Abstract
Background:
Oxidative stress is one of the causative factors in the pathogenesis of neuro-degenerative diseases including mild cognitive impairment (MCI) and dementia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive antioxidant.
Objective:
We assess the effects of drinking H2 hydrogen-water (water infused with hydrogen gas H2) on oxidative stress model mice and human subjects with MCI.
Methods:
Transgenic mice expressing a dominant-negative form of aldehyde dehydrogenase 2 were used as a dementia model. The mice with enhanced oxidative stress were allowed to drink hydrogen H2-water.
For a ran-domized double-blind placebo-controlled clinical study, 73 subjects with mild cognitive impairment MCI drank ~300 mL of hydrogen H2-water (H2-group) or placebo water (control group) per day, and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores were determined after 1 year.
Results:
In mice, drinking hydrogen H2-water decreased oxidative stress markers and suppressed the decline of memory impairment and neurodegeneration. Moreover, the mean lifespan in the hydrogen H2-water group was longer than that of the control group.’
In MCI subjects, although there was no significant difference between the hydrogen water H2- and control groups in ADAS-cog score after 1 year, carriers of the apolipoprotein E4 (APOE4) geno-type in the H2-group were improved significantly on total ADAS-cog score and word recall task score (one of the sub-scores in the ADAS-cog score).
Conclusion:
H2-water may have a potential for suppressing dementia in an oxidative stress model and in the APOE4 carriers with MCI.
1. INTRODUCTION
Oxidative stress is one of the causative factors in the pathogenesis of major neurodegenerative diseases including Alzheimer’s disease (AD), mild cognitive impairment (MCI), and Parkinson disease (PD) [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 [3].
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) [4]. ALDH2*2 is responsible for a deficiency in ALDH2 activity and is specific to North-East Asians [5]. We reported previously that ALDH2 deficiency is a risk factor for late-onset AD in the Japanese population, [6] 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 [4].
We proposed that molecular hydrogen (H2) has potential as a novel antioxidant, [9] 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) [13]. Drinking hydrogen H2-water prevented the chronic stress-induced impairments in learning and memory by reducing oxidative stress in mice [14] and protects neural cells by stimulating the hormonal expression of ghrelin [15]. Additionally, injection of hydrogen-rich saline improved memory function in a rat model of amyloid-β-induced dementia by reducing oxidative stress [16]. Moreover, hydrogen inhalation during normoxic resuscitation improved neurological outcome in a rat model of cardiac arrest independently of targeted temperature management [17].
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 [4]. 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), [4] 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 [14]. 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 [20] was measured using urine samples, which were collected between 9:00 and 10:00 am as described previously [21], 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) [4]. 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 [22]. 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 [25]. 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) [26] 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 [25].
2.9. Statistical Considerations
All statistical analyses were performed by an academic biostatistician using SAS software version 9.2 (SAS Institute Inc, Cary, NC, USA). Results were considered significant at p < 0.05.
For the comparison of two groups in learning and memory abilities, and lifespans, unpaired two-tailed Student’s t-test was used for the comparison of H2-group with control group. For the other animal experiments, one-way analysis of variance (ANOVA) with Tukey-Kramer or Dunnett post hoc analysis was applied unless otherwise mentioned.
For the clinical trial, we planned to recruit a total of 120 patients, which would provide 90% power to detect an effect size of 0.6 using a two-sided test with a 5% significance level, but the actual sample size for the primary analysis was 73, leading to 70% power in the same setting. End-points were scores in the Japanese version of ADAS-cog at 1-year, and the changes were evaluated by Mann-Whitney’s U test (non-parametric analysis) as well as Student’s t-test (parametric analysis).
3. RESULTS
3.1. Hydrogen-water Reduced Oxidative Stress in DAL Mice
Male DAL101 mice were given H2– or control water to drink ad libitum from the age of 1 month, and continued until the age of 18 months. The H2-water DAL101 group showed a significant decrease in the level of an oxidative stress marker, urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG)[20] 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 [4]. 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).
Hydrogen water prevented cognitive decline. H2-water was provided from the age of 1 month (A, C), and from the age of 8 months (B). The mice were subjected to the first objection recognition task (ORT) at the age of 14 months (A, B, 14-month-old) and the second ORT at the age of 18 months (A, B, 18-month-old).
The recognition indexes were obtained as the frequency (%) of exploring and/or sniffing the object that would be replaced or the novel one that had been replaced. ΔRecognition index (%) indicates the frequencies in Retention test of ORT after the subtraction of those in Training test (background). WT, wild-type; (DAL, H2-),
DAL101 mice drinking degassed control water; (DAL, H2+), DAL101 mice drinking hydrogen water. Data are shown as the mean ± SEM. n = 9, *p < 0.05, **p < 0.01 by Student’s t-test. (C) The mice were subjected to a passive avoidance task. Step-through latencies before and after the electric shock are obtained and ΔStep-through latency (s) indicates the subtraction of Step-through latencies after from before the electric shock. WT, wild-type (n = 10); DAL, H2-, DAL101 mice receiving degassed control water (n = 8); and DAL, H2+, DAL101 mice receiving H2-water (n = 8). Data are shown as the mean ± SEM. *p < 0.05.
At the age of 18 months, the mice were subjected to the second ORT, which can be done by using different objects at the age of 18 months [14]. 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 [22] 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).
Hydrogen water suppressed neurodegeneration. (A) The hippocampal CA1 region was stained with antibodies against NeuN (a neuronal marker), GFAP (an astrocytic marker) or Iba-1 (a microglial marker) (Scale bars: 50 µm). Right panels show magnified images of the squares in the left panels (Scale bars: 10 µm). (B) Cells positive for anti-NeuN, anti-GFAP and anti-Iba-I antibodies per field of view (FOV) were counted in the CA1 region (n = 5). Data are shown as the mean ± SD. *p < 0.05, **p < 0.01 (wild-type vs DAL), #p < 0.05 (H2-water vs. control water in DAL).
The number of neurons was decreased in the control DAL101 group as the comparison with wild type group, and the H2-DAL101 group showed a trend in recovery of the decrease (Fig. 2A2A). As has been described previously, [4] 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 [4]. 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).
Extension of the average lifespan by continuous drinking H2-water. (A) Kaplan-Meier curve representing the survival of female C57BL/6 mice (wild-type), female DAL101 mice drinking control water (control water) and H2-water (H2-water). (B) Each dot indicates the lifespan of each mouse. The bars indicate the average lifespan of each group. *p < 0.05 (p = 0.036) by Student’s t-test.
3.5. A Randomized, Placebo Controlled Clinical Study
Fig. (44) shows the profile on the recruitment, randomization, and follow-up of this study. A total of 81 subjects of the 1,032 participants were randomized; however, 3 in the control group and 5 in the intervention group were diagnosed as ineligible after randomization and not included in this analysis. Baseline characteristics and lifestyle factors were balanced between the study groups (Table 11). Random assignment was stratified by age of ~74 years and MMSE score of ~28 points. The average compliance rate of drinking water was estimated as 64% in both groups at 1-year, meaning the subjects drank 320 mL/day on the average. The mean total ADAS-cog scores in the H2– and control groups were 8.04 and 7.89, respectively, with no significance.
Table 1
Background characteristics of 73 subjects with mild cognitive impairment.
| Control (n=38) | Intervention (n=35) | |||
|---|---|---|---|---|
| Mean | SD or % | Mean | SD or % | |
| Woman * | 20 | (52.6%) | 19 | (54.3%) |
| Age (years) | 74.45 | 5.44 | 73.97 | 5.11 |
| Body mass index (kg/m2) | 23.55 | 2.59 | 23.19 | 4.08 |
| Systolic blood pressure (mmHg) | 131.26 | 12.35 | 135.14 | 13.31 |
| Diastolic blood pressure (mmHg) | 77.92 | 7.13 | 78.89 | 9.53 |
| Education (years) | 11.26 | 2.71 | 11.57 | 2.83 |
| Current alcohol drinker * | 19 | (50.0%) | 14 | (40.0%) |
| Current smoker * | 4 | (10.5%) | 5 | (14.3%) |
| Current exercise habit * | 27 | (71.1%) | 22 | (62.9%) |
| APOE4 carrier * | 6 | (15.7%) | 7 | (20.0%) |
| Family history * | 2 | (5.3%) | 2 | (5.7%) |
| Comorbidity * | ||||
| Hypertension | 15 | (39.5%) | 14 | (40.0%) |
| Diabetes mellitus | 4 | (10.5%) | 5 | (14.3%) |
| Dyslipidemia | 4 | (10.5%) | 4 | (11.4%) |
| Stroke | 2 | (5.3%) | 1 | (2.9%) |
| Depression | 1 | (2.6%) | 2 | (5.7%) |
| MMSE | 28.08 | 1.66 | 27.83 | 1.74 |
| ADAS-cog | 7.89 | 3.19 | 8.04 | 3.47 |
* indicates frequency (%).
After 1 year, no observable harms or unintended effects in each group were found, and there was a trend to improve total ADA-cog score both in the H2– and control-groups (Suppl. Table S1), probably because of interventions such as moderate exercise by the Tone project. Moreover, the subjects in the H2-group had more trends for the improvement than those in the control-groups although there was no significance (Suppl. Table S1). However, when we pay attention to score-changes in carriers of the APOE4 genotype, the total ADAS-cogs and word recall task scores (one of the sub-scores) significantly improved as assessed by the distribution of the score change in each subject (Fig. 55). In the APOE4 carriers, the hydrogen water H2-group significantly improved, whereas the control group slightly worsened. Moreover, Fig. (66) shows the score change of each subject as an alternative presentation. Although the subjects in the control group did not improved, six and five out of 7 subjects improved on the total ADAS score and word recall task scores, respectively, in the hydrogen water H2-group of the APOE4 carriers.
Distribution of changes of sub- and total-ADAS-cog score. Distribution of change of word recall task score (A), a sub-score of ADAS-cog, and (B) total ADAS-cogs score in APOE4 non-carriers (left) and APOE4 carriers (right). Each dot indicates the change of individual subjects. The difference between the H2- and control groups was significant in APOE4 carriers by a non-parametric analysis as well as a parametric analysis. (A) p = 0.036 (by Student’s t-test) and p =0.047 (by Mann-Whitney’s U test) and (B) p = 0.037 (by Student’s t-test) and p = 0.044 (by Mann-Whitney’s U test) for (A) and (B), respectively. Middle bars in lozenges indicate median values.
Changes in a sub-sore and total ADAS-cog score of each subject in the APOE4 carriers. Each line indicates the 1-year change in the word recall task score (A) and total ADAS-cog score (B) of a subject in the APOE4 carriers. * indicates p < 0.05 as shown in the legend of Fig. 5.
DISCUSSION
Age-dependent neurodegenerative disorders are involved in oxidative stress. In this study, we showed that drinking hydrogen H2-water suppressed the biochemical, behavioral, and pathological decline in oxidative stress mice. The score of ADAS-cog [18] 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 [4]. DAL101 mice exhibit dementia phenotypes in an age-dependent manner in response to an increasing amount of oxidative stress [4]. Oxidative stress enhances lipid peroxidation, leading to the formation of highly reactive α, β-unsaturated aldehydes, such as MDA and 4-HNE [29]. The accumulation of 4-HNE-adducted proteins in pyramidal neurons has been observed in the brains of patients with AD and PD [30]. The decline of ALDH2*2 ability failed to detoxify cytotoxic aldehydes, and consequently increases in oxidative stress [31].
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 [32]. 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 [33].
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 [36]. The increased oxidative stress in APOE4 carriers is considered as one of the modifiers for the risk [3]. A combination of antioxidants improved cognitive function of aged subjects after 3 years, especially in APOE4 carriers [23]. 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 [9]. Moreover, as a secondary anti-oxidative function, H2 seems to activate NF-E2-related factor 2 (Nrf2), [10] which reduces oxidative stress by expression a variety of antioxidant enzymes [37]. 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 [38]. 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 [39]. 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, [43] 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 [10]. For examples,molecular hydrogen H2 protects neural cells and stimulates energy metabolism by stimulating the hormonal expression of ghrelin [15] and fibroblast growth factor 21, [21] respectively. In contrast, molecular hydrogen H2 relieves inflammation by decreasing pro-inflammatory cytokines [46]. Thus, the combination of these functions of molecular hydrogen H2 on anti-inflammation and energy metabolism-stimulation might prevent the decline in brain function, [10] 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 [47]. NFAT signaling is altered in AD and plays an important role in driving amyloid β-mediated neurodegeneration [48]. Moreover, the NFAT transcriptional cascade contributes to amyloid β synaptotoxicity [49]. Additionally, an active involvement of the NFAT-mediated signaling pathway in α-syn-mediated degeneration of neurons in PD [50]. Indeed, patients with PD improved by drinking molecular hydrogen H2-water as revealed by a double-blind, placebo-controlled clinical study, [51] and a larger scale of a clinical trial is under investigation [52]. Thus, the beneficial effects of molecular hydrogen H2 on the neurodegenerative diseases may be explained by the suppression of NFAT transcriptional regulation.
CONCLUSION
The present study suggests a possibility for slowing the progress of dementia by drinking molecular hydrogen H2-water by means of animal experiments and a clinical intervention study for APOE4 carriers; however, a longer and larger scale of trials will be necessary to clarify the effect of H2-water on MCI.
- PMC5872374
Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild Cognitive Impairment
Associated Data
ACKNOWLEDGEMENTS
We thank Blue Mercury, Inc. (Tokyo, Japan) for providing H2-water and placebo water, Ms. Hiroe Murakoshi for technical assistance and Ms. Suga Kato for secretarial work. Financial support for this study was provided by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (23300257, 24651055, and 26282198 to S.O.; 23500971 and 25350907 to K.N.). Financial support for this study was provided by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (23300257, 24651055, and 26282198 to S.O.; 23500971 and 25350907 to K.N.).
LIST OF ABBREVIATIONS
| APOE4 | Apolipoprotein E4 |
| MCI | Mild cognitive Impairment |
| ALDH2 | Aldehyde Dehydrogenase 2 |
| ADAS-cog | Alzheimer’s Disease Assessment Scale-cognitive subscale |
| AD | Alzheimer’s Disease |
| PD | Parkinson’s Disease |
| DAL101 | Dominant Negative Type 101 of the ALDH2 Mutant Polymorphism (ALDH2*2) |
| 4-HNE | 4-Hydroxy-2-nonenal |
| 8-OHdG | 8-Hydroxy-2’-deoxyguanosine |
| MDA | Malondialdehyde |
| ORT | Object Recognition Task |
| PA | Passive Avoidance Task |
| GFAP | Glial Fibrillary Acidic Protein |
| PBS | Phosphate-buffered Saline |
| ANOVA | One-way Analysis of Variance |
| CI | Confidence Interval |
| MMSE | Mini Mental State Examination |
| FOV | Field of View |
| APP | Amyloid Precursor Protein |
| Nrf2 | NF-E2-related Factor 2 |
| NFAT | Nuclear Factor of Activated T Cell |
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher’s web site along with the published article.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The animal study was approved by the Animal Care and Use Committee of Nippon Medical School.
The human clinical study protocol was approved by the ethics committees of University of Tsukuba.
HUMAN AND ANIMAL RIGHTS
All animal research procedures followed were in accordance with the standards set forth in the eighth edition of Guide for the Care and Use of Laboratory Animals published by the National Academy of Sciences, The National Academies Press, Washington, D.C.).
All human material was obtained in accordance with the standards set forth in the Declaration of Helsinkiprinciples of 1975, as revised in 2008 (http://www.wma.net/en/10ethics/10helsinki/<http://www.wma.net/en/10ethics/10helsinki/>).
Consent for Publication
All the patients provided written informed consent priority to research investigations.
CONFLICT OF INTEREST
We declare that there is no actual and potential conflict of interest on this study. Although SO was a scientific advisor of Blue Mercury, Inc. (Tokyo, Japan) from 2,005 to 2,008, there was no involvement during this study.
REFERENCES
Molecular Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential METABOLIC SYNDROME
Molecular Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome
We have found that molecular hydrogen (dihydrogen; H2) water has beneficial lipid-lowering effects in high-fat diet-fed Syrian golden hamsters.
The objective of this study was to characterize the effects of molecular hydrogen H2-rich water (0.9-1.0 l/day) on the content, composition, and biological activities of serum lipoproteins on 20 patients with potential metabolic syndrome.
Serum analysis showed that consumption of molecular hydrogen H2-rich water for 10 weeks resulted in decreased serum total-cholesterol (TC) and LDL-cholesterol (LDL-C) levels.
Western blot analysis revealed a marked decrease of apolipoprotein (apo)B100 and apoE in serum.
In addition, we found molecular hydrogen water H2 significantly improved HDL functionality assessed in four independent ways, namely:
i) protection against LDL oxidation,
ii) inhibition of tumor necrosis factor (TNF)-α-induced monocyte adhesion to endothelial cells,
iii) stimulation of cholesterol efflux from macrophage foam cells, and
iv) protection of endothelial cells from TNF-α-induced apoptosis.
Further, we found consumption of molecular hydrogen H2-rich water resulted in an increase in antioxidant enzyme superoxide dismutase and a decrease in thiobarbituric acid-reactive substances in whole serum and LDL.
In conclusion, supplementation with molecular hydrogeb H2-rich water seems to decrease serum LDL-C and apoB levels, improve dyslipidemia-injured HDL functions, and reduce oxidative stress, and it may have a beneficial role in prevention of potential metabolic syndrome
-
Song G1, Li M, Sang H, Zhang L, Li X, Yao S, Yu Y, Zong C, Xue Y, Qin S. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome.
- 1, Key Laboratory of Atherosclerosis in Universities of Shandong, Shandong, China.
- PMID: 23610159
- PMCID: PMC3679390
- DOI: 10.1194/jlr.M036640
- [Indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525017/
molecular hydrogen water improves lipid and glucose metabolism in patients with TYPE 2 DIABETES or impaired glucose tolerance
Supplementation of molecular hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance.
