Safety & Health Benefits of Hydrogen Water – Nobel Prize Nominee, Dr. GARTH NICOLSON
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.
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.
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.
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).
H2-water may have a potential for suppressing dementia in an oxidative stress model and in the APOE4 carriers with MCI.
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) [1, 2]. 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 [7, 8]. 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 [10–12]. In addition to extensive animal experiments, more than 25 clinical studies examining the efficacy of molecular hydrogen H2 have been reported, [11, 12] 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) [18, 19] 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 [23, 24]. 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).
3.1. 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).
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).
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).
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.
|Control (n=38)||Intervention (n=35)|
|Mean||SD or %||Mean||SD or %|
|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|
|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%)|
* 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.
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 [27, 28]. 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 [34, 35]. 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 [40 – 42]. Moderate exercise enhances energy metabolism and suppresses the expression of pro-inflammatory cytokines,  and protects vascular systems [40, 44, 45].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.
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.
Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild Cognitive Impairment
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
|MCI||Mild cognitive Impairment|
|ALDH2||Aldehyde Dehydrogenase 2|
|ADAS-cog||Alzheimer’s Disease Assessment Scale-cognitive subscale|
|DAL101||Dominant Negative Type 101 of the ALDH2 Mutant Polymorphism (ALDH2*2)|
|ORT||Object Recognition Task|
|PA||Passive Avoidance Task|
|GFAP||Glial Fibrillary Acidic Protein|
|ANOVA||One-way Analysis of Variance|
|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 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.
- Drinking hydrogen water enhances endurance and relieves psychometric fatigue: a randomized, double-blind, placebo-controlled study
Acute physical exercise increases reactive oxygen species in skeletal muscle, leading to tissue damage and fatigue. Molecular hydrogen (H2) acts as a therapeutic antioxidant directly or indirectly by inducing antioxidative enzymes.
Here, we examined the effects of drinking hydrogen H2 water (H2-infused water) on psychometric fatigue and endurance capacity in a randomized, double-blind, placebo-controlled fashion.
In Experiment 1, all participants(humans) drank only placebo water in the first cycle ergometer exercise session, and for comparison they drank either hydrogen H2 water or placebo water 30 min before exercise in the second examination.In these healthy non-trained participants (n = 99), psychometric fatigue judged by visual analogue scales was significantly decreased in the hydrogen H2 water group after mild exercise. When each group was divided into 2 subgroups, the subgroup with higher visual analogue scale values was more sensitive to the effect of hydrogen water H2.
In Experiment 2, trained participants (n = 60) were subjected to moderate exercise by cycle ergometer in a similar way as in Experiment 1, but exercise was performed 10 min after drinking hydrogen H2 water. Endurance/fatigue were significantly improved/relieved in the hydrogen water H2 group as judged by maximal oxygen consumption and Borg’s scale, respectively.
Taken together, drinking hydrogen H2 water just before exercise exhibited anti-fatigue and improved endurance effects.
Can J Physiol Pharmacol. 2019 Jun 28:1-6. doi: 10.1139/cjpp-2019-0059. [Epub ahead of print]
Drinking hydrogen water enhances endurance and relieves psychometric fatigue: a randomized, double-blind, placebo-controlled study 1.
- 1 Department of Health and Sports Science, Nippon Medical School, Musashino, Tokyo 180-0023, Japan.
- 2 Fitness Club, Asahi Big S Mukogaoka, Kawasaki-city, Kanagawa pref. 214-0014, Japan.
- 3 Hydrogen Health Medical Laboratory, Co., Ltd., Arakawa-ku, Tokyo 116-0001, Japan.
- 4 Slovak Academy of Sciences, Centre of Experimental Medicine, Institute for Heart Research, Bratislava 84005, Slovak Republic.
- 5 Molecular Hydrogen Institute, Enoch, UT 84721, USA.
- 6Department of Neurology Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
Objective: This study aims to investigate the selective protective effect of hydrogen water on the free radical injury of athletes after high-intensity exercise and to provide a reliable method for reducing oxidative stress injury of athletes.
Methods: A total of 60 athletes from the swimming team in our city were selected as the research subjects. They were divided into the control group and hydrogen water group according to different intervention methods. The athletes in the control group were treated with placebo, and the athletes in the hydrogen water group were supplemented with hydrogen water. The serum superoxide anions, Serum Superoxide Dismutase (SOD) activities, and total antioxidant capacities of athletes were compared between the two groups.
Results: The serum superoxide anions, serum SOD activities, and total antioxidant capacities of athletes during and after training were significantly superior to those of the control group (P<0.05), and the difference was statistically significant.
Conclusion: Hydrogen water supplement could effectively reduce the oxidized substances in athletes before, during, and after exercise and could prevent the free radical injury caused by high-intensity exercise.
Hydrogen water is one of the antioxidants. Its low price, nontoxic side effects, being non-stimulant, and other benefits provide a decisive advantage in clinical application . Clinical study indicated that injection or drinking of hydrogen water in the human body or animals or breathing hydrogen has a therapeutic effect for periodontitis, foot swelling, traumatic pancreatitis, intestinal ischemia reperfusion injury, brain injury, and other diseases caused by oxidative stress . One-time injection of hydrogen water had a protective effect on the biological membrane damage of free radical after acute exhaustive exercise in rat. Meanwhile, they first proved the collective selective oxidation of hydrogen water . However, previous research on hydrogen water used animal experiments, and research in the field of sport medicine is still in the initial exploratory stage. The systematic analysis of athletes undergoing professional high-intensity exercise is yet to be conducted . In this study, 60 athletes from our swimming team in our city were selected as the research subjects. They were supplemented with hydrogen water at different time phases. The antioxidant effects were compared, and the detailed discussion of the research follows.
Materials and Methods
A total of 60 athletes from the swimming team in our city were selected as the research subjects. They were divided into the control group and hydrogen water group according to the different intervention methods. The athletes in the control group were treated with placebo, and the athletes in the hydrogen water group were supplemented with hydrogen water. Every group had 30 male athletes. In the control group, the athletes were aged 14-22 years old with average of (18.1 ± 1.3) years old and had the following characteristics: height 172-196 cm, average (180.2 ± 6.3) cm; body weight 62-78 kg, average (68.2 ± 4.5) kg; and exercise duration 1-7 years, average (4.1 ± 0.5) years. In the hydrogen water group, the athletes were aged 15-22 years old, average (17.9 ± 1.5) years old, and had the following characteristics: height 174-192 cm, average (179.8 ± 6.5) cm; body weight 65-76 kg, average (68.0 ± 4.3) kg; exercise duration 2-7 years, average (3.7 ± 0.7) years. No statistical difference in athlete age, height, weight, and exercise duration (P>0.05) was noted between the two groups.
