic carcinoma, have also been published by Folkers et al.[].

Likewise, Sachdanandam et al. recently reported on tumor control and remission caused by a combination treatment by coenzyme Q10, vitamins B2 and B3 (all of which are essential for the cellular energy generation) and tamoxifen in animal trials []. As a result, markedly lower levels of lipid peroxidation and cachexia over the tumor-induced non-treated control group was observed. Orienting clinical trials of Premkumar et al., involving 84 breast cancer patients, affirmed the anti-tumor action of said agent combination []. Inter alia, a decrease of the plasma concentration of urokinase plasminogen activator (UPA) by about 50% was observed, and the level of adhesion factors such as E-selectin and pro-angiogenic proteinase MMP-9 were found to be drastically decreased after only 90 days of treatment. Moreover, significantly reduced tumor marker levels (CA-15-3 and CEA) have been measured after 90 days of coenzyme Q10, vitamins B2 and B3 plus tamoxifen combination treatment []. UPA expression level was determined as correlating with the clinical outcome of breast cancer, and UPA inhibition has therefore been made the target of extensive research [].

Another approach addressing the stabilization of the course of breast cancer is the administration of bisphosphonates [] such as ibandronate, which stabilize the bone matrix and thus impede osteoclast-mediated bone lysis. In addition, certain bisphosphonates, such as the latter compound, have been shown to possess direct anti-tumor action in vitro and in vivo [,].

Finally, a further route towards the suppression of cancers is the suppression of nuclear factor kappa B (a gene transcription promoter involved in the inflammatory chain and in a tumor’s capability to invade, metastasize and evade apoptosis) []. NF-kappaB stimulates the expression of various pro-inflammatory genes [,], also in breast cancer []. Consequently, a number of approaches have been divulged lately which are concerned with inhibition of this factor. The different compounds, which hinder the activation of NF-kappaB, are e.g., EPA (see above), and 11-keto-17-hydroxy boswellic acid (AKBA) [], a compound which has been shown to abrogate the osteoclastogenesis by inhibition of NF-kappaB activation in vitro. AKBA was also shown to hinder the enzyme 5-lipoxygenase [], which plays a pivotal role in the biosynthesis of pro-inflammatory leucotrienes. Remarkably, it has been shown that NF-kappaB inhibitors effectively inhibited MCF-7 breast cancer stem-like cells [].

In the present case, refractory breast cancer, which had not or has poorly responded to initial chemo- and anti-hormonal therapy, showed drastic and ongoing response to a combination treatment including capecitabine and complementary treatment components; the latter include NF-kappaB blockers, and other inhibitors of the inflammatory chain, respiratory chain stimulants, plus alkaline therapy. The rationale for employing these agents has been explained in the preceding paragraphs. No resistance to the therapy was observed after 17 months, and the decrease of tumor marker levels correlated with imaging results. The obtained results are significant in view of the initial heavy disease progress and lack of relevant response to all preceding therapies.

The incremental contributions of each individual treatment element remain unclear. However, it is hypothesized that a synergetic action of the measures takes place. These have been selected by theoretical considerations in order to avoid potential antagonistic interferences, which could annihilate action. It should also be noted that concerns about the simultaneous intake of chemotherapeutics and antioxidants have been raised in the literature, especially in the context of cytostatics that have free radical formation as their believed primary mechanism of action. To our best knowledge, the primary mechanism of action of capecitabine, however, is not via free radicals but DNA synthesis and thymidylate synthase inhibition []. No antagonistic interaction with the remaining measures “base therapy” (addressing the immune suppression observed in the acidic tumor environment due to the purported suppression of T-cell development in the acidic tissue adjacent to tumors) and bone stabilization by bisphosphonates has been expected. On the contrary, the reported suppression of NF-kappaB expression by e.g. AKBA should reduce the RANKL-induced osteoclastogenesis, which is triggered by the transcription factor NF-kappaB [].

Whether all measures contribute to the observed results remains speculative. The progression-free interval of 17 months observed so far is encouraging in view of a median time to progression from 3–9 months reported for the first line treatment of metastatic breast cancer by capecitabine []. Randomized clinical trials appear to be indicated in view of the promising orienting results.

Note that ER positive/PR negative breast cancer constitutes a rather limited high risk subset within the broader patient collective suffering from luminal breast cancer. Lately, it has been hypothesized in the literature that the expression of progesterone receptor (genes) in breast cancer has a positive bearing on the disease malignity and outcome, correlating with a less aggressive phenotype, and that the expression of progesterone receptor genes may be hindered by AP-1 [,,]. AP-1 and NF-kappaB have been shown to bind to UPA promoter sequence and to cooperatively foster UPA expression. Consequently, it has been directly or indirectly suggested to therapeutically inhibit NF-kappaB in order to improve efficacy of antiestrogen treatment of patients associated to high risk hormone-dependent breast cancer [,].

Moreover, the reduced UPA expression mediated by Q10 described in the literature could also be a sign of a reduced activity of the transcription factor AP-1. At the same time, reduction of AP-1 activity could lead to a reversal of the blockage of the progesterone receptor expression caused by the inhibitory action of AP-1 and a consequent sensitization of ER-positive/PR-negative breast cancers to anti-estrogenic treatment by tamoxifen (compare to references [,]).

It is further hypothesized that the obtained orienting results hint (as already observed for DCA) at a revitalization of the mitochondrial respiratory chain at the expense of a pathologic increase of glycolysis. The reduction of glucose metabolism of the metastases was corroborated by reduced signal intensity in 18FDG-PET-CT scans during the treatment. Hence, the results are interpreted as a pointer towards the (at least partial) reversibility of the glycolytic switch and the associated changes in gene profile expression.

 

SEE ALL WATER IONIZERS – MOLECULAR HYDROGEN GENERATORS

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Link to Publisher's site
. 2011 Mar; 3(1): 1454–1466.
Published online 2011 Mar 17. doi: 10.3390/cancers3011454
PMCID: PMC3756422
PMID: 24212668

Clinical Response of Metastatic Breast Cancer to Multi-targeted Therapeutic Approach: A Single Case Report

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

Acknowledgements

Thanks are due to E. Rummeny and J. Gaa, both Department of Radiology, Klinikum Rechts der Isar, Technische Universitat Munchen, for kindly providing the MRI images and the image analysis.

Disclaimer

The author does not suggest that breast cancer can be healed by applying the described measures. Moreover, the author disclaims all responsibilities and liabilities as consequence of a potential application of the described treatment steps, either taken separately or in any combination by patients, third parties, institutions, or other persons, and for the correctness of the provided information. Questions concerning the disclosed treatment will be answered to physicians and clinical academia in general, only.

References

1. Morgan G., Ward R., Barton M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin. Oncol. 2004;16:549–560. [PubMed[]
2. Coley H. Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. Cancer Treat. Rev. 2008;34:378–390. [PubMed[]
3. Ozben T. Mechanisms and strategies to overcome multiple drug resistance in cancer. FEBS Lett. 2006;580:2903–2909. [PubMed[]
4. Morrison B., Schmidt C., Lakhani S., Reynolds B., Lopez J. Breast cancer stem cells: Implications for therapy of breast cancer. Breast Cancer Res. 2008:10–210. [PMC free article] [PubMed[]
5. Clark A., West K., Streicher S., Dennis P. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther. 2002;1:707–717.[PubMed[]
6. Dillon R., White D., Muller W. The phosphatidyl inositol 3-kinase signaling network: Implications for human breast cancer. Oncogene. 2007;26:1338–1345. [PubMed[]
7. Garg A., Aggarwal B. Nuclear transcription factor-κB as a target for cancer drug development. Leukemia. 2002;16:1053–1068. [PubMed[]
8. Li F., Sethi G. Targeting transcription factor NF-κB to overcome chemoresistance and radioresistance in cancer therapy. Biochim. Biophys. Acta. 2010;1805:167–180. [PubMed[]
9. Marignol L., Coffey M., Lawler M., Hollywood D. Hypoxia in prostate cancer: A powerful shield against tumour destruction? Cancer Treat. Rev. 2008;34:313–327. [PubMed[]
10. Walko C.M., Lindley C. Capecitabine: A review. Clin. Ther. 2005;27:23–44. [PubMed[]
11. Kallioniemi O., Oksa H., Aaran R., Hietanen T., Lehtinen M., Koivula T. Serum CA 15-3 assay in the diagnosis and follow-up of breast cancer. Br. J. Cancer. 1988;58:213–215. [PMC free article] [PubMed[]
12. Lässig D. Dissertation. Ludwigs-Maximilians-Universität; München, Germany: 2007. pp. 70–92. []
13. Moradali M., Mostafavi H., Ghods S., Hedjaroude G. Immunomodulating and anticancer agents in the realm of macromycetes fungi (macrofungi) Int. Immunopharmacol. 2007;7:701–724. [PubMed[]
14. Bohn J., BeMiller J. (1-3)Beta-D-Glucans as biological response modifiers: A review of structure-functional activity relationships. Carbohyd. Polym. 1995;28:3–14. []
15. Grossarth-Maticek R., Kiene H., Baumgartner S., Ziegler R. Use of Iscador, an extract of European Mistletoe (Viscum album) in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern. Ther. Health M. 2001;7:57–78. [PubMed[]
16. Timoshenko A., Lan Y., Gabius H., Lala P. Immunotherapy of C3H/HeJ mammary adenocarcinoma with interleukin-2, mistletoe lectin or their combination. effects on tumour growth, capillary leakage and nitric oxide (NO) production. Eur. J. Cancer. 2001;37:1910–1920. [PubMed[]
17. Caribik I., Baser K., Özel H., Ergun B., Wagner W. Immunologically Active Polysaccharides from the Aqueous Extract of Nerium Oleander. Planta Med. 1990;56:668. []
18. Swanepoel Marc. Sutherlandia OPC Website. Available online: http://www.sutherlandiaopc.com/(accessed on 16 March 2011)
19. Harguindey S., Orive G., Luis Pedraz J., Paradiso A., Reshkin S.J. The role of pH dynamics and the Na+/H+ antiporter in the etiopathogenesis and treatment of cancer. Two faces of the same coin–one single nature. Biochim. Biophys. Acta. 2005;1756:1–24. [PubMed[]
20. Warburg O. The Prime Cause and Prevention of Cancer—Part 1 with two prefaces on prevention, Revised lecture at the meeting of the Nobel-Laureates; Lindau, Lake Constance, Germany. 30 June 1966. []
21. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314. [PubMed[]
22. Isidoro A., Casado E., Redondo A., Acebo P., Espinosa E., Alonso A.M., Cejas P., Hardisson D., Fresno Vara J.A., Belda-Iniesta C., González-Barón M., Cuezva J.M. Breast Carcinomas Fulfill the WARBURG Hypothesis and Provide Metabolic Markers of Cancer Prognosis. Carcinogenesis. 2005;26:2095–2104. [PubMed[]
23. Borzillo G.V. Akt and emerging models for tumor cell energetics. Drug Discov. Today Therap. Strateg. 2005;2:331–336. []
24. Pedersen P.L. The cancer cell’s “power plants” as promising therapeutic targets: An overview. J. Bioenerg. Biomembr. 2007;39:1–12. [PubMed[]
25. Robey I.F., Baggett B., Kirkpatrick N., Roe D., Dosescu J., Sloane B., Hashim A., Morse D., Raghunand N., Gatenby R., Gillies R. Bicarbonate increases tumor pH and inhibits spontaneous metastases. Cancer Res. 2009;69:2260–2268. [PMC free article] [PubMed[]
26. Sartori H.E. Cesium Therapy in Cancer Patients. Pharmacol. Biochem. Be. 1984;21(Suppl. 1):11–13.[PubMed[]
27. Peskin B.S., Carter M.J. Chronic cellular hypoxia as the prime cause of cancer: what is the de-oxygenating role of adulterated and improper ratios of polyunsaturated fatty acids when incorporated into cell membranes? Med. Hypo. 2008;70:298–304. [PubMed[]
28. Schmitz G., Ecker J. The opposing effects of n-3 and n-6 fatty acids. Prog. Lipid Res. 2008;47:147–155. [PubMed[]
29. Ghosh-Choudhury T., Mandal C., Woodruff K, St Clair P, Fernandes G, Choudhury G., Ghosh-Choudhury N. Fish oil targets PTEN to regulate NFkappaB for downregulation of anti-apoptotic genes in breast tumor growth. Breast Cancer Res. Treat. 2009;118:213–228. [PMC free article] [PubMed[]
30. Musiek E., Brooks J., Joo M., Brunoldi E., Porta A., Zanoni G., Vidari G., Blackwell T., Montine T., Milne G., McLaughlin B., Morrow J. Electrophilic cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid. J. Biol. Chem. 2008;283:19927–19935. [PMC free article] [PubMed[]
31. Berquin I.M., Edwards I., Chen Y. Multi-targeted therapy of cancer by omega-3 fatty acids. Cancer Lett. 2008;269:363–377. [PMC free article] [PubMed[]
32. Manna S., Chakraborty T., Ghosh B., Chatterjee M., Panda A., Srivastava S., Rana A., Chatterjee M. Dietary fish oil associated with increased apoptosis and modulated expression of Bax and Bcl-2 during 7,12-dimethylbenz(α)anthracene-induced mammary carcinogenesis in rats. Prostag. Leukotr. Ess. 2008;79:5–14. [PubMed[]
33. Bougnoux P., Germain E., Chajès V., Hubert B., Lhuillery C., Le Floch O., Body G., Calais G. Cytotoxic drugs efficacy correlates with adipose tissue docosahexaenoic acid level in locally advanced breast carcinoma. Br. J. Cancer. 1999;79:1765–1769. [PMC free article] [PubMed[]
34. Farooqui A.A., Ong W.Y., Horrocks L.A., Chen P., Farooqui T. Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans. Brain Res. Rev. 2007;56:443–471. text section 8.4. [PubMed[]
35. Budwig J. Öl-Eiweiss-Kost. 8th ed. Sensei Verlag; Kernen, Germany: 2007. []
36. Anonymous. A Tape Transcription by Clifford Beckwith (Budwig diet & advanced prostate cancer) Available online: http://www.whale.to/a/beckwith.html (accessed on 28 February 2011)
37. Bonnet S., Archer S.L., Allalunis-Turner J., Haromy A., Beaulieu C., Thompson R., Lee C.T., Lopaschuk G.D., Puttagunta L., Harry G., Hashimoto K., Porter C.J., Andrade M.A., Thebaud B., Michelakis E.D. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007;11:37–51. [PubMed[]
38. Sun R.C., Fadia M., Dahlstrom J.E., Parish C.R., Board P.G., Blackburn A.C. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res. Treat. 2010;120:253–260. [PubMed[]
39. Xu R., Pelicano H., Zhou Y., Carew J.S., Feng L., Bhalla K.N., Keating M.J., Huang P. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005;65:613–621. [PubMed[]
40. Anonymous. Updating you on DCA and cancer. Available online: http://www.thedcasite.com/and references cited therein (accessed on 28 February 2011)
41. Lockwood K., Moesgaard S., Folkers K. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10. Biochem. Biophys. Res. Commun. 1994;199:1504–1508. [PubMed[]
42. Lockwood K., Moesgaard S., Yamamoto T., Folkers K. Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases. Biochem. Biophys. Res. Commun. 1995;212:172–177.[PubMed[]
43. Folkers K., Brown R., Judy W.V., Morita M. Survival of cancer patients on therapy with coenzyme Q10. Biochem. Biophys. Res. Commun. 1993;192:241–245. [PubMed[]
44. Perumal S.S., Shanti P., Sachdanandam P. Augmented efficacy of tamoxifen in rat breast tumorigenesis when gavaged along with riboflavin, niacin, and CoQ10: effects on lipid peroxidation and antioxidants in mitochondria. Chem. Biol. Interact. 2005;152:49–58. [PubMed[]
45. Premkumar V.G., Vuvaraj S., Sathish S., Shanti P., Sachdanandam P. Anti-angiogenic potential of Coenzyme Q10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy. Vascul. Pharmacol. 2008;48:191–201. [PubMed[]
46. Premkumar V.G., Yuvaraj S., Vijayasarathy K., Gangadaran S.G., Sachdanandam P. Effect of coenzyme Q10, riboflavin and niacin on serum CEA and CA 15-3 levels in breast cancer patients undergoing tamoxifen therapy. Biol. Pharm. Bull. 2007;30:367–370. [PubMed[]
47. Muehlenweg B., Sperl S., Magdolen V., Schmitt M., Harbeck N. Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumours. Expert Opin. Biol. Ther. 2001;1:683–691. [PubMed[]
48. Diehl I.J. Antitumour effects of bisphosphonates: First evidence and possible mechanisms. Drugs. 2000;59:391–399. [PubMed[]
49. Bauss F., Bergstrom B. Preclinical and clinical efficacy of the bisphosphonate ibandronate in cancer treatment. Curr. Clin. Pharmacol. 2008;3:1–10. [PubMed[]
50. Clézardin P., Ebetino F.H., Fournier P.G. Bisphosphonates and cancer-induced bone disease: Beyond their antiresorptive activity. Cancer Res. 2005;65:4971–4974. [PubMed[]
51. Kawasaki B.T., Hurt E.M., Mistree T., Farrar W.L. Targeting cancer stem cells with phytochemicals. Mol. Interv. 2008;8:174–184. [PubMed[]
52. Sethi G., Sung B., Aggarwal B.B. Nuclear factor-kappaB activation: From bench to bedside. Exp. Biol. Med. 2008;233:21–31. [PubMed[]
53. Aggarwal B.B., Vijayalekshmi R.V., Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin. Cancer Res. 2009;15:425–430. [PubMed[]
54. Zhou Y., Eppenberger-Castori S., Marx C., Yau C., Scott G.K., Eppenberger U., Benz C.C. Activation of nuclear factor-κB (NFκB) identifies a high-risk subset of hormone-dependent breast cancers. Int. J. Biochem. Cell Biol. 2005;37:1130–1144. [PubMed[]
55. Takada Y., Ichikawa H., Badmaev V., Aggarwal B.B. Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression. J. Immunol. 2006;176:3127–3140. [PubMed[]
56. Safayhi H., Mack T., Sabieraj J., Anazodo M.I., Subramanian L.R., Ammon H.P. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. J. Pharmacol. Exp. Therap. 1992;261:1143–1146.[PubMed[]
57. Zhou J., Zhang H., Gu P., Bai J., Margolick J.B., Zhang Y. NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells. Breast Cancer Res. Treat. 2008;111:419–427.[PMC free article] [PubMed[]
58. Gelmon K., Chan A., Harbeck N. The Role of Capecitabine in First-Line Treatment for Patients with Metastatic Breast Cancer. Oncologist. 2006;11:42–51. [PubMed[]
59. Arpino G., Weiss H., Lee A.V., Schiff R., De Placido S, Osborne C.K., Elledge R.M. Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. J. Natl. Cancer Inst. 2005;97:1254–1261. [PubMed[]
60. Loi S. Molecular analysis of hormone receptor positive (luminal) breast cancers: What have we learnt? Eur. J. Cancer. 2008;44:2813–2818. [PubMed[]
61. Wei B., Wang J., Bourne P., Yang Q., Hicks D, Bu H., Tang P. Bone metastasis is strongly associated with estrogen receptor-positive/progesterone receptor-negative breast carcinomas. Hum. Pathol. 2008;39:1809–1815. [PubMed[]
62. Nakshatri H., Bhat-Nakshatri P., Martin D.A., Goulet R.J., Jr., Sledge G.W., Jr. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol. Cell. Biol. 1997;17:3629–3639. [PMC free article] [PubMed[]

