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molecular hydrogen on higher plants and in agriculture

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While the medical effects of molecular hydrogen have been broadly analyzed, research into the effects of molecular hydrogen on higher plants has often been of lesser concern. Recent studies on the botanical effects of molecular hydrogen have shown that it is involved in signal transduction pathways of plant hormones and can improve the resistance of plants to stressors, such as drought, salinity, cold and heavy metals. In addition, molecular hydrogen could delay postharvest ripening and senescence of fruits. Observational evidence has also shown that molecular hydrogen can regulate the flowering time of plants. These results indicate that molecular hydrogen may have great potential applications within agricultural production, indicating that there may be a new ‘hydrogen agricultural era’ to come.

Introduction

molecular Hydrogen is the most widely distributed element in the world, accounting for more than 75% of the mass of the universe, and it is also the most abound element of human body composition. molecular Hydrogen gas is colorless, odorless and tasteless, and was considered to be physiologically inert molecule, regarding as a potential resource for clean energy in future.

From 1930s to 1940s, some of the bacteria and algae were found capable of producing molecular hydrogen [,]. After going through more than half a century, gain little application did the industrialization of molecular hydrogen production by bacteria and algae. But in 2007, things turned the corner. Scientists from Nippon Medical University published a paper about medical protective effect of hydrogen on Nature Medicine which completely updated our knowledge about hydrogen in biology-hydrogen can not only be considered as a source of energy, but also has an therapeutic potent in disease []. In this study, the authors found that the molecular hydrogen protected cerebral ischemia-reperfusion injury by selectively reducing · OH and ONOO which are two most toxic reactive oxygen species in body. This surprising discovery immediately attracted numerous researchers all over the world, and variously new medical and biological effects of molecular hydrogen have been reported after that. It is never coming to mind that molecular hydrogen which had been implied as respiration gas in diving for its inactive in mammals now seems to become a “wonder drug” in fighting diseases. Some researchers in Japan and China have also developed variety of molecular hydrogen related health products which are warmly pursued by the public. Therefore, many researchers also believed that, with deeper digging, molecular hydrogen may play a major role in promoting human health.

Since molecular hydrogen gradually becomes the most shining star in medicine, health care and cosmetic fields, gracefully waving in agricultural production is also hydrogen. People probably did not expect that molecular hydrogen can be used not only for medical treatment and health care, but also may be widely applied to agricultural production. This may lead us to embrace the coming of “the era of molecular hydrogen agricultural”!

molecular Hydrogen production in higher plants

Early in nineteenth century, researchers had realized the bacteria and algae could synthesis molecular hydrogen. In 1931, researchers reported the first bacteria enzyme which activates molecular hydrogen []. In 1942, photochemical production of molecular hydrogen in algae was firstly found []. If most bacteria and algae could produce molecular hydrogen under certain conditions [], what about higher plants? Can higher plants produce molecular hydrogen either?

In 1947, Boichenko claimed that chloroplasts isolated from algae can release molecular hydrogen. Scientists naturally come to the assumption that higher plants whose leaves also contain chloroplasts may able to produce molecular hydrogen []. In the year of 1961, the evidence of higher plants leaves releasing and absorbing molecular hydrogen was demonstrated by Sanadze []. In 1964, Renwick and his colleges denoted that many higher plants could release molecular hydrogen and exogenous molecular hydrogen could promote the germination rate of winter rye seed []. After that hydrogenase with activity of molecular hydrogen production was isolated by Maione and Gibbs from the chloroplast of Chlamydomonas reinhardtii. They had the hypothesis that hydrogenase should also exist in some higher plants []. Then confirming evidences–release of molecular hydrogen and detection of hydrogenase activity from barley roots–published by Torres showed that the higher plants can actually release molecular hydrogen []. Since then the study on higher plants for molecular hydrogen production is ignored for a long time. One reason for that probably to get clean energy not for its biological effects was the firstly intention of investigating on hydrogen production. Another reason is that the inconvenience of molecular hydrogen collection compared with collection in bacterial and algae.

molecular Hydrogen effects on higher plants

The first finding of molecular hydrogen effects on higher plants was in 1964, when Renwick et al. found molecular hydrogen treated winter rye seeds germinate more rapidly than control []. Unfortunately, scientists have not done further study since then. molecular Hydrogen effects on higher plants have not been followed until health effects of hydrogen are generally concerned. Recently, researchers in China preliminarily studied molecular hydrogen effects on higher plants, the results show that the molecular hydrogen has important regulation effect on plant physiological function, especially plays an important role in plant resistance to abiotic stress. The study shows that molecular hydrogen has an important effect on the mung bean, rice [] and alfalfa (Medicago sativa) [] seed germination, and the molecular hydrogen H2 pretreatment can improve the rice and Arabidopsis salt stress resistance [].

Researchers at the Nanjing Agricultural University found that molecular hydrogen H2 pretreatment can induce the expression of heme oxygenase (HO-1) gene, one of Alfalfa antioxidase gene, and enhance its enzyme activity, reducing the oxidative damage caused by paraquat []. They presumed that molecular hydrogen H2 might function as an important gaseous molecule that alleviates oxidative stress via HO-1 signalling. They also found that the molecular hydrogen H2pretreatment can improve salt tolerance in rice and Arabidopsis, and the improvement of salt tolerance may be related to the reduction of reactive oxygen species (ROS) injuries []. In addition, they found that molecular hydrogen enhances the resistance of alfalfa to cadmium and aluminum due to the improvement of alfalfa antioxidant capacity induced by molecular hydrogen [,].

Researchers at the Southern China Botanical Garden, Chinese Academy of Sciences, and Second Military Medical University in Shanghai confirmed the antioxidant role of molecular hydrogen in rice seedlings, and found that antioxidant enzyme gene expression was induced by H2. In addition, upregulation of several phytohormone receptor genes and genes that encode a few key factors involved in plant signaling pathways was detected in rice seedlings treated with molecular hydrogen water. molecular hydrogen H2 production was found to be induced by abscise acid, ethylene, and jasmonate acid, salt, and drought stress and was consistent with hydrogenase activity and the expression of putative hydrogenase genes in rice seedlings. The study suggests that molecular hydrogen might be an important plant gaseous signaling molecules, which may participate in the regulation of plant hormone signaling pathways involved in plant growth and stress adaptation [].

“molecular Hydrogen agricultural era” is waving to us

A major feature of modern agriculture is the extensive use of fertilizers and pesticides. Now, the abuse of pesticides and fertilizers causes serious environmental pollution, soil degradation and food safety issues. Due to the safety of molecular hydrogen H2, the convenience and economy of molecular hydrogen water usage, the prospect of its application in agricultural production will be very attractive. Recently, some field trials done by several agricultural research institutions in China shows that molecular hydrogen and molecular hydrogen water seems to be valuable for agricultural production especially for soilless cultivation of crops, and may also have a positive effect on the nutritional value of crops. In the future, farmers may use molecular hydrogen water to replace or partially substitute for pesticide and fertilizer to enhance crop resistance to disease, insect, drought and salinity stress, and improve product quality, increase the yield. How exciting the “molecular hydrogen agricultural era” is! The application of hydrogen in agricultural production may be in the following aspects:

Seed germination

Studies show that molecular hydrogen H2 can promote the seed germination rate of winter rye and alfalfa []. This finding may promote the application of molecular hydrogen in improving the seed germination rate of plants.

Regulation of flowering time

It has been observed that roses and other plants change flowering time after treatment of molecular hydrogen water. It was also found that molecular hydrogen can regulate the expression of plant blossom related plant hormone receptor protein gene []. This finding suggests that molecular hydrogen water will have broad application prospects in horticulture.

Improvement of crop stress resistance

Drought and salinity stresses often result in crop yield reduction and even death. Studies found that molecular hydrogen water can improve the resistance ability of rice, Arabidopsis and Medicago sativa plants to salinity, drought and other stresses [,]. The crops irrigation or sprinkler irrigation using molecular hydrogen water, will improve the stress resistance of crops, to achieve the purpose of disaster prevention and reduction.

Improvement of crop resistance to disease and pests

The study have found that molecular hydrogen can regulate the expression of receptor protein genes of many plant hormone, including some plant hormones associated with disease resistance, such as salicylic acid and jasmonic acid []. Irrigation of crops by the use of molecular hydrogen water will likely improve crop resistance to pest and disease leading to substitute for pesticides or reduce the use of pesticides thus it protect environment and improve food security.

Improvement of the quality of agricultural products

molecular Hydrogen water irrigation of crops, such as vegetables and fruits, might make them much more delicious.

Reducing fertilizer use

molecular hydrogen H2 can regulate the effects of plant hormones such as auxin, cytokine. molecular Hydrogen water treatment can promote the growth of the plant. It has been observed that molecular hydrogen water has a significant effect on the growth of mung bean plants []. Therefore, in the future, molecular hydrogen water may be attractively used to irrigate crops, promoting plant growth, and reducing the use of chemical fertilizers.

Crop products preservation

The study has been shown that molecular hydrogen water treatment could delay postharvest ripening and senescence of kiwifruit. Reduction of oxidative damage was considered be one of the main mechanisms by which the molecular hydrogen water treatment delays senescence and inhibits respiration of kiwifruit []. Owing to the antioxidant properties of molecular hydrogen, molecular hydrogen or molecular hydrogen gas mixtures with other gases may contribute to the preservation of agricultural products. Due to the security of molecular hydrogen, no poison, no residue, it has a strong advantage of food safety compared with other chemical treatment of fresh agricultural products.

“molecular Hydrogen agricultural era” is desirable, but it still requires amounts of deep research and development, which firstly should be to study the mechanism of molecular hydrogen effects on higher plants, to lay a solid theoretical foundation for the application of molecular hydrogen agriculture; and secondly be to do a large scale field experiment, to figure out the precise methods of molecular hydrogen or molecular hydrogen water application in the agricultural production. We believe that, with these problems being solved gradually, “molecular hydrogen agricultural era” will step to us.

Competing interest

We are here to formly state that all the authors have no competing interest on this article.

Authors’ contribution

JZ participated in conception, designing and writing the article. ZY and XS contributed to the critical review and revision of the manuscript. All authors have seen and approved the final version of the manuscript.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177722/
. 2014; 4: 15.
Published online 2014 Aug 20. doi:  10.1186/2045-9912-4-15
Progress in the study of biological effects of hydrogen on higher plants and its promising application in agriculture

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Articles from Medical Gas Research are provided here courtesy of Wolters Kluwer — Medknow Publications

molecular hydrogen treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial

Acarbose, which is clinically widely used to treat Type 2 Diabetes, is thought to act at the small intestine by competitively inhibiting enzymes that delay the release of glucose from complex carbohydrates, thereby specifically reducing post prandial glucose excursion. The major side-effect of treatment with acarbose, flatulence, occurs when undigested carbohydrates are fermented by colonic bacteria, resulting in considerable amount of molecular hydrogen.

We propose that enteric benefits of acarbose is partly attributable to be their ability to neutralise oxidative stress via increased production of molecular hydrogen H2 in the gastrointestinal tract.

CONTEXT:

The worldwide explosive increase in type 2 diabetes mellitus and its cardiovascular morbidity are becoming major health concerns.

OBJECTIVE:

To evaluate the effect of decreasing postprandial hyperglycemia with acarbose, an alpha-glucosidase inhibitor, on the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance (IGT).