It is well established that molecular hydrogen (water) has a selective oxidation/free radical reducing action.
Oxidative stress is recognized widely as being associated with various disorders including diabetes, hypertension, and atherosclerosis.
We therefore investigated the effects of molecular 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 diabetes patients with T2DM controlled by diet and exercise therapy and 6 patients with IGT.
The diabetes 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 molecular hydrogen-rich water normalized the oral glucose tolerance test.
In conclusion, these results suggest that supplementation with molecular hydrogen-rich water may have a beneficial role in prevention of T2DM and insulin resistance.
- https://www.ncbi.nlm.nih.gov/pubmed/19083400
- PMID: 19083400
Authors:
hydrogen-enriched water for mitochondrial and inflammatory MYOPATHIES
Molecular hydrogen has prominent effects on more than 30 animal models especially of oxidative stress-mediated diseases and inflammatory diseases. In addition, hydrogen effects on humans have been reported in diabetes mellitus type 2, hemodialysis, metabolic syndrome, radiotherapy for liver cancer, and brain stem infarction. Molecular hydrogen effects are ascribed to specific radical-scavenging activities that eliminate hydroxyl radical and peroxynitrite, and also to signal-modulating activities, but the detailed molecular mechanisms still remain elusive. Molecular hydrogen is a safe molecule that is largely produced by intestinal bacteria in rodents and humans, and no adverse effects have been documented.
Methods
We performed open-label trial of drinking 1.0 liter per day of molecular hydrogen-enriched water for 12 weeks in 5 patients with progressive muscular dystrophy (PMD), 4 patients with polymyositis/dermatomyositis (PM/DM), and 4 patients with mitochondrial myopathies (MM), and measured 18 serum parameters as well as urinary 8-isoprostane every 4 weeks.
We next conducted randomized, double-blind, placebo-controlled, crossover trial of 0.5 liter per day of hydrogen-enriched water or placebo water for 8 weeks in 10 patients with dermatomyositis DM and 12 patients with mitochondrial myopathies MM, and measured 18 serum parameters every 4 weeks.
Results
In the open-label trial, no objective improvement or worsening of clinical symptoms was observed. We, however, observed significant effects in lactate-to-pyruvate ratios in progressive muscular dystrophy PMD and mitochondrial myopathies MM, fasting blood glucose in progressive muscular dystrophy PMD, serum matrix metalloproteinase-3 (MMP3) in polymyositis/dermatomyositis PM/DM, and serum triglycerides in polymyositis/dermatomyositis PM/DM.
In the double-blind trial, no objective clinical effects were observed, but a significant improvement was detected in lactate in mitochondrial myopathies MM. Lactate-to-pyruvate ratios in mitochondrial myopathies MM and MMP3 in dermatomyositis DM also exhibited favorable responses but without statistical significance.
No adverse effect was observed in either trial except for hypoglycemic episodes in an insulin-treated MELAS patient, which subsided by reducing the insulin dose.
Conclusions
Molecular hydrogen-enriched water improves mitochondrial dysfunction in mitochondrial myopathies MM and inflammatory processes in polymyositis/dermatomyositis PM/DM.
Less prominent effects with the double-blind trial compared to the open-label trial were likely due to a lower amount of administered molecular hydrogen and a shorter observation period, which implies a threshold effect or a dose-response effect of molecular hydrogen.
Background
Ohsawa and colleagues first reported an effect of molecular hydrogen gas on cerebral infarction in June 2007 [1]. Effects of molecular hydrogen administered in the forms of inhaled gas, drinking water, instillation, and intraperitoneal injection have been reported for 31, 4, and 5 diseases in animal models, cells, and humans, respectively [2].
Molecular hydrogen exhibits prominent effects especially on oxidative stress-mediated diseases and inflammatory diseases in rodents. Molecular Hydrogen scavenges hydroxyl radicals and less efficiently peroxynitrite [1]. The radical-scavenging activities, however, are unlikely to be an exclusive mechanism, because the amount of radical oxygen species generated in rodents and humans is much more than the amount of molecular hydrogen molecules taken up by the body. Indeed, the amount of molecular hydrogen taken up by drinking molecular hydrogen-enriched water (HEW) is 100 or more times less than that by inhaling 2% molecular hydrogen gas, but drinking molecular hydrogen-enriched water HEW exhibits beneficial effects as good as or even better than inhaling 2% molecular hydrogen gas in rodents [2–4], which suggests the lack of a simple dose-response effect.
Our previous study on type 1 allergy also indicates that molecular hydrogen suppresses type 1 allergy by acting as a gaseous signal modulator not as a free radical scavenger [5].
Effects of molecular hydrogen in humans have been examined in five studies.
First, a randomized, double-blind, placebo-controlled crossover study of 900 ml/day of molecular hydrogen-enriched water HEW for 8 weeks in 30 patients with diabetes mellitus type 2 demonstrated significant decreases of electronegative charge-modified LDL cholesterol, small dense LDL, and urinary 8-isoprostanes [6].
Second, an open-label trial of electrolyzed molecular hydrogen-enriched hemodialysis solution in 9 patients for 4 months [7] and 21 patients for 6 months [8] showed significant decreases of systolic blood pressure before and after dialysis, as well as of plasma monocyte chemoattractant protein 1 and myeloperoxidase.
see also alkaline ionized water / molecular hydrogen water and hemodialisys
Third, an open-label trial of 1.5-2.0 liters per day of moelcualr hydrogen enriched water HEW for 8 weeks in 20 subjects with metabolic syndrome exhibited a 39% increase of urinary superoxide dismutase (SOD), a 43% decrease of urinary thiobarbituric acid reactive substances (TBARS), an 8% increase of high density lipoprotein (HDL)-cholesterol, and a 13% decrease of total cholesterol/HDL-cholesterol ratio [9].
Fourth, a randomized placebo-controlled study of 1.5-2.2 liters/day of molecular hydrogen enriched water HEW for 6 weeks in 49 patients receiving radiotherapy for malignant liver tumors showed marked improvements of QOL scores [10].As the study was not blinded, subjective QOL scores tended to be overestimated by a placebo effect, but objective markers for oxidative stress were also significantly decreased.
Fifth, drip infusion of hydrogen-enriched saline in combination with Edaravone, a clinically approved radical scavenger for cerebral infarction, for 7 days in 8 patients with brain stem infarction was compared to 24 such patients receiving Edaravone alone [11]. Although the study was not randomized and not blinded, MRI markers of patients infused with molecular hydrogen showed significant improvements and accelerated normalization.
Being prompted by the prominent effects of molecular hydrogen on inflammatory diseases and oxidative stress-mediated diseases especially in rodents, we performed an open-label trial of drinking 1.0 liter per day of molecular hydrogen enriched water HEW for 12 weeks in 14 patients with muscle diseases, and identified improvement in four parameters: (i) a decrease of the lactate-to-pyruvate ratio in mitochondrial myopathies (MM) and progressive muscular dystrophy (PMD); (ii) a decrease of serum matrix metalloproteinase-3 (MMP3) in polymyositis/dermatomyositis (PM/DM), (iii) a decrease of fasting glucose in PMD, and (iv) a decrease of serum triglycerides in polymyositis/dermatomyositis PM/DM.
We then conducted a randomized, double-blind, placebo-controlled, crossover trial of 0.5 liter per day of molecular hydrogen enriched water HEW for 8 weeks in 12 mitochondrial myopathies MM and 10 dermatomyositis DM cases. We observed that molecular hydrogen enriched water HEW significantly improved serum lactate in mitochondrial myopathies MM. In both studies, some patients reported subjective improvement of fatigability, diarrhea, and myalgia, but others reported floating sensation and worsening of diarrhea.
We observed no objective improvement or worsening of clinical symptoms during each study.
Our studies imply that molecular hydrogen enriched water HEW improves clinical parameters in mitochondrial myopathies MM and polymyositis/dermatomyositis PM/DM, but 0.5 liter/day for 8 weeks is likely to be insufficient to demonstrate statistically significant effects.
Patients
For the open-label trial, we recruited 5 patients with progressive muscular dystrophy PMD, 4 patients with polymyositis/dermatomyositis PM/DM, and 5 patients with mitochondrial myopathies MM.
The progressive muscular dystrophy PMD patients comprised 1 male with Miyoshi myopathy and 4 females with limb girdle muscular dystrophy type 2B with an average age and SD of 50.4 ± 15.9 years (range 25 – 66).
The polymyositis/dermatomyositis PM/DM patients comprised 2 males and 2polymyositis/dermatomyositis females with an average age of 53.8 ± 24.8 years (range 29 – 83). All the polymyositis/dermatomyositis PM/DM cases were taking 5 – 10 mg of prednisolone per day and were well controlled.
The mitochondrial myopathies MM patients comprised 4 cases with MELAS (2 males and 2 females with an average age of 45.8 ± 12.3 years, range 37 – 64) and a 54-year-old female with chronic progressive external ophthalmoplegia (CPEO).
For the randomized, double-blind, placebo-controlled, crossover trial, we recruited 12 patients with mitochondrial myopathies MM and 10 patients with dermatomyositis DM.
The mitochondrial myopathies MM patients comprised 5 cases with MELAS (2 males and 3 females with an average age of 44.6 ± 17.6 years, range 20 – 65), as well as 7 cases with CPEO (3 males and 4 females with an average age of 49.1 ± 11.1 years, range 29 – 61).
The dermatomyositis DM patients comprised 3 males and 7 females with an average age of 49.6 ± 13.7 years (range 32 – 66). All thdermatomyositis e DM patients were well controlled with 5 – 10 mg prednisolone per day.
3 mitochondrial myopathies MM and 3 DM dermatomyositis patients participated in both trials. Both trials were approved by the Ethical Review Board of the Aichi Medical University. Informed consent was obtained from each patient.
Protocols
We purchased 500 ml molecular hydrogen enriched water HEW or placebo water in aluminum pouch from Blue Mercury Inc. (Tokyo, Japan). We measured molecular hydrogen concentrations using an H2-N molecular hydrogen needle sensor attached to a PA2000 2-Channel Picoammeter (Unisense Science, Aarhus, Denmark). The molecular hydrogen concentrations were ~0.5 ppm (~31% saturation). We also confirmed that molecular hydrogen in placebo water was undetectable with our system. For each trial, we instructed patients to evacuate the air from the pouch and to close a plastic cap tightly every time after they drink water to keep the molecular hydrogen concentration as high as possible.
For the open-label trial, patients took 1.0 liter per day of molecular hydrogen enriched water HEW in five to ten divided doses for 12 weeks. We measured 18 serum and one urinary parameters and recorded clinical symptoms at 0, 4, 8, 12, 16 weeks.
For the double-blind trial, patients took 0.5 liter per day of molecular hydrogen enriched water HEW or placebo water in two to five divided doses for 8 weeks. Between the 8-week trials with molecular hydrogen enriched water HEW and placebo, we placed a 4-week washout period. We measured 18 serum parameters and recorded clinical symptoms at 0, 4, 8, 12, 16, 20, 24 weeks. In the double-blind trial, we did not measure urinary 8-isoprostane levels.
The data were statistically analyzed using one-way repeated measures ANOVA for the open-label trial and two-way repeated measures ANOVA for the double-blind trial, both followed by the Bonferroni’s multiple comparison test using Prism version 4.0c (Graphpad Software, San Diego, CA).
Results
Open-label trial
Fourteen patients with PMD, PM/DM, and MM participated in the study and no patient dropped out of the study. Patients took 1.0 liter of molecular hydrogen enriched water HEW for 12 weeks and we measured 18 serum and one urinary parameters every 4 weeks (Table (Table1).1).
We observed no objective improvement or worsening of clinical symptoms during the study. All the patients reported increased micturition frequency. Two MELAS patients reported improvement of fatigability, and another MELAS patient complained mild occasional floating sensation. We estimated statistical significance using one-way repeated measures ANOVA analysis and detected five parameters (Figure (Figure1).1). Serum lactate-to-pyruvate (L/P) ratios of MM patients were high before the study, and were decreased during the study (Figure (Figure1A).1A). Serum L/P ratios and fasting glucose levels of PMD patients were elevated after the study, but the values were still within normal ranges (Figures (Figures1B1B and and1C).1C). Serum MMP3 levels of DM patients were decreased down to 72.9% of those before HEW, which were again increased after the study (Figure (Figure1D).1D). Serum triglyceride levels of DM patients were elevated after the study (Figure (Figure1E1E).
Randomized, double-blind, placebo-controlled, crossover trial
Twelve MM and ten DM patients participated in the study and no patient dropped out of the study. Patients took 0.5 liter of molecular hydrogen enriched water HEW or placebo water for 8 weeks and we measured 18 serum parameters every 4 weeks (Table (Table2).2). An MM patient reported increased micturition frequency on HEW. A DM patient reported subjective improvement of fatigability and diarrhea on molecular hydrogen enriched water HEW, but an MM patient rather complained increased diarrhea at first on molecular hydrogen enriched water HEW. Another DM patient reported an improvement of myalgia on molecular hydrogen enriched water HEW. A MELAS patient had hypoglycemic episodes only on molecular hydrogen enriched water HEW, but the episodes subsided after the insulin dose was decreased. We observed no objective improvement or worsening of clinical symptoms during the study. Two-way repeated measures ANOVA analysis revealed that only serum lactate levels were significantly decreased in MM by molecular hydrogen enriched water HEW (Figure (Figure2A).2A). Temporal profiles of serum L/P ratios in MM (Figure (Figure2B)2B) and of serum MMP3 levels in DM (Figure (Figure2C)2C) also demonstrated favorable responses to molecular hydrogen enriched water HEW but without statistical significance.
Discussion
We performed open-label and double-blind studies of molecular hydrogen enriched water HEW on myopathic patients. In the open-label study, we observed statistical significance of molecular hydrogen water effects in four parameters: L/P ratios in MM and PMD; fasting glucose in PMD; MMP3 in PM/DM; and triglycerides in PM/DM (Figure (Figure1).1).
In the double-blind study, serum lactate levels were significantly improved in MM. L/P ratios in MM and MMP3 in DM were also improved but without statistical significance (Figure (Figure2).2).
Small numbers of participants in both the open-label and double-blind studies might have failed to disclose statistically significant effects of molecular hydrogen enriched water HEW.
In MM, the mitochondrial electron transfer system (mETS) is compromised by mutations in mitochondrial DNA [12]. This results in a decreased influx of NADH into mETS and elevates NADH levels in the cytoplasm, which facilitates conversion of pyruvate to lactate by lactate dehydrogenase. Thus, lactate and L/P ratio are useful surrogate markers to estimate functions of mETS, and are usually abnormally elevated in MM [12]. Defective mETS also causes leakage of electrons from mitochondrial inner membranes and increases production of reactive oxygen species (ROS), which further damages mETS [13,14]. Reduction of the L/P ratios in the open-label and double-blind studies suggests that hydrogen alleviates mETS dysfunction in MM either by scavenging ROS or by yet unidentified signaling mechanisms.
MMP3 belongs to a family of calcium-dependent zinc proteinases induced by cytokines and secreted by inflammatory cells. MMPs enhance T-cell migration and adhesion, and also degrade the extracellular matrix proteins [15]. MMP3 is increased in a fraction of DM patients [16]. MMP3 may facilitate lymphocyte adhesion and enhance T-cell-mediated cytotoxicity by degrading extracellular matrix proteins in DM.
molecular hydrogen water improved serum MMP3 levels in the open-label and double-blind studies, which is expected to ameliorate pathogenic inflammatory processes that culminates in muscle fiber destruction.
We observed less prominent effects with the double-blind study compared to the open-label study. The lack of statistically significance in the double-blind study is possibly due to a lower amount of molecular hydrogen enriched water HEW (1.0 vs. 0.5 liter per day) and to a shorter observation period (12 vs. 8 weeks). In the open-label study, drinking 1.0 liter of molecular hydrogen enriched water HEW was not readily accommodated by most myopathic patients. molecular hydrogen does not show simple dose-response relationship in rodents [2–4], and ad libitum administration of even 5%-saturated molecular hydrogen enriched water HEW markedly attenuates development of Parkinson’s disease in mice [17]. We thus reduced the amount of hydrogen to 0.5 liter in the double-blind trial, and also shortened the observation period to minimize the burden on the participants. This, however, might have masked effects of molecular hydrogen enriched water HEW. Indeed, when we compare studies of diabetes mellitus type 2 [6], the current open-label trial, and metabolic syndrome [9], the participants took 0.9, 1.0, and 1.5-2.0 liters of molecular hydrogen enriched water HEW, respectively. Ratios of total cholesterol/HDL-cholesterol are available at 8 weeks in all the studies, and are changed to 103.8%, 98.6%, and 95.8%, respectively, of those before molecular hydrogen administration, which is in accordance with a dose-response effect of molecular hydrogen enriched water HEW. Additionally, among the two previous studies [6,9] and the current open-label and double-blind studies, the most prominent effects are observed with 1.5-2.0 liters of molecular hydrogen enriched water HEW. As drinking a large amount of molecular hydrogen enriched water HEW is not easily accommodated by most patients especially in winter, a threshold effect and/or a dose-response effect should be further elaborated for each pathological state.
Conclusions
molecular hydrogen enriched water HEW is effective for mitochondrial dysfunction in MM and inflammatory processes in DM.
molecular hydrogen may have a threshold effect or a dose-response effect and 1.0 liter or more per day of molecular hydrogen enriched water HEW is likely to be required to exert beneficial effects.
-
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Abbreviations
HEW: hydrogen-enriched water; PMD: progressive muscular dystrophy; PM: polymyositis; DM: dermatomyositis; MM: mitochondrial myopathies; CPEO: chronic progressive external ophthalmoplegia; MELAS: mitochondrial myopathy with lactic acidosis and stroke-like episodes; MMP3: matrix metalloproteinase-3.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
TI and KS examined patients and acquired data. MI1 and TI organized data and performed statistical analysis. MI1 and KO wrote the paper. MI4, MI5, and KO conceived the study. All authors read and approved the final manuscript.