The hydrogen water in this study was purchased from Japan. It was authenticated as neither stimulant nor banned substance by the analeptic inspection center. All athletes were in good health during the intervention period and did not take any antioxidants, including vitamins C and E. The heart rates of athletes in the two groups were monitored. Meanwhile, the blood lactic acid of athletes was measured after exercise to ensure that exercise intensity was adequate. The study lasted for 8 d. A total of 5 ml fasting venous blood was drawn in the morning of the first day. The athletes were treated with the placebo (mineral water) and hydrogen water before, during, and after high-intensity exercise, tid, 200 ml each time. Venous blood was drawn after 2 h exercise. The intensities and amounts of training of all athletes were consistent in the study. The venous blood was labelled, naturally coagulated, and centrifuged by 3000 r/min in the refrigerated centrifuge. The separated serum was preserved in the refrigerator. The athletes were instructed to be mindful of their diet, and antioxidant nourishment was prohibited.
The selective antioxidant indexes (superoxide anion (O2-)), antioxidant defense system indexes (Superoxide Dismutase (SOD)), and serum Total Antioxidant Capacity (T-AOC) of athletes were monitored in the two groups.
The activity of resisting superoxide anion was measured through colorimetric method. The operation was in accordance with the kit instruction of Nanjing Bioengineering Institute, and the OD value of each tube was measured. The formula was as follows: anti O2- activity (U/L)=(OD value of the control tube-OD value of the measured tube)/(OD value of the control tube-OD value of the standard tube) × 1000 ml × concentration of standard sample × diluted times of the sample before test.
The SOD level in vivo was tested through biotin doubleantibody sandwich Enzyme-Linked Immunosorbent Assay (ELISA). The operation was in accordance with the kit instruction of human SOD from Shanghai Lianshuo Biological Technology Co., Ltd. SOD concentration was positively correlated with the color.
The T-AOC in vivo was determined through biotin doubleantibody sandwich ELISA. The operation was in accordance with the kit instruction of human SOD from Shanghai Lianshuo Biological Technology Co., Ltd. T-AOC concentration was positively correlated with the color.
In this study, all the data were imputed into the Excel table and analysed using the SPSS19.0 statistical software. The measurement data were expressed with (χ ± s) and compared using t test. P<0.05 showed that the difference was statistically significant.
Comparison of serum superoxide anion activities of athletes between the two groups
The serum antisuperoxide anion activities of athletes were not different between the two groups before exercise. Meanwhile, the serum antisuperoxide anion activities of athletes in the two groups decreased after exercise. However, the serum antisuperoxide anion activity of athletes in the hydrogen water group was decreased compared with that of the control group during and after exercise, as shown in Table 1.
|Group||N||Before exercise||During exercise||After exercise||P value|
|Blank group||30||146.60 ± 9.31||139.67 ± 9.07||117.17 ± 15.27||<0.05|
|Hydrogen water group||30||143.18 ± 7.88||95.86 ± 12.85||98.86 ± 8.30||<0.05|
Table 1: Comparison of serum antisuperoxide anion activities of athletes in the two groups (χ ± s; U/ml).
Comparison of serum superoxide dismutase activities of athletes between the two groups
The SOD activities of athletes were not different between the two groups before exercise. Meanwhile, the SOD of athletes in the blank group was decreased after exercise. However, the SOD activity of athletes in the hydrogen water group during and after exercise was significantly higher than that of the control group and higher than that before and during exercise, as shown in Table 2.
|Group||N||Before the training||During the training||After the training||P value|
|Blank group||30||57.07 ± 7.08||47.86 ± 7.31||45.65 ± 7.63||<0.05|
|Hydrogen water group||30||55.79 ± 9.20||56.88 ± 4.83||66.92 ± 6.70||<0.05|
Table 2: Comparison of serum superoxide dismutase activities of athletes between the two groups (χ ± s; U/L).
Comparison of serum total antioxidant capacities of athletes between the two groups at different time phases
The serum total antioxidant capacities of athletes was not different between the two groups before exercise. Meanwhile, the serum T-AOC of athletes in the blank group fluctuated after exercise. However, the serum T-AOC of athletes in the hydrogen water group during and after exercise was significantly higher than that of the control group and higher than that before and during exercise, as shown in Table 3.
|Group||N||Before exercise||During exercise||After exercise||P value|
|Blank group||30||2.48 ± 0.11||2.28 ± 0.16||2.35 ± 0.11||<0.05|
|Hydrogen water group||30||2.46 ± 0.13||2.52 ± 0.19||3.36 ± 0.12||<0.05|
Table 3: Comparison of serum total antioxidant capacities of athletes between the two groups at different time points (χ ± s; U/ml).
Free radicals are a kind of substance produced by the normal metabolism in the human body. They do not contain paired electrons, so its nature is lively. Free radicals will offensively target all cells and induce injury. The free radical has two types, and 95% of free radicals belong to oxygen free radicals . It has normal biological functions, such as sterilization, playing an important role in embryonic development, regulating angiotensin, and involvement in the biological initiation of various biological factors as a second messenger. However, the free radical is also cytotoxic. A large number of research  have reported that the free radical is closely related to cancer, inflammation, Alzheimer’s disease, depression, protein oxidative pyrolysis, and lipid peroxidation. Therefore, the free radical is regarded as a “double-edged sword,” and too much or too little will cause adverse effects or even damage. Superoxide anion free radical is a source of various free radicals. Free radicals will absorb the electrons in the endoplasmic reticulum, mitochondria, and nucleus through both non-enzymatic and enzymatic reaction; produce all kinds of oxygen free radicals; and cause damage . Under normal circumstances, the content of plasma Hb is little. However, after high-intensity exercise, a large number of free radicals generate in the body, and the erythrocyte membrane permeability is increased, resulting in the release of Hb into the blood. After drinking the hydrogen water, the antisuperoxide anion activity of athletes was significantly lower than that of the control group (P<0.01), suggesting that hydrogen water could inhibit the antisuperoxide anion activity to a certain extent and reduce the oxidative stress injury.