DESIGN, SETTING, AND PARTICIPANTS:

International, multicenter double-blind, placebo-controlled, randomized trial, undertaken in hospitals in Canada, Germany, Austria, Norway, Denmark, Sweden, Finland, Israel, and Spain from July 1998 through August 2001. A total of 1429 patients with IGT were randomized with 61 patients (4%) excluded because they did not have IGT or had no postrandomization data, leaving 1368 patients for a modified intent-to-treat analysis. Both men (49%) and women (51%) participated with a mean (SD) age of 54.5 (7.9) years and body mass index of 30.9 (4.2). These patients were followed up for a mean (SD) of 3.3 (1.2) years.

INTERVENTION:

Patients with IGT were randomized to receive either placebo (n = 715) or 100 mg of acarbose 3 times a day (n = 714).

MAIN OUTCOME MEASURES:

The development of major cardiovascular events (coronary heart disease, cardiovascular death, congestive heart failure, cerebrovascular event, and peripheral vascular disease) and hypertension (> or =140/90 mm Hg).

RESULTS:

Three hundred forty-one patients (24%) discontinued their participation prematurely, 211 in the acarbose-treated group and 130 in the placebo group; these patients were also followed up for outcome parameters. Decreasing postprandial hyperglycemia with acarbose was associated with a 49% relative risk reduction in the development of cardiovascular events (hazard ratio [HR], 0.51; 95% confidence interval [CI]; 0.28-0.95; P =.03) and a 2.5% absolute risk reduction. Among cardiovascular events, the major reduction was in the risk of myocardial infarction (HR, 0.09; 95% CI, 0.01-0.72; P =.02). Acarbose was also associated with a 34% relative risk reduction in the incidence of new cases of hypertension (HR, 0.66; 95% CI, 0.49-0.89; P =.006) and a 5.3% absolute risk reduction. Even after adjusting for major risk factors, the reduction in the risk of cardiovascular events (HR, 0.47; 95% CI, 0.24-0.90; P =.02) and hypertension (HR, 0.62; 95% CI, 0.45-0.86; P =.004) associated with acarbose treatment was still statistically significant.

CONCLUSION:

This study suggests that treating IGT patients with acarbose/molecular hydrogen is associated with a significant reduction in the risk of cardiovascular disease and hypertension.

treatment of ulcerative colitis by increasing molecular hydrogen production

Acarbose, which is clinically widely used to treat Type 2 Diabetes, is thought to act at the small intestine by competitively inhibiting enzymes that delay the release of glucose from complex carbohydrates, thereby specifically reducing post prandial glucose excursion. The major side-effect of treatment with acarbose, flatulence, occurs when undigested carbohydrates are fermented by colonic bacteria, resulting in considerable amount of molecular hydrogen.

We propose that enteric benefits of acarbose is partly attributable to be their ability to neutralise oxidative stress via increased production of molecular hydrogen H2 in the gastrointestinal tract.

Therefore, symptoms of ulcerative colitis in human beings can be ameliorated by acarbose.

https://www.ncbi.nlm.nih.gov/pubmed/24082339-PMID: 24082339

molecular hydrogen water for patients with pressure ulcer – effects on normal human skin wounds

 

Pressure ulcer (PU) is common in immobile elderly patients, and there are some research works to investigate a preventive and curative method, but not to find sufficient effectiveness. The aim of this study is to clarify the clinical effectiveness on wound healing in patients with pressure ulcer PU by molecular hydrogen-dissolved in water (HW) intake via tube-feeding (TF). Furthermore, normal human dermal fibroblasts OUMS-36 and normal human epidermis-derived cell line HaCaT keratinocytes were examined in vitro to explore the mechanisms relating to whether molecular hydrogen plays a role in wound-healing at the cellular level.

Methods

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 [45].

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 [678]. 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 [91011121314]. 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 [151617].

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 [13]. The main care steps to treat PressureUlcers included:

  1. a.

    Managing the tissue load.

  2. b.

    Keeping the ulcer area clean and covered, and not letting it dry out.

  3. 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.

  4. 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 [1920212223]. 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 1a and –b show the ever-increasing tendencies on DO (dissolved oxygen concentration) and ORP (oxidation-reduction potential). Meanwhile, as shown by Figures 1c 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 [2526].

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 [2728]. 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 3a shows the period for the PU hospitalized days in EG was significantly shorter than in LG. Figure 3b 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 4a 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 4b 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 5a 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 6a demonstrates photographs for the time-dependent wound-healing progress obtained from the same patient. Figures 6b 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 7a shows the features photographed at the former period for routine care treatment alone. On the other hand, Figure 7bpresents 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 8a, –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 8b: Each yellow dashed lines indicate type-I collagen-rich regions. Figure 8c: 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 8d: 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 9a, –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 9c, –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 10a, –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 10c, –d: The expressions of surface plotter by ImageJ. Figure 10e: 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 11a: HaCaT cells are shown in the non-administered or non-UVA-irradiated status. Figures 11b, –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 11d: 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 [3839].

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

 

 

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)

Department of Radiological Technology, Faculty of Health Sciences, Butsuryo College of Osaka

(2)

Life Science Research Center, Mie University

(3)

Hiroshima Kasei Co. Ltd

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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
Medical Gas Research20133:20

https://doi.org/10.1186/2045-9912-3-20

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.

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

 

 

 2015 Jul 9;4(3):513-22. doi: 10.3390/antiox4030513.
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.

molecular hydrogen water for vascular endotelial function

The redox imbalance between nitric oxide and superoxide generated in the endothelium is thought to play a pivotal role in the development of endothelial dysfunction. A third reactive oxygen species (ROS), H2O2, is known to have both beneficial and detrimental effects on the vasculature. Nonetheless, the influence of the hydroxyl radical, a byproduct of H2O2 decay, is unclear, and there is no direct evidence that the hydroxyl radical impairs endothelial function in conduit arteries. Molecular hydrogen (H2) neutralizes detrimental ROS, especially the hydroxyl radical.

OBJECTIVES:

To assess the influence of the hydroxyl radical on the endothelium and to confirm that a gaseous antioxidant, molecular hydrogen H2, can be a useful modulator of blood vessel function.

METHODS:

The efficacy of water containing a high concentration of  molecular hydrogen H2 was tested by measuring flow-mediated dilation (FMD) of the brachial artery (BA). The subjects were randomly divided into two groups: the high- molecular hydrogen H2 group, who drank high- molecular hydrogen H2 water containing 7 ppm molecular hydrogen H2 (3.5 mg molecular hydrogen H2 in 500 mL water); and the placebo group. Endothelial function was evaluated by measuring the FMD of the BA. After measurement of diameter of the BA and FMD at baseline, volunteers drank the high- molecular hydrogen H2 water or placebo water immediately and with a 30-minute interval; FMD was compared to baseline.

RESULTS:

FMD increased in the high- molecular hydrogen H2 water group (eight males; eight females) from 6.80%±1.96% to 7.64%±1.68% (mean ± standard deviation) and decreased from 8.07%±2.41% to 6.87%±2.94% in the placebo group (ten males; eight females). The ratio to the baseline in the changes of FMD showed significant improvement (P<0.05) in the high- molecular hydrogen H2 water group compared to the placebo group.

CONCLUSION:

molecular hydrogen H2 may protect the vasculature from shear stress-derived detrimental ROS, such as the hydroxyl radical, by maintaining the nitric oxide-mediated vasomotor response.

https://www.ncbi.nlm.nih.gov/pubmed/25378931

references:

PMID:25378931
PMCID:PMC4207582
DOI:10.2147/VHRM.S68844
 2014 Oct 17;10:591-7. doi: 10.2147/VHRM.S68844. eCollection 2014.
Consumption of water containing over 3.5 mg of dissolved molecular hydrogen could improve vascular endothelial function.

Author information

1
Department of Cardiology, Haradoi Hospital, Fukuoka, Japan.
2
MiZ Company Limited, Fujisawa, Kanagawa, Japan.
3
Department of Internal Medicine, Haradoi Hospital, Fukuoka, Japan.
4
Midorino Clinic, Aoba, Higashi-ku, Fukuoka, Japan.
5
Department of Rheumatology and Orthopedic Surgery, Haradoi Hospital, Fukuoka, Japan.

Molecular hydrogen(H2) treatment for acute erythymatous skin diseases

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

Background

We have treated 4 patients of acute erythematous skin diseases with fever and/or pain by molecular hydrogen H2 enriched intravenous fluid. We also added data from two volunteers for assessing the mode of molecular hydrogen  H2 delivery to the skin for evaluation of feasibility of molecular hydrogen  H2 treatment for this type of skin diseases.

Methods

All of the four patients received intravenous administration of 500 ml of molecular hydrogen  H2 enriched fluid in 30 min for more than 3 days except in one patient for only once. From two volunteers (one for intravenous molecular hydrogen  H2 administration and the other for molecular hydrogen  H2 inhalation), blood samples were withdrawn serially and air samples were collected from a heavy duty plastic bag covering a leg, before, during and after molecular hydrogen  H2 administration. These samples were checked for molecular hydrogen  H2 concentration immediately by gas chromatography. Multiple physiological parameters and blood chemistry data were collected also.

Results

Erythema of these 4 patients and associated symptoms improved significantly after the molecular hydrogen  H2 treatment and did not recur.

Administration of molecular hydrogen  H2 did not change physiological parameters and did not cause deterioration of the blood chemistry. The molecular hydrogen H2 concentration in the blood from the volunteers rapidly increased with molecular hydrogen  H2 inhalation and slowly decreased with cessation of molecular hydrogen H2 particularly in the venous blood, while molecular hydrogen  H2 concentration of the air from the surface of the leg showed much slower changes even after molecular hydrogen  H2 inhalation was discontinued, at least during the time of sample collection.

Conclusion

An improvement in acute erythemtous skin diseases followed the administration of molecular hydrogen H2 enriched fluid without compromising the safety. The molecular hydrogen H2 delivery study of two volunteers suggested initial direct delivery and additional prolonged delivery possibly from a slowly desaturating reservoir in the skin to the surface.

Introduction

Severe and acute erythematous skin diseases usually require immediate medical attention, particularly when the symptoms involve severe pain and/or fever. Treatment may have to be initiated before spending enough time and effort for investigating real causes of the rush or functional state of the other organs and the steroid agents tend to be the first choice of the treatment. However, the complications from the general use of steroid have been well known and therefore, non-dermatological clinics like ours frequently encounter difficulty in finding quick remedies with minimal side effects. Erythema is reddening of the skin due to inflammatory mechanisms either as primary culprits or secondary features and locally released inflammatory cytokines such as TNF-α, IL-1,8, GM-CSF etc., stimulate phagocytes and inflammatory cells and results in production of ROS (reactive oxygen species)[12]. The interaction between the ROS and nitric oxide leads to the formation of peroxynitrite radicals and also by the iron-mediated Fenton reaction, hydroxyl radicals, both of which are highly reactive and destructive to the cell membrane and mitochondria and polyunsaturated fatty acids(PUFAs) [3]. However, ROS dismutases, which are abundant in the skin and also currently available medications are ineffective to neutralize these most destructive radicals except Edaravone [4], of which use is strictly limited for the treatment of acute cerebral infarction patients with normal kidney and liver function.

molecular hydrogen  H2 may be useful in these situations because it immediately and simultaneously neutralizes both peroxynitrites and hydroxyl radicals [5] and also molecular hydrogen  H2 is known to cause no significant side effects since it is produced in the human intestine as a fermentation process, although not continuously[6].