Articles from Cancers are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

 

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]

Abstract

Effects of molecular hydrogen (water ) on various diseases have been documented for 63 disease models and human diseases in the past four and a half years(by 2012(. Most studies have been performed on rodents including two models of Parkinson’s disease and three models of Alzheimer’s disease. Prominent effects are observed especially in oxidative stress-mediated diseases including neonatal cerebral hypoxia; Parkinson’s disease; ischemia/reperfusion of spinal cord, heart, lung, liver, kidney, and intestine; transplantation of lung, heart, kidney, and intestine. Six human diseases have been studied to date: diabetes mellitus type 2, metabolic syndrome, hemodialysis, inflammatory and mitochondrial myopathies, brain stem infarction, and radiation-induced adverse effects.

Two enigmas, however, remain to be solved. First, no dose-response effect is observed. Rodents and humans are able to take a small amount of hydrogen by drinking hydrogen-rich water, but marked effects are observed. Second, intestinal bacteria in humans and rodents produce a large amount of hydrogen, but an addition of a small amount of hydrogen exhibits marked effects. Further studies are required to elucidate molecular bases of prominent hydrogen (water ) effects and to determine the optimal frequency, amount, and method of hydrogen administration for each human disease

1. Introduction

Molecular hydrogen (H2) is the smallest gas molecule made of two protons and two electrons. Hydrogen is combustible when the concentration is 4–75%. Hydrogen, however, is a stable gas that can react only with oxide radical ion (•O) and hydroxyl radical (•OH) in water with low reaction rate constants []:

O+H2H+OHk=8.0×107M1s1OH+H2H+H2Ok=4.2×107M1s1H+OHH2Ok=7.0×109M1s1.
(1)

The reaction rate constants of  •O and •OH with other molecules are mostly in the orders of 109 to 1010 M−1·s−1, whereas those with H2 are in the order of 107 M−1·s−1. Hydrogen, however, is a small molecule that can easily dissipate throughout the body and cells, and the collision rates of hydrogen with other molecules are expected to be very high, which is likely to be able to overcome the low reaction rate constants []. Hydrogen is not easily dissolved in water, and 100%-saturated hydrogen water contains 1.6 ppm or 0.8 mM hydrogen at room temperature( our note: see AlkaViva Vesta H2 water ionizer performance below)

In 1995, hydrogen was first applied to human to overcome high-pressure nervous syndrome in deep sea diving []. Hydrogen was used to reduce nitrogen (N2) toxicity and to reduce breathing resistance in the deep sea. In 2001, being prompted by the radical-scavenging activity of hydrogen, Gharib and colleagues examined an effect of molecular hydrogen on a mouse model of schistosomiasis-associated chronic liver inflammation []. Mice were placed in a chamber with 70% hydrogen gas for two weeks. The mice exhibited decreased fibrosis, improvement of hemodynamics, increased nitric oxide synthase (NOS) II activity, increased antioxidant enzyme activity, decreased lipid peroxide levels, and decreased circulating tumor-necrosis-factor-(TNF-)  α  levels. Although helium gas also exerted some protective effects in their model, the effect of helium gas was not recapitulated in a mouse model of ischemia/reperfusion injury of the liver [].

2. Effects of Hydrogen (water ) Have Been Reported in 63 Disease Models and Human Diseases

A major breakthrough in hydrogen research occurred after Ohsawa and colleagues reported a prominent effect of molecular hydrogen on a rat model of cerebral infarction in June 2007 []. Rats were subjected to left middle cerebral artery occlusion. Rats placed in 2–4% hydrogen gas chamber showed significantly smaller infarction volumes compared to controls. They attributed the hydrogen effect to the specific scavenging activity of hydroxyl radical (•OH). They also demonstrated that hydrogen scavenges peroxynitrite (ONOO) but to a lesser extent.

As have been previously reviewed [], effects of molecular hydrogen on various diseases have been reported since then. The total number of disease models and human diseases for which molecular hydrogen has been proven to be effective has reached 63 (by 2012)(Table 1). The number of papers is increasing each year (Figure 1). Among the 87 papers cited in Table 1, 21 papers showed an effect with inhalation of hydrogen gas, 23 with drinking hydrogen-rich water, 27 with intraperitoneal administration or drip infusion of hydrogen-rich saline, 10 with hydrogen-rich medium for cell or tissue culture, and 6 with the other administration methods including instillation and dialysis solution. In addition, among the 87 papers, 67 papers showed an effect in rodents, 7 in humans, 1 in rabbits, 1 in pigs, and 11 in cultured cells or cultured tissues.

An external file that holds a picture, illustration, etc. Object name is OXIMED2012-353152.001.jpg

Number of papers that report effects of molecular hydrogen since 2007 shown in Table 1.

Table 1

Sixty-three disease models and human diseases for which beneficial effects of hydrogen have been documented.

Diseases Species Administration
Brain
 Cerebral infarction [] Rodent, human Gas, saline
 Cerebral superoxide production [] Rodent Water
 Restraint-induced dementia [] Rodent Water
 Alzheimer’s disease [] Rodent Saline
 Senile dementia in senescence-accelerated mice [] Rodent Water
 Parkinson’s disease [] Rodent Water
 Hemorrhagic infarction [] Rodent Gas
 Brain trauma [] Rodent Gas
 Carbon monoxide intoxication [] Rodent Saline
 Transient global cerebral ischemia [] Rodent Gas
 Deep hypothermic circulatory arrest-induced brain damage [] Rodent Saline
 Surgically induced brain injury [] Rodent Gas
Spinal Cord
 Spinal cord injury [] Rodent Saline
 Spinal cord ischemia/reperfusion [] Rabbit Gas
Eye
 Glaucoma [] Rodent Instillation
 Corneal alkali-burn [] Rodent Instillation
Ear
 Hearing loss [] Tissue, rodent Medium, water
Lung
 Oxygen-induced lung injury [] Rodent Saline
 Lung transplantation [] Rodent Gas
 Paraquat-induced lung injury [] Rodent Saline
 Radiation-induced lung injury [] Rodent Water
 Burn-induced lung injury [] Rodent Saline
 Intestinal ischemia/reperfusion-induced lung injury [] Rodent Saline
Heart
 Acute myocardial infarction [] Rodent Gas, saline
 Cardiac transplantation [] Rodent Gas
 Sleep apnea-induced cardiac hypoxia [] Rodent Gas
Liver
 Schistosomiasis-associated chronic liver inflammation [] Rodent Gas
 Liver ischemia/reperfusion [] Rodent Gas
 Hepatitis [] Rodent Intestinal gas
 Obstructive jaundice [] Rodent Saline
 Carbon tetrachloride-induced hepatopathy [] Rodent Saline
 Radiation-induced adverse effects for liver tumors [] Human Water
Kidney
 Cisplatin-induced nephropathy [] Rodent Gas, water
 Hemodialysis [] Human Dialysis solution
 Kidney transplantation [] Rodent Water
 Renal ischemia/reperfusion [] Rodent Saline
 Melamine-induced urinary stone [] Rodent Water
 Chronic kidney disease [] Rodent Water
Pancreas
 Acute pancreatitis [] Rodent Saline
Intestine
 Intestinal transplantation [] Rodent Gas, medium, saline
 Ulcerative colitis [] Rodent Gas
 Intestinal ischemia/reperfusion [] Rodent Saline
Blood vessel
 Atherosclerosis [] Rodent Water
Muscle
 Inflammatory and mitochondrial myopathies [] Human Water
Cartilage
 NO-induced cartilage toxicity [] Cells Medium
Metabolism
 Diabetes mellitus type I [] Rodent Water
 Diabetes mellitus type II [] Human Water
 Metabolic syndrome [] Human, rodent Water
 Diabetes/obesity [] Rodent Water
Perinatal disorders
 Neonatal cerebral hypoxia [] Rodent, pig Gas, saline
 Preeclampsia [] Rodent Saline
Inflammation/allergy
 Type I allergy [] Rodent Water
 Sepsis [] Rodent Gas
 Zymosan-induced inflammation [] Rodent Gas
 LPS/IFNγ-induced NO production [] Cells Gas
Cancer
 Growth of tongue carcinoma cells [] Cells Medium
 Lung cancer cells [] Cells Medium
 Radiation-induced thymic lymphoma [] Rodent Saline
Others
 UVB-induced skin injury [] Rodent Bathing
 Decompression sickness [] Rodent Saline
 Viability of pluripotent stromal cells [] Cells Gas
 Radiation-induced cell damage [] Cells Medium
 Oxidized low density lipoprotein-induced cell toxicity [] Cells Medium
 High glucose-induced oxidative stress [] Cells Medium

Two papers, however, showed that hydrogen was ineffective for two disease models (Table 2). One such disease was moderate to severe neonatal brain hypoxia [], although marked effects of hydrogen gas [] and intraperitoneal administration of hydrogen-rich saline [] on neonatal brain hypoxia have been reported in rats [] and pigs []. We frequently observe that therapeutic intervention that is effective for mild cases has little or no effect on severe cases, and hydrogen is unlikely to be an exception. Another disease is muscle disuse atrophy []. Although oxidative stress is involved in the development of muscle disuse atrophy, oxidative stress may not be a major driving factor causing atrophy and thus attenuation of oxidative stress by hydrogen may not be able to exhibit a beneficial effect.

Table 2

Two disease models for which hydrogen has no effect.

Diseases Species Administration
Brain

Moderate to severe neonatal brain hypoxia [] Rodent Gas

Muscle

Muscle disuse atrophy [] Rodent Water

Effects of molecular hydrogen have been observed essentially in all the tissues and disease states including the brain, spinal cord, eye, ear, lung, heart, liver, kidney, pancreas, intestine, blood vessel, muscle, cartilage, metabolism, perinatal disorders, and inflammation/allergy. Among them, marked effects are observed in ischemia/reperfusion disorders as well as in inflammatory disorders. It is interesting to note, however, that only three papers addressed effects on cancers. First, molecular hydrogen caused growth inhibition of human tongue carcinoma cells HSC-4 and human fibrosarcoma cells HT-1080 but did not compromise growth of normal human tongue epithelial-like cells DOK []. Second, hydrogen suppressed the expression of vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis, in human lung adenocarcinoma cells A549, which was mediated by downregulation of extracellular signal-regulated kinase (ERK) []. Third, hydrogen protected BALB/c mice from developing radiation-induced thymic lymphoma []. Elimination of radical oxygen species by hydrogen should reduce a probability of introducing somatic mutations. Unlike other disease models, cancer studies were performed only with cells in two of the three papers. Hydrogen is likely to have a beneficial effect on cancer development by suppressing somatic mutations, but an effect on cancer growth and invasion needs to be analyzed further in detail.

3. Effects of Molecular Hydrogen on Rodent Models of Neurodegenerative Diseases

Parkinson’s disease is caused by death of dopaminergic neurons at the substantia nigra pars compact of the midbrain and is the second most common neurodegenerative disease after Alzheimer’s disease. Parkinson’s disease is caused by two mechanisms: excessive oxidative stress and abnormal ubiquitin-proteasome system []. The neurotransmitter, dopamine, is a prooxidant by itself and dopaminergic cells are destined to be exposed to high concentrations of radical oxygen species. An abnormal ubiquitin-proteasome system also causes aggregation of insoluble  α-synuclein in the neuronal cell body that leads to neuronal cell death. We made a rat model of hemi-Parkinson’s disease by stereotactically injecting catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in the right striatum []. Ad libitum administration of hydrogen-rich water starting one week before surgery completely abolished the development of hemi-Parkinson’s symptoms. The number of dopaminergic neurons on the toxin-injected side was reduced to 40.2% of that on the control side, whereas hydrogen treatment improved the reduction to 83.0%. We also started giving hydrogen-rich water three days after surgery, and hemi-Parkinson’s symptoms were again suppressed, but not as much as those observed in pretreated rats. The number of dopaminergic neurons on the toxin-injected side was 76.3% of that on the control side. Pretreated rats were also sacrificed 48 hrs after toxin injection, and the tyrosine hydroxylase activity at the striatum, where dopaminergic neurons terminate, was decreased in both hydrogen and control groups. This indicated that hydrogen did not directly detoxicate 6-OHDA but exerted a delayed protective effect for dopaminergic cells. Fujita and colleagues also demonstrated a similar prominent effect of hydrogen-rich water on an MPTP-(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-) induced mouse model of Parkinson’s disease []. MPTP is a neurotoxin that blocks complex I of the mitochondrial electron transport system and causes Parkinson’s disease in mice and humans. It is interesting to note that the concentration of hydrogen that they used for the MPTP mice was only 0.08 ppm (5% saturation), which is the second lowest among all the trials published to date for rodents and humans. The lowest hydrogen concentration ever tested is 0.048 ppm in the dialysis solution for patients receiving hemodialysis [].

Alzheimer’s disease is the most common neurodegenerative disease and is characterized by abnormal aggregation of β-amyloid (Aβ) and tau, the large aggregates of which are recognizable as senile plaques and neurofibrillary tangles, respectively []. Effects of molecular hydrogen on Alzheimer’s disease have been studied in three rodent models. First, Nagata and colleagues made a mouse model of dementia by restricting movement of mice for 10 hrs a day []. They analyzed cognitive functions through passive avoidance learning, object recognition tasks, and the Morris water maze and demonstrated that ad libitum administration of hydrogen-rich water efficiently ameliorated cognitive impairment. They also showed that neural proliferation in the dentate gyrus was restored by hydrogen water . Second, Li and colleagues made a rat model of Alzheimer’s disease by intracerebroventricular injection of Aβ1-42 []. They analyzed cognitive functions by the Morris water maze open field tasks, and electrophysiological measurement of long-term potentiation (LTP) and found that intraperitoneal injection of hydrogen-rich saline for 14 days efficiently ameliorated cognitive decline and preserved LTP. The same team later reported that the protective effects were mediated by suppression of abnormal activation of IL1β, JNK, and NFκB []. Third, Gu and colleagues used a senescence-accelerated mouse strain (SAMP8) that exhibits early aging syndromes including impairment in learning ability and memory []. Ad libitum administration of hydrogen-rich water for 30 days prevented cognitive decline, which was examined by the Morris water maze. Additionally, ad libitum drinking of hydrogen water for 18 weeks showed efficient amelioration of hippocampal neurodegeneration.