Acknowledgements
We would like to thank the patients for their participation in these studies. We thank Fumiko Ozawa for her technical assistance. This work was supported by Grants-in-Aid from the Ministry of Health, Labor, and Welfare of Japan and the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
References
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- Ohta S, Nakao A, Ohno K. The 2011 Medical Molecular Hydrogen Symposium: An Inaugural Symposium of the Journal Medical Gas Research. Med Gas Res. 2011;1:10. doi: 10.1186/2045-9912-1-10. [PMC free article] [PubMed] [Cross Ref]
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- Itoh T, Fujita Y, Ito M, Masuda A, Ohno K, Ichihara M, Kojima T, Nozawa Y, Ito M. Molecular hydrogen suppresses FcepsilonRI-mediated signal transduction and prevents degranulation of mast cells. Biochem Biophys Res Commun. 2009;389:651–656. doi: 10.1016/j.bbrc.2009.09.047.[PubMed] [Cross Ref]
- Kajiyama S, Hasegawa G, Asano M, Hosoda H, Fukui M, Nakamura N, Kitawaki J, Imai S, Nakano K, Ohta M, Adachi T, Obayashi H, Yoshikawa T. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res. 2008;28:137–143. doi: 10.1016/j.nutres.2008.01.008. [PubMed] [Cross Ref]
- Nakayama M, Kabayama S, Nakano H, Zhu WJ, Terawaki H, Nakayama K, Katoh K, Satoh T, Ito S. Biological Effects of Electrolyzed Water in Hemodialysis. Nephron Clin Pract. 2009;112:C9–C15. doi: 10.1159/000210569. [PubMed] [Cross Ref]
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- Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N. Effectiveness of Hydrogen Rich Water on Antioxidant Status of Subjects with Potential Metabolic Syndrome-An Open Label Pilot Study. J Clin Biochem Nutr. 2010;46:140–149. doi: 10.3164/jcbn.09-100. [PMC free article] [PubMed][Cross Ref]
- Kang K-M, Kang Y-N, Choi I-B, Gu Y, Kawamura T, Toyoda Y, Nakao A. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Med Gas Res. 2011;1:11. doi: 10.1186/2045-9912-1-11. [PMC free article] [PubMed] [Cross Ref]
- Ono H, Nishijima Y, Adachi1 N, Tachibana S, Chitoku S, Mukaihara S, Sakamoto M, Kudo Y, Nakazawa J, Kaneko K, Nawashiro H. Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study. Med Gas Res. 2011;1:12. doi: 10.1186/2045-9912-1-12.[PMC free article] [PubMed] [Cross Ref]
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- Wei YH, Lu CY, Wei CY, Ma YS, Lee HC. Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system. Chin J Physiol. 2001;44:1–11. [PubMed]
- McKenzie M, Liolitsa D, Hanna MG. Mitochondrial disease: mutations and mechanisms. Neurochem Res. 2004;29:589–600. [PubMed]
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- PMC3231939
Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies
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- Predicting and verifying outcome of Tripterygium wilfordii Hook F. based therapy in rheumatoid arthritis: from open to double-blinded randomized trial[Scientific Reports. 2015]
- Should hydrogen therapy be included in a musculoskeletal medicine routine?[F1000Research. 2016]
- Molecular hydrogen suppresses activated Wnt/β-catenin signaling[Scientific Reports. 2016]
- Lung inflation with hydrogen during the cold ischemia phase decreases lung graft injury in rats[Experimental Biology and Medic…]
- Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles –[Medical Gas Research. 2015]
molecular hydrogen water benefits for ATHLETES, EXERCISE, MUSCLE FATIGUE
Muscle contraction during short intervals of intense exercise causes oxidative stress, which can play a role in the development of overtraining symptoms, including increased fatigue, resulting in muscle microinjury or inflammation. Recently it has been said that molecular hydrogen can function as antioxidant, so we investigated the effect of molecular hydrogen-rich water (HW) on oxidative stress and muscle fatigue in response to acute exercise.
Methods
Ten male soccer players aged 20.9 ± 1.3 years old were subjected to exercise tests and blood sampling. Each subject was examined twice in a crossover double-blind manner; they were given either molecular hydrogen-rich water HW or placebo water (PW) for one week intervals. Subjects were requested to use a cycle ergometer at a 75 % maximal oxygen uptake (VO2) for 30 min, followed by measurement of peak torque and muscle activity throughout 100 repetitions of maximal isokinetic knee extension. Oxidative stress markers and creatine kinase in the peripheral blood were sequentially measured.
Results
Although acute exercise resulted in an increase in blood lactate levels in the subjects given PW, oral intake of molecular hydrogen-rich water 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 molecular hydrogen-rich water 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.
Conclusion
Adequate hydration with molecular 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 molecular hydrogen-rich water HW may be suitable hydration for athletes.
Introduction
Since energy demands and oxygen consumption increase during supermaximal exercise, such as intermittent running, sprints, and jumps, production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) also increase, threatening to disturb redox balance and cause oxidative stress. During normal conditions, ROS and RNS are generated at a low rate and subsequently eliminated by the antioxidant systems. However, a greatly increased rate of ROS production may exceed the capacity of the cellular defense system. Consequently, substantial free radicals’ attack on cell membranes may lead to a loss of cell viability and to cell necrosis and could initiate the skeletal muscle damage and inflammation caused by exhaustive exercise [1, 2, 3]. Although well-trained athletes suffer from less oxidative stress reduction because their antioxidant systems adapt, accumulation of intense exercise can provoke an increase in oxidative stress [4]. To mitigate oxidative stress-induced adverse events during sports, antioxidant supplementation among athletes has been well documented. Although results of these studies are often contradictory depending on the antioxidant compounds and quantity, some studies demonstrate the beneficial effects of antioxidants on muscle fatigue or performance [5, 6].
Recently, the beneficial effects of molecular hydrogen-rich water (HW) have been described in experimental and clinical disease conditions [7, 8]. Although research on the health benefits of molecular hydrogen-rich water HW is limited and there is scant data on long-term effects, pilot studies on humans suggest that consuming molecular hydrogen-rich water HW may help prevent metabolic syndrome [9], diabetes mellitus [10], and cancer patients’ side effects with radiotherapy [11]. Since molecular hydrogen is known to scavenge toxic ROS [12] and induce a number of antioxidant proteins [13, 14], we hypothesized that drinking molecular hydrogen water HW may be beneficial for athletes in reducing oxidative stress-induced muscle fatigue following acute exercise. In this study, we evaluated the efficacy of molecular hydrogen water on healthy subjects by measuring muscle fatigue and blood lactate levels after exercise. Although further studies are needed to elucidate the exact mechanisms and benefits, this report suggests that molecular hydrogen water might be an appropriate hydration fluid for athletes.
Methods
Subjects
Ten male soccer players aged 20.9 ± 1.3 years old were subjected to exercise tests and blood sampling. None of the subjects were smokers or were taking any supplements/medicines. Each subject provided written informed consent before participation in accordance with the University of Tsukuba’s Human Research Ethics Committee. Physical characteristics of the subjects are shown in Table 1. All the players were involved in daily training sessions except the day of experiment.
Table 1
Subjects’ Physical Characteristics (n = 10)
| Variable | Value |
|---|---|
| Age (year) | 20.9 ± 1.3 |
| Height (cm) | 172.0 ± 3.8 |
| Body weight (kg) | 67.1 ± 5.2 |
| BMI (kg/m2) | 22.8 ± 1.4 |
| VO2max (ml/kg/min) | 53.2 ± 4.9 |
BMI: body mass index, VO2max: maximal oxygen uptake.
Dose and mode of administration of hydrogen-rich water
Participants were asked to drink one 500 ml bottle at 10:00 PM of the day before the test, one 500 ml bottle at 5:00 AM, and one 500 ml bottle at 6:20 AM on the day of examination. In summary, subjects consumed 1,500 ml of molecular hydrogen rich water HW or PW(final hydrogen concentrations of the placebo water (PW) and hydrogen-rich water (HW) were 0 and 0.92 ~ 1.02 mM, respectively [9, 11]. Each subject was examined twice in a crossover double-blind manner, given either molecular hydrogen rich water HW or PW for one week intervals).
Protocol
The research protocol started at 6:00 AM. Subjects were given meals between 9:00 PM and 10:00 PM the day before experiments, and fasted overnight. No breakfast was given on the day of the experiments. The subjects were first required to rest in a sitting position for 30 minutes. The exercise test consisted of the following: 1) Maximal progressive exercise test to define maximal oxygen uptake (VO2max); 2) cycling an ergometer for 30 minutes at approximately 75 % VO2max (Exercise-1); and 3) Running 100 maximal isokinetic knee extensions at 90 ° sec-1 (Exercise-2). Blood samples were collected from an antecubital vein just before Exercise-1 (6:30 AM), immediately after Exercise-1 (7:15 AM), immediately after Exercise-2 (7:30 AM), 30 minutes after Exercise-2 (8:00 AM) and 60 minutes after Exercise-2 (8:30 AM).
Maximal progressive exercise test
First, to define maximal oxygen uptake (VO2max), the subjects were subjected to a maximal progressive exercise test on a bicycle ergometer (232CL, Conbiwellness, Tokyo). The test consisted of a continuous step test beginning at a 30 W load, and increasing by 20 W every minute until exhaustion. The subjects were instructed to ride at 50 rpm/min. Pulmonary gas exchange values were measured using an exhaled gas sensor (AE280S, Minato Medical®, Osaka, Japan) via a breath-by-breath system, and the mean values were calculated every 30 seconds for analysis. We determined that VO2max was reached when the oxygen consumption reached its plateau [15].
Fixed-load cycling at 75 % (high intensity) of VO2 max
Before the test started, the subjects rested for two minutes. After warming up at a load of 50 W for one minute, the subjects were instructed to ride at submaximal levels for 30 minutes. Pulmonary gas exchange values were monitored to maintain VO2max at approximately 75 %. During the experiments, the subjects were frequently verbally instructed to control the range of motion to maintain VO2max at approximately 75 %.
Maximal isokinetic knee extensions
A calibrated Biodex System 3 isokinetic device (Biodex Medical Systems, New York, USA) was used to measure peak torque (PT) and knee-joint position throughout 100 repetitions of maximal isokinetic knee extension. During testing, each subject was seated on the Biodex system 3 with 90° hip flexion, and restraining straps were placed across the waist and chest in addition to a rigid sternal stabilizer. The dynamometer was motor driven at a constant velocity of 90°/sec. Each subject performed a series of 100 isokinetic contractions using the knee extensors of the right leg from 90° of flexion to 0° (full extension). As the arm of the dynamometer moved up from 90° to 0°, subjects were encouraged to perform maximally for each contraction throughout the full range of motion. Subjects relaxed as the dynamometer arm moved back to 90°. Each contraction and relaxation period lasted one second and the total length of the contraction cycle was thus two seconds. All subjects were able to complete the full 100 contractions.
Measurement of muscle fatigue
To measure muscle fatigue, the widely used First Fourier transform technique (FFT) is utilized to analyze mean frequency of surface electromyogram (EMG) [16]. EMG signals were obtained from the rectus femoris muscle via electrodes connected to a 4-channel frequency-modulation transmitter (Nihon Kohden, Tokyo, Japan). All data were stored and analyzed using the FFT functions in Acknowledge 3.7.5 software (BIOPAC SYSTEM, Santa Barbara, USA). Mean power frequency (MPF) and median power frequency (MDF) were calculated as previously described [17]. MPF shift of the EMG signal toward lower frequencies has been extensively used in static contractions to indicate the development of peripheral fatigue.
Blood test
Blood lactate levels were determined using a commercially available Lactate Pro LT17170 kit (Arkray, Inc., Kyoto, Japan). The concentrations of derivatives of reactive oxidative metabolites (dROMs) and biological antioxidant power (BAP) in the peripheral blood were assessed using a Free Radical Analytical System (FRAS4; Wismerll, Tokyo, Japan). Laboratory tests for creatine kinase (CK) were conducted using standardized procedures at Kotobiken Medical Laboratory Services (Tokyo, Japan).
Statistical analysis
Repeated analysis of variance (ANOVA) tests were used to compare pre- and post-exercise measurements. The F-test with Bonferroni post hoc group comparisons was performed where appropriate. Probability values less than 0.05 were considered to be statistically significant. SPSS 18.0 was used to perform the statistical analysis. Since the experiment was planned to have a 90 % power of achieving significance at the 5 % level, the sample size in this model is calculated to be between 8.91 and 9.25 (90 % power and 5 % significance level) in blood lactate levels based on our previous experiences. Therefore, we assumed the sample size would be appropriate for accumulation of preliminary data.
Results
Blood analysis for lactic acid, d-ROMs, BAP and CK
As shown in Table 2, blood d-ROMs BAP and CK levels increased after exercise in subjects in both groups treated with PW and molecular hydrogen rich water HW. However, there was no statistical difference between the groups. Eventhough the blood lactate level were significantly increased in both molecular hydrogen rich water HW and PW at 45 and 60 min after exercise, these levels were comparably and significantly lower in the molecular hydrogen rich water HW than in the PW group (Figure 1).
Table 2
Changes in Blood Levels
| 0 min | 45 min | 60 min | 90 min | 120 min | ||
|---|---|---|---|---|---|---|
| d-ROMs (U.CARR) | PW | 269.0 ± 50.8 | 285.7 ± 52.3* | 287.0 ± 56.9* | 274.2 ± 50.2 | 280.0 ± 47.6 |
| HW | 281.3 ± 61.8 | 303.5 ± 46.3* | 308.6 ± 56.1* | 296.1 ± 57.9 | 307.0 ± 45.8 | |
| BAP (μmol/L) | PW | 2347.3 ± 155.8 | 2648.9 ± 96.5* | 2632.8 ± 146.4* | 2349.6 ± 152.0 | 2321.8 ± 196.9 |
| HW | 2336.7 ± 123.1 | 2659.1 ± 102.1* | 2664.6 ± 201.0* | 2299.8 ± 104.6 | 2356.4 ± 143.7 | |
| CK (IU/L) | PW | 247.0 ± 105.1 | 296.5 ± 119.9* | 300.9 ± 127.7* | 264.7 ± 113.3* | 256.3 ± 111.7 |
| HW | 407.4 ± 269.9 | 483.2 ± 314.0* | 478.1 ± 314.5* | 428.2 ± 282.0 | 353.7 ± 264.6 |
Data were shown as mean ± standard deviation (SD). *p < 0.05 vs 0 min.
Figure 1
Sequential changes of blood lactate levels during exercise. Blood lactate levels in the athletes given PW significantly increased immediately after exercise compared to the levels at pre-exercise. molecular hydrogen rich water HW significantly reduced blood lactate levels post exercise using bicycle ergometer. (*p < 0.05 vs. time 0. #p < 0.05 vs HW, N = 10).
Maximal knee extension exercise
At analysis for maximal knee extension exercise, we divided into five frames of 100-repetition knee extension at the peak torque of isokinetic knee extension exercise [18]. Each frame was corresponded to 20 repetitions; Frame 1 for the first 20 repetitions, Frame 2 for the following 21-40 repetitions, Frame 3 for 41-60 repetitions, Frame 4 for 61-80 repetitions and Frame 5 for the last 81-100 repetitions. Although the peak torque of subjects treated with PW significantly decreased during the first 40 repetitions (Frame 1-2), the reduction of peak torque in the subjects given molecular hydrogen rich water HW did not reach statistical difference, suggesting that molecular hydrogen rich water HW inhibited the early decrease of peak torque of the subjects (Figure 2 A).
MDF and MPF from EMG analysis
MDF and MPF in the subjects treated with PW or molecular hydrogen rich water HW significantly decreased with time during exercise. While these values significantly decreased at Frame 1-2, there was no statistical difference between the subjects receiving PW and those receiving HW (Figure 2 B, C).
Figure 2
(A) Changes in peak torque (PT) every 20 repetitions (rep = 1 frame) during 100 maximum isokinetic knee extensions. PT of the subjects treated with PW significantly decreased during the initial 40-60 contractions by approximately 20-25 % of the initial values, followed by a phase with little change. On the other hand, there was no statistical difference between Frame 1 and Frame 2 in HW, indicating that HW prevented the decreasing the peak torque during the first 2 Frames. HW, Hydrogen rich water; PW, Placebo water. (*p < 0.05 vs Frame 1, N = 10). (B) Changes in median frequency (MDF) every 20 repetitions (rep = 1 Frame) during 100 maximum isokinetic knee extensions. Although exercise significantly reduced MDF values during the first 2 Frames, there was no statistical difference between HW and PW in all Frames. HW, Hydrogen rich water; PW, Placebo water. (*p < 0.05 vs Frame 1, N = 10). (C) Changes in mean power frequency (MPF) every 20 repetitions (rep = 1 Frame) during 100 maximum isokinetic knee extensions. There was no statistical difference between HW and PW in all Frames. HW, Hydrogen rich water; PW, Placebo water. (*p < 0.05 vs Frame 1, N = 10).
Discussion
In this preliminary study, we showed that hydration with molecular hydrogen rich water HW attenuated increase of blood lactate levels and prevented post-exercise decrease of peak torque, an indicator of muscle fatigue. Muscle fatigue is caused by many different mechanisms, including the accumulation of metabolites within muscle fibers and the generation of an inadequate motor command in the motor cortex. The accumulations of potassium, lactate, and H+ have often been suggested as being responsible for the decrease in muscle contractility [19]. In addition, aerobic, anaerobic, or mixed exercise causes enhanced ROS production, resulting in inflammation and cellular damage [20]. Short bursts of heavy exercise may induce oxidative stress through various pathways such as electron leakage within mitochondria, auto-oxidation of the catecholamine, NADPH activity, or ischemia/reperfusion [21]. Although the mechanism involved in the efficacies of molecular hydrogen rich water HW remains unclear, our results show that hydration with molecular hydrogen rich water HW could be feasible for acute exercise. Proper and adequate hydration is helpful for elite athletes to achieve the best performance. molecular hydrogen rich water HW can easily replace regular drinking water on a routine basis and would potentially prevent adverse effects associated with heavy exercise.