SOD is an important substance of antioxidant system in body. It can effectively eliminate the superoxide anion during metabolism; prevent lipid peroxidation, aging, fatigue, and injury; and improve athletic ability. Monitoring SOD activity can effectively investigate the quantity of free radicals in vivo . The study found that the SOD activity of athletes in the blank group was decreased after exercise. However, the SOD activities of athletes in the hydrogen water group during and after exercise were significantly higher than those of the control group and also higher than those before and during exercise (P<0.01). T-AOC is a comprehensive index. It can measure the intergraded function of the antioxidant system in body. Its value is closely related to the body’s defense system and can directly reflect the health of the body . At present, reports on SOD activity after exercise are inconsistent. Compared with before exercise and other periods, the serum SOD activity was significantly increased. Meanwhile, the serum SOD activities were not significantly different among other time phases. The serum SOD activities were significantly decreased after anaerobic and aerobic exercises. The study found that in the blank group, serum T-AOC of athletes fluctuated after exercise . However, the serum T-AOC of athletes in the hydrogen group was significantly higher than that of the control group and higher than that before and during exercise (P<0.05).
Hydrogen water supplement can effectively reduce the oxidizing substance before, during, and after exercise, preventing free radical damage caused by high-intensity exercise. Whether or not it can be generally used in athletes still requires further research with a large sample size.
Biomedical Research (2017) Volume 28, Issue 10
Selective protective effect of hydrogen water on free radical injury of athletes after high-intensity exercise
- *Corresponding Author:
- Yue-Peng Sun
Department of Physical Education
Dalian Maritime University, PR China
Accepted date: March 14, 2017
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Positive effects of molecular hydrogen-water bathing in patients of psoriasis and parapsoriasis en plaques
Psoriasis and parapsoriasis en plaques are chronic inflammatory skin diseases, both representing therapeutic challenge in daily practice and adversely affecting the quality of life. Reactive oxygen species (ROS) has been evidenced to be involved in the pathogenesis of the chronic inflammatory diseases. We now report that molecular hydrogen water, an effective ROS scavenger, has significant and rapid improvement in disease severity and quality of life for patients with psoriasis and parapsoriasis en plaques. At week 8, our parallel-controlled trial revealed 24.4% of patients (10/41) receiving molecular hydrogen-water bathing achieved at least 75% improvement in Psoriasis Area Severity Index (PASI) score compared with 2.9% of patients (1/34) of the control group (Pc = 0.022, OR = 0.094, 95%CI = [0.011, 0.777]). Of patients, 56.1% (23/41) who received bathing achieved at least 50% improvement in PASI score compared with only 17.7%(6/34) of the control group (P = 0.001, OR = 0.168, 95%CI = [0.057, 0.492]). The significant improvement of pruritus was also observed (P = 3.94 × 10−4). Besides, complete response was observed in 33.3% of patients (2/6) of parapsoriasis en plaques and partial response in 66.7% (4/6) at week 8. Our findings suggested that molecular hydrogen-water bathing therapy could fulfill the unmet need for these chronic inflammatory skin diseases.
Psoriasis and parapsoriasis en plaques are both chronic inflammatory skin diseases characterized by persistently scaling and inflammatory eruptions1,2. They represent therapeutic challenge in daily practice and adversely affect the quality of life of patients3–6. Psoriasis is so common that has been recognized since ancient times, affecting about 1% to 3% of the general population7. It is associated with a high degree of morbidity. Indeed, disability and impact on quality of life secondary to psoriasis parallels that of heart disease and arthritis8,9. Parapsoriasis en plaques is a relatively rare group of disorders which has been classified into small plaque parapsoriasis (SPP) and large plaque parapsoriasis (LPP) according to the size of the lesions. Although the relation of SPP with mycosis fungoides (MF) is still a matter of discussion, there are about 10–30% of cases of LPP result in MF finally10–13. The interactive network of the immune system and skin cells is thought to play a vital role in the pathogenesis of both diseases. To be more accurate, psoriasis is considered a Th1⁄Th17-driven disease11–13, while parapsoriasis en plaques is a model of cutaneous T cell lympho-proliferative disorders and has been proved to be a monoclonal disorder in many cases. For a long period, conventional treatment to both diseases has not fully met the needs of patients while having well-known side-effects. The improved understanding of the autoimmune inflammatory pathways and associated changing concepts in pathogenesis have led to the development of biological drugs, which especially revolutionized the treatment of psoriasis4,14. However, slow onset of action, high cost, efficacy lost over time and the long-term safety profile of these biologics still remain unsolved3–5.
Recently, it has been evidenced that oxidative stress such as increased reactive oxygen species (ROS) production may be involved in the pathogenesis of chronic inflammatory diseases15,16. The possibility of using this information to develop novel strategies for treatment is of considerable interest. Hydrogen molecule (H2) has been used in medical applications as a safe and effective antioxidant and immunomodulator with minimal side effects16–18. Unlike other antioxidants, which are unable to target organelles, H2 can penetrate biomembranes and diffuse into the cytosol, mitochondria and nucleus19. Moreover, it has also been reported to selectively scavenge ROS17 and show positive influence in Th1, Th2, and pro-inflammatory cytokine imbalance20. Up to date, molecular hydrogen water (solubilized H2) as a treatment strategy for psoriasis-associated skin lesions has been tried by few case reports21, and neither has molecular hydrogen water for patients with parapsoriasis en plaques. Apart from drinking molecular hydrogen water, inhalation of molecular hydrogen gas and injecting H2-dissolved saline, molecular hydrogen-water bathing is a new approach highlights by its skin-directed, safe and painless administration. Thus, our study conducted a parallel-controlled trial in patients with psoriasis and a self-controlled trial in patients with parapsoriasis en plaques to evaluate the efficacy of molecular hydrogen-water bathing to these chronic inflammatory skin diseases.
