ArticleLiterature Review

Recent Advances in Hydrogen Research as a Therapeutic Medical Gas

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Recent basic and clinical research has revealed that hydrogen is an important physiological regulatory factor with antioxidant, anti-inflammatory and anti-apoptotic protective effects on cells and organs. Therapeutic hydrogen has been applied by different delivery methods including straightforward inhalation, drinking hydrogen dissolved in water and injection with hydrogen-saturated saline. This review summarizes currently available data regarding the protective role of hydrogen, provides an outline of recent advances in research on the use of hydrogen as a therapeutic medical gas in diverse models of disease and discusses the feasibility of hydrogen as a therapeutic strategy. It is not an overstatement to say that hydrogen's impact on therapeutic and preventive medicine could be enormous in the future.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Ayrıca gazın solunması kan basıncını etkilememektedir. Fakat tehlikeli durum oluşturmaması için hidrojen konsantrasyonu, ticari olarak temin edilebilen araçlarla izlenmeli ve sürdürülmelidir [10]. ...
... Aynı zamanda hidrojenle zenginleştirilmiş su tüketiminin hidrojen inhalasyonuyla karşılaştırılabilir etkileri bulunmaktadır (Antioksidan, antiinflamatuar, antiapoptotik). Hidrojenle zenginleştirilmiş su, hidrojen gazının suda yüksek basınç altında çözülmesi, elektroliz yoluyla hidrojenin suda çözülmesi ve magnezyumun su ile reaksiyona sokulması gibi çeşitli yöntemlerle elde edilebilmektedir [10,11]. ...
... Fakat sudaki hidrojenin zamanla kaybolması ve midede veya bağırsakta bir miktar hidrojen kaybının yaşanması, uygulanan hidrojen konsantrasyonunun kontrol edilmesini zorlaştırmaktadır. H2'nin enjekte edilebilir bir hidrojenli salin yoluyla uygulanması, hidrojenin daha kolay kontrol edilebilir olmasını sağlamaktadır [9,10]. Hidrojence zengin salin enjeksiyonu umut verici bir klinik yöntemdir. ...
... Ayrıca gazın solunması kan basıncını etkilememektedir. Fakat tehlikeli durum oluşturmaması için hidrojen konsantrasyonu, ticari olarak temin edilebilen araçlarla izlenmeli ve sürdürülmelidir [10]. ...
... Aynı zamanda hidrojenle zenginleştirilmiş su tüketiminin hidrojen inhalasyonuyla karşılaştırılabilir etkileri bulunmaktadır (Antioksidan, antiinflamatuar, antiapoptotik). Hidrojenle zenginleştirilmiş su, hidrojen gazının suda yüksek basınç altında çözülmesi, elektroliz yoluyla hidrojenin suda çözülmesi ve magnezyumun su ile reaksiyona sokulması gibi çeşitli yöntemlerle elde edilebilmektedir [10,11]. ...
... Fakat sudaki hidrojenin zamanla kaybolması ve midede veya bağırsakta bir miktar hidrojen kaybının yaşanması, uygulanan hidrojen konsantrasyonunun kontrol edilmesini zorlaştırmaktadır. H2'nin enjekte edilebilir bir hidrojenli salin yoluyla uygulanması, hidrojenin daha kolay kontrol edilebilir olmasını sağlamaktadır [9,10]. Hidrojence zengin salin enjeksiyonu umut verici bir klinik yöntemdir. ...
Article
Full-text available
ABSTRACT: Molecular hydrogen, which has the H2 formula, is a colorless, odorless, tasteless, non-metallic and non-toxic gas. Molecular hydrogen has a high diffusion rate and spreads rapidly in biological tissues and cells. Molecular hydrogen does not change the body's redox reactions and does not cause any side effects. H2 is a selective antioxidant due to its ability to neutralize strong oxidants such as hydroxyl radicals in cells. This case increases the potential use of molecular hydrogen for preventative and therapeutic applications. In addition, by regulating various gene expressions, H2 exhibits anti-inflammatory and anti-apoptotic properties. At the same time, unlike the drugs used in the treatment of diseases, H2 penetrates the cell membrane easily. Inhaling hydrogen gas, drinking hydrogen water, injection of hydrogen-enriched saline, bathing with a hydrogen-rich water, and hydrogen-rich eye drops are the common methods of molecular hydrogen applications in the health field. Numerous studies on the biological and medical benefits of hydrogen have been carried out up to date, and research is still ongoing. As a result; due to its beneficial effects on the body and the absence of side effects, molecular hydrogen can have promising potential applications against many diseases. ÖZET: H2 formülüne sahip olan moleküler hidrojen, renksiz, kokusuz, tatsız, metalik olmayan ve toksik olmayan bir gazdır. Moleküler hidrojen (H2), yüksek difüzyon hızına sahiptir ve biyolojik doku ve hücrelerde hızla yayılır. Moleküler hidrojen, vücudun redoks reaksiyonlarını değiştirmemekte ve hiçbir yan etki göstermemektedir. Hücrelerdeki hidroksil radikal gibi güçlü oksidanları inhibe etme özelliğinden dolayı seçici bir antioksidandır. Bu durum, moleküler hidrojenin önleyici ve tedavi edici uygulamalar için potansiyelini arttırmaktadır. Ek olarak, çeşitli gen ifadelerini düzenleyerek, antiinflamatuar ve antiapoptik özellik sergilemektedir. Aynı zamanda hastalıkların tedavisinde kullanılan ilaçların aksine moleküler hidrojen, hücre zarına kolaylıkla nüfuz etmektedir. Hidrojen gazı solumak, hidrojenle zenginleştirilmiş su içmek, hidrojenle zenginleştirilmiş salin enjeksiyonu, hidrojenli su banyosu yapmak ve hidrojenli göz damlaları kullanmak sağlık alanında moleküler hidrojen uygulamasının yaygın yöntemleridir. Bugüne kadar hidrojenin biyolojik ve tıbbi faydaları üzerine çok sayıda çalışma yapılmıştır ve araştırmalar halen devam etmektedir. Sonuç olarak; vücuttaki olumlu etkileri, yan etkisinin bulunmaması sebebiyle, moleküler hidrojen birçok hastalığa karşı umut verici bir potansiyele sahiptir.