Cerebrovascular diseases are the most frequently reported neurological diseases for which hydrogen (water )has prominent effects. As stated in Section 2, current hydrogen (water ) research has broken out after Ohsawa reported a prominent effect of 2–4% hydrogen for a rat model of left cerebral artery occlusion in 2007 [].

In addition to neurodegenerative disorders of Parkinson’s disease and Alzheimer’s disease, effects of molecular hydrogen (water ) have been reported in eight other brain diseases listed under the categories of “brain” and “perinatal disorders” in Table 1. The brain consumes a large amount of oxygen and is predisposed to be exposed to a large amount of radical oxygen species especially under pathological conditions. Molecular hydrogen is thus likely to exert a prominent beneficial effect on brain diseases.

4. Molecular Hydrogen Is Effective for Six Human Diseases(known by 2012)

As in other therapeutic modalities, effects of molecular hydrogen have been tested mostly on rodents but have also been studied in six human diseases( by 2012). The reported human diseases include diabetes mellitus type II [], metabolic syndrome [], hemodialysis [], inflammatory and mitochondrial myopathies [], brain stem infarction [], and radiation-induced adverse effects for liver tumor []. These studies are reviewed in detail here. In addition, a therapeutic trial for Parkinson’s disease is currently in progress and exhibits favorable responses as far as we know, but the details are not yet disclosed.

First, Kajiyama and colleagues performed a randomized, double-blind, placebo-controlled, crossover study in 30 patients with diabetes mellitus type II and 6 patients with impaired glucose tolerance []. The patients consumed either 900 mL of hydrogen-rich water or placebo water for 8 weeks, with a 12-week washout period. They measured 13 biomarkers to estimate lipid and glucose metabolisms at baseline and at 8 weeks after hydrogen water treatment. All the biomarkers were favorably changed with hydrogen, but statistical significance was observed only in improvement of electronegative charge-modified low-density lipoprotein-(LDL-) cholesterol, small dense LDL, and urinary 8-isoprostanes. In four of six patients with impaired glucose tolerance, hydrogen normalized the oral glucose tolerance test. Lack of statistical significance in their studies was likely due to the small number of patients and the short observation period. Lack of statistical significance, however, may also suggest a less prominent effect in human diabetes mellitus compared to rodent models [].

Second, Nakao and colleagues performed an open-label trial in 20 subjects with potential metabolic syndrome []. Hydrogen-rich water was produced by placing a metallic magnesium stick in water, which yielded 0.55–0.65 mM hydrogen water (70–80% saturation). The participants consumed 1.5–2.0 liters of hydrogen water per day for 8 weeks and showed a 39% increase in urinary superoxide dismutase (SOD), an enzyme that catalyzes superoxide anion (O2); a 43% decrease in urinary thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation; an 8% increase in high-density-lipoprotein-(HDL-) cholesterol; a 13% decrease in total cholesterol/HDL-cholesterol. The aspartate aminotransferase (AST) and alanine transaminase (ALT) levels remained unchanged, whereas the gamma glutamyl transferase (GGT) level was increased by 24% but was still within a normal range. Although the study was not double blinded and placebo controlled, improvements in biomarkers were much more than those in other hydrogen water studies in humans. As this study used a large amount of hydrogen water, the amount of hydrogen might have been a critical determinant. Alternatively, excessive hydration might have prevented the participants from excessive food intake.

Third, Nakayama and colleagues performed an open-label placebo-controlled crossover trial of 12 sessions of hemodialysis in eight patients [] and an open-label trial of 78 sessions of hemodialysis in 21 patients []. In both studies, continuous sessions of hemodialysis with hydrogen-rich dialysis solution decreased systolic blood pressure before and after dialysis. In the short-term study, plasma methylguanidine was significantly decreased. In the long-term study, plasma monocyte chemoattractant protein 1 and myeloperoxidase were significantly decreased.

Fourth, we performed an open-label trial of 1.0 liter of hydrogen water per day for 12 weeks in 14 patients with muscular diseases including muscular dystrophies, polymyositis/dermatomyositis, and mitochondrial myopathies, as well as a randomized, double-blind, placebo-controlled, crossover trial of 0.5 liter of hydrogen water or dehydrogenized water per day for 8 weeks in 22 patients with dermatomyositis and mitochondrial myopathies []. In the open-label trial, significant improvements were observed in lactate-to-pyruvate ratio, fasting blood glucose, serum matrix metalloproteinase-3 (MMP3), and triglycerides. Especially, the lactate-to-pyruvate ratio, which is a sensitive biomarker for the compromised mitochondrial electron transport system, was decreased by 28% in mitochondrial myopathies. In addition, MMP3, which represents the activity of inflammation, was decreased by 27% in dermatomyositis. In the double-blind trial, a statistically significant improvement was observed only in serum lactate in mitochondrial myopathies, but lactate-to-pyruvate ratio in mitochondrial myopathies and MMP3 in dermatomyositis were also decreased. Lack of statistical significance with the double-blind study was likely due to the shorter observation period and the lower amount of hydrogen compared to those of the open-label trial.

Fifth, Kang and colleagues performed a randomized placebo-controlled study of 1.5–2.0 liters of 0.55–0.65 mM hydrogen water per day for 6 weeks in 49 patients receiving radiation therapy for malignant liver tumors. Hydrogen water suppressed the elevation of total hydroperoxide levels, maintained serum antioxidant capacity, and improved the quality of life (QOL) scores. In particular, hydrogen water efficiently prevented loss of appetite. Although the patients were randomly assigned to the hydrogen and placebo groups, the study could not be completely blinded because hydrogen water was produced with a metallic magnesium stick, which generated hydrogen bubbles.

Sixth, Ono and colleagues intravenously administered hydrogen along with Edaravone, a clinically approved radical scavenger, in 8 patients with acute brain stem infarction and compared MRI indices of 26 patients who received Edaravone alone []. The relative diffusion-weighted images (rDWIs), regional apparent diffusion coefficients (rADCs), and pseudonormalization time of rDWI and rADC were all improved with the combined infusion of Edaravone and hydrogen.

No adverse effect of hydrogen has been documented in the six human diseases described above. Among the six diseases, the most prominent effect was observed in subjects with metabolic syndrome, who consumed 1.5–2.0 liters of hydrogen water per day [].

The amount of hydrogen water may be a critical parameter that determines clinical outcome.

It is also interesting to note that lipid and glucose metabolisms were analyzed in three studies and all showed favorable responses to hydrogen [].

Update : since 2012 more clinical trials have been performed.
Acarbose/MOLECULAR HYDROGEN TREATMENT AND THE RISK OF CARDIOVASCULAR DISEASE AND HYPERTENSION IN PATIENTS WITH IMPAIRED GLUCOSE TOLERANCE: THE STOP-NIDDM TRIAL

Molecular  Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome

Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases.

Molecular hydrogen(H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers

MOLECULAR HYDROGEN WATER FOR PATIENTS WITH PRESSURE ULCER – EFFECTS ON NORMAL HUMAN SKIN WOUNDS

MOLECULAR HYDROGEN WATER FOR PATIENTS WITH RHEUMATOID ARTHRITIS: AN OPEN-LABEL PILOT STUDY

EFFECTIVENESS OF ORAL AND TOPICAL MOLECULAR HYDROGEN FOR SPORTS-RELATED SOFT TISSUE INJURIES

MOLECULAR HYDROGEN WATER BENEFITS FOR ATHLETES, EXERCISE, MUSCLE FATIGUE

MOLECULAR HYDROGEN WATER FOR VASCULAR ENDOTELIAL FUNCTION

MOLECULAR HYDROGEN WATER-  PERIODONTITIS TREATMENT
Please see this section:Hydrogen water 

5. Molecular Bases of Hydrogen Effects

Effects of hydrogen on various diseases have been attributed to four major molecular mechanisms: a specific scavenging activity of  hydroxyl radical, a scavenging activity of peroxynitrite, alterations of gene expressions, and signal-modulating activities. The four mechanisms are not mutually exclusive and some of them may be causally associated with other mechanisms.

The first molecular mechanism identified for hydrogen was its specific scavenging activity of hydroxyl radical []. Indeed, oxidative stress markers like 8-OHdG, 4-hydroxyl-2-nonenal (4-HNE), malondialdehyde (MDA), and thiobarbituric acid reactive substances (TBARSs) are decreased in all the examined patients and rodents. As hydrogen can easily dissipate in exhalation, hydrogen in drinking water is able to stay in human and rodent bodies in less than 10 min (unpublished data). Hydrogen, however, can bind to glycogen, and the dwell time of hydrogen is prolonged in rat liver after food intake []. A question still remains if mice and humans can take a sufficient amount of hydrogen that efficiently scavenges hydroxyl radicals that are continuously generated in normal and disease states.

Another molecular mechanism of hydrogen effect is its peroxynitrite-(ONOO-) scavenging activity []. Although hydrogen cannot eliminate peroxynitrite as efficiently as hydroxyl radical in vitro [], hydrogen can efficiently reduce nitric-oxide-(NO-) induced production of nitrotyrosine in rodents []. NO is a gaseous molecule that also exerts therapeutic effects including relaxation of blood vessels and inhibition of platelet aggregation []. NO, however, is also toxic at higher concentrations because NO leads to ONOO-mediated production of nitrotyrosine, which compromises protein functions. A part of hydrogen effects may thus be attributed to the reduced production of nitrotyrosine.

Expression profiling of rat liver demonstrated that hydrogen has a minimal effect on expression levels of individual genes in normal rats []. Gene ontology analysis, however, revealed that oxidoreduction-related genes were upregulated. In disease models of rodents, expression of individual genes and proteins is analyzed. In many disease models, hydrogen downregulated proinflammatory cytokines including tumor necrosis-factor-(TNF-)  α, interleukin-(IL-) 1β, IL-6, IL-12, interferon-(IFN-)  γ, and high mobility group box 1 (HMGB1) []. Hydrogen also downregulated nuclear factors including nuclear factor kappa B (NFκB), JNK, and proliferation cell nuclear antigen (PCNA) []. Caspases were also downregulated []. Other interesting molecules studied to date include vascular endothelial growth factor (VEGF) []; MMP2 and MMP9 []; brain natriuretic peptide []; intercellular-adhesion-molecule-1 (ICAM-1) and myeloperoxidase []; B-cell lymphoma 2 (Bcl2) and Bcl2-associated X protein (Bax) []; MMP3 and MMP13 []; cyclooxygenase 2 (COX-2), neuronal nitric oxide synthase (nNOS), and connexins 30 and 43 []; ionized calcium binding adaptor molecule 1 (Iba1) []; fibroblast growth factor 21 (FGF21) []. Most molecules, however, are probably passengers that are secondarily changed by hydrogen administration, and some are potentially direct targets of hydrogen effects, which need to be identified in the future.

Using rat RBL-2H3 mast cells, we demonstrated that hydrogen attenuates phosphorylation of FcεRI-associated Lyn and its downstream signaling molecules []. As phosphorylation of Lyn is again regulated by the downstream signaling molecules and makes a loop of signal transduction pathways, we could not identify the exact target of hydrogen. Our study also demonstrated that hydrogen ameliorates an immediate-type allergic reaction not by radical-scavenging activity but by direct modulation of signaling pathway(s). In addition, using murine RAW264 macrophage cells, we demonstrated that hydrogen reduces LPS/IFNγ-induced NO production []. We found that hydrogen inhibits phosphorylation of ASK1 and its downstream signaling molecules, p38 MAP kinase, JNK, and IκBα  without affecting ROS production by NADPH oxidase. Both studies point to a notion that hydrogen is a gaseous signal modulator. More animal and cells models are expected to be explored to confirm that hydrogen exerts its beneficial effect as a signal modulator.

6. Enigmas of Hydrogen Effects

Two enigmas remain to be solved for hydrogen effects. First, no dose-response effect of hydrogen has been observed. Hydrogen has been administered to animals and humans in the forms of hydrogen gas, hydrogen-rich water, hydrogen-rich saline, instillation, and dialysis solution (Table 1). Supposing that a 60-kg person drinks 1000 mL of saturated hydrogen-rich water (1.6 ppm or 0.8 mM) per day, 0.8 mmoles of hydrogen is consumed by the body each day, which is predicted to give rise to a hydrogen concentration of 0.8 mmoles/(60 kg × 60%) = 0.022 mM (2.8% saturation = 0.022 mM/0.8 mM). As hydrogen mostly disappears in 10 min by dissipation in exhalation (unpublished data), an individual is exposed to 2.8% hydrogen only for 10 min. On the other hand, when a person is placed in a 2% hydrogen environment for 24 hrs, body water is predicted to become 2% saturation (0.016 mM). Even if we suppose that the hydrogen concentration after drinking hydrogen water remains the same for 10 min, areas under the curves of hydrogen water and 2% hydrogen gas are 0.022 mM × 1/6 hrs and 0.016 mM × 24 hrs, respectively. Thus, the amount of hydrogen given by 2% hydrogen gas should be 104 or more times higher than that given by drinking hydrogen water. In addition, animals and patients are usually not able to drink 100%-saturated hydrogen water. If the hydrogen concentration is 72% of the saturation level, the peak concentrations achieved by drinking hydrogen water and 2% hydrogen gas should be identical (0.022 mM × 72% = 0.016 mM). Nevertheless, hydrogen water is as effective as, or sometimes more effective than, hydrogen gas.

In addition, orally taken hydrogen can be readily distributed in the stomach, intestine, liver, heart, and lung but is mostly lost in exhalation. Thus, hydrogen concentrations in the arteries are predicted to be very low. Nevertheless, marked hydrogen effects are observed in the brain, spinal cord, kidney, pancreas muscle, and cartilage, where hydrogen is carried via arteries.

The second enigma is intestinal production of hydrogen gas in rodents and humans. Although no mammalian cells can produce hydrogen endogenously, hydrogen is produced by intestinal bacteria carrying hydrogenase in both rodents and humans. We humans are able to make a maximum of 12 liters of hydrogen in our intestines []. Specific-pathogen-free (SPF) animals are different from aseptic animals and carry intestinal bacteria that produce hydrogen. The amount of hydrogen taken by water or gas is much less than that produced by intestinal bacteria, but the exogenously administered hydrogen demonstrates a prominent effect.

In a mouse model of Concanavalin A-induced hepatitis, Kajiya and colleagues killed intestinal bacteria by prescribing a cocktail of antibiotics []. Elimination of intestinal hydrogen worsened hepatitis. Restitution of a hydrogenase-negative strain of E. coli had no effects, whereas that of a hydrogenase-positive strain of E. coli ameliorated hepatitis. This is the only report that addressed a beneficial effect of intestinal bacteria, and no human study has been reported to date. Kajiya and colleagues also demonstrated that drinking hydrogen-rich water was more effective than the restitution of hydrogenase-positive bacteria. If intestinal hydrogen is as effective as the other hydrogen administration methods, we can easily increase hydrogen concentrations in our bodies by an  α-glucosidase inhibitor, acarbose [], an ingredient of curry, turmeric [], or a nonabsorbable synthetic disaccharide, lactulose []. The enigma of intestinal bacteria thus needs to be solved in the future.

7. Summary and Conclusions

Effects of hydrogen have been reported in 63 disease models and human diseases (Table 1). Only two diseases of cerebral infarction and metabolic syndrome have been analyzed in both rodents and humans.

Lack of any adverse effects of hydrogen enabled clinical studies even in the absence of animal studies. Some other human studies including Parkinson’s disease are currently in progress, and promising effects of hydrogen are expected to emerge for many other human diseases. We also have to elucidate molecular bases of hydrogen effects in detail.

8. Added Note in Proof

We recently reported a line of evidence that molecular hydrogen has no dose-response effect in a rat model of Parkinson’s disease [].

 

Logo of oximed

Oxidative Medicine and Cellular Longevity
. 2012; 2012: 353152.
Published online 2012 Jun 8. doi:  [10.1155/2012/353152]
PMCID: PMC3377272
PMID: 22720117

Molecular Hydrogen as an Emerging Therapeutic Medical Gas for Neurodegenerative and Other Diseases

1Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan
2Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi 487-8501, Japan
3Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
Academic Editor: Marcos Dias Pereira
Received 2012 Jan 11; Revised 2012 Mar 24; Accepted 2012 Apr 13.

