Research Summary of available studies: Most cancer cells elongate telomere length to ensure immortality. ERW inhibits binding of telomerase to telomere region resulting in shortening of telomere length.1 H2 (Hydrogen) is able to rapidly diffuse across membranes. It can reach and react with cytotoxic ROS like hydroxyl radical. 2 Acute oxidative stress causes serious damage to tissues. Persistent oxidative stress is one of the causes of many common diseases, such as cancer and it may also accelerate the aging process. ERW has anti-inflammatory and anti-allergic effects and it may also improve mitochondrial disorders. 3 Alkaline reduced water with a high pH and low ORP, has an anti-diabetic and anti-cancer effect. Long term ingestion results in reduction in levels of glucose, triglycerides and total cholesterol in the blood. It showed tumour growth delay and the life span of rats was significantly lengthened. It also inhibited metastasis. It can also help to optimise the immune response (immunomodulator).4 ERW enhanced human lymphocyte resistance to DNA strand breaks by ROS. ERW could help prevent total RNA degradation. Enhances ascorbic acid (Vitamin C) about threefold when dissolved in ERW and it could have an inhibitory effect on the oxidation of ascorbic acid. 5 Long term use improved T-Cell apoptosis and cytokines in end stage renal patients with chronic haemodialysis. 6 ERW is an antioxidant and there is an enhanced inhibition effect of on leukaemia cells (HL60) with different combinations of Glutathione and ERW.7 ERW with Platinum nanoparticles is a potential new antioxidant against carcinogenesis.8 ERW suppresses growth of cancer cells and it exhibits a weak microbicidal effect, especially in low or smaller densities of the microorganisms. It may contribute to prevent the rot of food or improve the intestinal micro flora to prevent abnormal fermentation. 9 ERW with Platinum Nanoparticles brings about the process of programmed cell death in cancer cells. 10 The consumption of hydrogen-rich water for 6 weeks reduced reactive oxygen metabolites in the blood and maintained blood oxidation potential. Quality of Life scores during radiotherapy were significantly improved in patients treated with hydrogen-rich water compared to patients receiving placebo water. There was no difference in tumor response to radiotherapy between the two groups. Daily consumption of hydrogen-rich water is a potentially novel, therapeutic strategy for improving QOL after radiation exposure. Consumption of hydrogenrich water reduces the biological reaction to radiation-induced oxidative stress without compromising anti-tumor effects. 11 This study proved that a H2 rich medium reduced •OH. Radiation induced preprogrammed cell death in living mice and it also caused a depletion of white blood cells and platelets. H2 protected the immune system and alleviated the haematological injury induced by IR. 12 In this study it showed that platinum nanocolloid-supplemented hydrogendissolved water inhibits growth of human tongue carcinoma cells preferentially over normal cells. 13 Hydrogen has been reported to have neuron protective effects due to its antioxidant properties. Treatment with hydrogen water for 30 days prevented age-related declines in cognitive ability seen in mice as assessed by a water maze test and was associated with increased brain serotonin levels and elevated serum antioxidant activity. In addition, drinking hydrogen water for 18 weeks inhibited neurodegeneration in hippocampus, while marked loss of neurons was noted in control, aged brains of mice receiving regular water. On the basis of our results, hydrogen water merits further investigation for possible therapeutic/preventative use for age-related cognitive disorders. 14 Metabolic syndrome is characterized by cardio metabolic risk factors that include obesity, insulin resistance, hypertension and dyslipidaemia. Oxidative stress is known to play a major role in the pathogenesis of metabolic syndrome. The objective of this study was to examine the effectiveness of hydrogen rich water (1.5–2 L/day) in an open label, 8-week study on 20 subjects with potential metabolic syndrome. Hydrogen rich water was produced, by placing a metallic magnesium stick into drinking water (hydrogen concentration; 0.55– 0.65 mM), by the following chemical reaction; Mg + 2H2O → Mg (OH)2 + H2. The consumption of hydrogen rich water for 8 weeks resulted in a 39% increase (p<0.05) in antioxidant enzyme superoxide dismutase (SOD - they are an important antioxidant defence in nearly all cells exposed to oxygen.)2* and a 43% decrease (p<0.05) in thiobarbituric acid reactive substances in urine. Further, subjects demonstrated an 8% increase in high density lipoprotein (HDL)-cholesterol and a 13% decrease in total cholesterol/HDL-cholesterol from baseline to week 4. There was no change in fasting glucose levels during the 8 week study. In conclusion, drinking hydrogen rich water represents a potentially novel therapeutic and preventive strategy for metabolic syndrome. The portable magnesium stick was a safe, easy and effective method of delivering hydrogen rich water for daily consumption by participants in the study. TBARS is a widely used method of for investigating overall lipid peroxidation. 