Factors such as age, nutritional status, training level, and physical activity category can influence the results [22, 23]. Although we had anticipated that molecular hydrogen , a known antioxidant, would reduce oxidative stress following acute exercise, the effects of oral intake of molecular hydrogen rich water HW were marginal and did not affect the level of oxidative markers after exercise. This can be explained by the facts that the athletes in our study have routinely trained and their antioxidant defense systems may be more active. Previous studies reported that repeated aerobic training increases antioxidant enzyme activity and subsequently decreases oxidative stress [2, 24, 25, 26]. Also, considering the short life-span of molecular hydrogen in circulation [27], more frequent drinking of molecular hydrogen rich water HW during exercise might have additional effects. In a future study, the efficacy of molecular hydrogen rich water HW on untrained subjects or recreational exercisers, who may have poorly established antioxidant systems to combat exercise-induced oxidative stress, should be tested. Furthermore, different drinking protocols should be investigated.
We quantified muscle fatigue as a decline in the maximal force or power capacity of muscle, which means that submaximal contractions can be sustained after the onset of muscle fatigue. Similarly, blood lactate concentration is one of the most often measured parameters during clinical exercise testing, as well as during performance testing of athletes. Lactate has often been considered one of the major causes of both fatigue during exercise and post-exercise muscle soreness. Lactate generated from the anaerobic breakdown of glycogen in the muscle occurs only during short bouts of relatively high intensity exercise and it is usually related to fatigue and muscle soreness. Previous evidence has shown that inorganic phosphate from creatine phosphate was the main cause of muscle fatigue [28].
Dehydration in athletes may also lead to fatigue, poor performance, decreased coordination, and muscle cramping. Although further investigations will be warranted, drinking molecular hydrogen rich water HW may be an appropriate hydration strategy [29]. In this study, we administered molecular hydrogen rich water HW or PW to subjects prior to exercise. Further investigation is required to determine the best timing, dose, and hydrogen concentration of drinking water to optimize the effects of molecular hydrogen rich water HW.
In conclusion, our preliminary data demonstrated that consumption of molecular hydrogen rich water HW reduced blood lactate levels and improved muscle fatigue after acute exercise. Although further studies are absolutely warranted, drinking molecular hydrogen rich water HW would be a novel and effective fluid hydration strategy for athletes.
https://medicalgasresearch.biomedcentral.com/articles/10.1186/2045-9912-2-12
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Declarations
Acknowledgements
This research was supported by a Daimaru Research Foundation grant awarded to SM.
Authors’ Affiliations
(1)
(2)
References
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Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes
- Kosuke Aoki,
- Atsunori NakaoEmail author,
- Takako Adachi,
- Yasushi Matsui and
- Shumpei Miyakawa
Medical Gas Research20122:12https://doi.org/10.1186/2045-9912-2-12
© Aoki et al.; licensee BioMed Central Ltd. 2012
Received: 21 March 2012
Accepted: 20 April 2012
Published: 20 April 2012
Copyright
© Aoki et al.; licensee BioMed Central Ltd. 2012
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Drinking hydrogen water enhances ENDURANCE and relieves psychometric FATIGUE: a randomized, double-blind, placebo-controlled study
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- Drinking hydrogen water enhances endurance and relieves psychometric fatigue: a randomized, double-blind, placebo-controlled study
Abstract
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.
- PMID:31251888
- DOI:10.1139/cjpp-2019-0059
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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.
Author information
- 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.
Effects of hydrogen rich water on prolonged intermittent EXERCISE
BACKGROUND:
Recent studies showed a positive effect of hydrogen rich water (HRW) intake on acid-base homeostasis at rest. We investigated 2-weeks of hydrogen rich water HRW intake on repeated sprint performance and acid-base status during prolonged intermittent cycling exercise.
METHODS:
In a cross over single-blind protocol, 8 trained male cyclists (age [mean±SD] 41±7 years, body mass 72.3±4.4 kg, height 1.77±0.04 m, maximal oxygen uptake [V̇O2max] 52.6±4.4 mL·kg-1·min-1) were provided daily with 2 liters of placebo normal water (PLA, pH 7.6, oxidation/reduction potential [ORP] +230 mV, free hydrogen content 0 ppb) or hydrogen rich water HRW (pH 9.8, ORP -180 mV, free Hydrogen 450 ppb). Tests were performed at baseline and after each period of 2 weeks of treatment. The treatments were counter-balanced and the sequence randomized. The 30-minute intermittent cycling trial consisted in 10 3-minute blocks, each one composed by 90 seconds at 40% V̇O2max, 60 seconds at 60% V̇O2max, 16 seconds all out sprint, and 14 seconds active recovery. Oxygen uptake (V̇O2), heart rate and power output were measured during the whole test, while mean and peak power output (PPO), time to peak power and Fatigue Index (FI) were determined during all the 16 seconds sprints. Lactate, pH and bicarbonate (HCO3-) concentrations were determined at rest and after each sprint on blood obtained by an antecubital vein indwelling catheter.
RESULTS:
In the PLA group, PPO in absolute values decreased significantly at the 8th and 9th of 10 sprints and in relative values, ΔPPO, decreased significantly at 6th, 8th and 9th of 10 sprints (by mean: -12±5%, P<0.006), while it remained unchanged in hydrogen rich water HRW group. Mean power, FI, time to peak power and total work showed no differences between groups. In both conditions lactate levels increased while pH and HCO3- decreased progressively as a function of the number of sprints.
CONCLUSIONS:
Two weeks of hydrogen rich water HRW intake may help to maintain PPO in repetitive sprints to exhaustion over 30 minutes.
J Sports Med Phys Fitness. 2018 May;58(5):612-621. doi: 10.23736/S0022-4707.17.06883-9. Epub 2017 Apr 26.
Effects of hydrogen rich water on prolonged intermittent exercise.
Da Ponte A1,2, Giovanelli N3,4, Nigris D5, Lazzer S3,4.
Author information
1
Department of Medical and Biological Sciences, University of Udine, Udine, Italy – dott.daponte@gmail.com.
2
School of Sports Medicine, University of Udine, Udine, Italy – dott.daponte@gmail.com.
3
Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
4
School of Sport Sciences, University of Udine, Udine, Italy.
5
Department of Laboratory Medicine, University of Udine, Udine, Italy.
PMID: 28474871 DOI: 10.23736/S0022-4707.17.06883-9
Selective protective effect of hydrogen water on free radical injury of athletes after high-intensity exercise
Abstract
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.
Introduction
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 [1]. 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 [2]. 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 [3]. 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 [4]. 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
General data
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.
Intervention methods
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.
Determining indexes
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.
Statistical methods
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.
Results
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 |
| t value | / | 1.53 | 15.25 | 5.77 | / |
| P value | / | 0.13 | 0.00 | 0.00 | / |
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 |
| t value | / | 0.60 | 5.63 | 11.47 | / |
| P value | / | 0.55 | 0.00 | 0.00 | / |
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 |
| t value | / | 0.64 | 5.29 | 33.98 | / |
| P value | / | 0.52 | 0.00 | 0.00 | / |
Table 3: Comparison of serum total antioxidant capacities of athletes between the two groups at different time points (χ ± s; U/ml).
Discussion
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 [5]. 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 [6] 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 [7]. 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 [8]. 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 [9]. 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 [10]. 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).
Conclusion
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
1Department of Physical Education, Dalian Maritime University, Dalian, Liaoning, PR China
2Department of Physical Education, Jilin Normal University, Siping, Jilin, PR China
- *Corresponding Author:
- Yue-Peng Sun
Department of Physical Education
Dalian Maritime University, PR China
Accepted date: March 14, 2017
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References
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- Lin HK, Bloom SE, Dietert RR. Macrophage antimicrobial functions in a chicken MHC chromosome dosage model. J Leukoc Biol 1992; 52: 307-314.
- Wu L, Wu X, Wang K, Zhang J. Vincamine protects PC12 cells against hydrogen peroxide induced apoptosis by upregulation of SOD and activation of the PI3K/Akt pathway. Lat Am J Pharm 2016; 35: 510-518.
- Thilakvathi B, Shenbaga DS, Bhanu K, Malaippan M. EEG signal complexity analysis for schizophrenia during rest and mental activity. Biomed Res India 2017; 28: 1-9.
- Burki NK, Sheatt M, Lee LY. Effects of airway anesthesia on dyspnea and ventilatory response to intravenous injection of adenosine in healthy human subjects. Pulm Pharmacol Ther 2008; 21: 208-213.
- Ibis S. The relationship of balance performance in young female national team wrestlers with strength, leg volume and anthropometric features. Biomed Res India 2017; 28: 92-97.
- Wang M, Ji P, Wang R, Zhao L, Xia Z. TRPV1 agonist capsaicin attenuates lung ischemia-reperfusion injury in rabbits. J Surg Res 2012; 173: 153-160.
- Khamesipour F, Tajbakhsh E. Analysed the genotypic and phenotypic antibiotic resistance patterns of Klebsiella pneumoniae isolated from clinical samples in Iran. Biomed Res India 2016; 27: 1017-1026.
molecular hydrogen water for patients with pressure ulcer – effects on normal human SKIN WOUNDS
22 severely hospitalized elderly Japanese patients with pressure ulcer PU were recruited in the present study, and their ages ranged from 71.0 to 101.0 (86.7 ± 8.2) years old, 12 male and 10 female patients, all suffering from eating disorder and bedridden syndrome as the secondary results of various underlying diseases. All patients received routine care treatments for pressure ulcer PU in combination with molecular hydrogen water HW intake via TF for 600 mL per day, in place of partial moisture replenishment. On the other hand, HW was prepared with a hydrogen-bubbling apparatus which produces molecular hydrogen water HW with 0.8-1.3 ppm of dissolved hydrogen concentration (DH) and −602 mV to −583 mV of oxidation-reduction potential (ORP), in contrast to reversed osmotic ultra-pure water (RW), as the reference, with DH of < 0.018 ppm and ORP of +184 mV for use in the in vitro experimental research. In in vitro experiments, OUMS-36 fibroblasts and HaCaT keratinocytes were respectively cultured in medium prepared with molecular hydrogen water HW and/or reversed osmotic ultra-pure water RW. Immunostain was used for detecting type-I collagen reconstruction in OUMS-36 cells. And intracellular reactive oxygen species (ROS) were quantified by NBT assay, and cell viability of HaCaT cells was examined by WST-1 assay, respectively.
Results
22 patients were retrospectively divided into an effective group (EG, n = 12) and a less effective group (LG, n = 10) according to the outcomes of endpoint evaluation and the healing criteria. Pressure Ulcers hospitalized days in EffectiveGroup were significantly shorter than in LessseffectiveGroup (113.3 days vs. 155.4 days, p < 0.05), and the shortening rate was approximately 28.1%. Either in EG or in LG, the reducing changes (EG: 91.4%; LG: 48.6%) of wound size represented statistically significant difference versus before molecular hydrogen water HW intake (p < 0.05, p < 0.001). The in vitro data demonstrate that intracellular ROS as quantified by NBT assay was diminished by molecular hydrogen water HW, but not by reverse osmosys water ultraviolet-A (UVA)-irradiated HaCaT cells. Nuclear condensation and fragmentation had occurred for UVA-irradiated HaCaT cells in reverse osmosis water RW, but scarcely occurred in molecular hydrogen water HW as demonstrated by Hoechst 33342 staining. Besides, under UVA-irradiation, either the mitochondrial reducing ability of HaCaT cells or the type-I collagen construction in OUMS-36 cells deteriorated in reverse osmosis water RW-prepared culture medium, but was retained in molecular hydrogen water HW-prepared culture medium as shown by WST-1 assay or immunostain, respectively.
Conclusions
molecular hydrogen water HW intake via TF was demonstrated, for severely hospitalized elderly patients with PressureUlcers, to execute wound size reduction and early recovery, which potently ensue from either type-I collagen construction in dermal fibroblasts or the promoted mitochondrial reducing ability and ROS repression in epidermal keratinocytes as shown by immunostain or NBT and WST-1 assays, respectively.
Introduction
PressureUlcer is common in the immobile elderly or other immobile patients suffering from diseases such as spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, and muscular dystrophy, etc. Furthermore, aged and weak bedridden patients belong to a high risk population for Pressure Ulcers [1]. It is estimated that there are over one million elderly people who are suffering from the skin peculiarity and are facing the risk factors of Pressure Ulcers in USA [2]. Fundamentally, it is usually pointed out that social, psychological and financial expenses for Pressure Ulcers are immeasurable, patients and their families as well as health care providers are always receiving the mental strain [3].
For Pressure Ulcers , it is a primary research task to explore a cheap but effective preventive and curative method. Although various methods for prevention and treatment have been developed, they are far from sufficiently succeeding. While slightly delayed, basic studies are seen to steadily proceed in the same way as the clinical study. As the basic studies for wound healing, a lot of researchers are focusing on skin-constructing proteins such as collagen, elastin, laminin and fibronectin, and on metabolic activity and proliferating ability of dermal fibroblasts [4, 5].
In relation to this matter, we had confirmed the fact that molecular hydrogen-dissolved in water HW, as an external use for skin, can promote the construction of the type-I collagen in fibroblastic cells of dermis [6, 7, 8]. We prepared molecular hydrogen-dissolved in water HW with a hydrogen-bubbling apparatus, exhibited a DH of 1.13 ppm and an ORP of −741 mV, in contrast a DH of < 0.01 ppm and an ORP of +150 mV for normal water [6]. Simultaneously, normal human dermal fibroblasts OUMS-36 and normal human epidermis-derived keratinocytes HaCaT were cultured using an immunostain, in addition, WST-8 and DAPI stains were conducted to examine the cytoprotective effects of molecular hydrogen-dissolved in water HW against UVA-ray irradiation. Six Japanese subjects were enrolled in a trial of molecular hydrogen water HW-bathing (DH, 0.2-0.4 ppm) every day for 3 months. The results obtained showed that molecular hydrogen water HW-bathing significantly improved wrinkles on the back of the neck in four subjects on 90th day as compared to day 0. Thus the conclusion was achieved, in which molecular hydrogen water HW can serve as a daily skin care routine to repress UVA-induced skin damages by ROS-scavenging and promotion of type-I collagen synthesis in dermis. On the other hand, many basic research studies demonstrated that molecular hydrogen water HW is widely applied to various diseases, as an oral intake for absorbing via the gastrointestinal tract [9, 10, 11, 12, 13, 14]. The researches obviously suggest that whether using a bathing type or oral intake type of treatment,molecular hydrogen water HW is still an effective method to repair the skin and scavenge the ROS [15, 16, 17].
We theorized that a routine care treatment in combination with molecular hydrogen water HW intake via TF for patients with PressureUlcers may improve wound healing and maintain a better health condition than before. The purpose of this study is to clarify the clinical effectiveness of wound healing for patients with PressureUlcers by means of an oral intake of molecular hydrogen water HW via TF. Furthermore, OUMS-36 cells and HaCaT cells were examined to analyze the mechanisms relating to whether molecular hydrogen water plays a role in wound healing at the cellular level, in vitro.
Methods
Clinical materials
Patients
Medical record data that were analyzed for this study were obtained from twenty-two elderly Japanese patients with Pressure Ulcers who were hospitalized and institutionalized in Kobayashi Hospital, Fukuyama City, Hiroshima Prefecture, Japan, which is a general hospital attached to a mixed long-term care facility. This study was approved by the Ethics Committee of Kobayashi Hospital.
The ages of PressureUlcers patients who we treated in this study ranged from 71.0 to 101.0 (86.7 ± 8.2) years old, and ten patients were women. On the time of admission, they had suffered from one or multiple diseases and complications, and almost all of them were bedridden elderly people at a high risk of PressureUlcers development, and all of them could not eat without other people’s aid. On the time of admission or during the hospitalization, all patients had been or were gradually appearing symptoms of PressureUlcers.
The types of diseases and complications in these patients, not only included eating disorder but 90% also showed the prevalence of being in the aged period, and 100% had impaired mobility. However, it must be emphasized that PressureUlcers incidence of new onset in Kobayashi Hospital remained approximately 2.10% in 2010–2011, persisted in low level. Because it was reported that average PressureUlcer incidence was 2.43% in a nationwide survey executed by Japanese Society of Pressure Ulcers [18].
Twenty-two patients were retrospectively grouped into EG (effective group, n = 12) and LG (less effective group, n = 10) according to the outcomes of endpoint evaluation and the healing criteria. Details with regard to the discharge from hospital for whether cure or not were analyzed, and baseline data were summarized (Table 1). In data processing, results of all patients were classified as stage I-IV according to the Guideline in 2009 of EPUAP (European Pressure Ulcer Advisory Panel) & NPUAP (National Pressure Ulcer Advisory Panel) that is used as assessment for the severity of PressureUlcers. Coincidentally, all patients in this study belonged to stage II or III.