Improvement of psoriasis
In all, 41 psoriasis patients were assigned to treatment with molecular hydrogen-water bathing therapy and 34 patients were assigned to the control group. The treatment groups were well balanced with respect to demographics and baseline characteristics (Table 1). Only one patient of the control group withdrew during the course of the study at week 2 due to a lack of improvement and she was counted as a non-responder in the control group. Response was evident after 8-week bathing therapy. The mean Psoriasis Area Severity Index (PASI) score and median visual analog scale (VAS) score of the molecular hydrogen-water bathing group at week 8 was 5.8 and 0 respectively, significantly lower than the baseline scores (P = 7.08 × 10−6; P = 2.42 × 10−5).
|The molecular Hydrogen-water bathing group||The control group|
|Baseline||Week 8||Baseline||Week 8|
|Age||40 ± 15 (18–78)||40 ± 15 (18–78)||39 ± 12 (18–72)||39 ± 13 (18–72)|
|BMI||23.8 ± 3.8 (17.5–35.5)||23.7 ± 3.9 (17.2–35.6)||23.1 ± 4.2 (15.5–31.4)||23.0 ± 4.6 (15.3–31.4)|
|Waistline (cm)||82.7 ± 10.3 (63.3–103.3)||82.8 ± 9.8 (63.3–103.3)||76.8 ± 8.7 (58.2–95.4)||76.8 ± 8.9 (58.2–95.4)|
|PASI score||9.8 ± 5.9 (1.4–25.2)||5.8 ± 5.5 (0.2–25.2)||8.5 ± 4.1 (2.8–23.8)||7.9 ± 6.8 (0.8–34.5)|
|VAS score (median, range)||2 (0–8)||0 (0–4)||0 (0–7)||0 (0–9)|
PASI: Psoriasis Area Severity Index; VAS: the visual analog scale; BMI: Body Mass Index.
After 8 weeks of therapy, patients treated with molecular hydrogen-water bathing showed significantly greater improvement than those who were of the control group as evaluated by both PASI and VAS (Table 2 and Fig. 1). Of patients, 24.4% receiving molecular hydrogen-water bathing achieved the end point of at least 75% improvement in PASI score compared with 2.9% of patients of the control group (Pc = 0.022, OR = 0.094, 95%CI = [0.011, 0.777]). Of patients, 56.1% who received bathing achieved at least 50% improvement in PASI compared with only 17.7% of the control group (P = 0.001, OR = 0.168, 95%CI = [0.057, 0.492]). Molecular Hydrogen-water bathing treatment also resulted in substantial improvement in pruritus as measured by VAS. The median change from baseline to week 8 in the bathing group was −2, compared with a median change of 0 in the control group (P = 3.94 × 10−4).
|The Hydrogen-water bathing group||The control group||Pvalue|
|Baseline PASI score||Baseline PASI score|
|(N = 26)||(N = 11)||(N = 4)||(N = 41)||(N = 24)||(N = 9)||(N = 1)||(N = 34)|
|PASI (%)||>PASI90||1 (2.4)||1 (2.4)||0||2 (4.8)||0||0||0||0||>0.05|
|>PASI75||5 (12.2)||3 (7.3)||2 (4.9)||10 (24.4)||1 (2.9)||0||0||1 (2.9)||0.022*|
|>PASI50||13 (31.7)||8 (19.5)||2 (4.9)||23 (56.1)||4 (11.8)||2 (5.9)||0||6 (17.6)||0.001|
|VAS improvement (%)||≤−5||3 (7.3)||0 (0)||0.31*|
|≤−3||9 (22.0)||1 (2.9)||0.04*|
|<0||21 (51.2)||7 (20.6)||0.006|
|≥0||20 (48.8)||27 (79.4)||0.006|
*The corrected P (Pc) values were adjusted by using Yate’s correction for continuity.
Improvement of parapsoriasis en plaques
Six patients were included: 1 man and 5 women, with mean age of 32.8 ± 4.9 (range: 25–40) years and mean course duration of 34.4 ± 31.1 (range: 12–96) months. Four patients were categorized as LPP and two as SPP. Features of the patients were presented in Table 3. In all patients, an improvement in the morphology or distribution of lesions had occurred (Fig. 2). Complete response was observed in 33.3% of patients (2/6), partial response in 66.7% (4/6).
|Patients||Sex/Age||Type of parasporiasis||Distribution at initial presentation||Morphology at initial presentation||Duration of disease (month)||Clinical response at week 8|
|1||F/40||LPP||trunk and extremities||patch, plaque||25||PR|
|3||F/33||SPP||trunk and extremities||papule, patch, plaque||28||PR|
|5||M/35||LPP||trunk and extremities||patch, plaque||30||CR|
|6||F/25||LPP||trunk and extremities||patch, plaque||96||CR|
SPP: small plaque parapsoriasis; LPP: large plaque parapsoriasis; PR: partial response; CR: complete response.
Two psoriasis patients complained of the temperature of the molecular hydrogen water. The discomfort was relieved once the actual temperature was adjusted according to the satisfaction of patients. No other adverse reactions were found during the study.
The results of the parallel-controlled trial demonstrated that molecular hydrogen-water bathing therapy led to significant improvements in psoriasis for the majority of patients. The response rate observed was obviously higher than those seen with Alefacept and fumaric acid esters; and was similar to those seen with Efalizumab, low dose of oral methotrexate (MTX) (5–15 mg/week) and cyclosporine A (1.25 mg/kg/day)22–26. Furthermore, patients receiving molecular hydrogen-water bathing showed rapid onset of improvement from baseline. Approximately one forth of patients showed at least 75% improvement in PASI score 8 weeks after their initial bath, a level of response that has only been observed after 12 or more weeks of therapy in patients receiving some biologic agents23,24,27. Patients treated with molecular hydrogen-water bathing also showed substantial improvement in pruritus as assessed by VAS. This is beneficial to the quality of life of psoriasis, which is considered to be similar to, if not worse than, that of other major chronic diseases. Although concomitant treatment was used for the skin lesions, it should be noted that the dosage of MTX, UVB phototherapy and systemic retinoids concomitantly used were not effective for at least 4 months prior to participation in the present study. Surprisingly, 6 patients were able to reduce or even stop the drug dosage (4 patients: acitretin; 2 patients: MTX) after the bathing course. Although the possibility that the improvements were caused by concomitant treatment cannot be fully excluded, it is indicated that the quick relief of symptom was in great part owing to the bathing therapy.
To parapsoriasis en plaques, our result suggested that molecular hydrogen-water bathing was rapidly effective and safe for the control of the disease with 66.7% partial response and 33.3% complete response. Currently, PUVA and narrow-band UVB are used as main treatment options for parapsoriasis en plaques with up to 80% complete remission rates and a median time to clearance of 2–6 months6,28,29. In general, UVB is preferred in patients with patches and thin plaques and PUVA photochemotherapy should be used for patients with thick plaques, with phototypes ≥III and unresponsive to UVB6. However, in addition to requirement of long time to induce the response and the maintenance, all these therapies are associated with potential risk of photocarcinogenesis and photoaging limits their long-term use.