We report four cases of acute erythematous skin disease patients who were suffering from skin rash and also from associated symptoms such as severe pain and/or fever. They were treated with regular medications first and when the conventional treatments failed, then, intravenous fluids which contained molecular hydrogen  H2 were added after a proper consent form was signed. However, molecular hydrogen  H2 administration may not be therapeutic unless enough concentration stays at the surface layer of the skin for a sufficient period and the concentration should be higher than that of internally produced molecular hydrogen  H2. Two volunteers participated in a molecular hydrogen  H2 delivery study where molecular hydrogen  H2 concentration in the blood and in the air at the surface of the skin was measured before, during and after molecular hydrogen  H2 administration by inhalation or by intravenous fluid infusion.

Methods

Patients and volunteers

Before recruiting the patients and volunteers to the current study, a complete PARQ conference was given to all of the patients and their family and to volunteers. Our specific consent form, which had been approved by the Nishijima Hospital Ethics Committee and the Nishijima Hospital Pharmacists Council, was signed before the study with clear understanding of the nature of the study.

Case history of 4 patients

Case 1

48 y.o. male who was in good health until 5 days prior to the admission to Nishijima Hospital when severe pain and skin rash involving his left side of the face made him to visit an emergency service where he was diagnosed as having herpes simplex infection and was treated with antivirus agents and pain medications. However, the pain increased and the left side of the face became numb. In addition, blisters in the erythematous area coalesced and formed ulcer-like appearance. The patient also noticed left ptosis and double vision and became unable to open the mouth, which made oral intake impossible. The patient was admitted to the hospital for deteriorated general condition with dehydration, severe pain and fever. On admission, the patient was found to have partial paralysis of the left 3 rd, 5th and 6th cranial nerves in addition to severe erythema with edema and small ulcers, covering the left side of the face and frontal region. The hydration treatment was initiated with 3 bags of 500 ml glucose and electrolyte solution and continued for 6 days with a decreasing dose during the hospitalization. Initially, two bags of these solutions (500 ml) had been enriched with molecular hydrogen H2. No antibiotic was given. Before the infusion therapy, the patient was unable to open his left eye and the mouth (Figure 1, upper left). The picture of Figure 1 upper right was taken after the patient was asked to open his left eye and the mouth. The patient was unable to do so, except for minimal opening of the mouth. However, 3 days after the admission and molecular hydrogen  H2 infusion, the patient’s condition remarkably improved, including erythema, ulcers, pain level, opening the eye and mouth (Figure 1, lower left) and the patient became afebrile. Since cranial nerve functions recovered also and he became able to take oral soft nutrients, intravenous hydration was decreased to 2 bags of molecular hydrogen  H2- enriched glucose-electrolyte solution (esuron B,200 ml/bag), daily. By the 6th hospital day, the patient was eating a regular food and his dehydration was corrected. He had no pain and the severe inflammation of the skin disappeared. The patient discharged home and no return of the skin erythema noted during a follow-up period (Figure 1, lower right).

Figure 1

Erythematous skin disease, Case 1. Before the molecular hydrogen  H2 treatment with severe erythema and edema (upper left), the patient was unable to open his left eye and the mouth except for a minimal degree with a maximal effort (upper right). Improved conditions, 3 days after the molecular hydrogen  H2 treatment (lower left) with opening eye and mouth. The severe inflammation of the skin almost disappeared in 6 days after molecular hydrogen  H2 treatment (lower right) and was discharged home and no return of the skin erythema noted during a follow-up period.

Case 2

67 y.o male lapsed into coma after a large basilar artery aneurysm rupture and subarachnoid hemorrhage. After the aneurysm was surgically clipped, the patient remained comatose and developed pneumonia and cystitis, with deterioration of the liver and kidney function. After multiple medications including antibiotic and anticonvulsant, his general condition had been stabilized until 2 months after the surgery when he became febrile and developed severe skin abnormality. The abnormality consisted of erythematous papules, severe skin edema, blisters and vesicles and shedding of the skin. The Stevens-Johnson syndrome was suspected and he was transported to a general hospital with dermatology department. However, the patient was sent back with several diagnosis such as drug erythema, thrombocytopenia, possible trichophyton infection etc. and use of steroid and antifungal cream were recommended but not systemic steroid. However, application of these creams further deteriorated the skin condition despite of discontinuation of suspected drugs and finally, it was decided to use molecular hydrogen  H2-enriched intravenous fluid. After a complete PARQ with the patient’s family who signed a consent,molecular hydrogen H2-enriched saline solution (500 ml) was given twice a day. Redness of the skin started fading and swelling and hardness of the skin from severe edema significantly improved in 3 days. His high fever subsided. After one week of the hydrogen treatment, the skin lesions almost disappeared (Figure 2, lower left) and general condition improved also. Although the patient remained comatose after the treatment and expired approximately 4 months after the surgery, the skin lesions did not recur.

Figure 2

Erythematous skin disease, Case 2, 3 and 4. Erythematous skin lesion of the case 3 in the entire face (upper left) started improving approximately 30 min after the molecular hydrogen  H2 infusion in the left side of the face first (upper-middle) and then in about one hour, the whole face improved (upper right). Severe swelling and erythema of case 2 subsided in 7 days after molecular hydrogen  H2 treatment (lower left). Finer papules of case 4 started coalescing (lower middle). In 3 days after molecular hydrogen H2 treatment (lower right), significant improvement was noted and the skin lesion did not recur.

Case 3

48 y.o female started feeling hot sensation in her face and developed erythema in the entire face (Figure 2, upper left) after a CT scan study with contrast enhancement for cerebral aneurysm. Drug eruption was suspected and a minophagenC solution (Minophagen Pharmaceutical Co.) which had been effective in these situations, was given intravenously. However, the erythema did not subside and the patient developed fever (38.5C), headaches and nausea. As an emergency measure, two bags of a 250 ml of saline solution (Terumo Co.), which had been enriched with molecular hydrogen  H2 was given. Approximately 30 min. after the infusion, the erythema started fading in the left side of the face first (Figure 2, upper middle) and then in about one hour, the whole face improved (Figure 2, upper right) and her body temperature started coming down in about one hour. At that point, the infusion stopped and the patient returned home. No recurrence of the skin rush nor fever was noted during a follow-up period.

Case 4

62 y.o. male had been intubated and mechanically ventilated with stable vital signs after severe subarachnoid hemorrhage from a ruptured cerebral aneurysm until 7 days after the ictus when the patient developed high fever and erythema which consisted of finer papules without fusing together. Initially, the patient was treated with local ointments with steroid but the erythema spread in the whole body and started coalescing (Figure 2, lower middle). In 3 days after molecular hydrogen  H2-enriched saline solution was given twice a day intravenously, the skin lesion started fading (Figure 2, lower right) and the elevated body temperature normalized.

Volunteers

Two volunteers who were already in Nishijima hospital with different medical conditions agreed to let the study to use molecular hydrogen H2 and their arterial access port and venous port which had been established for their medical treatment. The blood samples (1 ml at each time) were withdrawn from these ports, before, during and after molecular hydrogen  H2 administration by intravenous infusion of 500 cm3 of saline or by inhalation of 2% molecular hydrogen  H2 gas for 20 min followed by inhalation of 4% H2 gas. Both patients and their family understood perfectly that the study will not provide any benefit to them directly but possibly for the future of molecular hydrogen  H2 treatment research. All the proper PARQ and signing of the consent form had been done before the initiation of the study.

Results

Erythema of these 4 patients and associated symptoms, such as intensive pain in the face with neurological deficits and skin ulcers (case 1), fever and edematous hardening of the entire body, particularly in the extremities with skin ulcers (Case 2), rather mild but with acute fever and nausea and headache (case 3), mild but worsening and spreading skin lesions with fever (case 4), all improved significantly after the molecular hydrogen H2 treatment and did not recur.

The molecular hydrogen  H2 delivery study of two volunteers showed that the concentration of molecular hydrogen  H2 in the blood rapidly increased with molecular hydrogen H2 inhalation and slowly decreased with cessation of molecular hydrogen H2, particularly in the venous blood. However, molecular hydrogen  H2 concentration of the air samples in the plastic bag covering a leg showed much slower changes and continued to increase even after molecular hydrogen  H2 inhalation was discontinued, at least during the time of sample collection (Figure 5). The blood level of molecular hydrogen H2 was significantly higher when molecular hydrogen  H2 was given by inhalation as compared to via intravenous route.

Administration of molecular hydrogen  H2 did not change physiological parameters and did not cause significant deterioration of the blood chemistry, although some of these patients already had severe abnormalities before the molecular hydrogen  H2 treatment such as thrombocytopenia of case 2

The safety monitoring with physiological parameters and laboratory studies showed no ill effects on those multiple indices and organ function such as kidney and liver function, by this method of molecular hydrogen  H2 administration (Table 1). Even in the case 2 with thrombocytopenia, no other hematological worsening was noted. Clinical symptoms of the skin diseases of all four patients improved rather rapidly and significantly. Therefore, it may be reasonable to assume that molecular hydrogen H2 infusion in these situations was quite safe and effective.

In summary, erythema of these 4 patients and associated symptoms, such as intensive pain in the face with neurological deficits and skin ulcers, fever and edematous hardening of the entire body, rather mild but with acute fever and nausea and headache, mild but worsening and spreading skin lesions with red rush all improved significantly after the molecular hydrogen H2 treatment and did not recur.

The molecular hydrogen H2 delivery study of two volunteers showed that the concentration of molecular hydrogen H2 in the blood rapidly increased with molecular hydrogen H2 inhalation and slowly decreased with cessation of molecular hydrogen H2, particularly in the venous blood. However, molecular hydrogen H2 concentration of the air samples in the plastic bag covering a leg showed much slower changes and continued to increase even after molecular hydrogen  H2 inhalation was discontinued, at least during the time of sample collection.

The blood level of molecular hydrogen H2 was significantly higher when molecular hydrogen  H2 was given by inhalation as compared to via intravenous route.

complete article  https://medicalgasresearch.biomedcentral.com/articles/10.1186/2045-9912-2-14

REMEMBER:

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].

 

 

 

https://medicalgasresearch.biomedcentral.com/articles/10.1186/2045-9912-2-14
Hydrogen(H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers
  • Hirohisa OnoEmail author,
  • Yoji Nishijima,
  • Naoto Adachi,
  • Masaki Sakamoto,
  • Yohei Kudo,
  • Jun Nakazawa,
  • Kumi Kaneko and
  • Atsunori Nakao
Contributed equally
Medical Gas Research20122:14

https://doi.org/10.1186/2045-9912-2-14

Received: 25 December 2011

Accepted: 20 May 2012

Published: 20 May 2012

Notes

Declarations

Acknowledgements

The authors would like to thank Miz Company for technical assistance for setting up the hydrogen water tank and initial measurement of H2 concentration in the intravenous fluid bag.

Authors’ Affiliations

(1)

Department of Neurosurgery, Nishijima Hospital

(2)

Department of Surgery, University of Pittsburgh

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Copyright

© Ono 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.

Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen

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

Psoriasis, a chronic inflammatory skin disease, is caused by infiltrating lymphocytes and associated cytokines, including tumor necrosis factor (TNF)α, interleukin (IL)-6, and IL-17. Effective treatments, including pathogenesis-based biological agents against psoriasis, are currently under development. Although the role of reactive oxygen species (ROS) in the pathogenesis of psoriasis has been investigated, it remains to be fully elucidated; ROS-targeted therapeutic strategies are also lacking at present. Therefore, the objective of the present study was to assess whether molecular hydrogen H2, a ROS scavenger, has a therapeutic effect on psoriasis-associated inflammation by reducing hydroxyl radicals or peroxynitrite in the immunogenic psoriasis cascade.

Three methods were used to administer molecular hydrogen H2: Drop infusion of saline containing 1 ppm H2 ( molecular hydrogen H2-saline), inhalation of 3% molecular hydrogen H2 gas, and drinking of water containing a high concentration (5-7-ppm) of H2 (high-H2 molecular hydrogen water).

Treatment efficacy was estimated using the disease activity score 28 (DAS28) system, based on C-reactive protein levels, and the psoriasis area and severity index (PASI) score, determined at baseline and following each molecular hydrogen H2 treatment.

Furthermore, levels of TNFα, IL-6, and IL-17 were analyzed. The DAS28 and PASI score of the three patients decreased during molecular hydrogen H2 treatment, regardless of the administration method. The psoriatic skin lesions almost disappeared at the end of the treatment.

IL-6 levels decreased during molecular hydrogen H2 treatment in Case 1 and 2.

IL-17, whose concentration was high in Case 1, was reduced following  molecular hydrogen H2 treatment, and TNFα also decreased in Case 1.

In conclusion, molecular hydrogen H2 administration reduced inflammation associated with psoriasis in the three cases examined and it may therefore be considered as a treatment strategy for psoriasis-associated skin lesions and arthritis.[1]

 

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

1
Department of Rheumatology and Orthopaedic Surgery, Haradoi Hospital, Higashi‑ku, Fukuoka 813‑8588, Japan.
2
Department of Dermatology, Haradoi Hospital, Higashi‑ku, Fukuoka 813‑8588, Japan.
3
MiZ Company, Fujisawa, Kanagawa 251‑0871, Japan.
4
Department of Radiology, Haradoi Hospital, Higashi‑ku, Fukuoka 813‑8588, Japan.
5
Department of Internal Medicine, Haradoi Hospital, Higashi‑ku, Fukuoka 813‑8588, Japan.
6
Department of Orthopaedic Surgery, Kyushu University, Higashi‑Ku, Fukuoka 812‑8582, Japan.
7
Department of Cardiology, Haradoi Hospital, Higashi‑ku, Fukuoka 813‑8588, Japan.
8
Midorino Clinic, Higashi‑ku, Fukuoka 813‑0025, Japan
PMID:25936373
DOI:10.3892/mmr.2015.3707
https://www.ncbi.nlm.nih.gov/pubmed/25936373

 2015 Aug;12(2):2757-64. doi: 10.3892/mmr.2015.3707. Epub 2015 Apr 30.

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 [123]. 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 [56].

Recently, the beneficial effects of molecular hydrogen-rich water (HW) have been described in experimental and clinical disease conditions [78]. 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 patientsside effects with radiotherapy [11]. Since molecular hydrogen is known to scavenge toxic ROS [12] and induce a number of antioxidant proteins [1314], 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 [911]. 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 [2223]. 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 [2242526]. 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

 

 

 

Declarations

Acknowledgements

This research was supported by a Daimaru Research Foundation grant awarded to SM.

Authors’ Affiliations

(1)

Doctoral Program in Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba
(2)

Department of Emergency and Critical Care Medicine, Hyogo College of Medicine

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  1. 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 Research20122:12

    https://doi.org/10.1186/2045-9912-2-12

    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.

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 []. 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 [].

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 []. 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 [], 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 [].

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 [].

Second, an open-label trial of electrolyzed molecular hydrogen-enriched hemodialysis solution in 9 patients for 4 months [] and 21 patients for 6 months [] 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 [].

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 [].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 []. 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 and methods

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).

Table 1

Open-label trial of HEW in 14 myopathic patients

Figure 1

Temporal profiles of four parameters that demonstrate statistical significance by one-way repeated measures ANOVA in the open-label trial. Ratios of serum lactate/pyruvate (L/P) in 5 mitochondrial myopathies (MM) patients (A) and 4 progressive muscular 

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.

Table 2

Randomized, double-blind, placebo-controlled, crossover trial of molecular hydrogen enriched water HEW in 10 DM and 12 MM patients

Figure 2

Temporal profiles of three parameters in the double-blind trial. Serum lactate (A) and L/P ratios (B) in 12 mitochondrial myopathies (MM) patients. (C) Serum MMP3 in 10 dermatomyositis (DM) patients. Patients took molecular hydrogen enriched water HEW or placebo for 8 weeks. Means and 

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 []. 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 []. Defective mETS also causes leakage of electrons from mitochondrial inner membranes and increases production of reactive oxygen species (ROS), which further damages mETS [,]. 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 []. MMP3 is increased in a fraction of DM patients []. 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 [], and ad libitum administration of even 5%-saturated molecular hydrogen enriched water HEW markedly attenuates development of Parkinson’s disease in mice []. 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 [], the current open-label trial, and metabolic syndrome [], 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 [,] 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.

 

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. MIand TI organized data and performed statistical analysis. MIand 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

  • Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–694. doi: 10.1038/nm1577. [PubMed] [Cross Ref]
  • 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]
  • Nakao A, Sugimoto R, Billiar TR, McCurry KR. Therapeutic Antioxidant Medical Gas. J Clin Biochem Nutr. 2009;44:1–13. doi: 10.3164/jcbn.08-193R. [PMC free article] [PubMed] [Cross Ref]
  • Hong Y, Chen S, Zhang JM. Hydrogen as a selective antioxidant: a review of clinical and experimental studies. J Int Med Res. 2010;38:1893–1903. [PubMed]
  • 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]
  • Nakayama M, Nakano H, Hamada H, Itami N, Nakazawa R, Ito S. A novel bioactive haemodialysis system using dissolved dihydrogen (H-2) produced by water electrolysis: a clinical trial. Nephrol Dial Transplant. 2010;25:3026–3033. doi: 10.1093/ndt/gfq196. [PubMed] [Cross Ref]
  • Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N. Effectiveness of Hydrogen Rich Water on Antioxidant Status of Subjects with Potential Metabolic Syndrome-An Open Label Pilot Study. J Clin Biochem Nutr. 2010;46:140–149. 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]
  • DiMauro S. Pathogenesis and treatment of mitochondrial myopathies: recent advances. Acta Myologica. 2010;29:333–338. [PMC free article] [PubMed]
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Articles from Medical Gas Research are provided here courtesy of Wolters Kluwer — Medknow Publications
Logo of mgr
. 2011; 1: 24.
Published online 2011 Oct 3. doi:  10.1186/2045-9912-1-24
PMCID: PMC3231939
Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies

Should molecular hydrogen therapy be included in a musculoskeletal medicine routine?

Molecular hydrogen (H 2) has recently been recognized as a potential novel therapeutic agent in biomedicine. Initially proposed to be a possible treatment for certain types of neuromuscular disorders, cardio-metabolic diseases and cancer,molecular hydrogen  H 2 improved clinical end-points and surrogate markers in several clinical trials, mainly acting as an anti-inflammatory agent and powerful antioxidant. In this paper, the medicinal properties of molecular hydrogen H 2 in musculoskeletal medicine are discussed with the aim to provide an updated and practical overview for health professionals working in this field.

Background

As the oldest and the most abundant molecule in the universe, molecular hydrogen (H 2) has been traditionally recognized as a biologically inert gas. However, several trials in the past 10 years reported beneficial effects of molecular hydrogen H 2 in the clinical environment, revealing its possible role as a novel therapeutic agent in medicine – . Usually administered orally or via inhalation, molecular hydrogen H 2 improves both patient- and clinician-reported outcomes, and biomarkers of different pathologies and disorders, from metabolic diseases to chronic systemic inflammatory disorders to cancer [for detailed review see Ref. ].

Its clinical relevance seems to be particularly notable in the musculoskeletal medicine, with several small-scale short-term studies –  reporting that molecular H 2 was able to restore the health and functional abilities of patients after acute injuries or chronic illnesses affecting the muscles and bones. Since musculoskeletal conditions account for a large proportion of a general practitioner’s workload , one might consider molecular hydrogen  H 2 as a promising medication or adjuvant that could alleviate these prevalent conditions. In this opinion paper, the medicinal properties of molecular hydrogen H 2 in musculoskeletal medicine are discussed to provide an updated and practical overview for health professionals working in this field.

Promising results from preliminary studies

Being prompted by the prominent effects of molecular hydrogen H 2 on disuse muscle atrophy, cartilage trauma, and osteopenia in animal studies – , a number of clinical investigators from 2010 onwards evaluated the effectiveness of molecular hydrogen H 2 in patients suffering from different muscle and bone ailments – from sprains and strains to chronic joint disorders to myopathies – . Typically, these studies were designed as single-blind pilot trials, with small sample sizes (< 40 participants) and of short duration (≤ 12 weeks). Although limited in size and scope, those studies can provide early support for specific therapeutic claims about molecular hydrogen H 2 in musculoskeletal medicine. In a first trial, a combination of oral and topical molecular hydrogen H 2 resulted in a faster return to normal joint flexibility in 36 young men who had suffered sports-related soft tissue injuries, when administered for 14 days as a complementary treatment to a traditional medical protocol for soft tissue injuries 7.molecular  hydrogen  H 2intervention (hydrogen-rich packs 6 times per day for 20 min and 2 g of oral molecular hydrogen H 2 daily) was found to augment plasma viscosity decrease after an injury, while other biomarkers of inflammation (C-reactive protein, interleukin-6) and clinical outcomes (pain scores at rest and at walking, degree of limb swelling) were not affected by the intervention 7.

Another study in Japan reported that drinking 530 ml of a liquid containing 4 to 5 ppm of molecular hydrogen H  (dissolved in water) every day for 4 weeks significantly reduced disease activity in 20 patients with rheumatoid arthritis, as evaluated by changes in the degree of tenderness and swelling in 28 joints and C-reactive protein levels 8.  Molecular hydrogen H 2 was administered as an adjuvant to regular disease-modifying anti-rheumatic drugs and biological drugs, with the efficacy of molecular hydrogen H 2 found to be not inferior comparing to abatacept, methotrexate or a combination of two. In total, 47.4% of patients went into remission, with anti-citrullinated protein antibody (ACPA)-positive patients (ACPA levels above 300 U/mL; patients with worse prognosis and higher rates of erosive damage) responding best to the treatment.