... H 2 gas is a colorless, odorless, fuel-intensive diatomic gas. There is less than 1 ppm hydrogen gas in the Earth's atmosphere [28]. H 2 does not react with most compounds, including oxygen gas, at room temperature. ...
... H 2 gas is only inflammable at temperatures exceeding 537 • C. H 2 (4-75%, v/v) is explosive due to the rapid oxidation chain reaction. H 2 can be dissolved in water under atmospheric pressure to 0.8 mM (1.6 ppm, w/v) [28]. ...
... H 2 has extensive and numerous effects on NDs including PD.Moreover, due to its beneficial efficacy with no adverse effects has been reported to date. The brain can be provided with detectable H 2 amounts through the inhalation of H 2 gas as well as HS injection [28]. On the other hand, the H 2 concentration is too low to detect using a conventional hydrogen sensor after HRW administration. ...
Article
Full-text available
Oxidative stress (OS) and neuroinflammatory stress affect many neurological disorders. Despite the clinical significance of oxidative damage in neurological disorders, still, no effective and safe treatment methods for neuro diseases are available. With this, molecular hydrogen (H2) has been recently reported as an antioxidant and anti-inflammatory agent to treat several oxidative stress-related diseases. In animal and human clinical trials, the routes for H2 administration are mainly categorized into three types: H2 gas inhalation, H2 water dissolving, and H2-dissolved saline injection. This review explores some significant progress in research on H2 use in neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, neonatal disorders of the brain, and other NDs (retinal ischemia and traumatic brain injury). Even though most neurological problems are not currently curable, these studies have shown the therapeutic potential for prevention, treatment, and mitigation of H2 administration. Several possible H2-effectors, including cell signal-ing molecules and hormones, which prevent OS and inflammation, will also be addressed. However , more clinical and other related studies are required to evaluate the direct H2 target molecule.
... Previous basic and clinical research has revealed that molecular hydrogen exerts multiple biological effects involving anti-oxidation, anti-inflammation, anti-fibrosis and antiapoptosis in many diseases of different systems (8). More recently, our group reported that inhalation of hydrogen gas can alleviate glyoxylate-induced CaOx deposition and metabolic disturbance of blood and urine in mice (9,10). ...
... Previous studies showed that the pathophysiological mechanisms that lead to kidney stone formation involve oxidative stress, inflammation and fibrosis (PMID: 33514941). Molecular hydrogen can act as an important physiological regulatory factor to cells and organs on the anti-oxidative, antiinflammatory, anti-fibrotic effects and other protective effects (8). ...
Article
Full-text available
Objective: To explore the theraputic effects and potential mechanisms of hydrogen-rich water (HRW) against oxalate-induced kidney injury. Methods: The mouse model of Calcium oxalate (CaOx) crystallization was established by feeding a soluble oxalate diet. Crystal deposition, tubular injury, fibrosis and reactive oxygen species (ROS) production in kidneys were examined by histology. Serum indexes of renal injury, inflammation and oxidative stress were detected by commercial kits. RNA sequencing (RNA-seq) was performed to screen potential pathways and the expressions of key molecules in these pathways were determined by western blotting and immunohistochemistry. Results: Crystal deposition, tubular injury, fibrosis and increased ROS production in kidneys of mice induced by oxalate diet were improved with HRW administration. The indexes of renal injury, inflammation and oxidative stress in serum of mice were upregulated by oxalate diet, which were reduced by HRW. A total of 3,566 differential genes were screened by RNA-seq and these genes were analyzed by pathway enrichment and PI3K/AKT, NF-κB, and TGF-β pathways were selected for further verification. The expressions of molecules related to PI3K-AKT pathway (PI3K, AKT, and p-AKT), NF-κB pathway (NF-κB p65, p- NF-κB p65, NLRP3, and IL-1β) and TGF-β pathway (TGF-β, TGF-βRI, TGF-βRII, p-Smad2, and p-Smad3) in renal tissues were increased by oxalate diet, which were reduced by HRW administration. Conclusion: HRW may alleviate oxalate-induced kidney injury with its anti-oxidative, anti-inflammatory and anti-fibrotic effects via inhibiting PI3K/AKT, NF-κB, and TGF-β pathways.
... As a result of this, research interest to assess adjuvant effects of strong antioxidant agents has been increasing recently in order to alleviate these issues. Studies have shown that molecular hydrogen (H 2 ) is a physiologically regulated gas molecule, which exerts antioxidant, anti-inflammatory, anti-apoptotic, and signal regulating properties [16,17]. Due to the fact that H 2 can neutralize and convert highly active oxidants like the hydroxyl radical ( • OH) and ONOO-into water, H 2 is found to be beneficial for human health. ...