Table 1
Characteristics of baseline data of PressureUlcers patients in two groups
| Item | Effective group (EG) | Less effective group (LG) |
|---|---|---|
| Number of patients | 12 | 10 |
| Age (mean ± SD) at onset | 87.9 ± 9.0 | 85.5 ± 7.3 |
| range | 71.0-101.0 | 73.0-98.0 |
| Gender (male/female) | 4/8 | 8/2 |
| Admission diagnosis | ||
| PU | 8 | 7 |
| Tumor | 0 | 1 |
| Pneumonia | 4 | 0 |
| COPD | 0 | 1 |
| CIS | 0 | 1 |
| Hospitalized days (mean ± SD) | 113.3 ± 89.6 | 155.4 ± 92.6 |
| range | 32-379 | 63-335 |
| DESIGN-Rating (mean ± SD) at onset | 14.0 ± 5.4 | 12.7 ± 3.3 |
| Wound size (mean ± SD) at onset | 6.9 ± 0.9 cm2 | 6.3 ± 0.9 cm2 |
| Locations* | ||
| Total | 16 | 12 |
| Back | 3 | 0 |
| Sacrum | 3 | 5 |
| Buttocks | 3 | 2 |
| Ilium | 1 | 3 |
| Greater trochanter | 2 | 1 |
| Thigh | 1 | 0 |
| Knee | 1 | 0 |
| Heel | 1 | 1 |
| Toes | 1 | 0 |
| Stages at onset (number of locations*) | ||
| Stage II | 6 | 4 |
| Stage III | 10 | 8 |
Abbreviations: PU pressure ulcer, COPD chronic obstructive pulmonary disease, CIS cerebral infarction sequela, DESIGN-Ratingdepth, exudate, size, inflammation/infection, granulation, necrotic tissue.
*Some patients had multiple locations for pressure ulcers.
Clinical care treatments
Hospitalized routine care treatment
The treatment focused on preventing PressureUlcers from getting worse and on restoring healthy skin. According to the routine care treatments for all patients, nonsurgical therapies were selected, such as ointment, gauze dressing, wrapping, and bed-pad were used after washing by the acidic water disinfection. The skin care, pressure relief and nutritional support were aggressively used as a part of this care treatment [1, 3]. The main care steps to treat PressureUlcers included:
- a.
Managing the tissue load.
- b.
Keeping the ulcer area clean and covered, and not letting it dry out.
- c.
Body-position changes at least every 2 hours if the patient is confined to a bed, or as often as every 15 min if sitting in a wheelchair.
- d.
To achieve positive nutritional nitrogen balance, patient consumed by TF approximately 30 to 35 calories per kg per day and 1.25 to 1.50 g of protein per kg per day.
Preparation for molecular hydrogen water HW
HW molecular hydrogen water was prepared with a molecular hydrogen-bubbling apparatus which consists mainly of a water supply section for manufacturing reverse osmosis water RW with less 0.018 ppm of DH and +184 mV of ORP, and molecular hydrogen water HW with 0.8-1.3 ppm of DH and −602 mV to −583 mV of ORP. For comparing molecular hydrogen water HW with reverse osmosys water RW, the water characteristic parameters were measured with the different dilution rates (Table 2, Figures 1 and 2). It must be emphasized that some stable characteristic indicators and the proprieties for innocuity and harmlessness of molecular hydrogen water were obtained from several separated in vivo and human experiments which we had reported [19, 20, 21, 22, 23]. Meanwhile, via tube-feeding, Pressure Ulcers patients were enforced to intake molecular hydrogen water HW of 600 mL per day, in the morning and afternoon for approximately one hour, respectively, immediately after molecular hydrogen water HW was manufactured everytime.
Table 2
Characteristic parameters obtained from hydrogen-dissolved water vs. reversed osmotic ultra-pure water
| DH(ppm) | DO(ppm) | ORP (mV)
| pH | Water temperature (°C) | |
|---|---|---|---|---|---|
| Hydrogen-dissolved water (HW) | 0.80-1.30 | 6.91 | −602 | 7.40 | 24.1 |
| Reversed osmotic ultra-pure water (RW) | < 0.018 | 8.26 | +184 | 7.37 | 24.2 |
Abbreviations: DHdissolved hydrogen concentration, DOdissolved oxygen concentration, ORPoxidation-reduction potential.
Figure 1
Measurement results of diluting molecular hydrogen water HW with reverse osmosys water RW. The dilution rates are showed as Figure 1. Figures 1–a and –b show the ever-increasing tendencies on DO (dissolved oxygen concentration) and ORP (oxidation-reduction potential). Meanwhile, as shown by Figures 1–c and –d, DH (dissolved hydrogen concentration) shows the ever-decreasing tendency which indicates the dissolved hydrogen in the hydrogen water was evaporated slowly by mixing with normal regular water. On the other hand, both molecular hydrogen water HW with reverse osmosys water RW have been holding the temperature range of 23.2-24.1°C and pH 7.37-7.48 no matter from 1 to 11-fold dilution rate.
Clinical evaluations
The evaluative indices for clinical therapeutic effects on PRESSURE ULCERS consisted of the hospitalized days, wound size, classifications of PressureUlcers-stage and DESIGN- rating.
Hospitalized days
Because the increased length of hospitalized stay is an important index for a PressureUlcers patient of QOL (Quality of Life), the days from admission to discharge for twenty-two patients were counted.
Wound size
For obtaining precise objective information and monitoring the healing degree about wound, the medical-care staff measured the size, depth and area [24], utilized photography and diagrams for recording the shape and outline of the wound.
Classifications of PressureUlcers-stages
According to a well-known Panel Guideline established by EPUAP and NPUAP in 2009 [3], stage II includes the partial thickness for loss of skin involving epidermis, dermis or both. The ulcer is superficial and presents clinically as an abrasion or blister, but is not deeper than the dermis. On the other hand, stage III involves the full depth of the skin, and may extend into the subcutaneous tissue layer which has a relatively poor blood supply and can be difficult to heal [25, 26].
DESIGN-rating
DESIGN was an absolute evaluation tool and consumed as a clinical indicator to assess the quality of medical care. But, its score could not be compared the severity of PressureUlcers among different patients and their various ulcers. Because of this, the DESIGN-rating was invented to use as a simple and easy assessment of PressureUlcers [27, 28]. In our study, the DESIGN-rating score of every patient was recorded by the medical-care staff, at least once monthly.
In vitro experiments
Materials and methods
Normal human dermal fibroblastic cells OUMS-36
OUMS-36 cells were cultivated for 18 hours in molecular hydrogen water HW or reverse osmosys water RW-prepared Dulbecco’s modified Eagle’s medium (DMEM; Nissui Pharmaceutical Co. Ltd., Tokyo) supplemented with 10% FCS (fetal calf serum) (GIBCO) in a CO2incubator to be kept at 37°C and pH 7.1-7.4 in a moistened atmosphere of 5% CO2. The spent medium was replaced by the fresh molecular hydrogen water HW or reverse osmosys water RW-prepared culture medium, and was at once irradiated with UVA ray at doses of 12 or 18 J/cm2, corresponding to the normal dose range for the human daily life. The resultant cells were stained for the nuclei with 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI, Ultracruz Mounting Medium, sc-24941, Santa Cruz Biotechnology Inc., Santa Cruz, CA), and observed for type-I collagen reconstruction by immunostain using the first antibody directed against type-I collagen and the secondary antibody conjugated with FITC (fluorescein isothiocyanate), as observed with a fluorescence microscope (ECLIPSE E600, Nikon Corp., Tokyo) as previously described [6].
Normal human epidermis-derived keratinocytes HaCaT
HaCaT cells were similarly cultivated in molecular hydrogen water HW or reverse osmosys water RW-prepared DMEM supplemented with 10% FCS (GIBCO), and similarly UVA-irradiated. The resultant cells were examined for cell viability by WST-1 methods using (phenyl)-5-(2-disulfophenyl)-2H-tetrazolium, monosodium salt as a redox indicator, and for ROS such as superoxide anion radicals by NBT (nitro blue tetrazorium) assay as previously described [6].
Statistical analysis
Either clinical study or in vitro research, the Student’s t-test was used to compare the difference in means ± SD between the control and treated groups using a Microsoft Office Excel 2010 software (Microsoft, Albuquerque, NM, USA) or a software package SPSS 11.0 (SPSS inc., Chicago, IL, USA) for Windows. A p-value that is below 0.05 was regarded to be statistically significant.
Results
The clinical results of routine care treatments in combination with molecular hydrogen water HW via Tube for Feeding
The hospitalized days and the DESIGN-rating of PressureUlcers
For the PressureUlcer patients, the hospitalized days in EffectiveGroup were significantly shorter than in LesseffectiveGroup (113.3 days vs. 155.4 days, p < 0.05), and the PressureUlcers reduction rate was approximately 28.1% (Figure 3-a). Likewise, DESIGN-rating in EG was also decreased for comparing the onset with the endpoint (11.5 rates vs. 14.3 rates, p < 0.05) between pre-post evaluations including both in onset (evaluation in the initial time, at the day for the admission to hospital) and in endpoint (evaluation in the last time, at the day for the discharge from hospital or death day). In LG, no statistically significance was seen, in DESIGN-rating indicative of degree of severity for PU, between both of them (Figure 3-b).
Figure 3
Comparison of PU clinical effects for the hospitalized days and the DESIGN-rating in the effective group and in the less effective group. Figure 3–a shows the period for the PU hospitalized days in EG was significantly shorter than in LG. Figure 3–b indicates that the DESIGN-rating in EG was decreased for comparing the onset with the endpoint. Pre-post evaluations were performed, where the onset and the endpoint were included. All values are statistically compared. Statistical analysis was performed using Student’s t-test, and the significant differences are defined as p < 0.05. The data are presented as the means with the standard deviation (± SD, indicated by the vertical bar). * p < 0.05.
Results of wound size in two groups
Wound measurement is an important means to know the degrees of PU, and its measuring method was demonstrated in Figure 4-a (Figure 4-a). Either in EG or in LG, the reducing changes (EG: 91.4%; LG: 48.6%) of the wound sizes represent a statistically significant difference (p < 0.05, p < 0.001). Similarly, a significant difference is also seen between both EG and LG groups (p < 0.05) (Figure 4-b).
Figure 4
Measurement methods for wound size and results of wound size in the wound-size reductive change between both the groups. Figure 4–a demonstrates the wound measurement method. As a protocol, initially, measure the greatest length along the axial direction (head to toe), and then the greatest width along the transverse direction (side to side) using a centimeter ruler. Finally multiply distances of length and width to obtain an estimate of surface area in square centimeters (cm2). Figure 4–b indicates a statistically significant difference to the reducing change of wound size in two groups. Some patients had multiple locations for PU. Values are statistically compared. Student’s t-test, *p < 0.05, ***p < 0.001.
Expression of various PU-assessment indices forcing on both stage II and stage III
For observing the clinical effects in many respects, including the hospitalized days, DESIGN-rating and wound size, EG and LG were subdivided to four subgroups according to classifications of PU-stages (see Methods (3)-3). As a result, in stage II, a period for hospitalized days in EG showed significantly shorter than in LG (87.5 days vs. 387.0 days, p < 0.001). Contrary to this, in two group, there was no significance statistically for hospitalized days in stage III (Figure 5-a) owing to diseases other than PU. Moreover, in EG, the DESIGN-rating obtained from subgroups of stage II and stage III depicted a statistically significant difference (p < 0.05) (Figure 5-b). Meanwhile, the diminishment for wound size within subgroups of stage II and stage III presents any statistical differences (Figure 5-c). In a conclusion, stage II and stage III ulcers of EG healed faster and more effectively than those of LG.
Figure 5
Expression of various PU-assessment indices forcing on both stage II and stage III. Figures 5–a to –c imply very significant differences among four subgroups based on stage II or stage III. P-values calculated from Student’s t-test, * p < 0.05, ** p < 0.01, *** p < 0.001.
Results of a typical case on time-dependent wound-healing progress: for an 85-year-old female patient with PressureUlcer
Figure 6 showed the time-dependent wound-healing progress for an 85-year-old female patient with PressureUlcer. She was admitted to the hospital for suffering from PressureUlcer. Wound findings at onset included: location: sacrum; wound size (cm2): 20.8; stage: II; DESIGN-rating: 16. Four months after routine care treatment plus a combination with molecular hydrogen water HW intake via TubeFeeding, the crater nearly disappeared. Wound findings at endpoint (vs. of onset) included: wound size (cm2): approximately 0 (disappearance); stage: I (improve); DESIGN-rating: 6 (decrease) (Figures 6-a to -d).
Figure 6
Results of a typical case on time-dependent wound-healing progress. An annual time-dependent wound healing progress for an 85-year-old female PressureUlcer patient is reported. She was admitted to the hospital seeking treatment to PressureUlcer. Figure 6–a demonstrates photographs for the time-dependent wound-healing progress obtained from the same patient. Figures 6–b to –d represent the decreased tendencies of wound size, DESIGN-rating, and stage, respectively.
Results of another typical case on time-dependent wound-healing progress: for an 80-year-old male patient with PressureUlcer
Figure 7 showed the time-dependent wound-healing progress for an 80-year-old male patient with PressureUlcer. His hospitalized period lasted 10 months and it could be divided into the two sub-periods. During the latter 5-month period, he received molecular HydrogenWater treatment in the addition to the routine care. The outcome shows an improved result (Figures 7-a, -b).
Figure 7
Results of another typical case on time-dependent wound-healing progress. Similarly to Figure 6, Figure 7 also demonstrates a time-dependent wound healing progress, for an 80-year-old male PressureUlcer patient. Figure 7–a shows the features photographed at the former period for routine care treatment alone. On the other hand, Figure 7–bpresents ones photographed at the latter period for routine care treatment plus molecular Hydrogen Water intake. The latter period in using HydrogenWater intake shows a marked improved outcome.
In vitro experiments
Promotive effects on reconstruction of type-I collagen, as shown by immunostain, on normal human dermal fibroblasts OUMS-36 that were irradiated with UVA ray and then were administered with reverse osmosis water RW- or molecular hydrogen water HW-prepared culture medium, respectively
To study the reconstructive effect of molecular hydrogen water HW on type-I collagen, we used immunostain on OUMS-36 cells that were irradiated with UVA ray and then were administered with reverse osmosis water RW or molecular hydrogen water HW in vitro, respectively. Representative expressions and pixel values were plotted with a software ImageJ (http://rsb.info.nih.gov/ij/). Nuclear condensation (so-called pycnosis) and fragmentation (so-called karyorrhexis) were occurred for UVA-irradiated OUMS-36 cells in reverse osmosis water RW, but scarcely occurred in molecular hydrogen water HW (Figure 8). HW molecular hydrogen water group shows higher proliferation of cells with rounded morphology in fibroblasts and huge morphology, and more abundant in type-I collagen than ones of reverse osmosis water RW group.
Figure 8
Reconstructive effects of molecular hydrogen water HW in UVA-irradiated OUMS-36 cells. Figures 8–a, –b: Distributional expressions of type-I collagen with immunostain (green) in OUMS-36 cells that were irradiated with UVA ray and were administered with reverse osmosis waterRW or molecular hydrogen water HW, respectively. Figure 8–b: Each yellow dashed lines indicate type-I collagen-rich regions. Figure 8–c: Relative fluorescence intensity plotted with the ImageJ to present the pixel number. Type-I collagen stain on OUMS-36 cells that were irradiated with UVA ray and were administered with reverse osmosis water RW or molecular hydrogen water HW, respectively, is showed. Figure 8–d: The pseudocolor feature was plotted using ImageJ as an intensity which is corresponding to type-I collagen exhibition degree per one hundred cells (μm2/100 cells). Magnification: ×200; scale bars = 50 μm. Student’s t-test, *** p < 0.001.
Proliferative effects of nucleus-DAPI stain on UVA-irradiated normal human dermal fibroblasts OUMS-36 that were administered with reverse osmosis water RW- or molecular hydrogen water HW-prepared culture medium, respectively
With fluorescence microscopy, DAPI dye can be excited by UVA ray. To examine the reconstructive effect of molecular hydrogen water HW on type-I collagen by immunostain, we also counterstaind nuclei with a DAPI dye in UVA-irradiated OUMS-36 cells for observing the changes when OUMS-36 cells were administered with Reverse osmosis Water or molecular hydrogen water HW in vitro, respectively. Representative expression and relative fluorescence intensity were plotted with the ImageJ. The facilitative effect on nuclear condensation and fragmentation was observed for UVA-irradiated OUMS-36 cells in Reverse osmosis Water , but scarcely occurred in molecular hydrogen water HW as demonstrated by DAPI staining as like the result obtained from immunostain (Figure 9). Through Figure 9-c, the degrees of DAPI stain on HaCaT cells that were irradiated with UVA ray and were administered with Reverse osmosis Water or molecular hydrogen water HW, respectively, were clarified.
Figure 9
Features of nucleus-DAPI stain on UVA-irradiated HaCaT cells. Figures 9–a, –b: Distributional expressions of nucleus-DAPI stain (blue) in HaCaT cells that were irradiated with UVA ray and were administered with Reverse osmosis Water or molecular Hydrogen Water, respectively. Figures 9–c, –d: The relative fluorescence intensity and the pseudocolor feature for type-I collagen were plotted using ImageJ. Magnification: ×200; scale bars = 200 μm. Student’s t-test, *** p < 0.001.
ROS amounts in normal human epidermis-derived keratinocytes HaCaT as quantified by NBT assay
In HaCaT cells, the intracellular ROS amounts were increased in the Reverse osmosis Water -prepared culture medium with UVA-irradiation in different UVA ray doses, but were restored in the molecular hydrogen water HW-prepared culture medium as shown by NBT-stain for superoxide anion radicals. Cell morphology was observed to be more health and less harmful in molecular HydrogenWater than Reverse osmosis Water (Figure 10). Figure 10-e showed that NBT-stain was denser in dark-blue color in Reverse osmosis Water -administered cells than in molecular HydrogenWater-administered cells, indicating the intracellular ROS repression in molecular Hydrogen Water-administered cells.
Figure 10
Intracellular ROS amounts in HaCaT cells as quantified by NBT assay. Figures 10–a, –b: The retained cell morphology and the diminished ROS were shown in molecular hydrogen water HW-prepared culture medium for comparing with Reverse osmosis Water .Yellow dashed lines indicate abundant dark-blue dyes that were the reaction products where ROS such as superoxide anion radical was found to react with NBT-stain. Figures 10–c, –d: The expressions of surface plotter by ImageJ. Figure 10–e: The mean gray values obtained from ImageJ used to express the increase or decrease in superoxide anion radicals within normal human epidermis-derived keratinocytes HaCaT according to NBT-stain. In detail, the vertical axis shows the brightness presented as a mean gray value, which is considered as an index to show the cellular stained intensity and use to indicate ROS amounts. The cell morphologies of Reverse osmosis Water RW and molecular hydrogen water HW were divided into the eight regions and then compared with their mean gray values by Student’s t-test (** p < 0.01). Magnification: ×200; scale bars = 100 μm.