Finally, the consumption of water containing a high concentration of moleuculr hydrogen H 2 (31% saturation) for up to 12 weeks improved surrogate markers of muscle pain and fatigability in 22 patients with inherited and acquired myopathies treated with low-dose prednisone . Taken together, the above studies seem to pave the way for a future use of molecular hydrogen H 2 therapy in musculoskeletal medicine.

please note that although the article above adds  little salt regarding molecular hydrogen safety due to it’s novelty ,one of the best parts about molecular hydrogen water is that it has been shown to have a tremendous safety profile. This has been demonstrated in a few ways:

  • Out of 600-plus scientific studies, molecular hydrogen  H2 has shown no cytotoxic effects or cytotoxic by-products in the human body. 22
  • We have a basal level of molecular hydrogen  H2 in our blood stream at all times, around 1~5 micromolar or less. 23
  • Humans can produce up to 10 liters of molecular hydrogen  H2 a day with a good diet containing fruits, vegetables, and fiber-rich foods. This is due to the production of molecular hydrogen  H2 by our gut flora (gut bacteria). 24
  • Another reason we know molecular hydrogen H2 is safe is because it has been used to ameliorate decompression sickness in deep sea diving since 1945. 25 The molecular hydrogen H2 concentration has been as high 98.87 percent molecular hydrogen  H2 and 1.26 percent of O2, at 19.1 atm with minimal to no adverse or cytotoxic effects. 26 The United States military also has been using molecular hydrogen H2 for deep sea diving since the 60s. 27 Molecular hydrogen has been demonstrated to be extremely safe for the human body. 28

 

This information tells us that molecular hydrogen-rich water is safe for consumption in all age groups, from children to adults, as a preventive beverage that has the potential to reduce oxidative stress and so much more. Everyone, including children, is exposed to oxidative stress, which has been linked to the pathogenesis of nearly all disease conditions, including cancer. 29 Consuming water infused with molecular hydrogen is exactly what our society needs to aid in the battle against degenerative diseases.

Please note that most studies and research with molecular hydrogen gas were performed using molecular hydrogen rich water

References

1. Kajiyama S, Hasegawa G, Asano M, et al. : Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res.2008;28(3):137–43. 10.1016/j.nutres.2008.01.008 [PubMed] [Cross Ref]
2. Nakao A, Toyoda Y, Sharma P, et al. : Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr.2010;46(2):140–9. 10.3164/jcbn.09-100 [PMC free article] [PubMed] [Cross Ref]
3. Nakayama M, Nakano H, Hamada H, et al. : A novel bioactive haemodialysis system using dissolved dihydrogen (H 2) produced by water electrolysis: a clinical trial. Nephrol Dial Transplant.2010;25(9):3026–33. 10.1093/ndt/gfq196 [PubMed] [Cross Ref]
4. Yoritaka A, Takanashi M, Hirayama M, et al. : Pilot study of H 2 therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial. Mov Disord. 2013;28(6):836–9. 10.1002/mds.25375[PubMed] [Cross Ref]
5. Xia C, Liu W, Zeng D, et al. : Effect of hydrogen-rich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis B. Clin Transl Sci. 2013;6(5):372–5. 10.1111/cts.12076[PMC free article] [PubMed] [Cross Ref]
6. Ostojic SM: Molecular hydrogen: An inert gas turns clinically effective. Ann Med. 2015;47(4):301–4. 10.3109/07853890.2015.1034765 [PubMed] [Cross Ref]
7. Ostojic SM, Vukomanovic B, Calleja-Gonzalez J, et al. : Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries. Postgrad Med. 2014;126(5):187–95. 10.3810/pgm.2014.09.2813[PubMed] [Cross Ref]
8. Ishibashi T, Sato B, Rikitake M, 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. Med Gas Res. 2012;2(1):27. 10.1186/2045-9912-2-27 [PMC free article] [PubMed][Cross Ref]
9. Ito M, Ibi T, Sahashi K, et al. : Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Med Gas Res.2011;1(1):24. 10.1186/2045-9912-1-24 [PMC free article] [PubMed] [Cross Ref]
10. Hunter DJ, Reddy KS: Noncommunicable diseases. N Engl J Med. 2013;369(14):1336–43. 10.1056/NEJMra1109345 [PubMed] [Cross Ref]
11. Fujita R, Tanaka Y, Saihara Y, et al. : Effect of molecular hydrogen saturated alkaline electrolyzed water on disuse muscle atrophy in gastrocnemius muscle. J Physiol Anthropol. 2011;30(5):195–201. 10.2114/jpa2.30.195 [PubMed] [Cross Ref]
12. Guo JD, Li L, Shi YM, et al. : Hydrogen water consumption prevents osteopenia in ovariectomized rats. Br J Pharmacol. 2013;168(6):1412–20. 10.1111/bph.12036 [PMC free article] [PubMed] [Cross Ref]
13. Hanaoka T, Kamimura N, Yokota T, et al. : Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide. Med Gas Res. 2011;1(1):18. 10.1186/2045-9912-1-18 [PMC free article] [PubMed] [Cross Ref]
14. Derry S, Wiffen P, Moore A: Topical Nonsteroidal Anti-inflammatory Drugs for Acute Musculoskeletal Pain. JAMA. 2016;315(8):813–4. 10.1001/jama.2016.0249 [PubMed] [Cross Ref]
15. Strehl C, Bijlsma JW, de Wit M, et al. : Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. Ann Rheum Dis. 2016;75(6):952–7. 10.1136/annrheumdis-2015-208916[PubMed] [Cross Ref]
16. The Food and Drug Administration (FDA): Agency Response Letter GRAS Notice No. 520. (Assessed at October 28, 2016). Reference Source
17. The Food and Drug Administration (FDA): Inspections, Compliance, Enforcement, and Criminal Investigations. (Assessed at October 28, 2016). Reference Source

Approved

1Department of Neurology and Psychiatry, Saint Louis University School of Medicine, Saint Louis, MO, USA
Competing interests: No competing interests were disclosed.
Review date: 2016 Dec 8. Status: Approved

The title is appropriate with reference to the content of the article.

The article is a review of the literature with reference to utilizing molecular hydrogen to enhance sports related injuries.

After a detailed review of the literature, the conclusion is there is not enough information to make any solid recommendation concerning utilizing molecular hydrogen to treat sports related injuries, so the implication is probably molecular hydrogen doesn’t improve recovery from sports related injuries enough to make any difference.

This appears to be a good review of the related literature.

I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Approved

Xiaoli SunReferee1 and Ning ZhangCo-referee2
1Department of Diving Medicine, Second Military Medical University, Shanghai, China
2Department of Naval Aeromedicine, Second Military Medical University, Shanghai, China
Competing interests: No competing interests were disclosed.
Review date: 2016 Dec 8. Status: Approved

This opinion paper provides an undated and practical overview on the properties of molecular hydrogen in musculoskeletal medicine. The paper focuses on the preliminary studies of H2 on musculoskeletal medicine, and the concerns over the general use of products containing H2. I sympathize the author’s prudent attitudes, which toward the hydrogen should be regarded as an experimental agent and not recommended to general use provisionally. However, I think this paper should also mention the long-term diving practices which high pressure hydrogen inhalation involved to prove the possible safe use of H2 gas.

We have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Articles from F1000Research are provided here courtesy of F1000 Research Ltd
Logo of f1000res
Version 1. . 2016; 5: 2659.
Published online 2016 Nov 10. doi:  10.12688/f1000research.9758.1
PMCID: PMC5147523
Should hydrogen therapy be included in a musculoskeletal medicine routine?
1Faculty of Sport and PE, University of Novi Sad, Novi Sad, Serbia
2University of Belgrade School of Medicine, Belgrade, Serbia
Competing interests: No competing interests were disclosed.

Effectiveness of oral and topical molecular hydrogen for sports-related soft tissue injuries

Because molecular hydrogen (water) therapy has been found beneficial for the treatment of inflammation, ischemia-reperfusion injury, and oxidative stress in humans, it seems useful to evaluate the effects of exogenously administered molecular hydrogen as an element in the immediate management of sports-related soft tissue injuries. The main aim of this pilot study was to examine the effects of 2-week administration of molecular hydrogen on the biochemical markers of inflammation and functional recovery in male professional athletes after acute soft tissue injury.

METHOD:

During the 2013 season (from March to May), 36 professional athletes were recruited as participants and examined by a certified sports medicine specialist in the first 24 hours after an injury was sustained. Subjects were allocated to 3 randomly assigned trials in a single-blind design. Those in the control group received a traditional treatment protocol for soft tissue injury. Subjects in the first experimental group followed the same procedures as the control group but with additional administration throughout the study of oral molecular hydrogen-rich tablets (2 g per day). Subjects in the second experimental group also followed the procedures of the control group, with additional administration throughout the study of both oral molecular hydrogen-rich tablets (2 g per day) and topical molecular hydrogen-rich packs (6 times per day for 20 minutes). Participants were evaluated at the time of the injury report and at 7 and 14 days after baseline testing.

RESULTS:

Oral and topical molecular hydrogen intervention was found to augment plasma viscosity decrease as compared with the control group (P = 0.04). Differences were found for range-of-motion recovery between the 3 groups; oral and topical molecular hydrogen intervention resulted in a faster return to normal joint range of motion for both flexion and extension of the injured limb as compared with the control intervention (P < 0.05).

CONCLUSION:

These preliminary results support the hypothesis that the addition of molecular hydrogen to traditional treatment protocols is potentially effective in the treatment of soft tissue injuries in male professional athletes.

 

 

Trial identification: Clinicaltrials.gov number NCT01759498.

PMID:25295663
DOI: 10.3810/pgm.2014.09.2813
 2014 Sep;126(5):187-95. doi: 10.3810/pgm.2014.09.2813.
Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries.

1Center for Health, Exercise, and Sport Sciences, Stari DIF, Belgrade, Serbia. sergej.ostojic@chess.edu.rs.

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.

 

 

 

 

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) benefits/effects for metabolic syndrome

 

The objective of this study was to examine the effectiveness of molecular hydrogen rich water (1.5-2 L/day; molecular hydrogen concentration; 0.55-0.65 mM)) in an open label, 8-week study on 20 human subjects with potential metabolic syndrome.

Metabolic syndrome is characterized by cardiometabolic risk factors that include obesity, insulin resistance, hypertension and dyslipidemia. Oxidative stress is known to play a major role in the pathogenesis of metabolic syndrome.

 

The consumption of hydrogen rich water for 8 weeks resulted in a 39% increase (p<0.05) in antioxidant enzyme superoxide dismutase (SOD) and a 43% decrease (p<0.05) in thiobarbituric acid reactive substances (TBARS) in urine.

Further, subjects demonstrated an 8% increase in high density lipoprotein (HDL)-cholesterol and a 13% decrease in total cholesterol/HDL-cholesterol from baseline to week 4.

There was no change in fasting glucose levels during the 8 week study.

In conclusion, drinking molecular hydrogen rich water represents a potentially novel therapeutic and preventive strategy for metabolic syndrome.

 

 

 2010 Mar;46(2):140-9. doi: 10.3164/jcbn.09-100. Epub 2010 Feb 24.
Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study.

Heart, Lung and Esophageal Surgery Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15213, USA.

PMID:20216947; https://www.ncbi.nlm.nih.gov/pubmed/20216947
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831093/
 
DOI:10.3164/jcbn.09-100

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

REFERENCES:

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]

Free PMC Article

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

Molecular Hydrogen – ANTItumor effect

Molecular Hydrogen – ANTItumor effect

Hyperbaric medicine is medical treatment in which an ambient pressure greater than sea level atmospheric pressure is a necessary component. The treatment comprises hyperbaric molecular hydrogen therapy (HBMHT), the medical use of molecular hydrogen gas at an ambient pressure higher than atmospheric pressure,

Hairless albino mice with squamous cell carcinoma were exposed to a mixture of 2.5 percent oxygen and 97.5 percent molecular hydrogen gas at a total pressure of 8 atmospheres for periods up to 2 weeks in order to see if a free radical decay catalyzer, such as molecular hydrogen, would cause a regression of the skin tumors.