Acknowledgments

Works performed in the authors’ laboratories were supported by Grants-in-Aid from the MEXT and MHLW of Japan and from the Priority Research Project of Aichi.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377272/

References

1. Buxton GV, Greenstock CL, Helman WP, Ross AB. Critical view of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (•OH/•OH) in aqueous solution. Journal of Physical and Chemical Reference Data1988;17:513–886.
2. Chuai Y, Gao F, Li B, et al. Hydrogen-rich saline attenuates radiation-induced male germ cell loss in mice through reducing hydroxyl radicals. Biochemical Journal2012;442:49–56. [PubMed]
3. Lafay V, Barthelemy P, Comet B, Frances Y, Jammes Y. ECG changes during the experimental human dive HYDRA 10 (71 atm/7,200 kPa) Undersea & Hyperbaric Medicine1995;22(1):51–60. [PubMed]
4. Gharib B, Hanna S, Abdallahi OMS, Lepidi H, Gardette B, De Reggi M. Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation. Comptes Rendus de l’Academie des Sciences—Serie III2001;324(8):719–724. [PubMed]
5. Fukuda KI, 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. Biochemical and Biophysical Research Communications2007;361(3):670–674. [PubMed]
6. Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nature Medicine2007;13(6):688–694. [PubMed]
7. Huang CS, Kawamura T, Toyoda Y, Nakao A. Recent advances in hydrogen research as a therapeutic medical gas. Free Radical Research2010;44(9):971–982. [PubMed]
8. Ohta S. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Current Pharmaceutical Design2011;17:2241–2252. [PMC free article][PubMed]
9. Matchett GA, Fathali N, Hasegawa Y, et al. Hydrogen gas is ineffective in moderate and severe neonatal hypoxia-ischemia rat models. Brain Research2009;1259:90–97. [PubMed]
10. Cai J, Kang Z, Liu WW, et al. Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neuroscience Letters2008;441(2):167–172. [PubMed]
11. Domoki F, Oláh O, Zimmermann A, et al. Hydrogen is neuroprotective and preserves cerebrovascular reactivity in asphyxiated newborn pigs. Pediatric Research2010;68(5):387–392. [PubMed]
12. Cai JM, Kang Z, Liu K, et al. Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Research2009;1256:129–137. [PubMed]
13. Fujita R, Tanaka Y, Saihara Y, et al. Effect of molecular hydrogen saturated alkaline electrolyzed water on disuse muscle atrophy in gastrocnemius muscle. Journal of Physiological Anthropology2011;30:195–201. [PubMed]
14. Saitoh Y, Okayasu H, Xiao L, Harata Y, Miwa N. Neutral pH hydrogen-enriched electrolyzed water achieves tumor-preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression. Oncology Research2008;17(6):247–255. [PubMed]
15. Ye J, Li Y, Hamasaki T, et al. Inhibitory effect of electrolyzed reduced water on tumor angiogenesis. Biological and Pharmaceutical Bulletin2008;31(1):19–26. [PubMed]
16. Zhao L, Zhou C, Zhang J, et al. Hydrogen protects mice from radiation induced thymic lymphoma in BALB/c mice. International Journal of Biological Sciences2011;7(3):297–300. [PMC free article][PubMed]
17. Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. The Lancet Neurology2008;7(1):97–109. [PubMed]
18. 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. Neuroscience Letters2009;453(2):81–85.[PubMed]
19. 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 ONE2009;4(9) Article ID e7247. [PMC free article] [PubMed]
20. Nakayama M, Nakano H, Hamada H, Itami N, Nakazawa R, Ito S. A novel bioactive haemodialysis system using dissolved dihydrogen (H2) produced by water electrolysis: a clinical trial. Nephrology Dialysis Transplantation2010;25(9):3026–3033. [PubMed]
21. Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Annals of Neurology2011;70:532–540. [PMC free article] [PubMed]
22. 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. Neuropsychopharmacology2009;34(2):501–508. [PubMed]
23. Li J, Wang C, Zhang JH, Cai JM, Cao YP, Sun XJ. Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Research2010;1328:152–161. [PubMed]
24. Wang C, Li J, Liu Q, et al. 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. Neuroscience Letters2011;491(2):127–132. [PubMed]
25. Gu Y, Huang CS, Inoue T, et al. Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. Journal of Clinical Biochemistry and Nutrition2010;46(3):269–276.[PMC free article] [PubMed]
26. 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. Nutrition Research2008;28(3):137–143. [PubMed]
27. 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. Journal of Clinical Biochemistry and Nutrition2010;46(2):140–149. [PMC free article] [PubMed]
28. Nakayama M, Kabayama S, Nakano H, et al. Biological effects of electrolyzed water in hemodialysis. Nephron2009;112(1):C9–C15. [PubMed]
29. Ito M, Ibi T, Sahashi K, Ichihara M, Ohno K. Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Medical Gas Research2011;1, article 24 [PMC free article] [PubMed]
30. Ono H, Nishijima Y, Adachi N, et al. Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study. Medical Gas Research2011;1, article 12 [PMC free article] [PubMed]
31. Kang KM, Kang YN, Choi IB, et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Medical Gas Research2011;1, article 11[PMC free article] [PubMed]
32. Li Y, Hamasaki T, Nakamichi N, et al. Suppressive effects of electrolyzed reduced water on alloxan-induced apoptosis and type 1 diabetes mellitus. Cytotechnology2011;63(2):119–131. [PMC free article][PubMed]
33. Kamimura N, Nishimaki K, Ohsawa I, Ohta S. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity2011;19(7):1396–1403. [PubMed]
34. Chen CH, Manaenko A, Zhan Y, et al. Hydrogen gas reduced acute hyperglycemia-enhanced hemorrhagic transformation in a focal ischemia rat model. Neuroscience2010;169(1):402–414.[PMC free article] [PubMed]
35. Yu P, Wang Z, Sun X, et al. Hydrogen-rich medium protects human skin fibroblasts from high glucose or mannitol induced oxidative damage. Biochemical and Biophysical Research Communications2011;409(2):350–355. [PubMed]
36. Zhang Y, Sun Q, He B, Xiao J, Wang Z, Sun X. Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion. International Journal of Cardiology2011;148(1):91–95. [PubMed]
37. Zhu WJ, Nakayama M, Mori T, et al. Intake of water with high levels of dissolved hydrogen (H2) suppresses ischemia-induced cardio-renal injury in Dahl salt-sensitive rats. Nephrology Dialysis Transplantation2011;26(7):2112–2118. [PubMed]
38. Hanaoka T, Kamimura N, Yokota T, Takai S, Ohta S. Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide. Medical Gas Research2011;1, article 18 [PMC free article] [PubMed]
39. Thomas DD, Ridnour LA, Isenberg JS, et al. The chemical biology of nitric oxide: implications in cellular signaling. Free Radical Biology and Medicine2008;45(1):18–31. [PMC free article] [PubMed]
40. Nakai Y, Sato B, Ushiama S, Okada S, Abe K, Arai S. Hepatic oxidoreduction-related genes are upregulated by administration of hydrogen-saturated drinking water. Bioscience, Biotechnology and Biochemistry2011;75(4):774–776. [PubMed]
41. Buchholz BM, Kaczorowski DJ, Sugimoto R, et al. Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. American Journal of Transplantation2008;8(10):2015–2024. [PubMed]
42. Kajiya M, Silva MJB, Sato K, Ouhara K, Kawai T. Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate. Biochemical and Biophysical Research Communications2009;386(1):11–15. [PubMed]
43. Kajiya M, Sato K, Silva MJB, et al. Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis. Biochemical and Biophysical Research Communications2009;386(2):316–321.[PubMed]
44. Mao YF, Zheng XF, Cai JM, et al. Hydrogen-rich saline reduces lung injury induced by intestinal ischemia/reperfusion in rats. Biochemical and Biophysical Research Communications2009;381(4):602–605. [PubMed]
45. Zheng X, Mao Y, Cai J, et al. Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radical Research2009;43(5):478–484. [PubMed]
46. Nakao A, Kaczorowski DJ, Wang Y, et al. Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. Journal of Heart and Lung Transplantation2010;29(5):544–553. [PubMed]
47. Liu Q, Shen WF, Sun HY, et al. Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice. Liver International2010;30(7):958–968. [PubMed]
48. Hayashi T, Yoshioka T, Hasegawa K, et al. Inhalation of hydrogen gas attenuates left ventricular remodeling induced by intermittent hypoxia in mice. American Journal of Physiology2011;301:H1062–H1069. [PubMed]
49. Yoon KS, Huang XZ, Yoon YS, et al. Histological study on the effect of electrolyzed reduced water-bathing on UVB radiation-induced skin injury in hairless mice. Biological and Pharmaceutical Bulletin2011;34:1671–1677. [PubMed]
50. Song G, Tian H, Liu J, Zhang H, Sun X, Qin S. H2 inhibits TNF-α-induced lectin-like oxidized LDL receptor-1 expression by inhibiting nuclear factor κB activation in endothelial cells. Biotechnology Letters2011;33(9):1715–1722. [PubMed]
51. Huang Y, Xie K, Li J, et al. Beneficial effects of hydrogen gas against spinal cord ischemia-reperfusion injury in rabbits. Brain Research2011;1378:125–136. [PubMed]
52. Sun Q, Cai J, Zhou J, et al. Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity. Critical Care Medicine2011;39(4):765–769. [PubMed]
53. Sun QA, Cai J, Liu S, et al. Hydrogen-rich saline provides protection against hyperoxic lung injury. Journal of Surgical Research2011;165(1):e43–e49. [PubMed]
54. Wang F, Yu G, Liu SY, et al. Hydrogen-rich saline protects against renal ischemia/reperfusion injury in rats. Journal of Surgical Research2011;167(2):e339–e344. [PubMed]
55. 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. Journal of Surgical Research2011;168(1):e95–e101. [PubMed]
56. Liu Y, Liu W, Sun X, et al. Hydrogen saline offers neuroprotection by reducing oxidative stress in a focal cerebral ischemia-reperfusion rat model. Medical Gas Research2011;1, article 15 [PMC free article][PubMed]
57. Shen L, Wang J, Liu K, et al. Hydrogen-rich saline is cerebroprotective in a rat model of deep hypothermic circulatory arrest. Neurochemical Research2011;36(8):1501–1511. [PubMed]
58. Yang X, Guo L, Sun X, Chen X, Tong X. Protective effects of hydrogen-rich saline in preeclampsia rat model. Placenta2011;32:681–686. [PubMed]
59. Buchholz BM, Masutani K, Kawamura T, et al. Hydrogen-enriched preservation protects the isogeneic intestinal graft and amends recipient gastric function during transplantation. Transplantation2011;92:985–992. [PubMed]
60. Huang CS, Kawamura T, Peng X, et al. Hydrogen inhalation reduced epithelial apoptosis in ventilator-induced lung injury via a mechanism involving nuclear factor-kappa B activation. Biochemical and Biophysical Research Communications2011;408(2):253–258. [PubMed]
61. Kubota M, Shimmura S, Kubota S, et al. Hydrogen and N-acetyl-L-cysteine rescue oxidative stress-induced angiogenesis in a mouse corneal alkali-burn model. Investigative Ophthalmology and Visual Science2011;52(1):427–433. [PubMed]
62. Sun H, Chen L, Zhou W, et al. The protective role of hydrogen-rich saline in experimental liver injury in mice. Journal of Hepatology2011;54(3):471–480. [PubMed]
63. Chen H, Sun YP, Hu PF, et al. The effects of hydrogen-rich saline on the contractile and structural changes of intestine induced by ischemia-reperfusion in rats. Journal of Surgical Research2011;167(2):316–322. [PubMed]
64. Itoh T, Fujita Y, Ito M, et al. Molecular hydrogen suppresses FcεRI-mediated signal transduction and prevents degranulation of mast cells. Biochemical and Biophysical Research Communications2009;389(4):651–656. [PubMed]
65. Sun Q, Kang Z, Cai J, et al. Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Experimental Biology and Medicine2009;234(10):1212–1219. [PubMed]
66. Hugyecz M, Mracskó É, Hertelendy P, Farkas E, Domoki F, Bari F. Hydrogen supplemented air inhalation reduces changes of prooxidant enzyme and gap junction protein levels after transient global cerebral ischemia in the rat hippocampus. Brain Research2011;1404:31–38. [PubMed]
67. Itoh T, Hamada N, Terazawa R, et al. Molecular hydrogen inhibits lipopolysaccharide/interferon γ-induced nitric oxide production through modulation of signal transduction in macrophages. Biochemical and Biophysical Research Communications2011;411(1):143–149. [PubMed]
68. Christl SU, Murgatroyd PR, Gibson GR, Cummings JH. Production, metabolism, and excretion of hydrogen in the large intestine. Gastroenterology1992;102(4):1269–1277. [PubMed]
69. Strocchi A, Levitt MD. Maintaining intestinal H2 balance: credit the colonic bacteria. Gastroenterology1992;102(4):1424–1426. [PubMed]
70. Suzuki Y, Sano M, Hayashida K, Ohsawa I, Ohta S, Fukuda K. Are the effects of α-glucosidase inhibitors on cardiovascular events related to elevated levels of hydrogen gas in the gastrointestinal tract? FEBS Letters2009;583(13):2157–2159. [PubMed]
71. Shimouchi A, Nose K, Takaoka M, Hayashi H, Kondo T. Effect of dietary turmeric on breath hydrogen. Digestive Diseases and Sciences2009;54(8):1725–1729. [PubMed]
72. Corazza GR, Sorge M, Strocchi A, et al. Non-absorbable antibiotics and small bowel bacterial overgrowth. Italian Journal of Gastroenterology1992;24(9):4–9. [PubMed]
73. Chen X, Zuo Q, Hai Y, Sun XJ. Lactulose: an indirect antioxidant ameliorating inflammatory bowel disease by increasing hydrogen production. Medical Hypotheses2011;76(3):325–327. [PubMed]
74. Ito M, Hirayama M, Yamai K, et al. Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Medical Gas Research2012;2, article 15 [PMC free article] [PubMed]
75. Sato Y, Kajiyama S, Amano A, et al. Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochemical and Biophysical Research Communications2008;375(3):346–350. [PubMed]
76. 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 Research2010;1354:196–205. [PubMed]
77. Eckermann JM, Chen W, Jadhav V, et al. Hydrogen is neuroprotective against surgically induced brain injury. Medical Gas Research2011;1, article 7 [PMC free article] [PubMed]
78. Chen C, Chen Q, Mao Y, et al. Hydrogen-rich saline protects against spinal cord injury in rats. Neurochemical Research2010;35(7):1111–1118. [PubMed]
79. Oharazawa H, Igarashi T, Yokota T, et al. Protection of the retina by rapid diffusion of hydrogen: administration of hydrogen-loaded eye drops in retinal ischemia-reperfusion injury. Investigative Ophthalmology and Visual Science2010;51(1):487–492. [PubMed]
80. Kikkawa YS, Nakagawa T, Horie RT, Ito J. Hydrogen protects auditory hair cells from free radicals. NeuroReport2009;20(7):689–694. [PubMed]
81. Taura A, Kikkawa YS, Nakagawa T, Ito J. Hydrogen protects vestibular hair cells from free radicals. Acta Oto-Laryngologica2010;130(563):95–100. [PubMed]
82. Lin Y, Kashio A, Sakamoto T, Suzukawa K, Kakigi A, Yamasoba T. Hydrogen in drinking water attenuates noise-induced hearing loss in guinea pigs. Neuroscience Letters2011;487(1):12–16. [PubMed]
83. Zheng J, Liu K, Kang Z, et al. Saturated hydrogen saline protects the lung against oxygen toxicity. Undersea and Hyperbaric Medicine2010;37(3):185–192. [PubMed]
84. Huang CS, Kawamura T, Lee S, et al. Hydrogen inhalation ameliorates ventilator-induced lung injury. Critical Care2010;14(6, article R234) [PMC free article] [PubMed]
85. Kawamura T, Huang CS, Tochigi N, et al. Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/reperfusion injury in rats. Transplantation2010;90(12):1344–1351.[PubMed]
86. Liu S, Liu K, Sun Q, et al. Consumption of hydrogen water reduces paraquat-induced acute lung injury in rats. Journal of Biomedicine and Biotechnology2011;2011:7 pages. Article ID 305086. [PMC free article] [PubMed]
87. Qian L, Cao F, Cui J, et al. The potential cardioprotective effects of hydrogenin irradiated mice. Journal of Radiation Research2010;51(6):741–747. [PubMed]
88. Terasaki Y, Ohsawa I, Terasaki M, et al. Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. American Journal of Physiology2011;301:L415–L426. [PubMed]
89. Chuai Y, Zhao L, Ni J, et al. A possible prevention strategy of radiation pneumonitis: combine radiotherapy with aerosol inhalation of hydrogen-rich solution. Medical Science Monitor2011;17(4):1–4.[PMC free article] [PubMed]
90. Fang Y, Fu XJ, Gu C, et al. Hydrogen-rich saline protects against acute lung injury induced by extensive burn in rat model. Journal of Burn Care and Research2011;32(3):e82–e91. [PubMed]
91. Hayashida K, Sano M, Ohsawa I, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochemical and Biophysical Research Communications2008;373(1):30–35. [PubMed]
92. 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 Chemotherapy and Pharmacology2009;64(4):753–761. [PubMed]
93. 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. British Journal of Radiology2010;83(990):509–514. [PMC free article] [PubMed]
94. 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. Japanese Journal of Radiology2011;29:503–512. [PubMed]
95. Cardinal JS, Zhan J, Wang Y, et al. Oral hydrogen water prevents chronic allograft nephropathy in rats. Kidney International2010;77(2):101–109. [PubMed]
96. Yoon YS, Kim DH, Kim SK, et al. The melamine excretion effect of the electrolyzed reduced water in melamine-fed mice. Food and Chemical Toxicology2011;49(8):1814–1819. [PubMed]
97. Chen H, Sun YP, Li Y, et al. Hydrogen-rich saline ameliorates the severity of l-arginine-induced acute pancreatitis in rats. Biochemical and Biophysical Research Communications2010;393(2):308–313.[PubMed]
98. Ohsawa I, Nishimaki K, Yamagata K, Ishikawa M, Ohta S. Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochemical and Biophysical Research Communications2008;377(4):1195–1198. [PubMed]
99. Hashimoto M, Katakura M. Effects of hydrogen-rich water on abnormalities in a SHR.Cg-Leprcp/NDmcr rat—a metabolic syndrome rat model. Medical Gas Research2011;1, article 26[PMC free article] [PubMed]
100. Xie K, Yu Y, Pei Y, et al. Protective effects of hydrogen gas on murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. Shock2010;34(1):90–97. [PubMed]
101. Xie KL, Yu YH, Zhang ZS, et al. Hydrogen gas improves survival rate and organ damage in zymosan-induced generalized inflammation model. Shock2010;34(5):495–501. [PubMed]
102. Ni XX, Cai ZY, Fan DF, et al. Protective effect of hydrogen-rich saline on decompression sickness in rats. Aviation Space and Environmental Medicine2011;82(6):604–609. [PubMed]
103. Kawasaki H, Guan J, Tamama K. Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials. Biochemical and Biophysical Research Communications2010;397(3):608–613. [PubMed]
104. Qian LR, Cao F, Cui J, et al. Radioprotective effect of hydrogen in cultured cells and mice. Free Radical Research2010;44(3):275–282. [PubMed]
105. Qian LR, Li BL, Cao F, et al. Hydrogen-rich PBS protects cultured human cells from ionizing radiation-induced cellular damage. Nuclear Technology and Radiation Protection2010;25(1):23–29.