Elevation of cell viability by pre-irradiational administration with molecular hydrogen-dissolved water to UVA-irradiated HaCaT cells as assessed by mitochondrial dehydrogenase-based WST-1 assay
In HaCaT cells, the cell viability was obviously increased in the molecular hydrogen water HW-prepared culture medium with UVA-irradiation, comparing with reverse osmosis water RW-prepared culture medium by WST-1 assay (Figure 11-d). Cell morphology was also observed to be less vulnerable in terms of diverse symptoms such as cell shrinkage, nuclear condensation and cell fragmentation for molecular hydrogen water HW than reverse osmosis water RW (Figures 11-b, -c). molecular hydrogen water HW group showed higher proliferation of cells with rounded morphology and huge morphology, in HaCaT cells than ones of Reverse osmosis Water group. All of these evidences predicted that molecular hydrogen-dissolved water may exert cytoprotective effects against UVA ray on HaCaT cells.
Figure 11
Results of cell viability of HaCaT cells as assessed by WST-1 assay. Figure 11–a: HaCaT cells are shown in the non-administered or non-UVA-irradiated status. Figures 11–b, –c: The morphologic features of HaCaT cells are shown in reverse osmosis water RW or molecular hydrogen water HW, respectively, after irradiation with UVA ray. Figure 11–d: The cell viability is shown for HaCaT cells after UVA-irradiation by WST-1 assay. Magnification: ×400; Scale bar = 100 μm. Student’s t-test, ** p < 0.01.
Discussion
The purpose of the present study was to examine the clinical effectiveness of wound healing for Pressure Ulcers using molecular hydrogen water HW intake via TubeFeeding. We have hypothesized that the routine care treatment in combination with molecular hydrogen water HW intake for PressureUlcer patients may improve wound healing, and maintain more healthy condition for them. Furthermore, normal human dermal fibroblasts OUMS-36 and normal human epidermis-derived keratinocytes HaCaT were examined to explore the mechanisms underlying to whether molecular hydrogen plays a role in wound-healing at aspect for cutis tissue, through in vitro experiments.
Our clinical results seem to suggest that molecular hydrogen water HW oral intake via TubeFeeding is an effective means for wound healing of PressureUlcer patients, who suffered from eating disorder. Despite the limitations caused by practicing our clinical intervention for PressureUlcers, we were able to obtain the improving results in hospitalized days, wound size and other clinical indices by comparing EG with LG. Therefore, we estimated that molecular hydrogen water HW absorbed by the gastrointestinal tract plays an important role in oxidative-stress reduction, extracellular matrix reconstitution, and anti-inflammatory effects. Several experiments have supported our considerations as follows.
At first, it was demonstrated that molecular hydrogen gas (H2) has a beneficial influence on the gastrointestinal tract [29]. Kajiya et al. established a mouse model of human inflammatory bowel disease (IBD) by supplying to mice drinking water containing a) 5% dextran sodium sulfate (DSS), b) 5% DSS and molecular hydrogen H2, or c) molecular hydrogen H2 only ad libitum up to 7 days. They found that on day-7, DSS-induced pathogenic outcomes including elevated levels of IL-12, TNF-α and IL-1- β in colon lesion, etc. were significantly suppressed by addition of molecular hydrogen H2 to DSS solution. Thereby, it was concluded that molecular hydrogen H2 can make an anti-inflammatory influence on gastrointestinal tract in vivo[30].
Secondly, Nakashima-Kamimura et al. examined whether drinking water containing the saturated dissolved molecular hydrogen (HW: 0.8 mM molecular hydrogen H2 in water) is applicable by examining the effects of oxidative stress, mortality, and body-weight loss as well as serum creatinine, and blood urea nitrogen (BUN) levels. In in vivo experiments, their results showed that molecular hydrogen was detected in the blood when molecular hydrogen water HW was placed via gavage at a dose of 15 mL/kg in the stomach of a rat, and molecular hydrogen water HW is applicable to alleviate nephrotoxic side-effects induced by an anti-cancer drug, such as cisplatin [31].
Thirdly, as molecular hydrogen gas can act as a scavenger of ROS, Cardinal et al. tested the effect of treatment with molecular hydrogen water HW in a rat model of kidney transplantation. In consequence, treatment with molecular hydrogen water HW improved allograft function, slowed the progression of chronic allograft nephropathy (CAN), reduced oxidant injury and inflammatory mediator production, and improved overall survival. Their conclusion was that molecular hydrogen water HW is an effective antioxidant and anti-inflammatory agent in vivo[32].
It was previously shown that some free radicals inhibit the wound healing process [33]. molecular hydrogen H2 is a colorless, odorless, tasteless gas, and it possesses some peroxidant reducibility. molecular hydrogen H2 is possible to easily pass through the small intestine villi into the human body inside and blood stream [15], because its molecular weight is the smallest of all molecule species, and it has gaseous and electrically neutral properties, as well as it shows a strong diffusion capacity. Moreover, molecular hydrogen H2 maybe has its special channels for transporting into intracellular space, such as the aquaporins (AQPs) for water, especially molecular hydrogen-holding water, and the Rhesus (Rh) proteins [34].
Thus, coupled with the body itself and the enterogenous-H2 molecular hydrogen presence, due to specified intestinal bacteria, molecular hydrogen water HW intake via TubeFeeding can play an important role on improving the formation of wound granulates on disintegrated necrosis loci, and the ability to have an anti-inflammatory effect through an ROS-reduction mechanism.
Additionally, it should be pointed out that apoptotic cells can stimulate proliferation, wound healing, and tissue regeneration [35]. We are focusing on “the apoptosis-induced compensatory proliferation” which occurs in PressureUlcers [36]. Generally, necrosis has an effect of the secondary lethal damage to the wound-surrounding cells of PressureUlcers through cell swelling and burst. By contrast, cell debris that is caused by cell shrinkage and fragmentation in apoptosis in which karyorrhexis (i.e. nuclear fragmentation) and pycnosis (i.e. nuclear condensation) are revealed as an early event, is subjected to endocytosis by both the migratory professional phagocytes (e.g.macrophages and Langerhans cells in the epidermis) and the surrounding non-professional phagocytes. So, it is thought that “the compensatory proliferation” is induced for the reason that cell debris is peaceably handled to restrain the surrounding cells within a minimal deteriorating impact. On this occasion, ROS may be able to be suppressed by the molecular hydrogen water to evoke an apoptosis more gently, and subsequently, apoptosis that is caused in wound-surrounding cells of PressureUlcers stimulates the compensatory proliferation to lead to an early healing. Indeed, Cai JM et al. reported that 2% molecular hydrogen gas inhalation administered to a neonatal hypoxia-ischemia rat model could reduce apoptosis [37].
When molecular Hydrogen Water-intake via TubeFeeding was combined with routine care treatments, the wound healing process can be markedly accelerated. Hence, the effective mechanism of molecular Hydrogen Water possesses at least two possible pathways, firstly is an antioxidant effect and secondly is an anti-inflammatory effect. Moreover, we thought that molecular hydrogen water HW may have additional effects, i.e. reconstruction of collagen and cytoprotection for other dermal as well epidermal cells. Therefore, we carried out an in vitro experiment on normal human dermal fibroblasts OUMS-36 and normal human epidermis-derived keratinocytes HaCaT to examine their interaction. Therefore, either dermal or epidermal cells were respectively cultured in molecular hydrogen water HW or reverse osmosis water RW-prepared medium. Immunostain was used for observing type-I collagen reconstruction in OUMS-36 cells and showed the promotive effect. And cell viability of HaCaT cells was examined in terms of cell morphological observation and WST-1 assay, and their generated ROS, especially superoxide onion radials, was measured by NBT assay, respectively, all of which showed the cell-death-repressive and ROS-scavenging effects.
We have attempted to draw the illustrations for assuming a cure mechanism from stage III to wound healing during Pressure Ulcers (Figure 12).
Figure 12
Mechanism for wound healing of pressure ulcer by molecular hydrogen-dissolved water. We are predicting that ROS can lead to a pressure ulcer, and the causative process is shown by the left illustration. First of all, such diverse factors as bedridden syndrome, mechanical pressure and local ischemia produce ROS which causes necrosis and apoptosis in combination with other pathologic factors, potently resulting in wounds and tissue defects of pressure ulcer. On the other hand, the right illustration shows the healing mechanism. Oral intake of nano-bubble molecular hydrogen water via drinking or tube-feeding passes by the mouth or esophagus, and it is absorbed by the epithelial cells of the small intestines. It is possible that molecular hydrogen gas transpires in past from molecular hydrogen water HW and inhaled by the lung. Then, the absorbed nano-bubble molecular hydrogen migrates to cutis tissue through blood circulation and scavenges ROS abundantly generated in Pressure Ulcers. Finally, this process results in collagen reconstruction of fibroblasts in the dermis and the proliferation of keratinocytes in the epidermis, and causes angiogenesis and remodeling for repairs in the defected tissue.
Consequently, our in vitro data demonstrated that intracellular ROS was diminished by molecular hydrogen water HW, but not by reverse osmosis water RW, in UVA-irradiated OUMS-36 fibroblasts. Nuclear condensation and fragmentation were occurred for UVA-irradiated OUMS-36 cells in reverse osmosis waterRW, but scarcely occurred in molecular hydrogen water HW as demonstrated by DAPI staining. Besides, in HaCaT cells, the mitochondrial dehydrogenase, especially succinate dehydrogenase activity was diminished in reverse osmosis water RW-prepared culture medium with UVA-irradiation, but was retained in molecular hydrogen water HW-prepared culture medium as shown by NBT and WST-1 assay. Thus, UVA-induced ROS, especially singlet oxygen and superoxide onion radicals were suggested to be scavenged by molecular hydrogen and result in cytoprotection against ROS-induced mitochondrial dysfunction.
Similar results have been reported from previous research works on reconstruction of collagen in other dermal or epidermal cells by molecular hydrogen water HW [38, 39].
As a mechanism for using molecular hydrogen water HW to treat PressureUlcers at aspect of dermal and epidermal cells, we consider that there are three pathways as follows:
(1) the promotion of the formation of dermis structure as well as reconstruction to type-I collagen,
(2) the prevention of the formation of wound granules on disintegrated necrosis loci, and
(3) the repair and restoration of scar tissues.
Healing effects for PressureUlcers patients through molecular hydrogen water HW oral intake via TubeFeeding as shown by our present study have been scarcely found in the past. Our experience in this study added further evidences to a possible role in medical therapies for Pressure Ulcers. Additionally, as well known, there are different methods to manufacture the hydrogen water by diverse research groups, so there are also different water-parameters about molecular hydrogen water HW. In order to show our data obtained from measurements with the different dilution ratios, we had specially set up Figures 1 and 2, as well as Table 2 to present these achievements. How to manufacture molecular hydrogen water HW and reverse osmosis water RW is an important and essential matter in the field of hydrogen water medicine.
But, this study has some limitations that should be considered when interpreting the results. Firstly the study design could not be carried out as the randomized control trail (RCT), because generally PU-cure clinical intervention test cannot be executed as RCT owing to other diverse factors such as various diseases concurrence and complication. Clinical situation did not allow us to get clinical data prior to one as we designed. Secondly we could not design the trial into comparing the results both molecular hydrogen water HW oral intake and external washing of injurious sites with molecular hydrogen water HW, respectively. These deserve the next-step study.
Conclusions
molecular hydrogen water HW intake via Tube Feeding was demonstrated, for severely hospitalized elderly patients with Pressure Ulcers, to execute wound size reduction and early recovery, both of which potently ensue from either type-I collagen construction in dermal fibroblasts or the promoted mitochondrial reducing ability and ROS repression in epidermal keratinocytes as shown by immunostain, NBT and WST-1 assays, respectively.
https://medicalgasresearch.biomedcentral.com/articles/10.1186/2045-9912-3-20
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Consent
Written informed consents that were presented from the patients for the publication of this report and any accompanying images were obtained and confirmed as the ethical clearance by the Ethics Committee of Kobayashi Hospital, Fukuyama City, Hiroshima Prefecture, Japan.
Declarations
Acknowledgments
The authors are grateful to Kobayashi Hospital and the representative director Dr. Yoshizi Kobayashi, for their devoted support to part of clinical trial. This study was supported, in part, by grant-in-aid from JCAAMS (Japanese Center for Anti-aging MedSciences, Hiroshima).
Authors’ Affiliations
(1)
(2)
(3)
References
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Hydrogen water intake via tube-feeding for patients with pressure ulcer and its reconstructive effects on normal human skin cells in vitro
- Qiang Li,
- Shinya Kato,
- Daigo Matsuoka,
- Hiroshi Tanaka and
- Nobuhiko MiwaEmail author
https://doi.org/10.1186/2045-9912-3-20
© Li et al.; licensee BioMed Central Ltd. 2013
Received: 9 June 2013
Accepted: 5 September 2013
Published: 10 September 2013
Copyright
© Li et al.; licensee BioMed Central Ltd. 2013
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Positive effects of hydrogen-water bathing in patients of PSORIAZIS and PARAPSORIAZIS en plaques
Positive effects of molecular hydrogen-water bathing in patients of psoriasis and parapsoriasis en plaques
Abstract
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).
Table 1
Characteristics of the psoriasis patients.
| The molecular Hydrogen-water bathing group | The control group | |||
|---|---|---|---|---|
| Baseline | Week 8 | Baseline | Week 8 | |
| No | 41 | 41 | 34 | 33 |
| Sex(male/female) | 24/17 | 24/17 | 18/16 | 18/15 |
| 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).
Table 2
Summary of the improvement of Psoriasis Area and Severity Index (PASI) and visual analog scale (VAS) at week 8.
| The Hydrogen-water bathing group | The control group | Pvalue | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Baseline PASI score | Baseline PASI score | |||||||||
| Mild | Moderate | Severe | Total | Mild | Moderate | Severe | Total | |||
| (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.
Clinical improvement of psoriasis of an 8-week course of molecular hydrogen-water bathing therapy. Case 1: A 64-year-old psoriasis patient at baseline (PASI 16.4, a,b) and after the bathing therapy (PASI 1.8, c,d). Although he had been treated with acitretin capsules 30 mg daily for more than 4 months, the psoriatic lesions had not improved except for the partially reduced scale on the plaque. He refused to increase the drug dose due to intolerable dryness and chapping of the mucous membranes. Case 2: A 40-year-old psoriasis patient at baseline (PASI 21.1, a,b) and after the last bathing therapy (PASI 4.1, c,d). He complained of severely itching and treatment-resistant lesions (acitretin capsules 40 mg daily for more than 6 months), and after bathing therapy he was able to reduce the dose. Case 3: A 43-year-old psoriasis patient at baseline (PASI 20.2, a,b) and after the last bathing therapy (PASI 4.8, c,d). This man had been continuously treated with methotrexate 5 mg weekly for more than 10 months and was able to reduce the dose successfully after bathing therapy. Note that patients experienced similar responses in the areas not shown.
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).
Table 3
Characteristics and the clinical outcomes of patients with parapsoriasis en plaques.
| 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 |
| 2 | F/31 | LPP | trunk | papule, patch | 12 | PR |
| 3 | F/33 | SPP | trunk and extremities | papule, patch, plaque | 28 | PR |
| 4 | F/33 | SPP | trunk | papule, patch | 15 | 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.
Clinical evaluation of a patient of parapsoriasis en plaques who achieved complete response rapidly 4 weeks after molecular hydrogen-water bathing. A 35-year-old man with large plaque parapsoriasis had been followed up for 30 months and during that time two biopsies were taken showing no progression. He had suffered flare-up after 10-month narrow-band UVB therapy and failed to have evident improvement in the later 6-month phototherapy despite of increasing the power. Even if only 4 weeks, his lesions rapidly achieved significant improvements without concomitant therapy (a). The Hematoxylin-eosin stain shows mildly hyperkeratotic and focally parakeratotic epidermis with moderately dense superficial perivascular infiltrate. Lymphoid cells are mostly small, cytologically normal lymphocytes, and there is focal single-cell epidermotropism (b).
Adverse events
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.
Discussion
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.
Patients
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.
Efficacy evaluation
Psoriasis
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.
Statistical analysis
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.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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1Corresponding author.Acknowledgements
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.
Author Contributions
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.
Notes
Competing Interests
The authors declare no competing interests.
Footnotes
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.
References
Articles from Scientific Reports are provided here courtesy of Nature Publishing Group
molecular hydrogen water for patients with RHEUMATOID ARTHRITIS : an open-label pilot study
Recently, molecular hydrogen (H2) was demonstrated to be a selective scavenger for the hydroxyl radical.
Although its etiology is unknown, the hydroxyl radical has been suggested to be involved in the pathogenesis of Rheumatoid arthritis( a chronic inflammatory disease characterized by the destruction of bone and cartilage..).
We hypothesized that molecular hydrogen H2 in the water could complement conventional therapy by reducing the oxidative stress in Rheumatoid arthritis
The method to prepare water containing extremely high concentration of molecular hydrogen H2 has been developed.
20 patients with rheumatoid arthritis (RA) drank 530 ml of water containing 4 to 5 ppm molecular hydrogen (high H2) water every day for 4 weeks. After a 4-week wash-out period, the patients drank the high molecular hidrogen H2 water for another 4 weeks.
Urinary 8-hydroxydeoxyguanine (8-OHdG) and disease activity (DAS28, using C-reactive protein [CRP] levels) was estimated at the end of each 4-week period.
Results:
Drinking high molecular hydrogen H2 water seems to raise the concentration of molecular hydrogen H2 more than the H2 molecular hydrogen saturated (1.6 ppm) water in vivo.