Psoriasis and parapsoriasis en plaques are known as representative diseases that show the orchestrated mechanisms of chronic inflammation. The clinical effectiveness of molecular hydrogen-water may partially be explained by H2 selectively scavenger ability against highly active oxidants, such as hydroxyl radical and peroxynitrite, and cytoprotective effects against oxidative stress17. Hydroxyl radical is known as a major trigger of the chain reaction of free radicals30, and the absence of the specific scavenger of this species spontaneously causes oxidative states in chronic inflammation31,32. Thus, H2 may have an advantage to suppress the chain reaction, which produces lipid peroxide and leads to the generation of oxidative stress markers, such as malondialdehyde (MDA)32 which has been proved to be in association with the exacerbation of psoriasis33. Another target of H2, peroxynitrite, which is generated from the reaction of nitric oxide with superoxide, activates p38 MAPK pathways which are related to production of inflammatory cytokines, such as TNF-α,IL-6, IL-8 and many others20, resulting in the development of plaque of psoriasis34. Subsequent studies indicate that the effect of H2 is mediated by Nrf2-Keap1 system35,36, a transcriptional factor known to be an activator of intrinsic protective mechanisms against oxidative stress, but the mechanisms remain to be solved. However, radical scavenging effects of H2cannot fully explain the anti-inflammatory and anti-apoptotic effects, which should involve a number of fine-tuned signaling pathways. Studies also have shown that H2 suppresses signaling pathways in allergies37 and inflammation38 without directly scavenging reactive oxygen/nitrogen species.
In fact, anti-oxidant therapies to psoriasis have already been tested, e.g. using fumaric acid esters particularly in Germany39. However, most of them exhibited limited therapeutic success. Furthermore, recent studies suggested that some ROS act as signaling messengers to regulate a wide variety of physiological process40,41. In view of this background, an ideal antioxidant is expected to mitigate excess oxidative stress, but not disturb redox homeostasis. H2 has the capability to scavenge specifically potent ROS but does not react with those that have important physiological roles17. The safety of H2 is also established by its intrinsic production in the human body and inertness against biogenic components. It has been already used for the prevention of decompression sickness in deep divers42. The clinical practice of H2 in the treatment of chronic inflammatory disease was recently attempted in patients of rheumatoid arthritis (RA)43. Moreover, a latest case report suggested H2 could relieve psoriasis-associated skin lesions and arthritis21. Apart from other methods of application,molecular hydrogen-water bathing is a new approach highlights by its skin-directed, safe and painless administration and can be carried out in daily life.
Regarding the present study, our results showed a decreased trend of BMI in psoriasis patients treated with bathing therapy without any lipid-lowering interventions. This result matches those of previous studies, which have demonstrated the clinical improvement in patients with psoriasis was associated with a reduction in the levels of lipid peroxidation and an increased serum antioxidant capacity44. In addition, it should be noted that the itching sensation was markedly reduced in most cases. The influence of molecular hydrogen water on itching sensation suggests the presence of neurogenic inflammation associated with ROS in the psoriatic lesion and the possibility of a therapeutic approach similar to that for neurological inflammatory disorders17. Some limitations of this study need to be pointed out. As an open trial of limited sample size, this study may include selection bias although the baseline characteristics of the psoriasis groups including primary PASI and VAS scores showed well balanced. Attention should be paid that the patients receiving molecular hydrogen-bathing therapy are those who have failed to conventional treatment for more than 4 months. This at least implied the disease activities of these “refractory” patients were in less stable condition. Secondly, this study did not involve a placebo control group owing to the ethics concern. However, all the ones of the control group had received tap-water bathing more than twice a week during this study. Thus, the control group of psoriasis was administered with the combination therapy of the conventional therapy and the placebo (tap-water) bathing.
In summary, patients with psoriasis and parapsoriasis en plaques who were treated with molecular hydrogen-water bathing therapy achieved significant and rapid improvement in disease severity and quality of life. We suggested that molecular hydrogen-water bathing therapy could fulfill the unmet need for an alternative therapeutic option for these patients. Further large randomized placebo-controlled trials are required to verify and extend these results. The mechanism and long-term efficacy of molecular hydrogen-water in these diseases are also warranted.
Forty-one patients of psoriasis and six patients of parapsoriasis en plaques were enrolled from February 2016 to April 2017 from Huashan Hospital affiliated to Fudan University and Huadong Hospital affiliated to Fudan University. The control group of psoriasis included thirty-four patients recruited from the dermatology clinics of Huashan Hospital. The study was registered and approved by China Ethics Committee of Registering Clinical Trials (ChiCTR-ONC-17013055, 2017/10/20). All patients signed an informed consent form and agreed to publish identifying information or images. All methods were performed in accordance with the relevant guidelines and regulation.
Patients of psoriasis had a history of plaque psoriasis for a minimum of 12 months. Among them, 21 patients were resistant to topical corticosteroid and calcipotriol ointments; the rest of patients suffered conventional treatment failure or failed to reduce the existing dosage of drugs beyond topical corticosteroid and calcipotriol ointments for more than 4 months. The failed therapeutic options include UVB phototherapy (10/41), MTX (3/41), and systemic retinoids (7/41). All the patients declined treatment of other drugs (include biologics) due to financial issues and safety concern. Patients of parapsoriasis en plaques were diagnosed based on clinical, histopathological and immunohistochemical findings (SPP: 2/6, LPP: 4/6). They had been followed up for more than 8 months. Among them, 4 patients had received UVA or narrow-band UVB therapy for more than 6 months without evident improvements. Two patients suffered flare-ups during phototherapy. All biopsies reported dense lymphocytic infiltrates, occasionally with lymphocyte exocytosis. None of the patients had axillary or inguinal lymphadenopathy. The laboratory results of all patients were unremarkable. Patients with serious cardiovascular diseases or infectious diseases, and those who were unable to receive treatment regularly were excluded.