... Due to the fact that H 2 can neutralize and convert highly active oxidants like the hydroxyl radical ( • OH) and ONOO-into water, H 2 is found to be beneficial for human health. H 2 specifically quenches the ROS, while maintaining the metabolic oxidationreduction reaction in the cell and can easily target organelles, including mitochondria and nuclei [16,18]. Several studies have reported that H 2 suppresses oxidative stress-induced injury in various organs, such as brain, liver, and heart with minimal toxicity [19][20][21]. ...
Article
Full-text available
Oxidative stress plays a crucial role in the development of airway diseases. Recently, hydrogen (H2) gas has been explored for its antioxidant properties. This study investigated the role of H2 gas in oxidative stress-induced alveolar and bronchial airway injury, where A549 and NCI-H292 cells were stimulated with hydrogen peroxide (H2O2) and lipopolysaccharide (LPS) in vitro. Results show that time-dependent administration of 2% H2 gas recovered the cells from oxidative stress. Various indicators including reactive oxygen species (ROS), nitric oxide (NO), antioxidant enzymes (catalase, glutathione peroxidase), intracellular calcium, and mitogen-activated protein kinase (MAPK) signaling pathway were examined to analyze the redox profile. The viability of A549 and NCI-H292 cells and the activity of antioxidant enzymes were reduced following induction by H2O2 and LPS but were later recovered using H2 gas. Additionally, the levels of oxidative stress markers, including ROS and NO, were elevated upon induction but were attenuated after treatment with H2 gas. Furthermore, H2 gas suppressed oxidative stress-induced MAPK activation and maintained calcium homeostasis. This study suggests that H2 gas can rescue airway epithelial cells from H2O2 and LPS-induced oxidative stress and may be a potential intervention for airway diseases.
... As a result of this, research interest to assess adjuvant effects of strong antioxidant agents has been increasing recently in order to alleviate these issues. Studies have shown that molecular hydrogen (H2) is a physiologically regulated gas molecule, which exerts antioxidant, anti-inflammatory, anti-apoptotic, and signal regulating properties [16,17]. Due to the fact that H2 can neutralize and convert highly active oxidants like the hydroxyl radical ( • OH) and ONOO-into water, H2 is found to be beneficial for human health. ...
... Due to the fact that H2 can neutralize and convert highly active oxidants like the hydroxyl radical ( • OH) and ONOO-into water, H2 is found to be beneficial for human health. H2 specifically quenches the ROS, while maintaining the metabolic oxidation-reduction reaction in the cell and can easily target organelles, including mitochondria and nuclei [16,18]. Several studies have reported that H2 suppresses oxidative stress-induced injury in various organs, such as brain, liver, and heart with minimal toxicity [19][20][21]. ...
Article
Full-text available
Oxidative stress plays a crucial role in the development of airway diseases. Recently, hydrogen (H2) gas has been explored for its antioxidant properties. This study investigated the role of H2 gas in oxidative stress-induced alveolar and bronchial airway injury, where A549 and NCI-H292 cells were stimulated with hydrogen peroxide (H2O2) and lipopolysaccharide (LPS) in vitro. Results show that time-dependent administration of 2% H2 gas recovered the cells from oxidative stress. Various indicators including reactive oxygen species (ROS), nitric oxide (NO), antioxidant enzymes (catalase, glutathione peroxidase), intracellular calcium, and mitogen-activated protein kinase (MAPK) signaling pathway were examined to analyze the redox profile. The viability of A549 and NCI-H292 cells and the activity of antioxidant enzymes were reduced following induction by H2O2 and LPS but were later recovered using H2 gas. Additionally, the levels of oxidative stress markers, including ROS and NO, were elevated upon induction but were attenuated after treatment with H2 gas. Furthermore, H2 gas suppressed oxidative stress-induced MAPK activation and maintained calcium homeostasis. This study suggests that H2 gas can rescue airway epithelial cells from H2O2 and LPS-induced oxidative stress and may be a potential intervention for airway diseases.
... Furthermore, hydrogen gas is lighter than air, as exemplified by its use in aircraft [64], so it is difficult to use as a treatment for ground-level plants. In the biomedical field this can be overcome by inhalation [65], but this is not an option for plants unless H 2 is used within a closed environment, which would require additional safety protocols. The volume of H 2 needed to treat widespread fields would simply not be practical from a production/delivery/application, or even from a cost analysis, point of view. ...
... Useful in biomedical arenas. [65,89] Hydrogen-rich water (HRW) ...
Article
Full-text available
Despite being trialed in other regions of the world, the use of molecular hydrogen (H2) for enhanced plant growth and the postharvest storage of crops has yet to be widely accepted in the UK. The evidence that the treatment of plants and plant products with H2 alleviates plant stress and slows crop senescence continues to grow. Many of these effects appear to be mediated by the alteration of the antioxidant capacity of plant cells. Some effects seem to involve heme oxygenase, whilst the reduction in the prosthetic group Fe3+ is also suggested as a mechanism. Although it is difficult to use as a gaseous treatment in a field setting, the use of hydrogen-rich water (HRW) has the potential to be of significant benefit to agricultural practices. However, the use of H2 in agriculture will only be adopted if the benefits outweigh the production and application costs. HRW is safe and relatively easy to use. If H2 gas or HRW are utilized in other countries for agricultural purposes, it is tempting to suggest that they could also be widely used in the UK in the future, particularly for postharvest storage, thus reducing food waste.
... Basic and clinical studies have shown that H 2 is an important regulator with antioxidant, anti-inflammatory, and antiapoptotic effects [7]. H 2 showed to have an antiinflammatory effect in LPS-activated macrophages, according to Hong et al. [8], by inhibiting the release of proinflammatory cytokines and increasing the release of the anti-inflammatory cytokine, which could be mediated by HO-1. ...