15 In this study rats were given HRW (Hydrogen Reduced Water) for sixteen weeks. The findings were: water intake and urine flow were greater in the rats given HRW. They found that the antioxidant capacity was significantly higher in the HRW than in the control group. They also found that the glomerulosclerosis score for the HRW group was significantly lower than in the control group. The present findings suggest that HRW conferred significant benefits against abnormalities in the metabolic syndrome model rats, at least by preventing and ameliorating glomerulosclerosis and creatinine clearance. 16 Our study demonstrates that H2 exerts metabolic effects similar to those of insulin and may be a novel therapeutic alternative to insulin in type 1 diabetes mellitus that can be administered orally. 17 Drinking HW significantly reduced neointima formation after vein grafting in rats. Drinking HW may have therapeutic value as a novel therapy for intimal hyperplasia and could easily be incorporated into daily life. 18 In a study performed by the Serbian Ministry of Science HRW demonstrated potential to be used as an alkalizing agent in individuals with exercise-induced metabolic acidosis. 19 This study indicates that the inhibitory effect of ERW on tumor invasion is due to, at least in part, its antioxidative effect. 20 Electrolyzed reduced water, which is capable of scavenging reactive oxygen species, is attracting recent attention because it has shown improved efficacy against several types of diseases including diabetes mellitus. Alloxan produces reactive oxygen species and causes type 1 diabetes mellitus in experimental animals by irreversible oxidative damage to insulin-producing β-cells. Here, we showed that electrolyzed reduced water prevented Alloxan-induced DNA fragmentation and the production of cells in sub-G1 phase in HIT-T15 pancreatic β-cells. Blood glucose levels in Alloxan-induced type 1 diabetes model mice were also significantly suppressed by feeding the mice with electrolyzed reduced water. These results suggest that electrolyzed reduced water can prevent apoptosis of pancreatic β-cells and the development of symptoms in type 1 diabetes model mice by alleviating the Alloxan-derived generation of reactive oxygen species. 21 Insulin-producing cells express limited activities of anti-oxidative enzymes. Therefore, reactive oxygen species (ROS) produced in these cells play a crucial role in cytotoxic effects. Furthermore, diabetes mellitus (DM) development is closely linked to higher ROS levels in insulin-producing cells. Hita Tenryosui Water® (Hita T. W., Hita, Japan) and Nordenau water (Nord. W., Nordenau, Germany), referred to as natural reduced waters (NRWs), scavenge ROS in cultured cells, and therefore, might be a possibility as an alternative to conventional pharmacological agents against DM. NRWs equally suppressed DNA fragmentation levels. Hita T. W. and Nord. W. ameliorated ALX-induced sub-G1 phase production from approximately 40% of control levels to 8.5 and 11.8%, respectively. NRWs restored serum insulin levels (p < 0.01) and reduced blood glucose levels (p < 0.01) in ALX-induced mice. Hita T. W. restored tissue superoxide dismutase (SOD) (p < 0.05) activity but not tissue catalase activity. Hita T. W. did not elevate SOD or catalase activity in HIT-T15 cells. Nord. W. restored SOD (p < 0.05) and catalase (p < 0.05) activity in both cultured cells and pancreatic tissue to normal levels. Even though variable efficacies were observed between Hita T. W. and Nord. W., both waters suppressed ALXinduced DM development in CD-1 male mice by administering NRWs for 8 weeks. Our results suggest that Hita T. W. and Nord. W. protect against ALXinduced β-cell apoptosis, and prevent the development of ALX-induced DM in experimental animals by regulating ALX-derived ROS generation and elevating anti-oxidative enzymes. Therefore, the two NRWs tested here are promising candidates for the prevention of DM development. 22 Since the first description of Parkinson's disease (PD) nearly two centuries ago, a number of studies have revealed the clinical symptoms, pathology, and therapeutic approaches to overcome this intractable neurodegenerative disease. 