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Molecular Hydrogen water effects on Mild Cognitive Impairment

Abstract

Background:

Oxidative stress is one of the causative factors in the pathogenesis of neuro-degenerative diseases including mild cognitive impairment (MCI) and dementia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive antioxidant.

Objective:

We assess the effects of drinking H2 hydrogen-water (water infused with hydrogen gas H2) on oxidative stress model mice and human subjects with MCI.

Methods:

Transgenic mice expressing a dominant-negative form of aldehyde dehydrogenase 2 were used as a dementia model. The mice with enhanced oxidative stress were allowed to drink hydrogen H2-water.

For a ran-domized double-blind placebo-controlled clinical study, 73 subjects with mild cognitive impairment MCI drank ~300 mL of hydrogen H2-water (H2-group) or placebo water (control group) per day, and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores were determined after 1 year.

Results:

In mice, drinking hydrogen H2-water decreased oxidative stress markers and suppressed the decline of memory impairment and neurodegeneration. Moreover, the mean lifespan in the hydrogen H2-water group was longer than that of the control group.’

In MCI subjects, although there was no significant difference between the hydrogen water H2- and control groups in ADAS-cog score after 1 year, carriers of the apolipoprotein E4 (APOE4) geno-type in the H2-group were improved significantly on total ADAS-cog score and word recall task score (one of the sub-scores in the ADAS-cog score).

Conclusion:

H2-water may have a potential for suppressing dementia in an oxidative stress model and in the APOE4 carriers with MCI.

1. INTRODUCTION

Oxidative stress is one of the causative factors in the pathogenesis of major neurodegenerative diseases including Alzheimer’s disease (AD), mild cognitive impairment (MCI), and Parkinson disease (PD) []. Moreover, the genotype of apolipoprotein E4 (APOE4) is a genetic risk for AD, and the increased oxidative stress in the APOE4 carriers is considered as one of the modifiers for the risk [].

To explore effective dietary antioxidants to mitigate age-dependent neurodegeneration, it may be useful to construct model mice in which AD phenotypes would progress in an age-dependent manner in response to oxidative stress. We constructed transgenic DAL101 mice expressing a polymorphism of the mitochondrial aldehyde dehydrogenase 2 gene (ALDH2*2) []. ALDH2*2 is responsible for a deficiency in ALDH2 activity and is specific to North-East Asians []. We reported previously that ALDH2 deficiency is a risk factor for late-onset AD in the Japanese population, [] which was reproduced by Chinese and Korean studies in their respective populations []. DAL101 mice exhibited a decreased ability to detoxify 4-hydroxy-2-nonenal (4-HNE) in cortical neurons, and consequently an age-dependent neurodegeneration, cognitive decline, and a shortened lifespan [].

We proposed that molecular hydrogen (H2) has potential as a novel antioxidant, [] and numerous studies have strongly suggested its potential for preventive and therapeutic applications []. In addition to extensive animal experiments, more than 25 clinical studies examining the efficacy of molecular hydrogen H2 have been reported, [] including double-blind clinical studies. Based on these studies, the field of hydrogen medicine is growing rapidly.

There are several methods to administer hydrogen H2, including inhaling hydrogen gas (H2-gas), drinking hydrogen H2-dissolved water (H2-water), and injecting hydrogen H2-dissolved saline (hydrogen-rich saline) []. Drinking hydrogen H2-water prevented the chronic stress-induced impairments in learning and memory by reducing oxidative stress in mice [] and protects neural cells by stimulating the hormonal expression of ghrelin []. Additionally, injection of hydrogen-rich saline improved memory function in a rat model of amyloid-β-induced dementia by reducing oxidative stress []. Moreover, hydrogen inhalation during normoxic resuscitation improved neurological outcome in a rat model of cardiac arrest independently of targeted temperature management [].

In this study, we examined whether drinking hydrogen H2-water could suppress aging-dependent memory impairment induced by oxidative stress in DAL101 mice. Next, in a randomized double-blind placebo-controlled study, we investigated whether H2-water could delay the progression of MCI as assessed by the scores on the Alzheimer’s Disease Assessment Scale-cognition sub-scale (ADAS-cog) [] from baseline at 1-year. We found a significant improvement in cognition at 1 year in carriers with the APOE4 genotype in the H2-group using sub- and total ADAS-cog scores.

2. MATERIALS AND METHODS

2.1. Ethical Approval and Consent to Participate

This animal study was approved by the Animal Care and Use Committee of Nippon Medical School. The methods were carried out in “accordance” with the relevant guidelines and regulations.

The clinical study protocol was approved by the ethics committees of University of Tsukuba, and registered in the university hospital medical information network (UMIN) as UMIN000002218 on July 17, 2009 at https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=history&action =list&type= summary&recptno= R000002-725&language=J.

Participants were enrolled from July 2009. All patients provided written informed consent prior to research investigations, which were conducted according to the Declaration of Helsinki and subsequent revisions.

2.2. Transgenic DAL101 Mice

Transgenic mice (DAL101) that express a transgene containing a mouse version of ALDH2*2 were constructed as described previously []. Since the number of mice used for each experiment was not consistent because of a breeding difficulty, the number of the mice used was specified. All mice were kept in a 12-hr light/dark cycle with ad libitum access to food and water. Examiners performed experiments in a blinded fashion. Since no significant decline was observed in cognitive impairment at the age of 18 months in wild-type mice with the same genetic background (C57BL/6), [] the effects of hydrogen H2-water were not assessed in this study.

2.3. Hydrogen Water

For animal experiments, saturated hydrogen H2-water was prepared as described previously []. In brief, hydrogen  H2 was dissolved in water under high pressure (0.4 MPa) to a supersaturated level, and the saturated H2-water was stored under atmospheric pressure in an aluminum bag with no headspace. As a control, H2-water was completely degassed by gentle stirring for one day. Mice were given water freely using closed glass vessels equipped with an outlet line containing two ball bearings, which kept the water from being degassed. The vessel was freshly refilled with H2-water 6 days per week at 2:00 pm. The hydrogen H2-concentration was still more than 0.3 mM on the next day.

For this clinical study, commercially available hydrogen H2-water was a gift from Blue Mercury, Inc. (Tokyo, Japan). The hydrogen H2-water (500 mL) was packed in an aluminum pouch with no headspace to maintain H2 concentration, and sterilized at 80°C for 30 min. The concentration of hydrogen H2 was measured using a hydrogen sensor (Unisense, Aarhus N, Denmark), and used if the value was more than 0.6 mM. Placebo water packed in an identical package (500 mL) was also provided by Blue Mercury Inc. This company played no role in collection of data, management, analysis, or interpretation of the data. One package with 500 mL of placebo or hydrogen H2-water per day was provided after showing previous empty packages, by which self-reported compliance rates in the intervention group were calculated as the volume of hydrogen  H2-water at 1-year.

2.4. Measurement of Oxidative Stress

As an oxidative stress marker, 8-OHdG [] was measured using urine samples, which were collected between 9:00 and 10:00 am as described previously [], by using a competitive enzyme-linked immunoassay (New 8-OHdG check; Japan Institute for the Control of Aging, Shizuoka, Japan). The values were normalized by urinary creatinine concentration, which was assayed using a standard kit (Wako, Kyoto, Japan). As an additional oxidative stress marker in the brain, accumulated MDA was determined using a Bioxytech MDA-586 Assay Kit (Percipio Biosciences, CA, USA). Malondialdehyde(MDA)levels were normalized against protein concentrations.

2.5. Measurement of Memory Impairment: Object Recognition Task

Learning and memory abilities were examined using objection recognition task (ORT) []. A mouse was habituated in a cage for 4 h, and then two different-shaped objects were presented to the mouse for 10 min as training. The number of times of exploring and/or sniffing each object was counted for the first 5 min (Training test). The frequencies (%) in training test were considered as the backgrounds. To test memory retention after 1 day, one of the original objects was replaced with a novel one of a different shape and then times of exploration and/or sniffing was counted for the first 5 min (Retention test). When mice would lose learning and memory abilities, the frequencies of exploration and/or sniffing of each object should be equal (about 50%) in the training session, indicating that mice showed a similar interest in each object because of lack of memory for the objects. Learning and memory abilities were evaluated as the subtraction of the frequencies (%) in the retention test from each background (Training test).

2.6. Measurement of Memory Impairment: Passive Avoidance Task (PA)

The apparatus consisted of two compartments, one light and the other dark, separated by a vertical sliding door []. On day 1, we initially placed a mouse in the light compartment for 20 s. After the door was opened, the mouse could enter the dark compartment (mice instinctively prefer being in the dark). On day 2, the mouse was again placed in the light section to allow the mouse to move into the dark section. After the mouse entered the dark compartment, the door was closed. After 20 s, the mouse was given a 0.3 mA electric shock for 2 s. The mouse was allowed to recover for 10 s, and was then returned to the home cage. On day 3, 24h after the shock, the mouse was again placed in the light section with the door opened to allow the mouse to move into the dark section. We examined the latency time for stepping through the door. Learning and memory abilities were assessed as the subtraction of the latency times after the electric shock from each background (before).

2.7. Immunostaining of the Hippocampal CA1 Region

To examine neuronal loss and glial activation, the hippocampus region was stained with a pyramidal neuron-specific anti-NeuN antibody (clone A60; Merck Millipore, Darmstadt, Germany), an astrocyte-specific anti-glial fibrillary acidic protein (anti-GFAP) antibody (Thermo Scientific, MA, USA) or a microglia-specific anti-IbaI antibody (Wako). Mice were transcardially perfused to be fixed with 4% paraformaldehyde in phosphate-buffered saline (PBS) under anesthesia, and their brains were cryoprotected with 30% sucrose, and then frozen brain was sectioned at 8 μm thickness. After incubation with each primary antibody, sections were treated with secondary antibodies (Vector Laboratories, CA, USA) and their immunereactivity was visualized by the avidin-biotin complex method (Vector Laboratories).

2.8. Subjects of the Clinical Study

This study was a randomized, double-blind, placebo-controlled trial undertaken as a part of Tone project, an ongoing epidemiological study conducted in Tone Town, Ibaraki, Japan as described in detail previously []. This town is located approximately 40 km northeast of central Tokyo and consists of 22 districts. The baseline survey of the Tone project included 1,032 participants in July 2009, and subjects of the present study were recruited from these participants.

Eligibility criteria are age 67 years or older, being able to give written informed consent for participation in the present study, with a diagnosis of MCI, being able to observe the following requirement: good compliance with water consumption; participation in the scheduled examinations for assessment; keeping a log-diary recording consumption of the water, with a modified Hachinski Ischemic score of 4 or less and a 15-item Geriatric Depression Scale score of 6 or less. In brief, 3 months before this clinical study, all participants underwent a group assessment which used a set of 5 tests that measured the following cognitive domains: attention; memory; visuospatial function; language; and reasoning as described previously []. Objective impairment in at least 1 cognitive domain based on the average of the scores on the neuropsychological measures within that domain and 1 SD cut-off using normative corrections for age, years of education, and sex.

Exclusion criteria were having “The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV TR” criteria for dementing illnesses, a serious or unstable illnesses, a history within the past 5 years of serious infectious disease affecting the brain and/or malignant diseases, a history of alcohol or drug abuse or dependence (on DSM-IV TR) within the past 5 years, and receiving any types of anti-Alzheimer drugs and recent (within 4 weeks) initiation of medications that affect the central nervous system. When the score of Mini Mental State Examination (MMSE) [] was less than 24, the subjects were excluded.

In this study, subjects were randomly assigned to either to an intervention group, who received H2-water every-day for 1 year, or a control group, who received placebo water. The allocation sequence was determined by computer-generated random numbers that were concealed from the investigators and subjects. Drs. Nakajima and Ikejima generated the random allocation sequence, enrolled participants, and assigned participants to interventions. Any participants and care providers were blindly masked.

In the original protocol, we planed to administer H2-water for 2 years and assess the secondary outcomes; however, we had to stop the project in 2011 by the Tsunami-disaster and could not obtained the 2-year data and secondary outcomes.

The APOE4 genotype was determined as described [].

2.9. Statistical Considerations

All statistical analyses were performed by an academic biostatistician using SAS software version 9.2 (SAS Institute Inc, Cary, NC, USA). Results were considered significant at p < 0.05.

For the comparison of two groups in learning and memory abilities, and lifespans, unpaired two-tailed Student’s t-test was used for the comparison of H2-group with control group. For the other animal experiments, one-way analysis of variance (ANOVA) with Tukey-Kramer or Dunnett post hoc analysis was applied unless otherwise mentioned.

For the clinical trial, we planned to recruit a total of 120 patients, which would provide 90% power to detect an effect size of 0.6 using a two-sided test with a 5% significance level, but the actual sample size for the primary analysis was 73, leading to 70% power in the same setting. End-points were scores in the Japanese version of ADAS-cog at 1-year, and the changes were evaluated by Mann-Whitney’s U test (non-parametric analysis) as well as Student’s t-test (parametric analysis).

3. RESULTS

3.1. Hydrogen-water Reduced Oxidative Stress in DAL Mice

Male DAL101 mice were given H2– or control water to drink ad libitum from the age of 1 month, and continued until the age of 18 months. The H2-water DAL101 group showed a significant decrease in the level of an oxidative stress marker, urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG)[] at the age of 14months (Suppl. Fig. S1A). Moreover, DAL101 mice increased oxidative stress in the brain as measured by the level of MDA as an alternative oxidative stress marker, and H2-water showed a significant recovery of this increased level of MDA in DAL101 mice (Suppl. Fig. S1B).

3.2. Hydrogen Water Suppressed a Decline in Learning and Memory Impairment

We examined learning and memory abilities using ORT []. As described in MATERIALS AND METHODS, learning and memory abilities were evaluated as the subtraction of the frequency (%) in Retention test from each background (Training test). Mice were provided with control or H2-water from the age of 1 month. At the age of 14 months, the H2-group significantly memorized the original objects and showed the preference for the novel object more than the control group (Fig. 1A1A 14-month-old).

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Hydrogen water prevented cognitive decline. H2-water was provided from the age of 1 month (A, C), and from the age of 8 months (B). The mice were subjected to the first objection recognition task (ORT) at the age of 14 months (A, B, 14-month-old) and the second ORT at the age of 18 months (A, B, 18-month-old).

The recognition indexes were obtained as the frequency (%) of exploring and/or sniffing the object that would be replaced or the novel one that had been replaced. ΔRecognition index (%) indicates the frequencies in Retention test of ORT after the subtraction of those in Training test (background). WT, wild-type; (DAL, H2-),

DAL101 mice drinking degassed control water; (DAL, H2+), DAL101 mice drinking hydrogen water. Data are shown as the mean ± SEM. n = 9, *p < 0.05, **p < 0.01 by Student’s t-test. (C) The mice were subjected to a passive avoidance task. Step-through latencies before and after the electric shock are obtained and ΔStep-through latency (s) indicates the subtraction of Step-through latencies after from before the electric shock. WT, wild-type (n = 10); DAL, H2-, DAL101 mice receiving degassed control water (n = 8); and DAL, H2+, DAL101 mice receiving H2-water (n = 8). Data are shown as the mean ± SEM. *p < 0.05.