... When protein aggregates become toxic, autophagy is activated, and once excessive autophagy Kidney Dis DOI: 10.1159/000520981 causes tissue damage, autophagy is blocked. H 2 appears to play a regulatory role [7]. Guan et al. [23] revealed that H 2 was able to ameliorate chronic intermittent hypoxia (CIH)-induced kidney injury by decreasing ER stress and activating autophagy by inhibiting OS-dependent p38 and JNK MAPK activation. ...
Article
Full-text available
Background: Hydrogen is a chemical substance that has yet to be widely used in medicine. However, recent evidence indicates that hydrogen has multi-faceted pharmacological effects such as antioxidant, anti-inflammatory, and antiapoptotic properties. An increased number of studies are being conducted on the application of hydrogen in various diseases, especially those affecting the renal system. Summary: Hydrogen can be inhaled, as a gas or liquid, and can be administered orally, intravenously, or locally. Hydrogen can rapidly enter suborganelles such as mitochondria and nucleus by simple diffusion, producing reactive oxygen species (ROS) and triggering DNA damage. Hydrogen can selectively scavenge hydroxyl radical (•OH) and peroxynitrite (ONOO-), but not other reactive oxygen radicals with physiological functions, such as peroxyanion (O2-) and hydrogen peroxide (H2O2). Although the regulatory effect of hydrogen on the signal transduction pathway has been confirmed, the specific mechanism of its influence on signal molecules remains unknown. Although many studies have investigated the therapeutic and preventive effects of H2 in cellular and animal experiments, clinical trials are few and still far behind. As a result, more clinical trials are required to investigate the role of hydrogen in kidney disease, as well as the effect of its dose, timing, and form on the overall efficacy. Large-scale randomized controlled clinical trials will be required before hydrogen can be used to treat renal illnesses. Key messages: This article reviews the mechanisms of hydrogen in the treatment of renal disease and explores the possibilities of its use in clinical practice.
... [9][10][11][12] Numerous experimental and clinical studies have demonstrated that hydrogen can protect cells, tissues, and organs from oxidative stress-induced injuries by scavenging ROS. 13,14 Hydrogenrich water also can increase the antioxidant capacity in cultured human gingival fibroblasts. 15 Hydrogen-enriched electrolyzed water is guaranteed for safety in human body 16 and hydrogen also has beneficial effects on the human body, including preventive effects on the development of metabolic syndrome, 10,17 improvement of lipid metabolism, 18 antiinflammatory effects, 19,20 reductive relieving effects on the side effects of oxidative cancer treatment, 21 and improvement of autonomic nerve functions. ...
... Therefore, hydrogen molecules can be distributed in the blood and tissues of an organism. 13,33 For example, it has been reported that after drinking hydrogenrich water, the concentration of hydrogen in exhaled breath from healthy adults reaches a peak at 15 minutes in a dosedependent manner. 34 Meanwhile, under inflammation and oxidative stress, the native CRP as the pentamer can be converted into monomeric CRP (Figure 11). ...
Article
This study compared the effects of hydrogen-water (HW) bath on the oxygen radical absorption-based antioxidant capacity and the inflammatory indicator, C-reactive protein (CRP), in serum between healthy volunteers and inflammatory/collagen disease-patients. The HW bath apparatus supplied nano-bubbles with a diameter of 110 ± 10 nm and 338-682 μg/L of dissolved hydrogen after 120 minutes electrolysis, and nano-bubbles increased to 9.91 × 107/mL along with the increase of correlative dissolved hydrogen. Ten-minute HW bath increased the oxygen radical absorption-based antioxidant capacity to 110.9 ± 9.2% at post-bathing 120 minutes, although unaltered with 10-minute normal water bath at 40°C in healthy subjects. The CRP level was repressed to 70.2 ± 12.1% at 120 minutes after HW bath, although rather increased for normal water bath. In the patients with connective tissue diseases, the CRP level was repressed to 3-24% upon 9 days to 4 months of HW bathing. In another six patients with diverse autoimmune-related diseases, upon daily HW bathing as long as 2-25 months, the pre-bathing CRP level of 5.31 mg/dL decreased to 0.24 mg/dL being within the standard-range, with relief of visible inflammatory symptoms for some cases. Thus, the HW bath with high-density nano-bubbles has beneficial effects on serum antioxidant capacity, inflammation, and the skin appearance. The study was approved by the Committee of Ethics, Japanese Center of Anti-Aging Medical Sciences (Authorization No. H-15-03-2, on January 15, 2019), which was a non-profitable organization officially authenticated by the Hiroshima Prefecture Government of Japan.
... In biomedical sciences, hydrogen has demonstrated effects against inflammation, allergies and apoptosis (i.e. programmed cell death) [154]. Other therapeutic applications of hydrogen are recognized in treating rheumatoid arthritis, brain stem infarction, diabetes mellitus, neurodegenerative diseases, cancer as well as exercise or sports-induced oxidative stress [155,156]. ...
... Hydrogen acts as a physiological and metabolic regulatory factor to control the phosphorylation of proteins and the expression of genes [156,157]. As an antioxidant, hydrogen could be administered through injection of hydrogen-saturated saline solution, inhaling of hydrogen gas, drinking or bathing under hydrogen-dissolved water or enhancing its production by intestinal bacteria [154,157]. ...