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 6hydroxydopamine (6-OHDA) are neurotoxins which produce Parkinsonian pathology. From the animal studies using these neurotoxins, it has become well established that oxidative stress is a primary cause of, and essential for, cellular apoptosis in dopaminergic neurons. Here, we describe the mechanism whereby oxidative stress evokes irreversible cell death, and propose a novel therapeutic strategy for PD using molecular hydrogen. Hydrogen has an ability to reduce oxidative damage and ameliorate the loss of nigrostriatal dopaminergic neuronal pathway in two experimental animal models. Thus, it is strongly suggested that hydrogen might provide a great advantage to prevent or minimize the onset and progression of PD. 23 Hydrogen has potential for improving the quality of life of patients during chemotherapy by efficiently mitigating the side effects of cisplatin. 24 Oxidative stress is implicated in atherogenesis; however most clinical trials with dietary antioxidants failed to show marked success in preventing atherosclerotic diseases. We have found that hydrogen (dihydrogen; H2) acts as an effective antioxidant to reduce oxidative stress [I. Ohsawa, M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K. Katsura, Y. Katayama, S, Asoh, S. Ohta, Hydrogen 32 acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Nat. Med. 13 (2007) 688–694]. Here, we investigated whether drinking H2-dissolved water at a saturated level (H2– water) ad libitum prevents arteriosclerosis using an apolipoprotein E knockout mouse (apoE/), a model of the spontaneous development of atherosclerosis. ApoE/ mice drank H2–water ad libitum from 2 to 6 months old throughout the whole period. Atherosclerotic lesions were significantly reduced by ad libitum drinking of H2–water (p = 0.0069) as judged by Oil-Red-O staining series of sections of aorta. The oxidative stress level of aorta was decreased. Accumulation of macrophages in atherosclerotic lesions was confirmed. Thus, consumption of H2-dissolved water has the potential to prevent arteriosclerosis. 25 Hydrogen-enriched water improves mitochondrial dysfunction in MM and inflammatory processes in PM/DM. Less prominent effects with the doubleblind trial compared to the open-label trial were likely due to a lower amount of administered hydrogen and a shorter observation period, which implies a threshold effect or a dose-response effect of hydrogen. 26 H2 acted to restore transcriptional alterations induced by ONOO-.These results imply that one of the functions of H2 exhibits cytoprotective (protecting cells from noxious chemicals or other stimuli) effects and transcriptional alterations through reducing ONOO-. Moreover, novel pharmacological strategies aimed at selective removal of ONOO- may represent a powerful method for preventive and therapeutic use of H2 for joint diseases. 27 Hydrogen water increased breath hydrogen concentrations from 8.6 ± 2.1 to 32.6 ± 3.3 ppm (mean and SEM, n = 8) in 10 min in healthy subjects. Lactulose increased breath hydrogen concentrations in 86% of healthy subjects and 59% of PD patients. Compared to monophasic hydrogen increases in 71% of healthy subjects, 32% and 41% of PD patients showed biphasic and no increases, respectively. Lactulose also increased breath hydrogen levels monophasically in 9 rats. Lactulose, however, marginally ameliorated 6-OHDA-induced PD in rats. Continuous administration of 2% hydrogen gas similarly had marginal effects. On the other hand, intermittent administration of 2% hydrogen gas prevented PD in 4 of 6 rats. Lack of dose responses of hydrogen and the presence of favourable effects with hydrogen water and intermittent hydrogen gas suggest that signal modulating activities of hydrogen are likely to be instrumental in exerting a protective effect against PD. 28 Drinking high H2 water seems to raise the concentration of H2 more than the H2 saturated (1.6 ppm) water in vivo. Urinary 8-OHdG was significantly reduced by 14.3% (p < 0.01) on average. DAS28 (Disease Activity Score for 28 Joints) 2* also decreased from 3.83 to 3.02 (p < 0.01) during the same period. After the wash-out period, both the urinary 8-OHdG and the mean DAS28 decreased, compared to the end of the drinking period. During the second drinking period, the mean DAS28 was reduced from 2.83 to 2.26 (p < 0.01). Urinary 8-OHdG was not further reduced but remained below the baseline value. All the 5 patients with early RA (duration < 12 months) who did not show antibodies against cyclic citrullinated peptides (ACPAs) achieved remission, and 4 of them became symptom-free at the end of the study. The results suggest that the hydroxyl radical scavenger H2 effectively reduces oxidative stress in patients with this condition. The symptoms of RA were significantly improved with high H2 water. 