During the duration of molecular hydrogen-water bathing therapy, the present treatments of psoriasis patients were continued the same as before (except for drug tapering), including systemic and topical therapy. The patients of the psoriasis-controlled group were administered the same traditional Chinese patent medicine called “Qu-Yin oral solution”, topical treatment of corticosteroid and calcipotriol ointments. One major ingredient of this widely-used solution is glycyrrhizin, which has been evidenced to enhance the clinical response of psoriasis with its anti-inflammatory and immune-modulating effect45. All the ones of the control group had received tap-water bathing more than twice a week during this study. Patients of parapsoriasis en plaques did not use any concomitant therapy, except for topical corticosteroid and emollients.
Molecular Hydrogen water bathing
Molecular Hydrogen-water bathing was administrated through skin by immersing whole body in the molecular hydrogen-water twice a week (interval of 3 days). Each bathing took 10 to 15 minutes. molecular Hydrogen water bathing paused one week in case of menstruation in female subjects. The molecular hydrogen-water bathing machine (provided by Shanghai Yiquan Investment Limited Partnership) freshly prepared molecular hydrogen water using nanobubble technology to dissolve hydrogen gas into pure deionized water. In briefly it contained the following process:
(1) Tap-water passed through a filtration system (composed of quartz sand, activated carbon, ultrafiltration and reverse osmosis membrane) and an ultraviolet disinfection unit to be deionized and disinfected.
(2) molecular Hydrogen generator electrolyzed treated tap-water into oxygen and molecular hydrogen and then collected pure molecular hydrogen gas.
(3) molecular Hydrogen gas was forced into micro-nano-level bubbles and the bubbles were then dissolved directly and evenly into deionized water. The freshly prepared molecular hydrogen water had the following physical and chemical characteristics: (1) pH 6.8–7.3.
(2) Temperature ranged from 38 to 42 °C (the actual temperature based on the satisfaction of patients).
(3) High content of dissolved molecular hydrogen with a concentration of 1.0 ppm (for reference, the dissolved molecular hydrogen of tap-water is less than 0.001 ppm).
(4) With an extremely negative oxidation reduction potential (ORP) of −580 mV~ −650 mV (for reference, tap water: +250 mV~ +350 mV). Each time before therapy the same equipment was used to test pH, temperature, ORP (RM-30P, DKK-TOA Corp., Japan) and molecular hydrogen concentration (ENH-1000, Trustlex Corp., Japan) to make sure molecular hydrogen water having the same properties.
Clinical assessments including physical examinations, vital signs, concomitant medications, adverse events and measures of psoriasis activity (PASI scores and photos) were estimated at baseline and following each bathing treatment. For the PASI, patients are rated on the basis of erythema, scaling, and thickness divided in four anatomical parts (head, trunk, upper extremities, and lower extremities). The area of each anatomical part is factored into the overall value46. The score was divided into mild (1–10), moderate (10–20) and severe (>20) PASI. The PASI score at week 8 was the predefined efficacy endpoint, where a favorable response was an improvement of at least 50% from the baseline PASI47. The pruritus of the skin lesions was measured by the VAS for itching 48.
Parapsoriasis en plaques
Clinical responses were evaluated at week 8, classified as complete response, >90% clearance of lesions; partial response, 50–90% clearance; no response, <50% clearance with persistent skin lesions despite continuing treatment. The pruritus of the skin lesions was measured by VAS as well.
Analyses of effectiveness endpoints were based on the intent-to-treat (ITT) population. The last-observation-carried-forward (LOCF) analysis was used to estimate the missing data for effectiveness variables. Descriptive variables were summarized by number (percentages), median or mean ± standard deviation. Measurement data were compared using paried t-test. Comparison of the count data or level data was performed using χ2 tests, Fisher’s exact tests or Mann-Whitney U tests. Odds ratio (OR) were calculated with Haldane’s modification, which adds 0.5 to all cells to accommodate possible zero counts49. P values were two-tailed. Differences were considered significant at P < 0.05. The corrected P (Pc) values were adjusted by using Yate’s correction for continuity. Data were analyzed by SPSS17.0 (SPSS Inc., Chicago, IL, USA) software.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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We would like to thank Shanghai Yiquan Investment Limited Partnership for the technical support. This study was supported by the HOPE Program launched by the Branch Association of Hydrogen Biomedicine, China-Japan Medical Science and Technology Exchanges Association.
Qinyuan Zhu wrote the main manuscript text, analyzed the data and prepared figures. Xiaoqun Luo, Yueshen Wu, Yongmei Li, Erhong Dai, Jianhua Wu and Bin Fan provided follow-up visits to the patients and collected the clinical data. Zihua Chen, Lanting Wang, Hao Xiong and Li Ping contributed to the supervision of regular molecular hydrogen-water bathing therapy. Xiaoqun Luo was in charge of the design and execution of this study. All authors reviewed the manuscript.
The authors declare no competing interests.
Qinyuan Zhu and Yueshen Wu contributed equally to this work.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Articles from Scientific Reports are provided here courtesy of Nature Publishing Group
In Japan, alkaline electrolyzed water (AEW) apparatus have been approved as a medical device. And for the patients with gastrointestinal symptoms, drinking AEW has been found to be effective in relieving gastrointestinal symptoms. But some users of AEW apparatus do not have abdominal indefinite complaint. Little attention has been given to the benefit for the users which have no abdominal indefinite complaint. The object of this study is to evaluate the effect on health, including gastrointestinal symptoms, when a person without abdominal indefinite complaint, etc., drinks AEW on a daily basis. A double-blind, randomized controlled trial has been designed. Four-week period of everyday water drinking, PW drinking group: drink purified tap water as a placebo, AEW drinking group: drink alkaline electrolyzed water which made by electrolysis of purified tap water. Before the experiment and after the 4-week period of water drinking, Blood tests, physical fitness evaluations, and questionnaire evaluations is conducted. In this study, we did not specifically select patients with gastrointestinal symptoms. Sufficiently clear effect could not be confirmed. But the stools were more normal, and, as shown in the previous report, that drinking AEW is considered to contribute to intestinal normalization. In addition, when drinking AEW, a high proportion of the respondents said that they felt they were able to sleep soundly, and the proportion of subjects who answered that they felt good when awakening increased. The effect of reducing oxidative stress, thus allowing for improved sleep, was exhibited by drinking AEW containing hydrogen, which is considered to be an antioxidant substance. This research were approved by the Ethics Committee of the Osaka City University Graduate School of Medicine (No. 837) and were registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000031800) on March 22, 2018.