Article
The increasing world population, as well as demands for energy and industrial commodities, have led to an overall rise in anthropogenic greenhouse gas emissions. Moreover, demands for fossil fuels and petrochemicals are also gradually escalating in the developing and underdeveloped countries to sustain the transportation sector, industrial power generation and commodity chemical production. To address these challenges and to meet the Paris Agreement on climate change, there has been a growing interest in the development of renewable energy resources. Hydrogen is considered a strong candidate for the next-generation energy infrastructures as an energy carrier and vector, as well as a precursor or auxiliary component for several industrial processes. This review outlines current researches and applications of hydrogen in the processing and upgrading of hydrocarbon fuels, fuel cells, platform chemicals synthesis, pharmaceuticals, aerospace and maritime uses, metallurgy and electronics. Besides, applications of hydrogen as a direct fuel, synthesis of liquid hydrocarbons via Fischer-Tropsch process and syngas fermentation to alcohols are also reviewed. The specific utilization of hydrogen in the metallurgical industry is highlighted for metal reduction and in the oxyhydrogen flame for cutting and welding of metals. Besides, the article also describes the use of hydrogen in pharmaceutical industries for drug discovery. Finally, a variety of socio-economic aspects of hydrogen as a renewable fuel is also outlined in this article.
... Moreover, molecular hydrogen inhalation therapy has been approved for advanced medical care by the Japanese Ministry of Health, Labor and Welfare. [3][4][5][6][7] A very interesting and epoch-making advantage of using hydrogen molecule for preventive medicine is that hydrogen molecules can be an easy preparation in each household by using a water electrolysis unit. In addition, hydrogen molecules are highly safe and easy to be administered to humans, and it is thought that ingested hydrogen molecules not only enter the bloodstream to circulate throughout the body but also diffuse into each part of the body without any side effect. ...
Article
Hydrogen molecules have attracted attention as a new antioxidant, but are left to be confirmedly verified whether the oral administration is highly safe or not, concurrently with retention of abundant hydrogen. When electrolysis was performed for 10 minutes using a direct-current electrolytic hydrogen-water generating bottle with tap water, "residual free chlorine" concurrently upon the production of molecular hydrogen (444 μg/L) could be appreciably decreased from 0.18 mg/L to 0.12 mg/L as quantified by a N,N-diethyl-p-phenylenediamine-dye colorimetric method. Moreover, the total chlorine concentration (residual bound chlorine plus free chlorine) was estimated to be decreased from 0.17 mg/L to 0.11 mg/L. Although a merit of electrolytic hydrogen-generating bottles exists in electrolysis for periods as short as 10 minutes, the 30-minute electrolysis brought about the more abundant hydrogen (479 μg/L) together with an oxidation-reduction potential of -245 mV; even upon this long-term electrolysis, the gross amounts of chlorine, hypochlorous acid and chloramine were shown not to be increased (0.09-0.10 mg/L from 0.11 mg/L for tap water) as detected by orthotolidine colorimetry. Above-mentioned levels of diverse-type chlorines might fulfill the World Health Organization guideline for drinking water below 5 mg/L. In addition, the dissolved ozone upon electrolytic generation of hydrogen-water was below the detection limit (< 0.05 mg/L) or undetectable, which fulfilled the official safety standards in Japan and the USA for drinking water below 0.1 mg/L, as evaluated by three methods such as an electrode-type ozone checker, indigo dye-utilizing ozone detector capillaries and potassium iodide-based colorimetry. Importantly, even when half the amount of tap water was poured into the tank of the apparatus and electrolyzed, both the residual chlorine and ozone concentrations measured were also below the safety standard. Thus, major potently harmful substances, such as residual free/bound chlorine, or hypochlorous-acid/chloramine, respectively, and dissolved ozone, as the drinking hydrogen-water was direct-current-electrolytically generated, were estimated to be repressed within safety concentration ranges with achievements of abundant hydrogen generation.
... Hydrogen (H 2 ) is an important physiological regulatory factor that has protective effects of anti-oxidation, anti-inflammation, and anti-apoptosis on cells and organs (Huang et al., 2010b). H 2 can reduce oxidative stress (Song et al., 2011), promote the scavenging of free radicals, and inhibit vascular aging (Iketani et al., 2018). ...
Article
Full-text available
Endotoxins and other harmful substances may cause an increase in permeability in endothelial cells (ECs) monolayers, as well as ECs shrinkage and death to induce lung damage. Lipopolysaccharide (LPS) can impair endothelial progenitor cells (EPCs) functions, including proliferation, migration, and tube formation. EPCs can migrate to the damaged area, differentiate into ECs, and participate in vascular repair, which improves pulmonary capillary endothelial dysfunction and maintains the integrity of the endothelial barrier. Hydrogen (H2) contributes to the repairment of lung injury and the damage of ECs. We therefore speculate that H2 protects the EPCs against LPS-induced damage, and it’s mechanism will be explored. The bone marrow-derived EPCs from ICR Mice were treated with LPS to establish a damaged model. Then EPCs were incubated with H2, and treated with PI3K inhibitor LY294002 and endothelial nitric oxide synthase (eNOS) inhibitor L-NAME. MTT assay, transwell assay and tube formation assay were used to detect the proliferation, migration and angiogenesis of EPCs. The expression levels of target proteins were detected by Western blot. Results found that H2 repaired EPCs proliferation, migration and tube formation functions damaged by LPS. LY294002 and L-NAME significantly inhibited the repaired effect of H2 on LPS-induced dysfunctions of EPCs. H2 also restored levels of phosphor-AKT (p-AKT), eNOS and phosphor-eNOS (p-eNOS) suppressed by LPS. LY294002 significantly inhibited the increase of p-AKT and eNOS and p-eNOS expression exposed by H2. L-NAME significantly inhibited the increase of eNOS and p-eNOS expression induced by H2. H2 repairs the dysfunctions of EPCs induced by LPS, which is mediated by PI3K/AKT/eNOS signaling pathway.