29 HRW inhibited glucose- and α,β-dicarbonyl compound-induced ROS production in kidney homogenates from Wistar rats in vitro. Furthermore, SHR.CgLeprcp/NDmcr rats treated with HRW showed a 34% decrease in ROS production. Moreover, their renal glyoxal, methylglyoxal, and 3deoxyglucosone levels decreased by 81%, 77%, and 60%, respectively. Positive correlations were found between renal ROS levels and renal glyoxal (r = 0.659, p = 0.008) and methylglyoxal (r = 0.782, p = 0.001) levels. These results indicate that HRW inhibits the production of α,β-dicarbonyl compounds and ROS in the kidneys of SHR.Cg-Leprcp/NDmcr rats. Therefore, it has therapeutic potential for renal dysfunction in patient with type 2 diabetes and metabolic syndrome. 30 Although acute exercise resulted in an increase in blood lactate levels in the subjects given PW, oral intake of HW prevented an elevation of blood lactate during heavy exercise. Peak torque of PW significantly decreased during maximal isokinetic knee extension, suggesting muscle fatigue, but peak torque of HW didn’t decrease at early phase. There was no significant change in blood oxidative injury markers (d-ROMs and BAP) or creatine kinease after exercise. Adequate hydration with hydrogen-rich water pre-exercise reduced blood lactate levels and improved exercise-induced decline of muscle function. Although further studies to elucidate the exact mechanisms and the benefits are needed to be confirmed in larger series of studies, these preliminary results may suggest that HW may be suitable hydration for athletes. 31 It has been shown that molecular hydrogen (H2) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H2-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine(MPTP). The concentration-dependency of H2 showed that H2 as low as 0.08 ppm had almost the same effect as saturated H2 water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H2-containing water, whereas production of superoxide (O2•−) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H2 in drinking water can reduce oxidative stress in the brain. Thus, drinking H2-containing water may be useful in daily life to prevent or minimize the risk of life stylerelated oxidative stress and neurodegeneration. 32 The properties and effects of neutral pH hydrogen-enriched electrolyzed water (NHE water) on tumor cells were examined. NHE water diminished hydroxyl radicals as demonstrated by ESR in a cell-free system. Human tongue carcinoma cells HSC-4 were inhibited for either colony formation efficiencies or colony sizes by NHE water without significant inhibition to normal human tongue epithelial-like cells DOK. Furthermore, NHE water caused growth inhibition, cell degeneration, and inhibition of invasion through the reconstituted basement membrane to human fibrosarcoma cells HT-1080. Intracellular oxidants such as hydroperoxides and hydrogen peroxides were scavenged in HSC-4 or HT-1080 cells by NHE water. In the human oral cavity, a dissolved hydrogen concentrations (DH) of NHE water was drastically declined from 1.1 to 0.5 ppm, but settled to 0.3-0.4 ppm until 180 s, upon static holding without gargling. Thus, NHE water was shown to achieve tumor-preferential growth inhibition and tumor invasion together with scavenging of intracellular oxidants, and is expected as a preventive material against tumor progression and invasion. 33 Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis. Tumor cells are exposed to higher oxidative stress compared to normal cells. Numerous reports have demonstrated that the intracellular redox (oxidation/reduction) state is closely associated with the pattern of VEGF expression. Electrolyzed reduced water (ERW) produced near the cathode during the electrolysis of water scavenged intracellular H2O2 and decreased the release of H2O2 from a human lung adenocarcinoma cell line, A549, and down-regulated both VEGF transcription and protein secretion in a timedependent manner. To investigate the signal transduction pathway involved in regulating VEGF expression, mitogen-activated kinase (MAPK) specific inhibitors, SB203580 (p38 MAPK inhibitor), PD98059 (ERK1/2 inhibitor) and JNKi (c-Jun N-terminal protein kinase inhibitor) were applied. The results showed that only PD98059 blocks VEGF expression, suggesting an important role for ERK1/2 in regulating VEGF expression in A549 cells. As well, ERW inhibited the activation of extracellular signal-regulated kinase (ERK) in a time-dependent manner. Co-culture experiments to analyse in vitro tubule formation assay revealed that A549 cell-derived conditioned medium significantly stimulated the formation of vascular tubules in all analysed parameters; tubule total area, tubule junction, number of tubules, and total tubule length. ERW counteracted the effect of A549 cell-conditioned medium and decreased total tube length (p<0.01). The present study demonstrated that ERW down-regulated VEGF gene transcription and protein secretion through inactivation of ERK.34 Molecular hydrogen has been reported to be effective for a variety of disorders and its effects have been ascribed to the reduction of