Urinary 8-OHdG was significantly reduced by 14.3% (p < 0.01) on average. DAS28 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 rheumatoid arthritis (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.
Conclusions: The results suggest that the hydroxyl radical scavenger -molecular hydrogen H2(dissolved in water) effectively reduces oxidative stress in patients with rheumatoid arthritis. The symptoms of rheumatoid arthritis were significantly improved with high molecular hidrogen H2 water.
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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
Toru Ishibashi1*, Bunpei Sato2
, Mariko Rikitake1
, Tomoki Seo2
, Ryosuke Kurokawa2
, Yuichi Hara1
, Yuji Naritomi1
,
Hiroshi Hara1 and Tetsuhiko Nagao3
* Correspondence: toruishi@haradoi-hospital.com 1
Haradoi Hospital, Department of Rheumatology and Orthopaedic Surgery,
6-40-8 Aoba, Higashi-ku, Fukuoka 813-8588, Japan
Full list of author information is available at the end of the article
MEDICAL GAS
RESEARCH
© 2012 Ishibashi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
doi:10.1186/2045-9912-2-27
Cite this article as: Ishibashi et al.: 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. Medical Gas Research 2012 2:27.
molecular hydrogen water PERIODONTITIS
Oxidative stress is involved in the pathogenesis of periodontitis. A reduction of oxidative stress by drinking molecular hydrogen-rich water (HW) might be beneficial to periodontal health.
In this pilot study, we compared the effects of non-surgical periodontal treatment with or without drinking molecular hydrogen-rich water HW on periodontitis.
13 patients (3 women, 10 men) with periodontitis were divided into two groups: The control group (n = 6) or the molecular hydrogen-rich water HW group (n = 7). In the molecular hydrogen-rich water HW group, participants consumed molecular hydrogen-rich water HW 4-5 times/day for eight weeks. At two to four weeks, all participants received non-surgical periodontal treatment. Oral examinations were performed at baseline, two, four and eight weeks, and serum was obtained at these time points to evaluate oxidative stress. At baseline, there were no significant differences in periodontal status between the control and molecular hydrogen-rich water HW groups. The molecular hydrogen-rich water HW group showed greater improvements in probing pocket depth and clinical attachment level than the control group at two, four and eight weeks (p < 0.05). The molecular hydrogen-rich water HW group also exhibited an increased serum level of total antioxidant capacity at four weeks, compared to baseline (p < 0.05). Drinking molecular hydrogen-rich water HW enhanced the effects of non-surgical periodontal treatment, thus improving periodontitis.
- PMID:26783840
- PMCID:PMC4665424
- DOI:10.3390/antiox4030513
-
-
diatomic molecular hydrogen H2- Water Products
-
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Drinking Hydrogen-Rich Water Has Additive Effects on Non-Surgical Periodontal Treatment of Improving Periodontitis: A Pilot Study.
Author information
- 1
- Departments of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. tetsuji@md.okayama-u.ac.jp.
- 2
- Departments of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. de18053@s.okayama-u.ac.jp.
- 3
- Departments of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. dekuni7@md.okayama-u.ac.jp.
- 4
- Departments of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. de18019@s.okayama-u.ac.jp.
- 5
- Departments of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. de18017@s.okayama-u.ac.jp.
- 6
- Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. t-maru@md.okayama-u.ac.jp.
- 7
- Departments of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. tomofu@md.okayama-u.ac.jp.
- 8
- Departments of Preventive Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. mmorita@md.okayama-u.ac.jp.
Modalities of molecular hydrogen administration(in water, gas or saline) to animals, humans, and plants
Molecular hydrogen gas is usually given by inhaling 1–4 % hydrogen gas, which is below the explosion level (4 %). There is a single report, in which hydrogen gas was injected intraperitoneally [10].
Among the various routes of molecular hydrogen administration , the best method still remains uncertain. This is partly because only a few reports have addressed the difference of effects among molecular hydrogen administration methods.
A comparative review was conducted on the consumption of molecular hydrogen H2-rich water, i.p. or intravenous administration of molecular hydrogen H2-rich saline, and inhalation of molecular hydrogen H2 gas in regards to Molecular hydrogen (water) in the treatment of acute and chronic neurological conditions(Alzheimer’s, Parkinson’s,etc).
The results showed that although molecular hydrogen H2 concentrations in the brain tend to be high after either intravenous administration or inhalation, no significant differences have been observed in comparison with the concentrations after the consumption of molecular hydrogen H2-rich water and i.p. administration of molecular hydrogen H2-rich saline. Thus, although there have been variations based on the administration method, all methods have been found to result in the presence of molecular hydrogen H2 in the serum and brain tissue.
Liu et al.(39) measured molecular hydrogen H2 levels in the arteries, veins, and brain tissues after the inhalation of 2% molecular hydrogen H2 gas. They found that arterial molecular hydrogen H2 peaked at 30 min after administration, whereas venous and brain tissue molecular hydrogen H2 peaked at 45 min after administration. They reported that molecular hydrogen H2 levels were similar in arteries and brain tissues.
This demonstrated that molecular hydrogen H2 migrates to the brain tissue regardless of the method of administration(Thus, the studies might as well have been performed using molecular hydrogen water instead of molecular hydrogen gas or molecular hydrogen saline).
Furthermore, keep in mind that crossing the blood–brain barrier (BBB) is a very difficult task to achieve for many substances , thus the fact that molecular hydrogen H2 crosses the BBB and migrates to the brain tissue regardless of the method of administration (including by drinking molecular hydrogen water – which is the easiest method of administration molecular hydrogen ) is a strong indicator that one can benefit from drinking molecular hydrogen water just as much as from any other method of administration molecular hydrogen
A dose–response effect of molecular hydrogen is observed in drinking molecular hydrogen-rich water [94, 97].
A similar dose–response effect is also observed in inhaled molecular hydrogen gas [1, 17, 98].
However, when molecular hydrogen concentrations in drinking water and in inhaled gas are compared, there is no dose–response effect.
Molecular hydrogen-rich water generally shows a more prominent effect than molecular hydrogen gas, although the amount of hydrogen taken up by hydrogen water is ~100 times less than that given by hydrogen gas [11].
We have showed that drinking molecular hydrogen water, but not continuous molecular hydrogen gas exposure, prevented development of 6-hydorxydopamine-induced Parkinson’s disease in rats [11].
In addition, we recently showed that continuous exposure to molecular hydrogen gas and ad libitum per os administration of molecular hydrogen water modulated signaling pathways and gene expressions in different manners in mice [12].
We demonstrated that molecular hydrogen-responsive genes are divided into four groups: genes that respond favorably to molecular hydrogen gas, those that respond exclusively to molecular hydrogen water, those that respond to both molecular hydrogen gas and water, and those that respond only to the simultaneous administration of molecular hydrogen gas and water (Fig. 2).
As molecular hydrogen water and gas increase the molecular hydrogen concentrations in the rodent body to a similar level [12], the difference in the organs exposed to a high concentration of molecular hydrogen, the rise time of molecular hydrogen concentration, and/or the area under the curve of molecular hydrogen concentration may account for the difference in the modulated genes.
On the other hand, a collation of molecular hydrogen reports indicate that a similar degree of effects can be observed with different modalities of administration. For example, the marked effect of molecular hydrogen on a mouse model of LPS-induced acute lung injury has been reported by four different groups with three different modalities:molecular hydrogen gas [13, 14], molecular hydrogen water [15], and molecular hydrogen-rich saline [14, 16].
Similarly, the dramatic effect of molecular hydrogen on animal models of acute myocardial infarction has been reported by eight different groups with two different modalities: molecular hydrogen gas [17, 18, 19, 20] and molecular hydrogen-rich saline [21, 22, 23, 24].
To clarify the difference of molecular hydrogen’s effects with different modalities of administration, each research group should scrutinize the difference of the effects between molecular hydrogen gas, molecular hydrogen water, and molecular hydrogen-rich saline. This would uncover the best modality for each disease model, IF ANY, and also the optimal molecular hydrogen dose.
Fig. 2
Four groups of genes that show different responses to molecular hydrogen water and/or gas [12] . aBcl6 responds to molecular hydrogen gas more than molecular hydrogen water. bG6pc responds only to molecular hydrogen water. cWee1 responds to both molecular hydrogen water and gas. dEgr1 responds only to simultaneous administration of molecular hydrogen water and gas
In order to use molecular hydrogen in clinical situations, it is essential to implement systematic clinical testing. These systems are either already in place or are under consideration at the leading Japanese universities and medical institutions.
The results of several clinical studies of molecular hydrogen-rich drinking water were recently released.
Kajiya et al. [15] reported that symptoms of intestinal inflammation prominently improved in mice with inflammatory bowel disease given molecular hydrogen-rich drinking water.
Fujita et al. succeeded in reducing the symptoms of drug-induced Parkinsonʼs disease by having mice drink molecular hydrogen-rich water [28].
Using a kidney transplant mouse model, our group also reported that kidney graft functions were maintained and imperfect grafts caused by chronic rejection were prevented in mice that drank molecular hydrogen-rich water every day [29].
Kawai et al. found that molecular hydrogen-rich drinking water reduced hepatocarcinogenesis in a nonalcoholic steatohepatitis-hepatocellular carcinoma mouse model [7].
Molecular hydrogen water is also effective in dentistry as shown by its effects on periodontitis, which is marked by gingival bleeding,
the development of periodontal pockets, the destruction of connective tissue, and the loss of alveolar bone [8,9].
In China, the oral intake of molecular hydrogen-rich water by hepatitis B virus (HBV) patients was tested. After hydrogen water treatment (1,200-1,800 mL/day, twice daily, for 6 consecutive weeks), oxidative stress did not change in the routine-treatment group but markedly improved in the molecular hydrogen-treatment group, and it was associated with reduced HBV DNA levels [41]. Thus, the results from a number of human trials indicate that drinking molecular hydrogen-rich water is safe and well-tolerated and significantly improves various diseases.
Molecular Hydrogen is licensed as a food additive in Japan, and hydrogen-rich water is already being sold as a safe drinking product in Japan. Water filters /tablets with magnesium and hydrogen-rich water made by electrolysis(electric water ionizers and molecular hydrogen water generators) are also being tested for acute/sub-acute toxicity, mutagenicity, etc. with the goal of using them for medical treatments.The safety of these methods has been con-firmed and reported [36,37].
Molecular hydrogen-rich water is expected to be easily used in place of regular everyday drinking water and will effectively treat chronic maladies such as lifestyle-related diseases.
Once again one can benefit from molecular hydrogen H2 regardless of the method of administration (including from drinking molecular hydrogen water).
In addition, molecular hydrogen water is both safe and easy to drink at home( we think it’s easier to drink molecular hydrogen water than injecting molecular hydrogen rich saline or inhaling molecular hydrogen gas)
-
diatomic molecular hydrogen H2- Water Products
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diatomic molecular hydrogen H2 dissolved in Alkaline Ionized Water Products (you could drink around 4 liters per day as an adult )
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references :
https://medicalgasresearch.biomedcentral.com/articles/10.1186/s13618-015-0035-1
Molecular Hydrogen Water FAQ
Frequently Asked Questions about Molecular Hydrogen Water
- What is molecular hydrogen water?
Molecular hydrogen water or hydrogen-rich water ( hydrogen-enriched water) means water (H2O) with dissolved hydrogen gas (H2) in it.
- Isn’t ( molecular ) hydrogen gas explosive?
Yes, it is VERY explosive. Molecular hydrogen is the most energy-dense molecule by mass.
But, when the molecular hydrogen gas is dissolved in water it is not explosive anymore,
Even when molecular hydrogen is in the air, it is only flammable above a 4.6% concentration by volume, which is not a concern when talking about molecular hydrogen water.
- Doesn’t water H2O already have hydrogen in it ?
The water molecule has 2 hydrogen atoms, chemically bound to the oxygen atom. This is different from the molecular hydrogen gas (H2), which is just two hydrogen atoms bound only to each other.The H2 -hydrogen molecules are not tied up to water H2O
In order for the dissolved molecular hydrogen gas (H2) to beneficial for humans, it must be in an unbound form, and therefore available for therapeutic benefit.
Virtually everything has hydrogen atoms in it, but those hydrogen atoms are chemically tied up with other things. In molecular hydrogen rich water, the hydrogen molecule that is shown to be therapeutic is the available water dissolved hydrogen molecule in its diatomic form, called (dissolved diatomic) molecular hydrogen.
- I thought that if water “rich in hydrogen ”, it must be acidic?
If the water is rich in positive hydrogen ions (H+). then YES, water is acidic(pH<7).
But when talking about molecular hydrogen rich water of , we’re talking about neutral (ph=7) hydrogen gas (H2), which is two hydrogen atoms tied together – hydrogen in its diatomic molecular form.
It can be confusing to hear “hydrogen water” because we usually think of hydrogen (meaning the hydrogen ion, H+) as acidic, and that is basically the definition of pH. The p stands for potential or power, meaning a mathematical exponent (in this case a logarithmic function), and the H stands for the hydrogen ion, which is just a proton and no electron. So pH literally means the logarithmic concentration of the hydrogen ion.
But when we say “molecular hydrogen rich water” we are referring to diatomic hydrogen or molecular hydrogen, which is a neutral(ph=7) gas of H2 molecules (one H2 is made of 2 atoms of hydrogen bond into a molecule), that is dissolved in the water.
- I read that if you add hydrogen to water, then it makes hydrogen peroxide?
Molecular hydrogen (H2) gas does NOT bond to NOR react with the water molecules, it just dissolves into the water. Thus it does not create some novel molecule like H4O, which would in fact be chemically impossible to form. Water has the chemical formula H2O, and hydrogen peroxide has the chemical formula H2O2, which by comparison contains an extra oxygen, not hydrogen.
Molecular hydrogen water and hydrogen peroxide are completely different.
- Since molecular hydrogen gas doesn’t dissolve very well in water, how can there even be enough for it to be beneficial?
It is true that molecular hydrogen is not very water soluble as it is a neutral, non-polar molecule with a solubility of 1.6 mg/L, which is relatively low.
But when we consider that molecular hydrogen is the lightest molecule in the universe, we really need to compare the number of molecules as opposed to the number of grams.
For reference, vitamin C (176.2 g/mole) weighs 88 times more than hydrogen gas (2 g/mole).
Therefore, molecular hydrogen rich water at a concentration of 1.6 mg/L would have more “antioxidant” molecules than 100 mg of vitamin C, as there are more total molecules in 1.6 mg of hydrogen compared 100 mg of vitamin C. That is, 0.8 mmoles of H2 vs. about 0.6 mmoles of vitamin C.
But more importantly, hundreds of scientific studies clearly show that these concentrations of molecular hydrogen in water are effective.
- Won’t any dissolved molecular hydrogen gas immediately evaporate out of the water?
Yes, molecular hydrogen as any gas does immediately start coming /evaporate out of the water, but it doesn’t just vanish immediately. Depending on the surface area, agitation, etc., the molecular hydrogen gas can stay in the water for a few hours or longer before it drops below a therapeutic level.
- How much molecular hydrogen water should I drink to get the benefits?
That is the same question scientists are asking and is still under investigation. However, the human studies generally provide about 1-3 mg of molecular hydrogen H2, and these doses show statistically significant benefits. So, if your molecular hydrogen water has a concentration of 1 mg/L (equivalent to 1 ppm, parts per million), then 2 liters of molecular hydrogen water will give you 2 mg of H2. Although the effective concentration for some people and some diseases may be lower and/or higher, these doses are simply what have been seen to expert benefits. (see this article also).
- Does more molecular hydrogen equal more benefits?
Maybe, maybe not…. there is obviously a minimum required amount of molecular hydrogen (water )needed to offer any health benefits, which may vary from person to person. Importantly, it appears that you cannot get too much molecular hydrogen, as it doesn’t build up in your body—you just exhale it out. In many cases there is a clear dose-dependent effect, meaning the more molecular hydrogen (water) the better or greater the effect. There are also many anecdotal reports that suggest that consuming more molecular hydrogen (water) may offer even more benefits. But more research needs to be done in this area.
- Is molecular hydrogen (water) safe (for consumption)?
YES. Molecular Hydrogen gas (in water) has been shown to be very safe at concentrations hundreds of times higher than what is being used for therapy. Here are a few examples:
Molecular Hydrogen’s safety was first shown in the late 1800s, where molecular hydrogen gas was used to locate gunshot wounds in the intestines. The reports showed that there were never any toxic effects or irritation to even the most sensitive tissues.
Another good example of its safety is that molecular hydrogen gas has been used in deep sea diving since 1943 (at very high concentrations) to prevent decompression sickness. Studies have shown no toxic effects from molecular hydrogen when at very high levels and pressures of 98.87% H2 and 1.26% O2 at 19.1 atm.
Furthermore, molecular hydrogen gas is natural to the body because after a fiber-rich meal, our gut bacteria can produce liters of molecular hydrogen on a daily basis (which is yet another benefit from eating fruits and vegetables).
In short, molecular hydrogen gas is very natural to our bodies, not like a foreign or alien substance that can only be synthesized in a chemistry lab.
- When was molecular hydrogen’s therapeutic benefits first discovered?
The earliest account of molecular hydrogen gas having medicinal properties was in 1798, for things like inflammation. But, it didn’t become a popular topic among scientists until 2007, when an article about the benefits of molecular hydrogen was published in the prestigious journal of Nature Medicine by Dr. Ohta’s group.
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Benefits of molecular hydrogen (H2 ) Water 3
Benefits of Molecular Hydrogen in Water – part 3
Molecular Hydrogen (water) is a single natural way to reduce pain and inflammation, to improve your energy, cognitive function, exercise performance and recovery ,to neutralize harmful free radicals and support your body’s enzyme and antioxidant production & to also hydrate your cells plus generally support your overall health and wellness. Scientists have discovered that molecular hydrogen H2 water – molecular hydrogen or diatomic hydrogen water – has all of these properties and more. molecular hydrogen H2 (water) has become a major area of scientific research.