... However, recent studies reversed this notion by representing that H 2 reacts with extremely reactive oxygen species (ROS) like hydroxyl radical (•OH) and peroxynitrite (ONOO-) in cells. Basic and clinical research has revealed that molecular hydrogen demonstrates important medicinal properties with antioxidant, anti-inflammatory and anti-apoptopic protective effect on cells and organs [1][2][3][4][5]. To date, about two thousand scientific articles on the direction of hydrogen therapy have already been published on experimental animal models and human studies. ...
Preprint
Full-text available
Background: Hydrogen was determined to have good efficacy for reducing key blood level biomarkers associated with liver injury suggesting the compound may provide novel option for the treatment of several liver diseases by decreasing of accumulation of toxins and reduction of levels of serum liver enzymes. Materials and methods: The present pharmacological study was conducted to evaluate the effectiveness of a gastric hydrogen generating powder called "AquaActive" (AA) in a rat model of liver injury, the partial bile duct ligation (pBDL), following administration of 0.2% AA formulated in rat pellets food for 14 days. Results: The data indicate that treatment with AA at a dose of 150 mg/kg/day can effectively slow the progression of liver injury that is triggered by bile duct ligation in rats. At both 7 and 14 days post-pBDL surgery, treatment with AA exhibited reductions in ALT, AST, ALP, GGT and total bilirubin, most of which were statistically significant. At 7 days, the compound showed statistically significant decreases in ALP, GGT and total bilirubin levels. Although the values of some parameters decreased in the vehicle group by 14 days, additional reductions due to AA treatment were sustained for ALP, AST and for GGT and total bilirubin. GGT and total bilirubin level after 14 days of treatment compared to the vehicle-treated control group were observed to be highly significant (p<0.05). Conclusion: Thus AA, gastric hydrogen generating powder demonstrated a good efficacy for reducing key parameters associated with liver function in the pBDL model.
... H 2 is considered nontoxic in breathing gas mixture even at high concentrations of up to 49% vol/vol [97] and its role in cellular function, cell signalling, and the tissue healing process via biochemical and biomechanical (owing to gas accumulation in the tissue) pathways has been gradually uncovered in some recent studies. H 2 is a well-known reductive and therapeutic gas [98,99] that can efficiently decrease oxidative stress [100] and inflammation [101]. H 2 attenuated lipopolysaccharide (LPS)-induced inflammation by reducing the cytotoxic reactive oxygen species (ROS) that are produced in the inflamed tissues [102]. ...
... On a pragmatic note, treatment with H2 in the form of HRW was suggested to be useful for delaying postharvest spoilage of fruit [5]. Therefore, it is known, like animal cells [1,130], that H2 has effects, and such actions may be harnessed for future manipulation of plant growth and crop enhancement [131]. ...
Article
Full-text available
Molecular hydrogen (H2) is now considered part of the suite of small molecules that can control cellular activity. As such, H2 has been suggested to be used in the therapy of diseases in humans and in plant science to enhance the growth and productivity of plants. Treatments of plants may involve the creation of hydrogen-rich water (HRW), which can then be applied to the foliage or roots systems of the plants. However, the molecular action of H2 remains elusive. It has been suggested that the presence of H2 may act as an antioxidant or on the antioxidant capacity of cells, perhaps through the scavenging of hydroxyl radicals. H2 may act through influencing heme oxygenase activity or through the interaction with reactive nitrogen species. However, controversy exists around all the mechanisms suggested. Here, the downstream mechanisms in which H2 may be involved are critically reviewed, with a particular emphasis on the H2 mitigation of stress responses. Hopefully, this review will provide insight that may inform future research in this area.
... Animal models showed that hydrogen delivered in various ways induced therapeutic effects. Preclinical studies used intraperitoneal injections of hydrogen-saturated saline Chen et al., 2014), oral intake of hydrogen-saturated water (Zhang et al., 2012), and inhalation of gaseous H 2 (Fukuda et al., 2007;Huang et al., 2010;Kurioka et al., 2014). Inhalation of H 2 also prevented hearing loss caused by the antineoplastic drug cisplatin (Fransson et al., 2017). ...
Article
Full-text available
Noise exposure is the most important external factor causing acquired hearing loss in humans, and it is strongly associated with the production of reactive oxygen species (ROS) in the cochlea. Several studies reported that the administration of various compounds with antioxidant effects can treat oxidative stress-induced hearing loss. However, traditional systemic drug administration to the human inner ear is problematic and has not been successful in a clinical setting. Thus, there is an urgent need to develop rescue treatment for patients with acute acoustic injuries. Hydrogen gas has antioxidant effects, rapid distribution, and distributes systemically after inhalation.The purpose of this study was to determine the protective efficacy of a single dose of molecular hydrogen (H 2 ) on cochlear structures. Guinea pigs were divided into six groups and sacrificed immediately after or at 1 or 2 weeks. The animals were exposed to broadband noise for 2 h directly followed by 1-h inhalation of 2% H 2 or room air. Electrophysiological hearing thresholds using frequency-specific auditory brainstem response (ABR) were measured prior to noise exposure and before sacrifice. ABR thresholds were significantly lower in H 2 -treated animals at 2 weeks after exposure, with significant preservation of outer hair cells in the entire cochlea. Quantification of synaptophysin immunoreactivity revealed that H 2 inhalation protected the cochlear inner hair cell synaptic structures containing synaptophysin. The inflammatory response was greater in the stria vascularis, showing increased Iba1 due to H 2 inhalation.Repeated administration of H 2 inhalation may further improve the therapeutic effect. This animal model does not reproduce conditions in humans, highlighting the need for additional real-life studies in humans.