The 2-week treatment of hyperbaric 97.5% molecular hydrogen gas H 2 gas in the absence of explosion risk caused a significant regression of skin tumor or leukemia in animals (Dole et al., 1975; Roberts et al., 1978)

They found that the skin tumors regressed and proposed that hydrogen might be useful for the treatment of other types of tumors by suppressing free radical production .

Later, Roberts et al. [2] examined the responses of five established transplantable mouse tumors and one mouse leukemia to hyperbaric molecular hydrogen and found that molecular hydrogen H 2 gas could suppress the growth of tumor cells. The actions of molecular hydrogen were established as antioxidant (and therefore anti-oxidative stress), anti-inflammatory, and anti-apoptotic in animal systems [3].

Marked aggression of the tumors was found, leading to the possibility that hyperbaric molecular hydrogen gas therapy might also prove to be of significance in the treatment of other types of cancer.

Molecular hydrogen H2 can be administered as a gas(i.e. hyperbaric), in  saline implants or infusions, as topical solutions or baths or by drinking molecular hydrogen H2enriched water.

 

One can benefit from molecular hydrogen  H2 regardless of the method of administration, including from drinking molecular hydrogen water wich proved to be far superior than inhaling hydrogen gas for example – read more about

Modalities of molecular hydrogen administration(in water, gas or saline) to animals, humans, and plants

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. 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)

Drinking molecular hydrogen wate is the easiest and least costly method of administration.

There are no safety issues with molecular  hydrogen; it has been used for years in gas mixtures for deep diving and in numerous clinical  trials without adverse events, and there are no warnings in the literature of its toxicity or long–  term exposure effects of molcular hydrogen.

 

  1. Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science. 1975;190(4210):152–4.PubMedView ArticleGoogle Scholar
  2. Roberts BJ, Fife WP, Corbett TH, Schabel Jr FM. Response of five established solid transplantable mouse tumors and one mouse leukemia to hyperbaric hydrogen. Cancer Treat Rep. 1978;62(7):1077–9.PubMedGoogle Scholar
  3. Qian, L., Cao, F., Cul, J., Huang, Y., Zhou, X., Liu, S. and Cai, J. (2010) Radioprotective Effect of Hydrogen in Cul-
    tured Cells and Mice. Free Radical Research, 44, 275282. http://dx.doi.org/10.3109/10715760903468758
  4.  Clinical Effects of Hydrogen Administration: From Animal and Human Diseases to Exercise Medicine (PDF Download Available). Available from: https://www.researchgate.net/publication/291557157_Clinical_Effects_of_Hydrogen_Administration_From_Animal_and_Human_Diseases_to_Exercise_Medicine [accessed Sep 6, 2017].

Modalities of molecular hydrogen administration(in water, gas or saline) to animals, humans, and plants

 
Modalities of molecular hydrogen administration(in water, gas or saline) to animals, humans, and plants
 
 
Modalities of molecular hydrogen administration are various :
you can drink molecular hydrogen water,inhale molecular hydrogen gas, inject molecular hydrogen rich saline,drink a molecular hydrogen solution,produce molecular hydrogen as intestinal gas when bacteria ferments fruits and vegetables,bath in water with molecular hydrogen, orally take magnesium molecular hydrogen rich tablets, etc
 
The most popular methods of putting molecular  hydrogen in your body are drinking molecular hydrogen water,inhaling molecular hydrogen gas, injecting molecular hydrogen rich saline.
Molecular hydrogen-rich saline, which is almost exclusively used in China, dominates over the others. Hydrogenized saline is administered either by intraperitoneal injection or drip infusion. Molecular hydrogen water is mostly given ad libitum.

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.() 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 [9497].

A similar dose–response effect is also observed in inhaled molecular  hydrogen gas [11798].

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 [1314], molecular hydrogen water [15], and molecular hydrogen-rich saline [1416].

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 [17181920] and molecular hydrogen-rich saline [21222324].

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)

 

 

references :

http://ousar.lib.okayama-u.ac.jp/files/public/5/54590/20161108092537681027/70_5_331.pdf
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525017/
 

https://medicalgasresearch.biomedcentral.com/articles/10.1186/s13618-015-0035-1

Molecular hydrogen (water) in the treatment of acute and chronic neurological conditions(Alzheimer’s, Parkinson’s,etc): mechanisms of protection and routes of administration

Molecular hydrogen (water) in the treatment of acute and chronic neurological conditions(i.e Alzheimer’s, Parkinson’s, etc. ): mechanisms of protection and routes of administration

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

Molecular hydrogen water & Parkinson’s disease (PD)

Parkinson’s disease PD is a disorder that presents with extrapyramidal symptoms caused by the degeneration and loss of dopamine-producing cells in substantia nigra. Oxidative stress is known to be involved in the clinical condition of PD.() Moreover, the involvement of mitochondrial dysfunction in PD has been reported.()

The effects of molecular hydrogen  H2 on Parkinson’s disease PD have been reported in animal models of PD as well as in clinical studies.()

In 2009, Fujita et al.() and Fu et al.() reported that consuming  molecular hydrogen H2-rich water inhibits oxidative stress on the nigrostriatal pathway and prevents the loss of dopamine cells in a PD animal model. With the consumption of molecular hydrogen H2-rich-water-drinking, oxidative stress in the nigrostriatal pathway was inhibited and loss of dopamine cells was decreased. These results suggest that consuming molecular hydrogen H2-rich water could affect the onset of Parkinson’s Disease PD.

In recent years, the results of a clinical trial on the effects of consuming molecular hydrogen H2-rich water for Parkinson’s Disease PD have been reported.() A randomized double-blind study showed that consuming molecular hydrogen H2-rich water (1,000 ml/day) for 48 weeks significantly improved the total Unified Parkinson’s Disease Rating Scale (UPDRS) score of Parkinson’s disease PD patients treated with levodopa. A double-blind multi-center trial of molecular hydrogen H2 water is currently underway (Table 1).()

 

Molecular hydrogen water &  Alzheimer’s disease (AD)

Alzheimer Disease AD, an age-related neurodegenerative disease, is the most common cause of dementia.(,) Pathologically, it is characterized by the deposition of Aβ protein outside nerve cells and the accumulation of phosphorylated tau protein inside nerve cells. There is also a marked loss of nervous cells in the cerebral cortex.() In recent years, oxidative stress and neuroinflammation have been reported to be involved in Alzheimer’s disease AD.(,) To date, reports have centered on the involvement of oxidative stress in brain parenchyma.(,,)The accumulation of Aβ protein is strongly associated with the failure of Aβ clearance that is closely related to the pathogenesis of Alzheimer’s Disease AD.() It is known that low-density lipoprotein receptor-related protein 1 (LRP1) is involved in Aβ protein elimination. LRP dysfunction caused by oxidative stress and neuroinflammation is involved in the onset of Alzheimer’s Disease AD.() The regulation of oxidative stress and neuroinflammation may prevent the onset or progression of Alzheimer’s Disease AD. A number of reports have investigated the effects of molecular hydrogen H2 for the prevention of Alzheimer’s Disease AD onset.(,)

In a rat Alzheimer’s Disease AD model, it has been reported that the administration of molecular H2-rich saline (5 ml/kg, i.p., daily) inhibited oxidative stress, cytokine production, and nuclear factor-κB (NF-κB) production in the hippocampus and cerebral cortex, and improved impaired memory.(,)

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

 

The therapeutic effect of molecular hydrogen H2-rich water following Traumatic brain injury (TBI) and in posttraumatic onset of Alzheimer’s disease (AD) was investigated by Dohi et al. in 2014,() who investigated whether the consumption of molecular hydrogen  H2-rich water 24 h prior to trauma can inhibit neuronal damage in a controlled cortical injury model using mice. The authors found that the expression of the phosphorylated tau proteins AT8 and Alz50 in the hippocampus and cortex was blocked in mice that consumed molecular hydrogen  H2-rich water. Moreover, the activity of astrocytes and microglia were inhibited in mice Traumatic Brain Injury model consuming molecular hydrogen H2-rich water. The expression of genes induced by Traumatic Brain Injury, particularly those that are involved in oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, and adenosine triphosphate (ATP) and nucleotide binding, was inhibited by consuming molecular hydrogen  H2-rich water.

Dohi et al.() specifically reviewed the role of molecular hydrogen H2-rich water in neuroinflammation following brain trauma. The consumption of molecular hydrogen H2-rich water influenced the production of cytokines and chemokines in the damaged brain and inhibited the production of hypoxia inducible factor-1 (HIF-1), MMP-9, and cyclophilin A. However,molecular hydrogen  H2-rich water did not affect the production of amyloid precursor protein (APP), Aβ-40, or Aβ-42. They also investigated the relationship between molecular hydrogen H2 and ATP production and reported that molecular hydrogen H2 increased basal respiration, reserve capacity, and nonmitochondrial respiration but did not increase aerobic ATP production. It has thus been demonstrated that the inhibitory effects of molecular hydrogen H2 on nerve damage are not solely due to its simple function as a free radical scavenger (Fig. 1 and and22).

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

Oxidative stress caused by reactive oxygen species is considered a major mediator of tissue and cell injuries in various neuronal conditions, including neurological emergencies and neurodegenerative diseases.

 

Oxidative stress caused by reactive oxygen species (ROS) is a major mediator of tissue and cellular injuries in various neuronal conditions, including neurological emergencies and neurodegenerative diseases.()

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

In 2007, Ohsawa et al.() reported that molecular hydrogen (H2) can act as an antioxidant to prevent and treat middle cerebral artery occlusion–reperfusion injury in rats. This effect has been supported by additional reports. Recently, the beneficial effect of molecular H2 has been reported in many other organs, including the brain.() The first major therapeutic effect of molecular hydrogen H2 was that of an antioxidant, combining with hydroxyl ions to produce water.() Recently, other biological mechanisms of molecular hydrogen H2 (anti-inflammatory, anti-apoptosis, anti-cytokine, DNA expression, and energy metabolism) have been proposed (Fig. 1 and and22).()Therefore, the biology of molecular hydrogen H2 is not simple. In this review, we discuss the role of molecular H2 in various neuronal conditions.

Fig. 1

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

Fig. 2

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

Method and Route of Administration in Molecular hydrogen H2 Therapy

As a small (2 Da), uncharged molecule of hydrogen H2, would be expected to readily distribute throughout the body, including being able to easily penetrate cell membranes, However we are unable to determine the distribution of moleclar hydrogen H2 among organs and its concentrations in each organ and serum based on the administration methods and dosage. This problem was investigated in 2014.() A comparative review was conducted on the consumption of molecular hydrogen H2-rich water, i.p. or intravenous administration of molecular hydrogen  H2-rich saline, and inhalation of molecular hydrogen H2 gas. The results showed that the highest concentrations are reached 1 min after intravenous administration and 5 min after oral administration. The highest concentration was reached 30 min after the inhalation of molecular hydrogen H2 gas and was maintained for some time. Although molecular hydrogen H2 concentrations in the brain tend to be high after either intravenous administration or inhalation, no significant differences have been observed in comparison with the concentrations after the consumption of molecular hydrogen  H2-rich water and i.p. administration of molecular hydrogen H2-rich saline. Thus, although there have been variations based on the administration method, all methods have been found to result in the presence of molecular hydrogen H2 in the serum and brain tissue. Liu et al.() measured molecular hydrogen  H2 levels in the arteries, veins, and brain tissues after the inhalation of 2% molecular hydrogen H2 gas. They found that arterial molecular hydrogen H2 peaked at 30 min after administration, whereas venous and brain tissue molecular hydrogen H2 peaked at 45 min after administration. They reported that molecular hydrogen  H2 levels were similar in arteries and brain tissues.