At the age of 18 months, the mice were subjected to the second ORT, which can be done by using different objects at the age of 18 months []. The aged DAL101 mice drinking H2-water still significantly memorized the original objects and preferred the novel one more than the control group (Fig. 1A1A 18-month-old).

Next, to test the drinking effects of H2-water from the later stage, we started giving H2-water to male DAL101 mice at the age of 8 months instead of 1 month, and subjected to ORT at the age of 14 months (Fig. 1B1B 14-month-old) and the second ORT at the age of 18 months (Fig. 1B1B 18-month-old). Even when the mice began to drink at the age of 8 months, H2-water significantly suppressed the decline in the learning and memory abilities at the age of 18 months as well as at the age of 14 months (Fig. 1B1B).

Moreover, we subjected the mice to PA [] at the age 18 months as an alternative method. One day after a 0.3 mA electric shock for 2 s was given, wild-type C57BL/6 mice memorized the shock as evaluated by the subtraction of the latency time (s) to re-enter the dark compartment from each background (Fig. 1C1C). The H2-water group significantly suppressed the decline in learning and memory more than the control group (Fig. 1C1C).

Thus, drinking hydrogen H2-water suppressed the learning and memory impairment in the oxidative stress mice.

3.3. Hydrogen-water Suppressed Neurodegeneration

To examine whether hydrogen H2-water could prevent neurodegeneration in aged DAL101 mice, we stained the hippocampus with a neuron-specific anti-NeuN antibody (Fig. 2A2A). Neurodegeneration was evaluated by glial activations using an anti-GFAP antibody and a microglia-specific anti-Iba-I antibody. Immune-positive cells per field of view (FOV) were counted in the CA1 region (Fig. 2B2B).

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Hydrogen water suppressed neurodegeneration. (A) The hippocampal CA1 region was stained with antibodies against NeuN (a neuronal marker), GFAP (an astrocytic marker) or Iba-1 (a microglial marker) (Scale bars: 50 µm). Right panels show magnified images of the squares in the left panels (Scale bars: 10 µm). (B) Cells positive for anti-NeuN, anti-GFAP and anti-Iba-I antibodies per field of view (FOV) were counted in the CA1 region (n = 5). Data are shown as the mean ± SD. *p < 0.05, **p < 0.01 (wild-type vs DAL), #p < 0.05 (H2-water vs. control water in DAL).

The number of neurons was decreased in the control DAL101 group as the comparison with wild type group, and the H2-DAL101 group showed a trend in recovery of the decrease (Fig. 2A2A). As has been described previously, [] the control DAL101 mice exhibited an increase in glial activation, and the H2-water group suppressed the enhanced glial activation in the CA1 region (Fig. 22, GFAP and Iba-I).

3.4. Hydrogen-water Extended the Average Lifespan of Mice

DAL101 mice showed a shorter lifespan, which has also been described previously []. To examine whether consumption of hydrogen H2-water attenuated the shortened lifespan, female DAL101 mice started drinking control or H2-water at the age of 1 month. Although hydrogen H2-water did not extend the maximum lifespan (Fig. 3A3A), hydrogen H2-water significantly extended the mean of lifespan of DAL101 mice (Fig. 3B3B).

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Extension of the average lifespan by continuous drinking H2-water. (A) Kaplan-Meier curve representing the survival of female C57BL/6 mice (wild-type), female DAL101 mice drinking control water (control water) and H2-water (H2-water). (B) Each dot indicates the lifespan of each mouse. The bars indicate the average lifespan of each group. *p < 0.05 (p = 0.036) by Student’s t-test.

3.5. A Randomized, Placebo Controlled Clinical Study

Fig. (44) shows the profile on the recruitment, randomization, and follow-up of this study. A total of 81 subjects of the 1,032 participants were randomized; however, 3 in the control group and 5 in the intervention group were diagnosed as ineligible after randomization and not included in this analysis. Baseline characteristics and lifestyle factors were balanced between the study groups (Table 11). Random assignment was stratified by age of ~74 years and MMSE score of ~28 points. The average compliance rate of drinking water was estimated as 64% in both groups at 1-year, meaning the subjects drank 320 mL/day on the average. The mean total ADAS-cog scores in the H2– and control groups were 8.04 and 7.89, respectively, with no significance.

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Profile of the recruitment, randomization, and follow-up of this study. This study was a randomized, double-blind, placebo-controlled trial undertaken as a part of Tone project, an ongoing epidemiological study conducted in Tone Town, Ibaraki, Japan [].

Table 1

Background characteristics of 73 subjects with mild cognitive impairment.

Control (n=38) Intervention (n=35)
Mean SD or % Mean SD or %
Woman * 20 (52.6%) 19 (54.3%)
Age (years) 74.45 5.44 73.97 5.11
Body mass index (kg/m2) 23.55 2.59 23.19 4.08
Systolic blood pressure (mmHg) 131.26 12.35 135.14 13.31
Diastolic blood pressure (mmHg) 77.92 7.13 78.89 9.53
Education (years) 11.26 2.71 11.57 2.83
Current alcohol drinker * 19 (50.0%) 14 (40.0%)
Current smoker * 4 (10.5%) 5 (14.3%)
Current exercise habit * 27 (71.1%) 22 (62.9%)
APOE4 carrier * 6 (15.7%) 7 (20.0%)
Family history * 2 (5.3%) 2 (5.7%)
Comorbidity *
Hypertension 15 (39.5%) 14 (40.0%)
Diabetes mellitus 4 (10.5%) 5 (14.3%)
Dyslipidemia 4 (10.5%) 4 (11.4%)
Stroke 2 (5.3%) 1 (2.9%)
Depression 1 (2.6%) 2 (5.7%)
MMSE 28.08 1.66 27.83 1.74
ADAS-cog 7.89 3.19 8.04 3.47

* indicates frequency (%).

After 1 year, no observable harms or unintended effects in each group were found, and there was a trend to improve total ADA-cog score both in the H2– and control-groups (Suppl. Table S1), probably because of interventions such as moderate exercise by the Tone project. Moreover, the subjects in the H2-group had more trends for the improvement than those in the control-groups although there was no significance (Suppl. Table S1). However, when we pay attention to score-changes in carriers of the APOE4 genotype, the total ADAS-cogs and word recall task scores (one of the sub-scores) significantly improved as assessed by the distribution of the score change in each subject (Fig. 55). In the APOE4 carriers, the hydrogen  water H2-group significantly improved, whereas the control group slightly worsened. Moreover, Fig. (66) shows the score change of each subject as an alternative presentation. Although the subjects in the control group did not improved, six and five out of 7 subjects improved on the total ADAS score and word recall task scores, respectively, in the hydrogen water H2-group of the APOE4 carriers.

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Distribution of changes of sub- and total-ADAS-cog score. Distribution of change of word recall task score (A), a sub-score of ADAS-cog, and (B) total ADAS-cogs score in APOE4 non-carriers (left) and APOE4 carriers (right). Each dot indicates the change of individual subjects. The difference between the H2- and control groups was significant in APOE4 carriers by a non-parametric analysis as well as a parametric analysis. (Ap = 0.036 (by Student’s t-test) and p =0.047 (by Mann-Whitney’s U test) and (Bp = 0.037 (by Student’s t-test) and p = 0.044 (by Mann-Whitney’s U test) for (A) and (B), respectively. Middle bars in lozenges indicate median values.

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Changes in a sub-sore and total ADAS-cog score of each subject in the APOE4 carriers. Each line indicates the 1-year change in the word recall task score (A) and total ADAS-cog score (B) of a subject in the APOE4 carriers. * indicates p < 0.05 as shown in the legend of Fig. 5.

DISCUSSION

Age-dependent neurodegenerative disorders are involved in oxidative stress. In this study, we showed that drinking hydrogen H2-water suppressed the biochemical, behavioral, and pathological decline in oxidative stress mice. The score of ADAS-cog [] is the most widely used general cognitive measure in clinical trials of AD []. The ADAS-cog score assesses multiple cognitive domains including memory, language, praxis, and orientation. Overall, the ADAS-cog has proven successful for its intended purpose. The present clinical study shows that drinking hydrogen H2-water significantly improved the ADAS-cog score of APOE4 genotype-carriers.

We have previously showed that DAL101 mice show age-dependent neurodegeneration and cognitive decline and the shorten lifespan []. DAL101 mice exhibit dementia phenotypes in an age-dependent manner in response to an increasing amount of oxidative stress []. Oxidative stress enhances lipid peroxidation, leading to the formation of highly reactive α, β-unsaturated aldehydes, such as MDA and 4-HNE []. The accumulation of 4-HNE-adducted proteins in pyramidal neurons has been observed in the brains of patients with AD and PD []. The decline of ALDH2*2 ability failed to detoxify cytotoxic aldehydes, and consequently increases in oxidative stress [].

Moreover, double-transgenic mice were constructed by crossing DAL101 mice with Tg2576 mice, which express a mutant form of human amyloid precursor protein (APP). They showed accelerated amyloid deposition, tau phosphorylation, and gliosis, as well as impaired learning and memory abilities. The lifespan of APP/DAL mice was significantly shorter than that of APP and DAL101 mice []. Thus, these model animals may be helpful to explore antioxidants that could be able to prevent age-dependent dementia. Indeed, a diet containing Chlorella showed mitigated effects on cognitive decline in DAL101 [].

One of the most potent risk factors for AD is carrier status of the APOE4 genotype, and the roles of APOE4 on the progression of AD have been extensively examined from various aspects []. APOE4 also increase the number of atherogenic lipoproteins, and accelerate atherogenesis []. The increased oxidative stress in APOE4 carriers is considered as one of the modifiers for the risk []. A combination of antioxidants improved cognitive function of aged subjects after 3 years, especially in APOE4 carriers []. This previous clinical result agrees with the present study. hydrogen H2 acts as an efficient antioxidant inside cells owing to its ability to rapidly diffuse across membranes []. Moreover, as a secondary anti-oxidative function, H2 seems to activate NF-E2-related factor 2 (Nrf2), [] which reduces oxidative stress by expression a variety of antioxidant enzymes []. We reported that drinking hydrogen H2-water prevented arteriosclerosis using APOE knockout mice, a model of the spontaneous development of atherosclerosis accompanying a decrease in oxidative stress []. Thus, it is possible that drinking H2-water improves vascular damage by decreasing oxidative stress as a direct or indirect antioxidant, leading to the improvement of a demintia model and MCI subjects. In this study, we focused on the genotype of APOE-isoforms; however, the polymorphism of the APOE gene in the promoter region influences the expression of the APOE gene []. Thus, it will be important to examine the effect of hydrogen H2-water under this polymorphism.

For mitigating AD, significant attention has been given to regular, moderate exercise to help reduce the risk of dementia and prevent MCI from developing in aging patients [ – ]. Moderate exercise enhances energy metabolism and suppresses the expression of pro-inflammatory cytokines, [] and protects vascular systems [].molecular hydrogen H2 exhibits multiple functions by a decrease in the levels of pro-inflammatory cytokines and an increase in energy metabolism in addition to anti-oxidative roles. To exert multiple functions, molecular hydrogen H2 regulates various signal transduction pathways and the expression of many genes []. For examples,molecular hydrogen H2 protects neural cells and stimulates energy metabolism by stimulating the hormonal expression of ghrelin [] and fibroblast growth factor 21, [] respectively. In contrast, molecular hydrogen H2 relieves inflammation by decreasing pro-inflammatory cytokines []. Thus, the combination of these functions of molecular hydrogen H2 on anti-inflammation and energy metabolism-stimulation might prevent the decline in brain function, [] both of which are improved by regular and moderate exercise. Thus, it is possible that the multiple functions of molecular hydrogen H2, including energy metabolism-stimulation and anti-inflammation, may contribute to the improvement of the dementia model and the MCI subjects.

As an alternative aspect, molecular hydrogen H2 suppresses the nuclear factor of activated T cell (NFAT) transcription pathway to regulate various gene expression patterns []. NFAT signaling is altered in AD and plays an important role in driving amyloid β-mediated neurodegeneration []. Moreover, the NFAT transcriptional cascade contributes to amyloid β synaptotoxicity []. Additionally, an active involvement of the NFAT-mediated signaling pathway in α-syn-mediated degeneration of neurons in PD []. Indeed, patients with PD improved by drinking molecular hydrogen H2-water as revealed by a double-blind, placebo-controlled clinical study, [] and a larger scale of a clinical trial is under investigation []. Thus, the beneficial effects of molecular hydrogen H2 on the neurodegenerative diseases may be explained by the suppression of NFAT transcriptional regulation.

CONCLUSION

The present study suggests a possibility for slowing the progress of dementia by drinking molecular hydrogen H2-water by means of animal experiments and a clinical intervention study for APOE4 carriers; however, a longer and larger scale of trials will be necessary to clarify the effect of H2-water on MCI.

PMCID: PMC5872374
PMID: 29110615
Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild Cognitive Impairment
This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

Associated Data

Supplementary Materials

ACKNOWLEDGEMENTS

We thank Blue Mercury, Inc. (Tokyo, Japan) for providing H2-water and placebo water, Ms. Hiroe Murakoshi for technical assistance and Ms. Suga Kato for secretarial work. Financial support for this study was provided by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (23300257, 24651055, and 26282198 to S.O.; 23500971 and 25350907 to K.N.). Financial support for this study was provided by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (23300257, 24651055, and 26282198 to S.O.; 23500971 and 25350907 to K.N.).

LIST OF ABBREVIATIONS

APOE4 Apolipoprotein E4
MCI Mild cognitive Impairment
ALDH2 Aldehyde Dehydrogenase 2
ADAS-cog Alzheimer’s Disease Assessment Scale-cognitive subscale
AD Alzheimer’s Disease
PD Parkinson’s Disease
DAL101 Dominant Negative Type 101 of the ALDH2 Mutant Polymorphism (ALDH2*2)
4-HNE 4-Hydroxy-2-nonenal
8-OHdG 8-Hydroxy-2’-deoxyguanosine
MDA Malondialdehyde
ORT Object Recognition Task
PA Passive Avoidance Task
GFAP Glial Fibrillary Acidic Protein
PBS Phosphate-buffered Saline
ANOVA One-way Analysis of Variance
CI Confidence Interval
MMSE Mini Mental State Examination
FOV Field of View
APP Amyloid Precursor Protein
Nrf2 NF-E2-related Factor 2
NFAT Nuclear Factor of Activated T Cell

 

SUPPLEMENTARY MATERIAL

Supplementary material is available on the publisher’s web site along with the published article.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The animal study was approved by the Animal Care and Use Committee of Nippon Medical School.

The human clinical study protocol was approved by the ethics committees of University of Tsukuba.

HUMAN AND ANIMAL RIGHTS

All animal research procedures followed were in accordance with the standards set forth in the eighth edition of Guide for the Care and Use of Laboratory Animals published by the National Academy of Sciences, The National Academies Press, Washington, D.C.).

All human material was obtained in accordance with the standards set forth in the Declaration of Helsinkiprinciples of 1975, as revised in 2008 (http://www.wma.net/en/10ethics/10helsinki/<http://www.wma.net/en/10ethics/10helsinki/>).

Consent for Publication

All the patients provided written informed consent priority to research investigations.

CONFLICT OF INTEREST

We declare that there is no actual and potential conflict of interest on this study. Although SO was a scientific advisor of Blue Mercury, Inc. (Tokyo, Japan) from 2,005 to 2,008, there was no involvement during this study.