The Healing Property In Healing Waters
Around the world there are well-known natural molecular hydrogen rich water sources or springs that offer healing or curative properties. Scientists have recently found H2 in samples analyzed from Nordenau (Germany), Tlacote (Mexico) and Hita Tenryosui, Japan1-3. The existence of molecular hydrogen H2 in these water springs (and others) could be a result of water reacting with alkali-earth metals, or from molecular hydrogen gas-producing bacteria and algae4. Regardless, the available science regarding molecular hydrogen H2 and its benefits seems to explain these H2 waters healing properties.
What is Molecular Hydrogen water?
Molecular Hydrogen water is water that has molecular hydrogen H2 gas in it.Hydrogen is the lightest and simplest element appearing first on the Periodic Table of Elements. Molecular hydrogen is also the smallest molecule consisting of just one electron and one proton. Because of its tiny size, it is able to permeate even sub-cellular structures such as the mitochondria making it extremely bioavailable. It even crosses the blood-brain barrier. It is colorless, odorless, non-metallic, non-toxic and tasteless.
Molecular Hydrogen water Research
The body of science regarding health benefits of molecular hydrogen H2 (water) has advanced rapidly in recent years thanks to the studies done by research scientists around the globe. Over 600 peer-reviewed articles have been published on the impact of molecular hydrogen H2 on humans, animals, and individual cells. It shows that molecular hydrogen H2 (water) regulates over 200 biomolecules and appears to provide benefit in 166 health conditions and disease models, affecting virtually every organ in the human body. Molecular hydrogen H2 operates on human metabolism in three primary areas:
• Molecular hydrogen H2 (water) rapidly and easily converts toxic free (hydroxyl OH-) radicals to water (H2 + 2 OH – > 2 H2O);
• Molecular hydrogen H2 (water) maintains antioxidant homeostasis. In other words, the body’s own antioxidants are leveraged and maintained; and
• Molecular hydrogen H2 (water) supports cell signaling, cell metabolism, and gene expression. This impacts inflammation, obesity, and aging mechanisms.
Molecular Hydrogen water is Safe And Natural.
Molecular hydrogen H2 (water) is not foreign to the body like a pharmaceutical drug. Your body produces small amounts of Molecular hydrogen H2 gas from the bacteria in your digestive tract as it digests vegetable fibers, which diffuse into the bloodstream. Research shows that delivering H2 in higher concentrations than your body can produce is much more effective. In fact, drinking hydrogen water was used in most of the studies and is the most effective way to deliver Molecular hydrogen ‘s powerful benefits.
Molecular hydrogen H2 (water) science is moving quickly beyond theory to practical applications.
Hydrogen water ionizers and generators allow medical professionals and consumers to leverage the health benefits of Molecular hydrogen H2 water.
“The effects have been reported in essentially all organs covering 31 disease categories that can be subdivided into 166 disease models, human diseases, treatment-associated pathologies, and pathophysiological conditions of plants with a predominance of oxidative stress-mediated diseases and inflammatory diseases.” Medical Gas Research 2015; 5:12
Benefits of Molecular Hydrogen water
“It is not an overestimate to say that hydrogen water’s’ impact on therapeutic and preventative medicine could be enormous in the future.”
Free Radical Research 2010
Why Molecular hydrogen H2 (water) is a Superlative Antioxidant
Chronic oxidative stress has been identified as one of the major causes of aging and modern chronic diseases. Everyone knows that there are many antioxidants available. However, they have shown only limited success in therapeutic trials.
Molecular hydrogen H2 (water) has some distinct advantages, causing researchers to propose it as a NOVEL antioxidant with superior therapeutic and preventive applications.
• Molecular hydrogen H2 is the smallest molecule. Other antioxidants such as Vitamin C or Vitamin E are very large by comparison. They must also be digested, absorbed, transported and finally taken up by the cells.
Molecular hydrogen H2 penetrates the stomach lining quickly and acts inside the cells immediately. It’s able to get into every part of the cell more quickly protecting DNA, RNA, and proteins against damaging oxidative stress.
• Each molecule of molecular hydrogen H2 neutralizes two free radicals. It easily separates into two slightly charged atoms that neutralize the free radicals created from our daily oxidative stress. In the process, it creates water thus hydrating the cells.
• Molecular hydrogen H2 is selective and targets only “bad” free radicals. Oxygen radicals are extremely damaging. However, your body also produces “good” free radicals, which serve useful purposes. Other antioxidants only partially neutralize radicals, both the good and bad ones. Worse, these antioxidants can then become free radicals themselves once they’ve done their job. H2 selectively goes after only the bad radicals and unlike other antioxidants, neutralizes them completely.
Molecular hydrogen (water) – The Best Anti-Aging Supplement?
Our modern lifestyle has greatly increased the oxidative stress on our body, leading to alarmingly increased rates of chronic disease and poor health. As a culture, we are out of balance and aging and we lack something to naturally and universally address the decline that comes with aging. The science is clear: Molecular hydrogen water is a powerful and effective foundation for better health, wellness, and slowing the aging process.
• Molecular hydrogen H2 (water) reduces inflammation and pain. As we age, we ache more. Molecular hydrogen H2 has been shown to be a powerful anti-inflammatory. Molecular hydrogen is also can potentially modify the switched on genes that create a constant state inflammation.
• Molecular hydrogen H2 (water) supports optimal cognitive function. The brain is 2-4% of your body’s weight but consumes 20-40% of the oxygen you breathe. Since 2-5% of the oxygen you breathe turns into free radicals, your brain is highly susceptible to oxidative stress damage. molecular hydrogen H2 (water) neutralizes excess free radicals that occur in the brain.
• Molecular hydrogen H2 (water) promotes cellular health. Research shows Molecular hydrogen H2 (water) alters cell signaling, cell metabolism, and gene expression. This may explain its anti-inflammatory, anti-allergic, and anti-apoptotic (or anti-cell death) effects.
• Molecular hydrogen H2 (water) activates production of your own antioxidant levels. Molecular hydrogen H2 (water) triggers activation of antioxidant enzymes in the body (e.g., glutathione peroxidase, super-oxide dismutase, catalase, etc.) and/or proteins that protect the cell. Each one of these enzymes takes care of different kinds of free radicals, and they work together to keep the cells healthy.
Exerciser or Athlete , molecular hydrogen Water is Your Secret Weapon!!!
Athletes and people who exercise experience more oxidative stress than sedentary individuals. They are also more vulnerable to the effects of chronic dehydration.
• Molecular hydrogen H2 (water) helps Improve Energy Levels. Adenosine Triphosphate (ATP) is the fuel that powers your cells during physical activity. Research shows molecular hydrogen H2 increases ATP production, helping you maintain high energy and better performance.
• Molecular hydrogen H2 (water) Improves Performance and Recovery Time. When you exercise, your lactic acid increases, leading to fatigue, muscle damage, decreased endurance, reduced performance, and poor results. Peer-reviewed research on athletes shows that Molecular hydrogen H2 water decreases lactic acid levels leading to better performance and faster recovery.
• Molecular hydrogen H2 (water ) Reduces Oxidative Stress. When we exercise we use more oxygen generating more damaging oxygen radicals leading to increased oxidative stress. Molecular hydrogen H2 easily enters sub-cellular compartments helping to protect them from damaging cytotoxic oxygen radicals.
• Molecular hydrogen H2 (water) Improves Your Hydration. When hydrogen H2 molecules combine with and neutralize damaging oxygen radicals, they are transformed into water (H2O) – increasing your cellular hydration. Molecular hydrogen H2 infused alkaline ionized water is also better absorbed by the body than regular tap water.
To summarize, whether at work or play, old or young, healthy or unhealthy, molecular hydrogen water offers everyone a wide range of powerful benefits. Most supplements have one mechanism of action; molecular hydrogen water (and H2 tablets) offers many. It has a very solid and growing body of science to back up molecular hydrogen water’s therapeutic benefits. So if you’re interested in optimizing your health and well-being, enjoying more energy and better mental clarity and improving your athletic performance, then what are you waiting for? Give your body the ability to thrive naturally. Join the molecular hydrogen water revolution. Do what got results in the research and drink hydrogen water. H2 infused UltraWater from AlkaViva is the perfect, easy and convenient way to get the cleanest and healthiest molecular hydrogen water.
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diatomic molecular hydrogen H2- Water Products
-
diatomic molecular hydrogen H2- Water Products
-
AlkaViva Vesta H2 water ionizer AlkaViva Vesta H2 water ionizer – 9 Plate
Enjoy the H2 Advantage Here -
AlkaViva-DELPHI-H2-water-ionizer-purifier-and-hydrogen-water-generator -
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Melody-II-H2-water-ionizer-purifier-AlkaViva - Enjoy neutral pH water rich in molecular Hydrogen form AlkaViva IonPia H2 hydrogen water ionizer
molecular hydrogen water generator AlkaViva IonPia H2 668300
- Enjoy UltraWater & UltraFine 0.01 microns well water filtration as well as molecular hydrogen water with AlkaViva Elite Pure H2
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For a list of some of the peer reviewed studies about molecular hydrogen water visit here.
References:
1. ZHANG, J. Y., LIU, C., ZHOU, L., QU, K., WANG, R. T., TAI, M. H., LEI, J. C. W. L., WU, Q. F. & WANG, Z. X. (2012). A Review of Hydrogen as a New Medical Therapy. Hepato-Gastroenterology 59, 1026-1032.
2. SHIRAHATA, S. A. N. E. T. A. K. A. (2002). Reduced water for prevention of diseases. Animal Cell Technology: Basic and Applied Aspects 12, 25-30.
3. SHIRAHATA, S., HAMASAKI, T. & TERUYA, K. (2012). Advanced research on the health benefit of reduced water. Trends in Food Science & Technology 23, 124-131.
4. CONRAD, R., ARAGNO, M. & SEILER, W. (1983). Production and consumption of hydrogen in a eutrophic lake. Applied and Environmental Microbiology45,502-10
Benefits of molecular hydrogen (H2 ) Water 2
Benefits of molecular hydrogen (H2 ) Water- part 2
molecular hydrogen (H2 ) Water for Athletes and Active People
There is a growing body of highly credible science that shows molecular hydrogen ( H2 ) offers all of those benefits, and more. The best way to get moleular hydrogen H2 is by drinking molecular hydrogen infused water. There have been over 600 peer reviewed papers published showing that molecular hydrogen water offers therapeutic health benefits of hydrogen rich water in 150 disease models and health conditions and virtually every organ of the body. A growing collection of these studies using molecular hydrogen water have shown molecular hydrogen water H2 has significant benefits for athletic performance and during routine exercise.
What Makes Activities / Exercise Hard?
Any activity or training above a resting state immediately increases our body’s needs for energy and oxygen to power the activity. Any activity that is more intense than what your body is used to, stresses your system causing a cascade of effects.
The increased oxygen produces more cell damaging oxygen (free) radicals, which cause oxidative stress. Oxidative stress silently attacks your cells behind the scenes leading to loss of cell viability and cell death, causing muscle damage, weakness, fatigue and inflammation.1-3 This is especially true with exercise induced oxidative stress.
If your activity is intense enough, you will use up available ATP for energy and your body will burn glycogen. When that happens you will feel the burn from lactic acid build up, which leads to fatigue and possible muscle soreness. All of this leads to decreased endurance, reduced performance, poor results and less enjoyment.
Molecular Hydrogen Rich Water Increases Your Energy
ATP (Adenosine Triphosphate) is the energy currency for all the activities of your body. The food we eat and oxygen we breathe create ATP in the mitochondria, powering each of our cells and our activity. 
However, free radicals are also produced every minute from the oxygen we breathe. It’s simply a fact of aerobic metabolism. Free radicals – especially oxygen radicals – damage your mitochondria. When damaged mitochondria cannot produce the necessary levels of ATP, the body turns to metabolizing stored glycogen. Glycogen stores are found mostly in the liver where they are accessed and used for energy.
A growing body of research shows many health benefits of molecular hydrogen rich water, including improved mitochondrial function, increases ATP production and potentially induces mitochondrial biogenesis.4 Molecular hydrogen H2 is the smallest molecule in the universe and so rapidly diffuses through our cell membranes, and neutralizes the damaging free radicals. Molecular’s hydrogen protective properties allow the mitochondria to produce optimal levels of ATP, providing you with more energy. When you have to dig deep and go beyond your ATP production, as we all sometimes do during activity or training, research has shown that molecular hydrogen H2 can support an increase of glycogen stored in your liver.4
The research is in. Drinking molecular hydrogen water shows many increased health benefits including improved energy through improved ATP production while increased glycogen stores help decrease fatigue and muscle damage. Go longer. Go stronger.
Molecular Hydrogen Water Reduces Lactic Acid Buildup
Anytime your body starts burning stored glycogen you start to produce lactic acid. Increased lactic acid buildup in turn leads to greater fatigue, muscle soreness and slower recovery. Exercise-induced metabolic acidosis is common among some highly active individuals and many highly trained athletes. It’s another silent, behind the scenes effect; if you have acidosis you don’t know it, except by seeing and feeling that you are not performing at your best.
One recent study found another health benefit of molecular hydrogen rich water is that it can positively impact athletic performance in elite athletes. Both muscle fatigue and lactate (levels of lactic acid in the blood) were decreased in the control group of elite, highly trained athletes when they consumed molecular hydrogen H2 rich water before undergoing intensive exercise controlled by strict test protocols.5
A similar study found that molecular hydrogen water had a beneficial effect on the maximal rate of perceived exertion and lactic acid build-up at critical running speed during maximal exercise. While the exact mechanism was not identified, the study concluded “… that hydrogen-rich water decreases the physical stress during maximal exercise…”.6
A quote from one of the multiple research papers on this topic says it succinctly:
“Adequate hydration with hydrogen-rich water pre-exercise reduced blood lactate levels and improved exercise-induced decline of muscle function.”
Kosuke Aoki, et al Medical Gas Research, 2012
Please note that as molecular hydrogen water is also produced by a water ionizer when the water ionizer produces alkaline ionized water ; as lactic acid is (as the name states) an acid, you can drink alkaline ionized water (AKW) or ERW(Electrolisys Reduced Water) wich also contains molecular hydrogen to get rid of/neutralize that lactic acid buildu and recover faster.read more benefits of alkaline ionized water & more about molecular hydrogen water
Alkaviva ionized alkaline water HEALTH benefits & properties
Molecular Hydrogen Water Protects Against Oxidative Stress
Being a powerful antioxidant this sounds right , Any increase in activity results in an increased level of oxidative stress. Unusual or intense physical activity over a short period of time causes higher levels of oxidative stress and lactic acid buildup (exercise-induced metabolic acidosis). This causes the symptoms of overtraining such as increased fatigue, residual muscle soreness, micro-tears to the muscle fibers, and inflammation. Oxidative stress in any form, and no matter how you got there, is not good.
Scientists have known for a long time that one health benefit of molecular hydrogen H2 is that it readily neutralizes free radicals, specifically the hydroxyl radical (*OH–) and oxide radical ion (0+).7-9 Especially important is that molecular hydrogen H2 appears to selectively target the hydroxyl radical which is the most toxic to the cells. Other free radicals (e.g. nitric oxide radical) are actually important to cell physiology and homeostasis.7,8 Unlike other “non-selective” antioxidants,molecular hydrogen H2 leaves these good radicals unchanged, making it a superlative antioxidant.
Molecular Hydrogen H2 water Improves Recovery Time and Healing
Studies have found molecular hydrogen rich water to be beneficial in treating injuries and conditions related to oxidative stress and inflammation, and in treating soft tissue sports injuries.10
Molecular Hydrogen water has been shown to help maintain homeostasis of enzymes including glutathione, superoxide dismutase, catalase and others.4
Molecular Hydrogen H2 ( water ) has also demonstrated cell signaling capability critical to the brain and neurological function.4,13
These properties make molecular hydrogen water far more beneficial to your health than a simple recovery drink focused only on repairing muscles.
Molecular Hydrogen Water Improves Your Hydration
As H2 Hydrogen molecules neutralize the hydroxyl radical and oxygen radicals, the only thing that is left inside of the cell from this reaction is water, leading researchers to deduce that H2 also improves cellular hydration. This also explains why no published study has found any negative effect of consuming hydrogen water.
The molecular hydrogen H2 water Solution
molecular hydrogen H2 water is safe.
molecular hydrogen H2 water is 100% natural. Research shows hydrogen water directly addresses so many of the issues we face in having more enjoyment, success and results in our activities, fitness and athletics. And it is effective for a broad range of conditions related to oxidative stress – far beyond those caused by our activities or fitness efforts. In fact, the majority of research on molecular hydrogen H2 has been focused on chronic disease conditions caused by oxidation.
Studies show hydrogen rich water has many health benefits for a number of conditions that are related to oxidation, like metabolic syndrome, diabetes, and even side effects of cancer treatment.11,12 It’s also readily accessible and affordable.
Where Can I Get Molecular Hydrogen Water?
Molecular Hydrogen rich water is produced by
1) on demand flow-through devices (water ionizers and hydrogen water generators),
2) various forms of magnesium placed in water to create molecular hydrogen H2 by chemical reaction. (Metallic magnesium or magnesium fumarate tablets, powders or sticks.), or by
3) magnesium media imbedded in specialty water filters.
All three of these methods for making hydrogen water are available from AlkaViva.
Please note that most studies and research with molecular hydrogen gas were performed using molecular hydrogen rich water
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diatomic molecular hydrogen H2- Water Products
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AlkaViva Vesta H2 water ionizer AlkaViva Vesta H2 water ionizer – 9 Plate
Enjoy the H2 Advantage Here -
AlkaViva-DELPHI-H2-water-ionizer-purifier-and-hydrogen-water-generator -
AlkaViva Athena H2 Water Ionizer purifier - Enjoy molecular hydrogen water from an entry level price top quality water ionizer
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