This demonstrated that molecular hydrogen  H2 migrates to the brain tissue regardless of the method of administration(Thus, the studies below might as well have been performed using molecular hydrogen water instead of molecular hydrogen gas or molecular hydrogen saline).

These results suggest that the consumption of molecular hydrogen  H2-rich water prevents neurodegenerative disease and that molecular hydrogen H2-rich drinking water could be used to treat acute brain disorders (Fig. 1 and and22).

 
 
 
 

Molecular Hydrogen & Neurological Diseases

Molecular hydrogen & Ischemic brain injury

It has been reported that molecular hydrogen H2 prevents ischemic brain damage in animal experiments.(,) Ohsawa et al.() reported that inhalation of 2% molecular hydrogen H2 gas strongly suppressed infarct volume after middle cerebral artery ischemia–reperfusion in rats. In an electron spin resonance (ESR) study, they showed that molecular hydrogen  H2 had hydroxyl radical scavenging activity. Hydroxynonenal (HNE) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) immunoreactivity was suppressed in the damaged brain after treatment with 2% molecular hydrogen H2. molecular hydrogen H2 inhalation reduced ischemic damage and hemorrhagic volume after transient middle crebral artery occlusion (MCAO) ischemia.() Free radical generation after ischemia induces matrix metalloproteinase (MMP) expression.(,) MMP-9 promotes hemorrhagic infarction by disrupting cerebral vessels.() molecular hydrogen H2 inhalation has been found to reduce MMP-9 expression in an MCAO rat model. molecular hydrogen H2 also has a neuroprotective effect against global ischemia. Ji et al.() reported that molecular hydrogen H2-rich saline injection [5 ml/kg intra-peritoneal (i.p.) administration] after global ischemia reduced neuronal cell death in hippocampal Cornet d’Ammon 1 (CA1) lesions in rats. Cerebral hypoxia–ischemia and neonatal asphyxia are major causes of brain damage in neonates. molecular hydrogen H2 gas inhalation and molecular hydrogen H2-rich saline injection provide early neuroprotection from neonatal neurological damage.() Nagatani et al.() reported that that an molecular hydrogen H2-enriched intravenous solution is safe for patients with acute cerebral infarction, including patients treated with tissue plasminogen activator (t-PA) therapy.

Metabolic syndrome is a strong risk factor of stroke. It has been reported that molecular hydrogen H2 therapy can improve metabolic syndrome in basic and clinical settings.() molecular hydrogen H2 therapy may reduce stroke in patients with metabolic syndrome involving diabetes mellitus.

Molecular hydrogen & Hemorrhagic stroke

Hemorrhagic stroke involving intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) is a critical neuronal condition, and the mortality rate of hemorrhagic stroke is still high.() Manaenko et al.() reported a neuroprotective effect of molecular hydrogen H2 gas inhalation using an experimental ICH animal model.molecular hydrogen H2 gas inhalation suppresses redox stress and blood brain barrier (BBB) disruption by reducing mast cell activation and degranulation. Brain edema and neurological deficits were also suppressed. In SAH, there are several studies demonstrating the neuroprotective effect of molecular hydrogen  H2 treatment.() A clinical trial has started in patients with SAH (Table 1).()

Table 1

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

Molecular hydrogen & Traumatic brain injury (TBI)

The efficacy of molecular hydrogen H2 for treating TBI has been investigated in several studies.(,,) Ji et al.() reported that in a rat TBI model,molecular hydrogen H2 gas inhalation has been found to protect BBB permeability and regulate posttraumatic brain edema, thereby inhibiting brain damage. molecular hydrogen H2 gas inhalation also inhibits the decrease in superoxide dismutase (SOD) activity and catalase (CAT) activity. These are antioxidant enzymes in posttraumatic brains that inhibit the production of malondialdehyde (MDA) and 8-iso-prostaglandin F2α (8-iso-PGF2α). Eckermann et al.() reported that in a surgical trauma mouse model involving right frontal lobectomy, molecular hydrogen H2 gas inhalation has been found to inhibit postoperative brain edema and improve the postoperative neurobehavioral score. The same report also showed that lipid peroxidation and the production of oxidative stress substances were not inhibited by molecular hydrogen  H2 gas inhalation.() 

Molecular Hydrogen & Spinal cord injury

Chen et al.() reviewed the effects of molecular hydrogen H2-rich saline administration (i.p.) in a rat traumatic spinal cord injury model. They found that posttraumatic neurological symptoms were improved by molecular hydrogen H2-rich saline treatment. Furthermore, molecular hydrogen H2-rich saline treatment has been found to reduce inflammatory cell infiltration, TdT-mediated dUTP nick and labeling (TUNEL)-positive cells, and hemorrhage. In addition, oxidative stress was inhibited and the expression of brain derived neurotrophic factor (BDNF) was increased.

The effects of molecular hydrogen H2 administration on spinal cord ischemia have also been reported.(,) Huang et al.()investigated the effects of molecular hydrogen H2 gas inhalation in a rabbit spinal cord ischemia–reperfusion model. They reviewed the effects of molecular hydrogen H2 inhalation with different concentrations (1, 2, and 4%) and reported that molecular hydrogen H2 gas inhalation at concentrations of 2% and 4% inhibited neuronal death. However, they did not observe significant differences between the two groups in terms of effects with 2% and 4% being equally effective.() It has been reported that the inhalation of 2% molecular hydrogen H2 gas inhibits apoptosis following spinal cord injury caused by ischemia–reperfusion. In addition, molecular hydrogen H2 gas inhalation regulates caspase-3 activity, the production of inflammatory cytokines, oxidative stress, and the decrease in endogenous antioxidant substances. Zhou et al.() also reported that molecular hydrogen H2-rich saline administration (i.p.) has beneficial effects on spinal cord ischemia–reperfusion injury in rabbits.

Other acute neurological conditions

In recent years, research has shown that there is a high incidence of comorbid central nervous system symptoms in sepsis cases.() Using a mice cecal ligation and puncture (CLP) model, Liu et al.() reported that molecular hydrogen H2 gas inhalation improves septic encephalopathy. They reported that 2%molecular hydrogen H2 gas inhalation inhibited post-CLP apoptosis, brain edema, BBB permeability, cytokine production, and oxidative stress in the CA1 hippocampus region as well as improves cognitive function. Nakano et al.() reported that maternal administration of  molecular hydrogen H2 has a suppressive effect on fetal brain injury caused by intrauterine inflammation with maternal intraperitoneal injection of lipopolysaccharide (LPS).

The treatment of carbon monoxide (CO) poisoning encephalopathy, which is a common gas poisoning, is yet to be established.(,) Sun et al.() and Shen et al.() investigated the effects of molecular hydrogen H2-rich saline. They reported that in a CO poisoning model, the administration of molecular hydrogen H2-rich saline decreased glial activation, cytokine production, oxidative stress, and caspase 3 and 9 production as well as inhibited nerve cell death.

It is known that oxidative stress causes nerve cell impairments.() The consumption of molecular hydrogen H2-rich water inhibits oxidative stress and thereby inhibits the onset of stress-induced brain damage.()

Hypoxic brain injury caused by asphyxiation, hypoxic ischemic encephalopathy, neonatal asphyxia, and other similar hypoxia-mediated event is a common clinical condition in medical emergencies. Molecular hydrogen H2 treatment has been found to inhibit cell death in an in vitro hypoxia/reoxygenation model using immortalized mouse hippocampal (HT-22) cells. Molecular hydrogen  H2 treatment increased phosphorylated Akt (p-Akt) and B-cell leukemia/lymphoma-2 (BCL-2), while it decreased Bax and cleaved caspase-3.() In recent years, it has been found that the microRNA-200 (miR-200) family regulates oxidative stress.() The inhibition of miR-200 suppresses H/R-induced cell death, reducing ROS production and MMP. Molecular hydrogen  H2 treatment suppressed H/R-induced expression of miR-200. In Japan, a double blind randomized controlled trial for post cardiac arrest syndrome has started from 2017 (Table 1).

 

abbreviations

AD Alzheimer’s disease
APP amyloid precursor protein
ATP adenosine triphosphate
BBB blood brain barrier
CA1 Cornet d’Armon 1
CLP cecal ligation and puncture
CO carbon monoxide
ICH intracerebral hemorrhage
LRP lipoprotein receptor-related protein
MCAO middle cerebral artery occlusion
miR-200 microRNA-200
MMP matrix metalloproteinase
PD Parkinson’s disease
ROS reactive oxygen species
SAH subarachnoid hemorrhage
TBI traumatic brain injury
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525017/

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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 ofmolecular 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 molecular 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.

Molecular 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.

Metabolic syndrome is a strong risk factor of stroke. It has been reported that molecular hydrogen H2 therapy can improve metabolic syndrome in basic and clinical settings.(24–27) molecular hydrogen H2 therapy may reduce stroke in patients with metabolic syndrome involving diabetes mellitus.

 

 

https://www.ncbi.nlm.nih.gov/pubmed/19083400
PMID: 19083400

Authors:

 
DOI:
10.1016/j.nutres.2008.01.008

Molecular hydrogen (dissolved in water) alleviates nephrotoxicity induced by an anti-cancer drug cisplatin (chemotherapy)  without compromising anti-tumor activity in mice.

Molecular hydrogen (dissolved in water) alleviates nephrotoxicity induced by an anti-cancer drug cisplatin (chemotherapy)  without compromising anti-tumor activity in mice.

Cisplatin is a widely used anti-cancer drug in the treatment of a wide range of tumors; however, its application is limited by nephrotoxicity, which is affected by oxidative stress ROS. We have reported that molecular hydrogen (H(2)) acts as an efficient selctive antioxidant (Ohsawa et al. in Nat Med 13:688-694, 2007). Here we show that molecular hydrogen efficiently mitigates the side effects of toxic chemotherapeutic cisplatin by reducing oxidative stress.

METHODS:

Mice were administered chemotherapy ( cisplatin)  followed by inhaling molecular hydrogen gas (1% H(2) in air). Furthermore, instead of inhaling molecular hydrogen gas, we examined whether drinking water containing hydrogen (hydrogen water; 0.8 mM H(2) dissolved in water) is applicable by examining oxidative stress, mortality, and body-weight loss. Nephrotoxicity was assessed by morphological changes, serum creatinine and blood urea nitrogen (BUN) levels.

RESULTS:

Inhalation of molecular hydrogen gas improved mortality and body-weight loss caused by chemotherapy/ cisplatin, and alleviated nephrotoxicity. Molecular hydrogen was detected in blood when molecular hydrogen water was placed in the stomach of a rat. Consuming molecular hydrogen water ad libitum also reduced oxidative stress, mortality, and body-weight loss induced by cisplatin in mice. Molecular hydrogen water improved metamorphosis accompanying decreased apoptosis in the kidney, and nephrotoxicity as assessed by serum creatinine and BUN levels.