REFERENCES

1. Lin M.T., Beal M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443:787–795. [PubMed[]
2. Mecocci P., Polidori M.C. Antioxidant clinical trials in mild cognitive impairment and Alzheimer’s disease. Biochim. Biophys. Acta. 2012;1822:631–638. [PubMed[]
3. Jofre-Monseny L., Minihane A.M., Rimbach G. Impact of apoE genotype on oxidative stress, inflammation and disease risk. Mol. Nutr. Food Res. 2008;52:131–145. [PubMed[]
4. Ohsawa I., Nishimaki K., Murakami Y., Suzuki Y., Ishikawa M., Ohta S. Age-dependent neurodegeneration accompanying memory loss in transgenic mice defective in mitochondrial aldehyde dehydrogenase 2 activity. J. Neurosci. 2008;28:6239–6249. [PMC free article] [PubMed[]
5. Chen C.H., Ferreira J.C., Gross E.R., Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol. Rev. 2014;94:1–34. [PMC free article] [PubMed[]
6. Kamino K., Nagasaka K., Imagawa M., Yamamoto H., Yoneda H., Ueki A., et al. Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer’s disease in the Japanese population. Biochem. Biophys. Res. Commun. 2000;273:192–196. [PubMed[]
7. Jo S.A., Kim E.K., Park M.H., Han C., Park H.Y., Jang Y., et al. A Glu487Lys polymorphism in the gene for mitochondrial aldehyde dehydrogenase 2 is associated with myocardial infarction in elderly Korean men. Clin. Chim. Acta. 2007;382:43–47. [PubMed[]
8. Wang B., Wang J., Zhou S., Tan S., He X., Yang Z., et al. The association of mitochondrial aldehyde dehydrogenase gene (ALDH2) polymorphism with susceptibility to late-onset Alzheimer’s disease in Chinese. J. Neurol. Sci. 2008;268:172–175. [PubMed[]
9. 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;13:688–694. [PubMed[]
10. 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[]
11. 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[]
12. Iketani M., Ohsawa I. Molecular Hydrogen as a Neuroprotective Agent. Curr. Neuropharmacol. 2017;15:324–331. [PMC free article] [PubMed[]
13. Ohta S. Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical applications. Methods Enzymol. 2015;555:289–317. [PubMed[]
14. 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. 2009. [PubMed]
15. Matsumoto A., Yamafuji M., Tachibana T., Nakabeppu Y., Noda M., Nakaya H. Oral ‘hydrogen water’ induces neuroprotective ghrelin secretion in mice. Sci. Rep. 2013;3:3273. [PMC free article] [PubMed[]
16. Li J., Wang C., Zhang J.H., Cai J.M., Cao Y.P., Sun X.J. 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[]
17. Hayashida K., Sano M., Kamimura N., Yokota T., Suzuki M., Ohta S., et al. Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest, independent of targeted temperature management. Circulation. 2014;130:2173–2180. [PubMed[]
18. Rosen W.G., Mohs R.C., Davis K.L. A new rating scale for Alzheimer’s disease. Am. J. Psychiatry. 1984;141:1356–1364. [PubMed[]
19. Connor D.J., Sabbagh M.N. Administration and scoring variance on the ADAS-Cog. J. Alzheimers Dis. 2008;15:461–464. [PMC free article] [PubMed[]
20. de Zwart L.L., Meerman J.H., Commandeur J.N., Vermeulen N.P. Biomarkers of free radical damage applications in experimental animals and in humans. Free Radic. Biol. Med. 1999;26:202–226. [PubMed[]
21. Kamimura N., Nishimaki K., Ohsawa I., Ohta S. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity (Silver Spring) 2011;19:1396–1403. [PubMed[]
22. O’Riordan K.J., Huang I.C., Pizzi M., Spano P., Boroni F., Egli R., et al. Regulation of nuclear factor kappaB in the hippocampus by group I metabotropic glutamate receptors. J. Neurosci. 2006;26:4870–4879.[PMC free article] [PubMed[]
23. Bun S., Ikejima C., Kida J., Yoshimura A., Lebowitz A.J., Kakuma T., et al. A combination of supplements may reduce the risk of Alzheimer’s disease in elderly Japanese with normal cognition. J. Alzheimers Dis. 2015;45:15–25. [PubMed[]
24. Miyamoto M., Kodama C., Kinoshita T., Yamashita F., Hidaka S., Mizukami K., et al. Dementia and mild cognitive impairment among non-responders to a community survey. J. Clin. Neurosci. 2009;16:270–276. [PubMed[]
25. Sasaki M., Kodama C., Hidaka S., Yamashita F., Kinoshita T., Nemoto K., et al. Prevalence of four subtypes of mild cognitive impairment and APOE in a Japanese community. Int. J. Geriatr. Psychiatry. 2009;24:1119–1126. [PubMed[]
26. Arevalo-Rodriguez I., Smailagic N., Roque I.F.M., Ciapponi A., Sanchez-Perez E., Giannakou A., et al. Mini-Mental State Examination (MMSE) for the detection of Alzheimer’s disease and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst. Rev. 2015;3:CD010783.[PMC free article] [PubMed[]
27. Ihl R., Ferris S., Robert P., Winblad B., Gauthier S., Tennigkeit F. Detecting treatment effects with combinations of the ADAS-cog items in patients with mild and moderate Alzheimer’s disease. Int. J. Geriatr. Psychiatry. 2012;27:15–21. [PubMed[]
28. Karin A., Hannesdottir K., Jaeger J., Annas P., Segerdahl M., Karlsson P., et al. Psychometric evaluation of ADAS-Cog and NTB for measuring drug response. Acta Neurol. Scand. 2014;129:114–122.[PubMed[]
29. Schneider C., Tallman K.A., Porter N.A., Brash A.R. Two distinct pathways of formation of 4-hydroxynonenal. Mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals. J. Biol. Chem. 2001;276:20831–20838. [PubMed[]
30. Csala M., Kardon T., Legeza B., Lizak B., Mandl J., Margittai E., et al. On the role of 4-hydroxynonenal in health and disease. Biochim. Biophys. Acta. 2015;1852:826–838. [PubMed[]
31. Endo J., Sano M., Katayama T., Hishiki T., Shinmura K., Morizane S., et al. Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart. Circ. Res. 2009;105:1118–1127. [PubMed[]
32. Kanamaru T., Kamimura N., Yokota T., Iuchi K., Nishimaki K., Takami S., et al. Oxidative stress accelerates amyloid deposition and memory impairment in a double-transgenic mouse model of Alzheimer’s disease. Neurosci. Lett. 2015;587:126–131. [PubMed[]
33. Nakashima Y., Ohsawa I., Konishi F., Hasegawa T., Kumamoto S., Suzuki Y., et al. Preventive effects of Chlorella on cognitive decline in age-dependent dementia model mice. Neurosci. Lett. 2009;464:193–198. [PubMed[]
34. De Marco M., Vallelunga A., Meneghello F., Varma S., Frangi A.F., Venneri A. ApoE epsilon4 allele related alterations in hippocampal connectivity in early Alzheimer’s disease support memory performance. Curr. Alzheimer Res. 2017;14:766–777. [PubMed[]
35. Shackleton B., Crawford F., Bachmeier C. Apolipoprotein E-mediated modulation of ADAM10 in Alzheimer’s disease. Curr. Alzheimer Res. 2017;14:578–585. [PMC free article] [PubMed[]
36. Hanson A.J., Craft S., Banks W.A. The APOE genotype: modification of therapeutic responses in Alzheimer’s disease. Curr. Pharm. Des. 2015;21:114–120. [PubMed[]
37. Johnson D.A., Johnson J.A. Nrf2-a therapeutic target for the treatment of neurodegenerative diseases. Free Radic. Biol. Med. 2015;88:253–267. [PMC free article] [PubMed[]
38. 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;377:1195–1198. [PubMed[]
39. Maloney B., Ge Y.W., Petersen R.C., Hardy J., Rogers J.T., Perez-Tur J., et al. Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2010;153B:185–201. [PMC free article] [PubMed[]
40. Uemura K., Doi T., Shimada H., Makizako H., Yoshida D., Tsutsumimoto K., et al. Effects of exercise intervention on vascular risk factors in older adults with mild cognitive impairment: a randomized controlled trial. Dement. Geriatr. Cogn. Disord. Extra. 2012;2:445–455. [PMC free article] [PubMed[]
41. Gates N., Fiatarone Singh M.A., Sachdev P.S., Valenzuela M. The effect of exercise training on cognitive function in older adults with mild cognitive impairment: a meta-analysis of randomized controlled trials. Am. J. Geriatr. Psychiatry. 2013;21:1086–1097. [PubMed[]
42. Suzuki T., Shimada H., Makizako H., Doi T., Yoshida D., Ito K., et al. A randomized controlled trial of multicomponent exercise in older adults with mild cognitive impairment. PLoS One. 2013;8:e61483.[PMC free article] [PubMed[]
43. Smart N.A., Steele M. The effect of physical training on systemic proinflammatory cytokine expression in heart failure patients: a systematic review. Congest. Heart Fail. 2011;17:110–114. [PubMed[]
44. Cooper C., Li R., Lyketsos C., Livingston G. Treatment for mild cognitive impairment: systematic review. Br. J. Psychiatry. 2013;203:255–264. [PMC free article] [PubMed[]
45. Lavie C.J., Arena R., Swift D.L., Johannsen N.M., Sui X., Lee D.C., et al. Exercise and the cardiovascular system: clinical science and cardiovascular outcomes. Circ. Res. 2015;117:207–219.[PMC free article] [PubMed[]
46. Buchholz B.M., Kaczorowski D.J., Sugimoto R., Yang R., Wang Y., Billiar T.R., et al. Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am. J. Transplant. 2008;8:2015–2024. [PubMed[]
47. Iuchi K., Imoto A., Kamimura N., Nishimaki K., Ichimiya H., Yokota T., et al. Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators. Sci. Rep. 2016;6:18971. [PMC free article] [PubMed[]
48. Abdul H.M., Sama M.A., Furman J.L., Mathis D.M., Beckett T.L., Weidner A.M., et al. Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J. Neurosci. 2009;29:12957–12969. [PMC free article] [PubMed[]
49. Hudry E., Wu H.Y., Arbel-Ornath M., Hashimoto T., Matsouaka R., Fan Z., et al. Inhibition of the NFAT pathway alleviates amyloid beta neurotoxicity in a mouse model of Alzheimer’s disease. J. Neurosci. 2012;32:3176–3192. [PMC free article] [PubMed[]
50. Luo J., Sun L., Lin X., Liu G., Yu J., Parisiadou L., et al. A calcineurin- and NFAT-dependent pathway is involved in alpha-synuclein-induced degeneration of midbrain dopaminergic neurons. Hum. Mol. Genet. 2014;23:6567–6574. [PMC free article] [PubMed[]
51. Yoritaka A., Takanashi M., Hirayama M., Nakahara T., Ohta S., Hattori N. Pilot study of H(2) therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial. Mov. Disord. 2013;28:836–839. [PubMed[]
52. Yoritaka A., Abe T., Ohtsuka C., Maeda T., Hirayama M., Watanabe H., et al. A randomized double-blind multi-center trial of hydrogen water for Parkinson’s disease: protocol and baseline characteristics. BMC Neurol. 2016;16:66. [PMC free article] [PubMed[]

Hydrogen-rich water for improvements of MOOD,ANXIETY and AUTONOMIC NERVE FUNCTION in daily life

Abstract

Health and a vibrant life are sought by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent various diseases, evaluations of the effects of potentially QOL-increasing factors are important. Chronic oxidative stress and inflammation cause deteriorations in central nervous system function, leading to low QOL. In healthy individuals, aging, job stress, and cognitive load over several hours also induce increases in oxidative stress, suggesting that preventing the accumulation of oxidative stress caused by daily stress and daily work contributes to maintaining QOL and ameliorating the effects of aging. Hydrogen has anti-oxidant activity and can prevent inflammation, and may thus contribute to improve QOL. The present study aimed to investigate the effects of drinking hydrogen-rich water (HRW) on the QOL of adult volunteers using psychophysiological tests, including questionnaires and tests of autonomic nerve function and cognitive function. In this double-blinded, placebo-controlled study with a two-way crossover design, 26 volunteers (13 females, 13 males; mean age, 34.4 ± 9.9 years) were randomized to either a group administered oral hydrogen-rich water HRW (600 mL/d) or placebo water (PLW, 600 mL/d) for 4 weeks. Change ratios (post-treatment/pre-treatment) for K6 score and sympathetic nerve activity during the resting state were significantly lower after hydrogen-rich water HRW administration than after PLW administration. These results suggest that hydrogen-rich water HRW may reinforce QOL through effects that increase central nervous system functions involving mood, anxiety, and autonomic nerve function.

Introduction

Health and a vibrant life are much craved by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent the onset of various diseases, evaluation of interventional effects for improving QOL is important. The high metabolic rate of the brain results in the generation of disproportionate amounts of reactive oxygen and nitrogen species, leading to increased oxidative stress. Increased oxidative stress and lipid peroxidation initiate a cascade of proinflammatory signals, leading to inflammation. Altered homeostasis of oxidation, inflammation, and protein aggregation has been suggested to contribute to the death of neurons, which is directly related to impairments in various cognitive domains. As such, chronic oxidative stress and inflammation may cause deteriorations in the function of the central nervous system, leading to reductions in QOL. Hydrogen has antioxidant activity and can prevent inflammation.,, The distribution of hydrogen throughout the brain and body indicates actions both in the central and peripheral nervous systems. Previous clinical studies have shown that hydrogen-rich water (HRW) reduces concentrations of markers of oxidative stress in patients with metabolic syndrome,,improves lipid and glucose metabolism in patients with type 2 diabetes, improves mitochondrial dysfunction in patients with mitochondrial myopathies, and reduces inflammatory processes in patients with polymyositis/dermatomyositis. In another study, exercise-induced declines in muscle function among elite athletes were also improved by administering hydrogen-rich water HRW. Although such findings suggest that hydrogen-rich water HRW may help alleviate symptoms of several diseases and increase the physical performance of athletes, the effects of prolonged  hydrogen-rich water HRW ingestion on the QOL of individuals in the general population remain unknown.

Some reports have demonstrated that oxidative stress is associated with QOL in patients with chronic obstructive pulmonary disease and cervical cancer., During oncological treatment among patients with cervical cancer, antioxidant supplementation was found to be effective in improving QOL. In addition, Kang et al. reported that treatment with hydrogen-rich water HRW for patients receiving radiotherapy for liver tumors decreased oxidative stress and improved QOL. Although the association between oxidative stress and QOL in healthy individuals is still unclear, aging, job stress, and cognitive load over the course of several hours in healthy individuals have also been found to induce increases in oxidative stress,,,, suggesting that preventing the accumulation of oxidative stress caused by daily stress and daily work may contribute to the maintenance of QOL and amelioration of the effects of aging. Continuous hydrogen-rich water HRW intake might therefore be expected to reduce accumulation of oxidative stress, thus helping to prevent decreases in QOL.

The aim of the present study was to investigate the effects of drinking 600 mL of hydrogen-rich water HRW per day for 4 weeks on the QOL of adult volunteers using questionnaires for sleep, fatigue, mood, anxiety, and depression, an autonomic function test, and a higher cognitive function test.

Subjects and Methods

Subjects

Thirty-one adult volunteers between 20 and 49 years old participated in this double-blinded, randomized, placebo-controlled study with a two-way crossover design. Exclusion criteria comprised: history of chronic illness; chronic medication or use of supplemental vitamins; employment in shift work; pregnancy; body mass index ≤ 17 or ≥ 29 kg/m2; food allergy; history of smoking; or history of drinking excessive amounts of alcohol (≥ 60 g/day). Shift workers were excluded because the water was administered at breakfast and dinner, the timings of which are irregular among shift workers. In addition, the mental and physical conditions of shift workers can be greatly affected by the shift schedule for the preceding 2 days, which may impact the results obtained from the questionnaires used in this study. Before each experiment, participants were asked to refrain from drinking alcohol, since drinking excessive amounts of alcohol carries significant risks of fluctuations in physical condition. All experiments were conducted in compliance with national legislation and the Code of Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association (the Declaration of Helsinki) and registered to the UMIN Clinical Trials Registry (No. UMIN000022382). The study protocol was approved by the Ethics Committee of Osaka City University Center for Health Science Innovation (OCU-CHSI-IRB No. 4), and all participants provided written informed consent for participation in the study.

Study design

We used a double-blinded, placebo-controlled study with a two-way crossover design, as summarized in Figure 1. After admission to the study, participants were randomized in a double-blinded manner to receive hydrogen-rich water HRW in an aluminum pouch (0.8–1.2 ppm of hydrogen, 300 mL/pouch; Melodian Corporation, Yao, Japan) or placebo water (PLW), representing mineral water from the same source (i.e., same components without hydrogen) in an aluminum pouch (0 ppm of hydrogen, 300 mL/pouch; Melodian Corporation) twice a day for 4 weeks. Fifteen participants were administered PLWfirst, and then hydrogen-rich water HRW. The remaining 16 participants were administered HRW hydrogen-rich water first, and then PLW. Participants consumed water within 5 minutes twice a day, at breakfast and dinner in their home, and confirmed the water intake at breakfast and dinner in a daily journal for 4 weeks. We assessed the intake rate of water by checking the daily journal every 4 weeks, on the 2nd and 4th experimental days. No participants reported any difference in taste between hydrogen-rich water HRW and PLW. Previous studies have reported interventional effects of administering hydrogen-rich water HRW to humans at hydrogen concentrations under 1.3 ppm., We therefore used a similar concentration of 0.8–1.2 ppm in the present study. Absolute volumes (600 mL) of  hydrogen-rich water HRW and PLW were provided to participants rather than a volume proportional to body mass, based on previously reported results.,,, The duration of supplementation was set based on previous findings with hydrogen-rich water HRW administration for 2–8 weeks.,, A 4-week washout period was provided between hydrogen-rich water HRW and PLW administrations based on a previous study.The day before starting each experiment, participants were told to finish dinner by 21:00, and were required to fast overnight to avoid any influence of diet on concentrations of measured parameters (markers of inflammation and oxidative stress) in blood samples. At 09:00 the next day, participants completed the questionnaires after confirming that they had refrained from drinking alcohol, had finished dinner by 21:00, and had fasted overnight. Autonomic nerve function was measured at 09:30. Cognitive function testing was conducted at 09:45. Blood samples were collected at 10:00. These measurements were performed a total of four times for each participant, before (pre) and after (post) each of the two 4-week administration periods. From 24 hours (the day before the visit day) before each visit for measurements, participants were told to refrain from drinking alcohol or performing strenuous physical activity and to follow their normal diets, drinking habits, and sleeping hours. During the 4-week PLW or hydrogen-rich water HRW administration periods, daily daytime activity (amount of physical exertion) of participants was measured using a pedometer and participants kept a daily journal to record drinking volume and times of PLW or HRW intake, physical condition (e.g., pain, lassitude, and indefinite complaints), sleeping times, etc.