In Japan, water which is obtained on the cathode side by the electrolysis of tap water is called alkaline electrolyzed water (AEW) or reduced hydrogen water.1 Improvement of gastrointestinal symptoms by ingesting AEW has been confirmed by Japanese researchers. For example, Naito et al.2 reported the inhibitory effect of AEW ingestion on gastric mucosal disorder caused by aspirin, and Hayakawa et al.3reported the inhibitory effect of AEW ingestion on abnormal intestinal fermentation. Tashiro et al.4examined the effect of ingesting AEW or purified tap water (PW; as a placebo) at a rate of at 500 mL per day for 4 weeks in patients who had abdominal pain such as heartburn, stomach discomfort, abdominal bloating, diarrhea, constipation, etc., and reported that the results of the AEW group were superior to those of the placebo group.5,6 From these results, apparatus that produce AEW have been approved as medical devices by the Japanese Ministry of Health, Labour and Welfare. AEW is thought to be effective for functional gastrointestinal disorders.5
Since AEW is produced by electrolyzing water, hydroxide ions, which are alkaline in nature, are generated. Hydrogen molecules are also generated on the electrode surface and dissolved in water. Therefore, AEW is alkaline water containing hydrogen.1 In conventional efficacy studies, evaluations with respect to ingesting AEW have typically been conducted focusing on the alkalinity of the water.2,3,4,5 In recent years, however, the assumed effectiveness of the antioxidant effect of dissolved hydrogen on various diseases has been reported.7,8,9,10,11,12,13,14,15 Nevertheless, some users of AEW apparatus do not have any definite abdominal symptoms. In many cases, they are drinking AEW on a daily basis to improve their health, and many users also feel health benefits such as improvement in exercise capacity12. These may be thought to be due to the action of dissolved hydrogen. There have been no researched studies of these in detail. The object of this study is to evaluate the effect of daily ingestion of AEW on health, including gastrointestinal symptoms, in subjects without any definite abdominal symptoms.
Participants and Methods
Healthy men and women (20–60 years) who use the Osaka City Citizen Health Development Consultation Center were selected as test subjects to determine the health effect of daily AEW ingestion. It was aimed to clarify whether general subjects without gastrointestinal symptoms have another good effect besides gastrointestinal symptoms by drinking AEW which is good for gastrointestinal symptoms. We explained this purpose to the subjects and asked for research participation. Written informed consent was obtained from all subjects. All procedures used in this research were approved by the Ethics Committee of the Osaka City University Graduate School of Medicine (No. 837) and were registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000031800) on March 22, 2018. This study follows the Consolidated Standards of Reporting Trials (CONSORT) guidelines. A double-blind, randomized controlled trial has been designed, and the research design is shown in Figure 1.
Subjects were randomly divided into two groups, with an AEW group (n = 30) and a PW group (n = 30). Blood tests, physical fitness evaluations, and questionnaire evaluations were conducted before the experiment was initiated. Subjects were provided with AEW apparatus1 that had been modified to produce only AEW or PW. They ingested 500 mL or more of freshly produced AEW or PW per day (they were required to ingest 200 mL immediately after awakening, and 300 mL or more during the rest of the day). After the end of the four-week period, blood tests, physical fitness evaluations, and questionnaire evaluations were conducted again to check whether the ingestion of AEW for four weeks had beneficial effects on the health of the subjects.
General blood test: Red blood cell count, white blood cell count, hemoglobin, hematocrit, and platelet count.
Blood biochemical examination: Total protein, albumin, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), γ-GTP, total cholesterol, high-density lipoprotein (HDL), cholesterol, low-density lipoprotein (LDL) cholesterol, neutral fat, uric acid, creatinine, and blood sugar.
Urinalysis: Urine sugar, urine protein, urine occult blood, and urine pH.
Right/left grip strength, right/left leg muscle strength, vertical jump, whole body reaction time, standing time on one leg with eyes closed, sit-up, seated forward bend, and resting blood pressure.
Gastrointestinal symptoms (stomachache, heartburn, heavy stomach, lower abdominal pain, bloated stomach), urinary frequency, condition of the stools (fecal properties and bowel movement), and physical condition (sleep quality and upon awakening).
In the blood data, the urinalysis and physical measurement values, the statistical significance of the average difference (before and after AEW, PW drinking) was analysed using a paired t-test (Statcel 4 Software [OMS Publishing, Saitama, Japan). The questionnaire data (before and after AEW, PW drinking) was analysed by the Wilcoxon signed-rank test using the same Statcel 4 software. Differences for which Pvalues of < 0.05 and < 0.01 were inferred as significant.
Conditions of subjects and water quality
Subjects with abdominal symptoms such as heartburn, stomach discomfort, abdominal bloating, diarrhea, and constipation were used in the study previously performed.4,5 For the current study, subjects aged 20 to 69 years were randomly selected among medical checkup examinees who visited the Osaka City Citizen Health Development Consultation Center, and then divided into two groups. One group ingested PW while the other ingested AEW. Neither the subjects nor the experimenters knew which group the subjects belonged to. Figure 2 shows that no significant differences were found in dispersion of mean values and distribution values.
Each subject was provided with an AEW apparatus that had been modified to either produce or not produce AEW, and asked to install it at their home. In order to verify the quality of the drinking water, the water produced by the apparatus was taken into aluminum containers and collected when the subjects came in for measurement. Figure 3 shows the water quality distribution of each drinking water.
Because we selected subjects who live in or around Osaka City, the tap water from either the same or a nearby water source was used for the evaluation. For this reason, the tests have been conducted using water of equivalent quality and which shows little bias in the distribution of ions.
Regarding the water before and after the electrolysis, the pH was 7.6 ± 0.2 for the PW group, and 9.2 ± 0.2 for the AEW group. Dissolved hydrogen concentration was not measurable at the subjects’ houses because hydrogen easily escapes water. However, for non-electrolyzed and electrolyzed tap water from the same water source and using the same water apparatus, the hydrogen concentration was confirmed as 0 mg/L in the PW group and 0.2 mg/L for the AEW group for the characteristics of the device.
Comparison of hematological values
The hematological data of subjects in the PW group and the AEW group were compared before and after the four-week period, but no significant differences were observed in both groups. This is consistent with the contents of the previous report.5 However, the HDL cholesterol level, a newly measured value this time, of the AEW group showed a tendency to increase with P = 0.097, as shown in Figure 4.