... While the mechanism of H 2 protection has not been fully determined, many experts believe that its protective action is based on antioxidant properties with direct effects on ROS (101)(102)(103)(104). Mitochondrial respiration chain, xanthine oxidase, uncoupling of NOS, and the family of nicotinamide adenine dinucleotide phosphate oxidases are significant sources of ROS (105). ...
Article
Full-text available
Despite recent advances in the management of post-cardiac arrest syndrome (PCAS), the survival rate, without neurologic sequelae after resuscitation, remains very low. Whole-body ischemia, followed by reperfusion after cardiac arrest (CA), contributes to PCAS, for which established pharmaceutical interventions are still lacking. It has been shown that a number of different processes can ultimately lead to neuronal injury and cell death in the pathology of PCAS, including vasoconstriction, protein modification, impaired mitochondrial respiration, cell death signaling, inflammation, and excessive oxidative stress. Recently, the pathophysiological effects of inhaled gases including nitric oxide (NO), molecular hydrogen (H 2), and xenon (Xe) have attracted much attention. Herein, we summarize recent literature on the application of NO, H 2 , and Xe for treating PCAS. Recent basic and clinical research has shown that these gases have cytoprotective effects against PCAS. Nevertheless, there are likely differences in the mechanisms by which these gases modulate reperfusion injury after CA. Further preclinical and clinical studies examining the combinations of standard post-CA care and inhaled gas treatment to prevent ischemia-reperfusion injury are warranted to improve outcomes in patients who are being failed by our current therapies.
... Molecular hydrogen reduces oxidative stress not only directly, but also indirectly by inducing antioxidation systems, including heme oxygenase-1 (HO-1) [60,61], superoxide dismutase (SOD) [7,9], catalase [62], and myeloperoxidase ( Figure 1) [62,63]. In a rat model of traumatic brain injury, it was observed that the beneficial effects of hydrogen inhalation were mediated by the reduction of oxidative stress and the stimulation of enzymatic activities of the endogenous antioxidants SOD and catalase [64]. ...
Article
Full-text available
The increased production of reactive oxygen species and oxidative stress are important factors contributing to the development of diseases of the cardiovascular and central nervous systems. Molecular hydrogen is recognized as an emerging therapeutic, and its positive effects in the treatment of pathologies have been documented in both experimental and clinical studies. The therapeutic potential of hydrogen is attributed to several major molecular mechanisms. This review focuses on the effects of hydrogen on the cardiovascular and central nervous systems, and summarizes current knowledge about its actions, including the regulation of redox and intracellular signaling, alterations in gene expressions, and modulation of cellular responses (e.g., autophagy, apoptosis, and tissue remodeling). We summarize the functions of hydrogen as a regulator of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated redox signaling and the association of hydrogen with mitochondria as an important target of its therapeutic action. The antioxidant functions of hydrogen are closely associated with protein kinase signaling pathways, and we discuss possible roles of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and Wnt/β-catenin pathways, which are mediated through glycogen synthase kinase 3β and its involvement in the regulation of cellular apoptosis. Additionally, current knowledge about the role of molecular hydrogen in the modulation of autophagy and matrix metalloproteinases-mediated tissue remodeling, which are other responses to cellular stress, is summarized in this review.
... 5 Hydrogen gas (H 2 ), as the most widespread gas in the universe, has been identified as a therapeutic medical gas for many diseases due to its antioxidant, anti-inflammatory and anti-apoptotic effects. 6 Earlier studies by our group have shown that 2% hydrogen inhalation has a significant relief and therapeutic effect on sepsis and multiple organ damage related to sepsis including lung, brain and intestine. [7][8][9] In addition, it has been demonstrated that H 2 can also prevent intestinal damage caused by sepsis in vitro. ...
Article
Full-text available
Objective: Sepsis-associated intestinal injury has a higher morbidity and mortality in patients with sepsis, but there is still no effective treatment. Our research team has proven that inhaling 2% hydrogen gas (H2) can effectively improve sepsis and related organ damage, but the specific molecular mechanism of its role is not clear. In this study, isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics analysis was used for studying the effect of H2 on intestinal injury in sepsis. Methods: Male C57BL/6J mice were used to prepare a sepsis model by cecal ligation and puncture (CLP). The 7-day survival rates of mice were measured. 4-kd fluorescein isothiocyanate-conjugated Dextran (FITC-dextran) blood concentration measurement, combined with hematoxylin-eosinstain (HE) staining and Western blotting, was used to study the effect of H2 on sepsis-related intestinal damage. iTRAQ-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used for studying the proteomics associated with H2 for the treatment of intestinal injury. Results: H2 can significantly improve the 7-day survival rates of sepsis mice. The load of blood and peritoneal lavage bacteria was increased, and H2 treatment can significantly reduce it. CLP mice had significant intestinal damage, and inhalation of 2% hydrogen could significantly reduce this damage. All 4194 proteins were quantified, of which 199 differentially expressed proteins were associated with the positive effect of H2 on sepsis. Functional enrichment analysis indicated that H2 may reduce intestinal injury in septic mice through the effects of thyroid hormone synthesis and nitrogen metabolism signaling pathway. Western blot showed that H2 was reduced by down-regulating the expressions of deleted in malignant brain tumors 1 protein (DMBT1), insulin receptor substrate 2 (IRS2), N-myc downregulated gene 1 (NDRG1) and serum amyloid A-1 protein (SAA1) intestinal damage in sepsis mice. Conclusion: A total of 199 differential proteins were related with H2 in the intestinal protection of sepsis. H2-related differential proteins were notably enriched in the following signaling pathways, including thyroid hormone synthesis signaling pathway, nitrogen metabolism signaling pathways, digestion and absorption signaling pathways (vitamins, proteins and fats). H2 reduced intestinal injury in septic mice by down-regulating the expressions of SAA1, NDRG1, DMBT1 and IRS2.