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Time course of the experiments.

Note: Participants were randomly divided into two study groups. The experiment consisted of 4 weeks of hydrogen-rich water (HRW) administration or placebo water (PLW) administration, a 4-week washout period, and then another 4 weeks of PLW administration or hydrogen-rich water HRW administration. Before (pre) and after (post) each period of hydrogen-rich water HRW or PLW administration, subjective and objective measurements for quality of life were obtained, such as results for sleep, mood, anxiety, feelings of depression, autonomic nerve function, and cognitive function.

Questionnaire

Severity of fatigue was measured using the Chalder Fatigue Scale (CFS) and a modified version of the Osaka City University Hospital Fatigue Scale. Mood and anxiety were evaluated using the K6 scale.Symptoms of depression were measured using the Center for Epidemiologic Studies Depression Scale.General sleepiness and daytime sleepiness scores were calculated using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale, respectively. The reliability and validity of the Japanese versions of these questionnaires have been confirmed.,,,,,

Autonomic function test

Participants underwent simultaneous electrocardiography and photoplethysmography using a Vital Monitor 302 system (Fatigue Science Laboratory, Osaka, Japan) while sitting quietly with their eyes closed for 3 minutes. These data were analyzed using MemCalc software (GMS, Tokyo, Japan). Frequency analyses for R-R interval variation from electrocardiography and a-a interval variation as the second derivative of photoplethysmography (accelerated plethysmography) were performed using the maximum entropy method, which is capable of estimating the power spectrum density from short time series data, and is adequate for examining changes in heart rate variability under different conditions of short duration.,The power spectrum resolution was 600 Hz. For frequency analyses, the low-frequency component power (LF) was calculated as the power within a frequency range of 0.04–0.15 Hz, and the high-frequency component power (HF) was calculated as that within a frequency range of 0.15–0.4 Hz. HF is vagally mediated,,, whereas LF originates from a variety of sympathetic and vagal mechanisms., Some review articles,, mentioned that LF reflects sympathetic nerve activity and is used as a marker of sympathetic nerve activity in original articles. Before autonomic nerve function testing was conducted for 3 minutes, a practice test was conducted for a period of 1 minute, in accordance with previous studies.,, The reliability of these tests has been confirmed.,

Cognitive function test

Since previous studies have revealed that a switching attention task is useful for evaluating reduced performance under fatigue conditions,,, we used task E of the modified advanced trail making test (mATMT) as a switching attention task for evaluating executive function., Circles with numbers (from 1 to 13) or kana (Japanese phonograms, 12 different letters) were shown in random locations on a screen, and participants were required to use a computer mouse to alternately touch the numbers and kana; this task thus required switching attention. When participants touched a target circle, it remained in the same position, but its color changed from black to yellow. Participants were instructed to perform the task as quickly and correctly as possible, and continuously performed this task for 5 minutes. We evaluated three indices of task performance: the total count of correct responses (number of correctly touched numbers and letters); the total count of errors (number of incorrectly touched numbers and letters); and the motivational response (reaction time from a finished trial to the next trial). Based on our previous study, before participants performed task E of the mATMT on each experimental day, they practiced for a period of 1 minute. The reliability of this test has been confirmed.,

Blood sample analyses

Blood samples were collected from the brachial vein. The amount of blood sampled was 13 mL per experimental day. We thus collected blood samples on four occasions (once per experimental day) in the study. Blood samples for serum analyses were centrifuged at 1,470 × g for 5 minutes at 4°C. The concentration of high-sensitivity C-reactive protein (hs-CRP) in each serum sample was assessed by particle-enhanced immunonephelometry using a BNII analyzer (BN II ProSpec; Siemens, Munich, Germany). Oxidative activity in each serum sample was assessed with the reactive oxygen metabolites-derived compounds (d-ROMs) test (Diacron International, Grosseto, Italy), while anti-oxidative activity was measured with the biological anti-oxidant potential (BAP) test (Diacron International) using a JCABM1650 automated analyzer (JEOL, Tokyo, Japan). The concentrations of ROMs are expressed in Carratelli units (1 CARR U = 0.08 mg of hydrogen peroxide/dL). The oxidative stress index (OSI) was calculated using the following formula: OSI = C × (d-ROMs/BAP), where C denotes a coefficient for standardization to set the mean OSI in healthy individuals at 1.0 (C = 8.85). All supernatants were stored at -80°C until analyzed. Assays for hs-CRP were performed at LSI Medience Corporation (Tokyo, Japan) and those for serum d-ROMs and BAP were performed at Yamaguchi University Graduate School of Medicine.

Daily daytime activity and daily journal

Daily daytime activity, representing the expenditure of calories and amount of physical activity (METs × time) was recorded using an Active style Pro HJA-350IT pedometer (OMRON, Kyoto, Japan). A daily journal was kept for 4 weeks, and included information on fatigue (based on a visual analogue scale from 0, representing “no fatigue”, to 100, representing “total exhaustion”) just after waking up and before bedtime, sleeping times, physical condition (1, good; 2, normal; or 3, bad), and special events (if the day was different from a usual day: 1, no; or 2, yes). We carefully checked the daily journal every four weeks, on the 2nd, 3rd, and 4th experimental days.

Statistical analyses

First, we tested the normality (parametric or non-parametric distributions) of each measured parameter using the Kolmogorov-Smirnov test. Values are presented as the mean ± standard deviation or median and interquartile range based on the results of Kolmogorov-Smirnov test. The Wilcoxon signed-rank test for non-parametric parameters and paired t-test for differences between hydrogen-rich water HRW and PLW administrations after two-way repeated-measurement analysis of variance for parametric parameters were conducted. If significant changes were observed by comparisons within each condition (pre- vs. post-HRW; pre- vs. post-PLW) or between post-treatment values (post-HRW vs. post-PLW), then we compared change ratios between post-HRW/pre-HRW and post-PLW/pre-PLW using the Wilcoxon signed-rank test or paired t-test. All P values were two-tailed, and those less than 0.05 were considered statistically significant. Statistical analyses were performed using IBM SPSS Statistical Package version 20.0 (IBM, Armonk, NY, USA).

Results

General results

During the study, we excluded five participants from data analyses due to symptoms of hay fever, prolonged medication use because of a cold, insufficient intake of hydrogen-rich water HRW or PLW intake (≥ 85%), or a frequency of special events ≤ 15% as recorded in the daily diary. We thus analyzed data from a total of 26 participants (13 females, 13 males; mean age, 34.4 ± 9.9 years; mean body mass index, 21.5 ± 2.6 kg/m2). No side, order, and carry-over effects were observed from the oral administrations of hydrogen-rich water HRW and PLW in any participant.

Questionnaire results

Results from the questionnaires are summarized in Table 1. No questionnaire scores at baseline (pre) showed any significant differences between hydrogen-rich water HRW and PLW administration groups. With HRW administration, scores for K6, CFS, and PSQI were significantly decreased after the 4-week administration period. In addition, the change ratio (post/pre) for K6 score was significantly lower in the hydrogen-rich water HRW administration group than in the PLW administration group (Figure 2). No significant changes were seen in any other questionnaire scores (modified version of the Osaka City University Hospital Fatigue Scale, Center for Epidemiologic Studies Depression Scale or Epworth Sleepiness Scale) after hydrogen-rich water HRW administration and no significant changes in any of the scores were seen after PLW administration. Likewise, these scores did not differ significantly between HRW and PLW after administration.

Table 1

Changes in parameters related to quality of life due to hydrogen-rich water (HRW) or placebo water (PLW) administration

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Comparison of change ratios (post-treatment/pre-treatment) for parameters related to quality of life with administration of hydrogen-rich water (HRW) or placebo water (PLW) for 4 weeks.

Note: Change ratios for K6 score for mood (A) and anxiety and the low-frequency component power (LF) for autonomic nerve function (B). *P < 0.05.

Autonomic function results

Results for the autonomic nerve function are summarized in Table 1. LF, HF, and LF/HF ratio at baseline (pre) did not differ significantly between hydrogen-rich water HRW and PLW administrations, indicating similar autonomic nerve function in the two groups before water intake. Although the HF and LF/HF ratio were not significantly affected by 4-week administrations of hydrogen-rich water HRW or PLW, LF after hydrogen-rich water HRW administration was significantly lower than that after PLW administration. The change ratio (post/pre) for LF was also significantly lower in the hydrogen-rich water HRW administration group than in the PLW administration group (Figure 2).

Cognitive function results

Results for the cognitive function test are shown in Table 1. Motivational response and total counts of correct responses and errors at baseline (pre) did not differ significantly between hydrogen-rich water HRW and PLW administrations, indicating similar cognitive function between groups before water intake. Motivational response after hydrogen-rich water HRW administration was significantly faster than that before hydrogen-rich water HRW administration. The change ratio (post/pre) for motivational response was not significantly different in the hydrogen-rich water HRW administration group than in the PLW administration group. No significant differences in motivational response, total counts of correct responses, or errors after water administration were seen between hydrogen-rich water HRW- and PLW-administered conditions.

Blood sample results

No significant differences were seen in any blood parameters (hs-CRP, d-ROMs, BAP, and OSI) before hydrogen-rich water HRW or PLW administration (Table 1), indicating the comparability of the two groups before water intake. After hydrogen-rich water HRW and PLW administrations, we again found no significant differences in these blood parameters.

Daily daytime activity and daily journal results

The daily expenditure of calories and amount of physical activity during the 4-week administration periods did not differ significantly between hydrogen-rich water HRW and PLW administration conditions (Table 2). Similarly, visual analogue scale scores for fatigue just after waking and before bedtime, sleeping times, physical condition, and counts of special events were comparable between hydrogen-rich water HRW and PLW administration conditions (Table 2), indicating that living habits were successfully controlled during the experimental period in the two groups.

Table 2

Daily daytime activity and data recorded in the daily journal during the hydrogen-rich water (HRW) or placebo water (PLW) administration period (4 weeks)

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Discussion

The present findings suggest that hydrogen-rich water HRW administration for 4 weeks may have improved the QOL of adult volunteers in terms of improved mood and anxiety and reduced activity of the sympathetic nervous system at rest.

In terms of associations between hydrogen and the central nervous system, a report by Ohsawa et al. was the first to demonstrate that molecular hydrogen acts, at least in part, as an anti-oxidant as it binds to hydroxyl ions produced in central nervous system injuries. Previous studies have proposed that hydrogen-rich water HRW administration has neuroprotective effects and anti-aging effects on periodontal oxidative damage in healthy aged rats. In a rat model of Alzheimer’s disease, hydrogen-rich saline prevented neuroinflammation and oxidative stress, and improved memory function. In terms of the association between hydrogen-rich water HRW and QOL, only one study reported that HRW hydrogen-rich water administration for 6 weeks improved QOL scores in patients treated with radiotherapy for liver tumors. Although reports on the effects of HRW hydrogen-rich water administration in healthy populations have not been accumulated, job stress, and acute fatigue caused by mental and physical loading for several hours, have been shown to enhance oxidative stress. As for physical fatigue, in order to alleviate acute physical fatigue in healthy volunteers not including athletes, we have previously demonstrated that treatment with antioxidant supplements is effective.,, The present study provided new findings that HRW hydrogen-rich water affects not only physical condition but also mental conditions such as mood, anxiety, and autonomic nerve function. One of the advantages of HRW hydrogen-rich water is the ability to cross the blood-brain barrier, offering high potential to reduce oxidative stress in the brain. A previous study in rats found that levels of malondialdehyde, a marker of oxidative stress, were around 4.8-fold higher in the brain than in the blood (plasma). These results suggest that HRW hydrogen-rich water may be effective for reducing accumulated oxidative stress in the brain in daily life, potentially contributing to the maintenance of central nervous system activity and preventing decreases in QOL.

In the present study, mood and anxiety levels improved after HRW hydrogen-rich water administration. These negative emotions are also known to be involved in conditions related to oxidative stress; social phobia,,depression, anxiety,, and other neuropsychiatric disorders have been shown to be associated with increased oxidative stress. Neuroinflammation is also related to fatigue, mood, anxiety, and sleep.,,, In older mice, HRW hydrogen-rich water administration succeeded in suppressing depression-like behaviors. These findings suggest that administration of HRW hydrogen-rich water for 4 weeks may be effective for controlling such negative emotions by reducing oxidative stress and inflammation of the central nervous system. Increasing evidence suggests that oxidative stress and inflammation in neurons are involved in the pathological manifestations of many neurological and neuropsychiatric disorders, and HRW hydrogen-rich water administration may thus help alleviate the symptoms of these disorders. Previous study revealed that oxidative stress of the brain causes cognitive and motivational deficits in a mouse model of neuropsychiatric disorder (schizophrenia). In the present study, motivational response of cognitive function test was improved by prolonged HRW hydrogen-rich water intake, suggesting that a reduction of oxidative stress in the brain by the intake of HRW hydrogen-rich water may increase motivational performance of cognitive task.

Stressors can enhance sympathetic hyperactivity, promote oxidative stress, and boost pro-inflammatory cytokine production.,, Autonomic nerve function is thus closely associated with oxidative stress and inflammation. Attenuation of sympathetic nervous system activity during the resting state in adult volunteers may therefore be the result of decreases in inflammation and oxidative stress as an effect of prolonged HRW hydrogen-rich water administration. However, the lack of changes in oxidative stress markers noted in the present study after HRW intake for 4 weeks could be due to the low severity of oxidative stress in the participants. Actually, serum d-ROMs (307.1 ± 49.4 CARR U) and BAP (2,549 ± 194 µM) concentrations at the first measurement point in the present study were within normal ranges based on the results of serum d-ROMs (286.9 ± 100.2 CARR U) and BAP (2,541 ± 122 µM) concentrations measured in 312 healthy participants in our previous study. However, levels of oxidative stress fluctuate depending on daily work load and stress. In addition, the rat study by García-Niño et al. that found malondialdehyde levels around 4.8-fold higher in the brain than in plasma indicate that oxidative stress in the brain is more severe. Daily administration of HRW hydrogen-rich water for 4 weeks may thus contribute to attenuation of and prevention from the cumulative oxidative stress in the brain. Mood, anxiety, and autonomic nerve function could thus potentially be improved. Although the range of sympathetic nerve activity in the present study considers to be normal based on our previous studies,, sympathetic nerve activity also fluctuates depending on daily work load and stress. Therefore, lower sympathetic nerve activity of resting state may contribute to suppress an excessive increase in sympathetic nerve activity after the daily work load and stress.

We conducted this study with a limited number of participants. Before our results can be generalized, studies involving larger numbers of participants are essential.

Although we mainly examined the effects of HRW hydrogen-rich water on the central nervous system, we did not directly evaluate the dynamics of inflammation and oxidation in the brain. Neuroimaging studies using positron emission tomography and magnetic resonance imaging are thus underway in our laboratory to identify the mechanisms underlying the effects of HRW intake on the central nervous system that can improve QOL.

In conclusion, HRW hydrogen-rich water administration for 4 weeks in adult volunteers improved mood, anxiety, and autonomic nerve function, suggesting that HRW hydrogen-rich water administration may offer an effective method to reinforce QOL and maintain good health. In a further study, we will try to identify the effects of HRW hydrogen-rich water administration in participants with ongoing stress or chronic fatigue.

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Link to Publisher's site
. 2017 Oct-Dec; 7(4): 247–255.
Published online 2018 Jan 22. doi:  [10.4103/2045-9912.222448]
PMCID: PMC5806445
PMID: 29497485
Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life

Acknowledgments

We would like to thank Ms. Mika Furusawa for her excellent technical assistances and Forte Science Communications for editorial help with this manuscript.

Footnotes

Conflicts of interest

This work was presented at Japanese Society of Fatigue Science, Yamaguchi City, Japan on May 16, 2016. Yasuyoshi Watanabe received funding for the present study from Melodian Corporation. The other authors have no conflicts of interest to declare.

Research ethics

All experiments were conducted in comp