Comparison of data related to physical abilities
For the seated forward bend, vertical jump, right/left grip strength, and sit-up, there was no significant difference before and after the 4-week period for both the PW group and the AEW group.
Regarding the whole body reaction time, no significant differences were observed before and after the 4-week period in the case of the PW group, as seen in Figure 5B. However, a significant difference (decrease) (P < 0.05) was observed in the AEW group, as seen in Figure 5A. As for standing time on one leg with eyes closed, longer times were observed in the AEW group (P = 0.09), as seen in Figure 6A.
Questionnaire to subjects
As for the questionnaire items, we asked the subjects to provide answers in 3 to 5 points about gastrointestinal symptoms (Table 1), defecation and urination (Table 2), and physical condition (Table 3).
|Stomachache||Not at all||Slightly||Quite a lot||Very much|
|Heartburn||Not at all||Slightly||Quite a lot||Very much|
|Heavy stomach||Not at all||Slightly||Quite a lot||Very much|
|Lower abdominal pain||Not at all||Slightly||Quite a lot||Very much|
|Bloated stomach||Not at all||Slightly||Quite a lot||Very much|
Note: Scoring 1 to 4, where: Not at all = 1, and Very much = 4.
|Uninary frequency||Very often||Often||Sometimes||Occasionally||Rarely|
|Fecal properties||Hard||Slightly hard||Normal||Slightly soft||Soft|
|Bowel movement||Very good||Good||Normal||Bad||Very bad|
|Sleep quality||Good||Neither nor||Bad|
|Waking up||Good||Neither nor||Bad|
Note: Scoring 1 to 3, where: Good = 1, and Bad = 3.
First, as seen in Figures 77 to to11,11, as for gastrointestinal symptoms, sufficiently clear effect could not be confirmed in this study. Next, as seen in Figure 12, the urinary frequency significantly increased in both groups, likely due to an increase in urine volume resulting from water ingestion. Regarding bowel movement, the stools slightly changed from slightly soft to normal or slightly hard, or from soft to normal (P < 0.05) in the AEW group, as can be seen in Figure 13A. There was no difference between subjects of the two groups who had answered that they were in “good” or “bad” physical condition.
Regarding sleep quality, there was a significant increase (P < 0.01) in the number of AEW group subjects who responded that they were able to sleep well, as shown in Figure 14A, and there was a significant increase (P < 0.05) in the number of subjects from the same group who said that they felt good upon awakening, as seen in Figure 15A.
In Japan, AEW apparatus have been approved as medical devices, and ingesting AEW has been found to be effective in relieving gastrointestinal symptoms. A clinical evaluation of this effect was conducted with patients with gastrointestinal symptoms (heartburn, stomach discomfort, and abdominal symptoms such as abdominal bloating, diarrhea, and constipation).5
Antioxidant action by hydrogen and gastric acid neutralization by alkaline pH have been considered.6 In addition, recent studies have shown that the intestinal bacterial flora distribution changes. It seems that these are involved in the normalization of the gastrointestinal activity.11 However, for this study, patients with gastrointestinal symptoms were not specifically selected. As for these as well as the previous results, in general, there was no difference in the hematological values between the PW group and the AEW group.5 However, the newly measured HDL cholesterol value showed a tendency to increase with P = 0.097. The increase in HDL cholesterol by ingesting water containing hydrogen is reported by Gadek and colleagues.16 The effect of hydrogen can be considered to have had an effect in the AEW group this time as well.
As for gastrointestinal symptoms—which showed a significant difference during the previous study (significant improvement of abdominal symptoms and improvement of abnormal bowel movement)4,5—sufficiently clear effect could not be confirmed by this study because the subjects did not show gastrointestinal symptoms, and very few of them responded that they had abnormal abdominal symptoms and bowel movement before participating in this study. Therefore, we believe this is the reason the answers of the subjects were the same before and after their participation in the study.
However, with respect to bowel movement, the stools slightly changed from soft to normal or slightly hard, or from loose to normal in the AEW group. This reflects that the stools are more normal, and, as shown in the previous report, that ingesting AEW is considered to contribute to intestinal normalization.4,5,6Regarding items other than the gastrointestinal tract, a high proportion of the respondents said that they felt they were able to sleep well, and the proportion of subjects who answered that they felt good when awakening increased. Various studies on the relationship between the ingestion of antioxidant substances and the condition of sleep have been undertaken,17 and the effect of reducing oxidative stress, thus allowing for improved sleep quality, is exhibited by ingesting AEW containing hydrogen, which is considered an antioxidant substance.
Regarding sports performance, various reports on the effects of sleep on sports performance have concluded that willingly sleeping longer can lead to faster running, shortened reaction time, and improved motivation during practice and games.18 Improved sleep quality by ingesting AEW is, therefore, believed to help reduce fatigue, ensure appropriate endurance recovery, and improve overall sports performance.
The findings of this study indicate that ingesting AEW on a daily basis improves health and exercise capacity, even in healthy people who do not have gastrointestinal symptoms.
Funding: The study was supported by a grant from Matsushita Electric Works Co., Ltd. Home Appliances R&D Center (to HN).
Conflicts of interest
The corresponding author (YT) is a salaried employee of the Panasonic Corporation. One of the authors (SY) was a salaried employee of the Panasonic Corporation. This study does not alter our adherence to Medical Gas Research policies on sharing data and materials. Another authors (KI and HN) report no conflict of interest related to this manuscript.
The study was supported by a grant from Matsushita Electric Works Co., Ltd. Home Appliances R&D Center (to HW).
Institutional review board statement
All procedures used in this research were approved by the Ethics Committee of the Osaka City University Graduate School of Medicine (No. 837) and were registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000031800) on March 22, 2018.
Declaration of participant consent
The authors certify that they have obtained participant consent forms. In the form, participant have given their consent for their images andother clinical information to be reported in the journal. The patients understand that their names and initials not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
This study follows the Consolidated Standards of Reporting Trials (CONSORT) guidelines.
The statistical methods of this study were reviewed by the biostatistician of the Osaka City University, Osaka, Japan.
Copyright license agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Study protocol and informed consent form will be available immediately following publication, without end date. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
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Externally peer reviewed.
Daily ingestion of alkaline electrolyzed water containing hydrogen influences human health, including gastrointestinal symptoms
Articles from Medical Gas Research are provided here courtesy of Wolters Kluwer — Medknow Publications
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