oxidative stress. However, we have recently demonstrated that hydrogen inhibits type I allergy through modulating intracellular signal transduction. These results suggested a role for molecular hydrogen as a signal modulator. Finally, oral intake of hydrogen-rich water alleviated anti-type II collagen antibody-induced arthritis in mice, a model for human rheumatoid arthritis. Taken together, our studies indicate that hydrogen inhibits LPS/IFNγ-induced NO production through modulation of signal transduction in macrophages and ameliorates inflammatory arthritis in mice, providing the molecular basis for hydrogen effects on inflammation and a functional interaction between two gaseous signalling molecules, NO and molecular hydrogen.35 Hydrogen-enriched water improves mitochondrial dysfunction in MM and inflammatory processes in PM/DM. Less prominent effects with the doubleblind trial compared to the open-label trial were likely due to a lower amount of administered hydrogen and a shorter observation period, which implies a threshold effect or a dose-response effect of hydrogen. One of the patients who was an insulin-treated MELAS patient had a hypoglycaemic episode. This was rectified by lowering the insulin dose. 36 Molecular hydrogen ameliorates oxidative stress-associated diseases in animal models. We found that oral intake of hydrogen-rich water abolishes an immediate-type allergic reaction in mice. In the immediate-type allergic reaction, hydrogen exerts its beneficial effect not by its radical scavenging activity but by modulating a specific signalling pathway. Effects of hydrogen in other diseases are possibly mediated by modulation of yet unidentified signalling pathways. 37 Oxidative stress is recognized widely as being associated with various disorders including diabetes, hypertension, and atherosclerosis. It is well established that hydrogen has a reducing action. We therefore investigated the effects of hydrogen-rich water intake on lipid and glucose metabolism in patients with either type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). We performed a randomized, double-blind, placebo-controlled, crossover study in 30 patients with T2DM controlled by diet and exercise therapy and 6 patients with IGT. The patients consumed either 900 mL/d of hydrogen-rich pure water or 900 mL of placebo pure water for 8 weeks, with a 12-week washout period. Several biomarkers of oxidative stress, insulin resistance, and glucose metabolism, assessed by an oral glucose tolerance test, were evaluated at baseline and at 8 weeks. Intake of hydrogen-rich water was associated with significant decreases in the levels of modified low-density lipoprotein (LDL) cholesterol (ie, modifications that increase the net negative charge of LDL), small dense LDL, and urinary 8-isoprostanes by 15.5% (P < .01), 5.7% (P < .05), and 6.6% (P < .05), respectively. Hydrogen-rich water intake was also associated with a trend of decreased serum concentrations of oxidized LDL and free fatty acids, and increased plasma levels of adiponectin and extracellular-superoxide dismutase. In 4 of 6 patients with IGT, intake of hydrogen-rich water normalized the oral glucose tolerance test. In conclusion, these results suggest that supplementation with hydrogen-rich water may have a beneficial role in prevention of T2DM and insulin resistance. 38 Basal cellular viability and function to generate superoxide radicals of PMNs were better preserved by e-RO application. In the clinical trial, reductions of blood pressure were noted, but no adverse events were observed. There were no changes in the blood dialysis parameters, although methylguanidine levels were significantly decreased at the end of study. The present study demonstrated the capacity of e-RO to preserve the viability of PMNs, and the clinical feasibility of applying this water for HD treatment. The clinical application of this technology may improve the bio-compatibility of HD treatment. 39 In this study there was a significant decrease in systolic blood pressure (SBP) before and after dialysis. A significant number of patients achieved SBP <140 mmHg after Haemodialysis. This system could offer a novel therapeutic option for control of uraemia. 