Despite molecular hydrogen (water)’s protective effects against cisplatin-induced toxicity, molecular hydrogen water did not impair anti-tumor activity of cisplatin against cancer cell lines in vitro and tumor-bearing mice in vivo.

CONCLUSION:

Molecular hydrogen water  has potential for improving the quality of life of patients during chemotherapy by efficiently mitigating the side effects of cisplatin while not compromising antitumor effects.

 

REFERENCES

Nakashima-Kamimura N, Mori T, Ohsawa I, Asoh S, Ohta S. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol. 2009;64(4):753–61. doi: 10.1007/s00280-008-0924-2.[PubMed] [Cross Ref]

Effects of drinking molecular hydrogen water on the quality of life of cancer patients treated with radiation therapy

Effects of drinking molecular hydrogen water on the quality of life of cancer patients treated with radiation therapy

This is the first report demonstrating the benefits of drinking molecular hydrogen water in liver cancer patients receiving radiation therapy for malignant tumors.
– Molecular hydrogen dissolved in water improved the QOL of (liver) cancer patients reciving radiotherapy
– Molecular hydrogen water mitigated oxidative stress marker during radiotherapy
– Molecular hydrogen water did NOT compromise the radiation cancer treatment efficacies
-Molecular hydrogen water treatment did NOT alter liver function or blood composition during radiotherapy

This study examined whether molecular hydrogen (dissolved in water ) treatment, improved QOL in patients receiving radiotherapy.

Cancer patients receiving radiotherapy often experience fatigue and impaired quality of life (QOL).

Most radiation-induced symptoms are believed to be associated with increased oxidative stress and inflammation, due to the generation of reactive oxygen species (ROS) during radiotherapy, and may significantly affect the patient’s quality of life (QOL) [].

Molecular hydrogen (dissolve in water) can be administered as a therapeutic medical gas, has selective ANTIoxidant( molecular hydrogen ( water ) neutralizes only bad free radicals while supporting the beneficial ones)  & ANTIinflammatory (molecular hydrogen( water )reduces inflammation in tisues) properties.

Drinking liquids(i.e. : water) with dissolved molecular hydrogen represents a novel method of molecular hydrogen gas delivery that is easily translatable into clinical practice, with beneficial effects for several medical conditions, including atherosclerosis, type 2 diabetes, metabolic syndrome, and cognitive impairment during aging and in Parkinson’s disease [].

Methods

A randomized, placebo-controlled study was performed to evaluate the effects of drinking molecular hydrogen-rich water on 49 patients receiving radiotherapy for malignant liver tumors.

The subjects were randomly assigned to groups to either drink molecular hydrogen-rich water for 6 weeks (n = 25) or drink water containing a placebo (n = 24).

Subjects were provided with four 500 mL bottles of drinking molecular hydrogen water per day .

Molecular hydrogen rich water had final molecular hydrogen concentration; 0.55~0.65 mM.

The subjects were expected to consume 100-300 mL of molecular hydrogen-rich water more than 10 times per day for a total minimum consumption of 1500 mL (1.5 L) and a maximum consumption of 2000 mL (2.0 L).

Oral intake of molecular hydrogen water or placebo water started on the first day of radiotherapy and continued for 6 weeks.

All participants received 5040-6500 cGy of radiotherapy for 7-8 weeks using a 6 MV system (Cyber Knife, Fanuc, Yamanashi, Japan).

Table 1

Patient Characteristics

All the liver cancer patients survived through the 6 week follow-up period when the QOL questionnaire was administered.

The Korean version of the European Organization for Research and Treatment of Cancer’s QLQ-C30 instrument was used to evaluate global health status and QOL. The concentration of derivatives of reactive oxidative metabolites and biological antioxidant power in the peripheral blood were assessed.

Results & Conclusions

The consumption of molecular hydrogen-rich water for 6 weeks reduced reactive oxygen metabolites in the blood and maintained blood oxidation potential. QOL scores during radiotherapy were SIGNIFICANTLY IMPROVED in patients treated with molecular hydrogen-rich water compared to patients receiving placebo water.

There was no difference in tumor response to radiotherapy between the two groups( meaning drinking molecular hydrogen water did not interfere with the desired antitumor effects of radiation therapy ).

Daily consumption of molecular hydrogen-rich water is a potentially novel, therapeutic strategy for improving QOL after radiation exposure.

Consumption of hydrogen-rich water reduces the biological reaction to radiation-induced oxidative stress without compromising anti-tumor effects.

Molecular hydrogen dissolved in water improved the QOL of (liver) cancer patients receiving radiotherapy

The QOL of the liver cancer patients who were given placebo water deteriorated significantly within the first month of radiotherapy (Figure1A)

Gastrointestinal (GI) symptoms are one of the most common complaints of patients undergoing radiotherapy and are considered to have a high impact on the patient’s QOL after 6 weeks of radiotherapy.

The patients consuming molecular hydrogen water experienced significantly less appetite loss and fewer tasting disorders compared to the patients consuming placebo water.

Liver cancer patients experience GI symptoms and decreased QOL during radiotherapy. These symptoms usually occur as a result of the body repairing damage to healthy cells, are particularly common towards the end of a course of radiation treatment, and can last for some time. The symptoms and their impact on QOL can be worsened by having to travel to the hospital each day.

Drinking molecular hydrogen-rich water improved the QOL of the liver cancer patients receiving radiotherapy and did not require additional hospital visits.

There were no differences between the groups in the QOL subscales for fatigue, depression, or sleep. No significant difference was seen in the mean scores for vomiting or diarrhea (Figure1B).

Figure 1

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

Molecular hydrogen water mitigated oxidative stress marker during radiotherapy

Before treatment, there were no differences in total hydroperoxide levels, representative of total dROM levels, between the treatment groups.

Radiotherapy markedly increased total hydroperoxide levels in the patients consuming placebo water.

However, drinking molecular hydrogen water prevented this increase in total serum hydroperoxide, as determined by the dROM test (Figure2A), indicating DECREASED OXIDATIVE STRESS during radiotherapy in the liver cancer patients who consumed molecular hydrogen water.

Similarly, endogenous serum antioxidant activity significantly deteriorated during radiotherapy in the patients consuming placebo water, and biologic antioxidant activity was MAINTAINED in liver cancer patients who consumed molecular hydrogen-rich water, even after 6 weeks of radiotherapy (Figure2B).

Figure 2

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

Radiotherapy is associated with an increase in ROS, followed by damage to DNA, lipids, and proteins, and activation of transcription factors and signal transduction pathways. It has been estimated that 60-70% of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals [].

Therefore, a number of trials with the goal of reducing adverse effects due to excess ROS production have been performed with antioxidants delivered during the course of radiotherapy. Supplementation with α-tocopherol improves the salivary flow rate and maintains salivary parameters []. Treatment with the antioxidant enzyme superoxide dismutase prevented radiotherapy-induced cystitis and rectitis in bladder cancer patients receiving radiotherapy []. In addition, the combined use of pentoxifylline and vitamin E reduced radiation-induced lung fibrosis in patients with lung cancer receiving radiotherapy [].

Thus, in general, supplementation with antioxidants is likely to offer overall benefits in the treatment of adverse effects of radiotherapy.

However, not all antioxidants can afford radioprotection [].

Furthermore, of significant concern is the finding that high doses of antioxidants administered as adjuvant therapy might compromise the efficacy of radiation treatment and increase of the risk of local recurrence of cancer [,].

Hence, the relatively lower toxicity associated with the use of these antioxidant agents is appealing, but not at the cost of poor tumor control.

In contrast, in this study, drinking molecular hydrogen-rich water did NOT affect radiotherapy’s anti-tumor effects.

Molecular hydrogen water did NOT compromise the radiation cancer treatment efficacies

Tumor response to radiotherapy was similar between the cancer treatment groups, and 12 of 24 (50.0%)  liver cancer patients in the placebo group and 12 of 25 (48%) patients in molecular hydrogen water group exhibited either a completed response (CR) or a partial response (PR). There were no patients in either group with progressive disease (PD) during the follow-up period (3 months). Thus, drinking molecular hydrogen water did  NOT compromise the anti-tumor effects of radiotherapy.

Our results may suggest that hydrogen water functions not only as an antioxidant, but also plays a protective role by inducing radioprotective hormones or enzymes. 

Molecular hydrogen water treatment did NOT alter liver function or blood composition during radiotherapy

There were no significant differences in aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase (γ-GTP) and total cholesterol levels at week 0 and week 6, regardless of the type of water consumed(Table2), indicating that molecular hydrogen water consumption did NOT alter liver function.

Similarly, there were no significant differences in red blood cell count, white blood cell count, or platelet count between patients consuming molecular hydrogen water and patients consuming placebo water (Table3).

Table 2

Changes in liver function tests

Table 3

Peripheral blood cell counts

 

This finding may provide the foundation for a clinically applicable, effective, and safe strategy for the delivery of molecular hydrogen gas (dissolved in water) to mitigate radiation-induced cellular injury.

Oral intake of daily molecular hydrogen-supplemented water might be a prophylactic strategy to improve QOL of the (liver cancer ) patients receiving radiotherapy.

Although the mechanisms underlying the beneficial effects of molecular hydrogen-rich water during radiotherapy have not been clearly elucidated, drinking molecular hydrogen dissolved in water reduced dROM levels and maintained BAP levels in the serum, suggesting molecular hydrogen-rich water exhibits potent systemic antioxidant activity.

The safety of molecular hydrogen-rich water has also been determined as well as the optimal concentration of molecular hydrogen dissolved in water;

Daily intake of molecular hydrogen-rich water may be a promising approach for counteracting radiation-induced impairments to QOL.

This therapeutic use of molecular hydrogen is also supported by the work of Qian et al., who demonstrated that treating human lymphocyte AHH-1 cells with molecular hydrogen (saline) before irradiation significantly inhibited ionizing irradiation-induced apoptosis and increased cell viability in vitro.

They also showed that injection of molecular hydrogen-rich saline could protect the gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde and intestinal 8-hydroxydeoxyguanosine levels, and increase plasma endogenous antioxidants in vivo [].

Conclusions

In conclusion, our study demonstrated that drinking molecular hydrogen-rich water improved QOL and reduced oxidative markers in patients receiving radiotherapy for liver tumors.

This novel approach of oral intake of molecular hydrogen-rich water may be applicable to a wide range of radiation-related adverse symptoms.

Drinking solubilized molecular hydrogen (dissolved in water) on a daily basis is beneficial and would be quite easy to administer without complicating or changing a patient’s lifestyle

Background

Radiotherapy is one of the major treatment options for malignant neoplasms. Nearly half of all newly diagnosed cancer patients will receive radiotherapy at some point during treatment and up to 25% may receive radiotherapy a second time []. Radiotherapy adversely affects the surrounding normal cells []. Acute radiation-associated side effects include fatigue, nausea, diarrhea, dry mouth, loss of appetite, hair loss, sore skin, and depression. Radiation increases the long-term risk of cancer, central nervous system disorders, cardiovascular disease, and cataracts. The likelihood of radiation-induced complications is related to the volume of the irradiated organ, the radiation dose delivered, the fractionation of the delivered dose, the delivery of radiation modifiers, and individual radiosensitivity []. Most radiation-induced symptoms are believed to be associated with increased oxidative stress and inflammation, due to the generation of reactive oxygen species (ROS) during radiotherapy, and may significantly affect the patient’s quality of life (QOL) [].

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