40 First, we show that hepatic glycogen accumulates H2 after oral administration of H2-water, explaining why consumption of even a small amount of H2 over a short span time efficiently improves various disease models. This finding was supported by an in vitro experiment in which glycogen solution maintained H2. Next, we examined the benefit of ad libitum drinking H2-water to type 2 diabetes using db/db obesity model mice lacking the functional leptin receptor. Drinking H2-water reduced hepatic oxidative stress, and significantly alleviated fatty liver in db/db mice as well as high fat-diet-induced fatty liver in wild-type mice. Long-term drinking H2-water significantly controlled fat and body weights, despite no increase in consumption of diet and water. Moreover, drinking H2-water decreased levels of plasma glucose, insulin, and triglyceride, the effect of which on hyperglycaemia was similar to diet restriction. To examine how drinking H2-water improves obesity and metabolic parameters at the molecular level, we examined gene-expression profiles, and found enhanced expression of a hepatic hormone, fibroblast growth factor 21 (FGF21), which functions to enhance fatty acid and glucose expenditure. Indeed, H2 stimulated energy metabolism as measured by oxygen consumption. The present results suggest the potential benefit of H2 in improving obesity, diabetes, and metabolic syndrome. 41 References for research summary: 1 Telomere Shortening in Cancer Cells by Electrolyzed-Reduced Water Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals 3 Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases 4 Alkaline Reduced Water produced by UMQ showed Anti-cancer and Antidiabetic effect 5 Electrolyzed-reduced water protects against oxidative damage to DNA, RNA, and protein. 6 Electrolysed-reduced water dialysate improves T-cell damage in end-stage renal disease patients with chronic haemodialysis 7 Enhanced Induction of Mitochondrial Damage and Apoptosis in Human Leukaemia HL-60 Cells due to Electrolyzed-Reduced Water and Glutathione 8 Electrolyzed Reduced Water Supplemented with Platinum Nanoparticles Suppresses Promotion of Two-stage Cell Transformation. 9 Suppressive Effect of Electrolyzed-Reduced Water on the Growth of Cancer Cells and Microorganisms 10 Induction of Caspase-3-dependent Apoptosis by Electrolyzed Reduced Water/platinum Nanoparticles in Cancer Cells 11 Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors 12 Hydrogen-rich saline protects immunocytes from radiation-induced apoptosis 13 Platinum nanocolloid-supplemented hydrogen-dissolved water inhibits growth of human tongue carcinoma cells preferentially over normal cells 14 Drinking Hydrogen Water Ameliorated Cognitive Impairment in SenescenceAccelerated Mice 15 Effectiveness of Hydrogen Rich Water on Antioxidant Status of Subjects with Potential Metabolic Syndrome - An Open Label Pilot Study 16 Effects of hydrogen-rich water on abnormalities in a SHR.Cg-Leprcp/NDmcr rat - a metabolic syndrome rat model 17 Hydrogen Improves Glycaemic Control in Type1 Diabetic Animal Model by Promoting Glucose Uptake into Skeletal Muscle 18 Oral intake of hydrogen-rich water inhibits intimal hyperplasia in arterialized vein grafts in rats 2 19 Serum Alkalinization and Hydrogen-Rich Water in Healthy Men Suppressive effects of electrochemically reduced water on matrix etalloproteinase-2 activities and in vitro invasion of human fibrosarcoma HT1080 cells 21 Suppressive effects of electrolyzed reduced water on Alloxan-induced apoptosis and type 1 diabetes mellitus 22 Suppressive effects of natural reduced waters on Alloxan-induced apoptosis and type 1 diabetes mellitus 23 Therapeutic Effects of Hydrogen in Animal Models of Parkinson's disease 24 Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. 25 Consumption of hydrogen water prevents atherosclerosis in apolipoprotein 3E knockout mice 26 Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies 27 Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide 28 Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamineinduced Parkinson’s disease in rats 29 Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study 30 Hydrogen-rich water inhibits glucose and α,β -dicarbonyl compound-induced reactive oxygen species production in the SHR.Cg-Leprcp/NDmcr rat kidney 31 Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes 32 Hydrogen in Drinking Water Reduces Dopaminergic Neuronal Loss in the 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mouse Model of Parkinson's Disease 33 Neutral pH Hydrogen-Enriched Electrolyzed Water Achieves TumorPreferential Clonal Growth Inhibition over Normal Cells and Tumor Invasion Inhibition Concurrently With Intracellular Oxidant Repression 34 Inhibitory Effect of Electrolyzed Reduced Water on Tumor Angiogenesis 35 Molecular hydrogen inhibits lipopolysaccharide/interferon γ-induced nitric oxide production through modulation of signal transduction in macrophages 20 36 Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies 37 Molecular hydrogen suppresses FcepsilonRI-mediated signal transduction and prevents degranulation of mast cells. 38 Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. 39 Biological effects of electrolyzed water in haemodialysis 40 A novel bioactive haemodialysis system using dissolved dihydrogen (H2) produced by water electrolysis: a clinical trial. 41 Molecular Hydrogen Improves Obesity and Diabetes by Inducing Hepatic FGF21 and Stimulating Energy Metabolism in db/db Mice