... H 2 is excreted in three main ways: through breathing, flatulence and metabolization by microorganisms in the colon (143). The human body can obtain exogenous H 2 through inhalation and drinking or injection of hydrogen-rich water (144). Studies have shown that drinking hydrogen-rich water in daily life is beneficial for some chronic diseases (145). ...
Article
Full-text available
Myocardial ischemic injury is among the top 10 leading causes of death from cardiovascular diseases worldwide. Myocardial ischemia is caused mainly by coronary artery occlusion or obstruction. It usually occurs when the heart is insufficiently perfused, oxygen supply to the myocardium is reduced, and energy metabolism in the myocardium is abnormal. Pathologically, myocardial ischemic injury generates a large number of inflammatory cells, thus inducing a state of oxidative stress. This sharp reduction in the number of normal cells as a result of apoptosis leads to organ and tissue damage, which can be life-threatening. Therefore, effective methods for the treatment of myocardial ischemic injury and clarification of the underlying mechanisms are urgently required. Gaseous signaling molecules, such as NO, H2S, H2, and combined gas donors, have gradually become a focus of research. Gaseous signaling molecules have shown anti-apoptotic, anti-oxidative and anti-inflammatory effects as potential therapeutic agents for myocardial ischemic injury in a large number of studies. In this review, we summarize and discuss the mechanism underlying the protective effect of gaseous signaling molecules on myocardial ischemic injury.
... These symptoms may be relieved without intervention after the patient stops hydrogen treatment. At the same time, these symptoms have no serious adverse events, and the associated harm is minimal (Atsunori et al., 2010;Huang et al., 2010b). ...
Article
Full-text available
Hydrogen has been shown to have antioxidant, anti-inflammatory, hormone-regulating, and apoptosis-resistance properties, among others. Based on a review of the research, the use of hydrogen might reduce the destructive cytokine storm and lung injury caused by SARS-CoV-2 during COVID-19 (Corona Virus Disease 2019) in the early stage, stimulating ropy sputum drainage, and ultimately reducing the incidence of severe disease. Molecular hydrogen treatment has the potential to become a new adjuvant therapy for COVID-19, but its efficacy and safety require large clinical trials and further confirmation.
... Molecular hydrogen (H 2 ) is a colorless, tasteless, odorless, and minimal molecule with high flammability [1]. Most mammals, including humans, do not synthesize hydrogenase, which is a catalyst for the activation of H 2 [2]. ...
Article
Full-text available
We investigated effects of molecular hydrogen (H2) supplementation on acid-base status, pulmonary gas exchange responses, and local muscle oxygenation during incremental exercise. Eighteen healthy, trained subjects in a randomized, double-blind, crossover design received H2-rich calcium powder (HCP) (1500 mg/day, containing 2.544 µg/day of H2) or H2-depleted placebo (1500 mg/day) for three consecutive days. They performed cycling incremental exercise starting at 20-watt work rate, increasing by 20 watts/2 min until exhaustion. Breath-by-breath pulmonary ventilation (VE) and CO2 output (VCO2) were measured and muscle deoxygenation (deoxy[Hb + Mb]) was determined via time-resolved near-infrared spectroscopy in the vastus lateralis (VL) and rectus femoris (RF). Blood gases' pH, lactate, and bicarbonate (HCO3−) concentrations were measured at rest and 120-, 200-, and 240-watt work rates. At rest, the HCP group had significantly lower VE, VCO2, and higher HCO3−, partial pressures of CO2 (PCO2) versus placebo. During exercise, a significant pH decrease and greater HCO3− continued until 240-watt workload in HCP. The VE was significantly lower in HCP versus placebo, but HCP did not affect the gas exchange status of VCO2 or oxygen uptake (VO2). HCP increased absolute values of deoxy[Hb + Mb] at the RF but not VL. Thus, HCP-induced hypoventilation would lead to lower pH and secondarily impaired balance between O2 delivery and utilization in the local RF during exercise, suggesting that HCP supplementation, which increases the at-rest antioxidant potential, affects the lower ventilation and pH status during incremental exercise. HPC induced a significantly lower O2 delivery/utilization ratio in the RF but not the VL, which may be because these regions possess inherently different vascular/metabolic control properties, perhaps related to fiber-type composition.
... Besides, the inhalation of helium aid the reversal of airflow obstruction by reducing the resistance to flow in the airways and the work of breathing in severe COPD [15], since helium has a low density and molecular weight (MW). In recent years, molecular hydrogen has been accepted to have potential for preventive and therapeutic applications against many diseases due to its extensive effects, such as antioxidant, anti-inflammatory, anti-apoptotic and rapidly diffuses [16,17]. Moreover, hydrogen is the lightest and smallest gas molecule, and more importantly, it found to function as an antioxidant to improve lung function [18]. ...
Article
Full-text available
Background To investigate whether the administration of hydrogen/oxygen mixture was superior to oxygen in improving symptoms in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods This prospective, randomized, double-blind, controlled clinical trial in 10 centres enrolled patient with AECOPD and a Breathlessness, Cough, and Sputum Scale (BCSS) score of at least 6 points. Eligible patients were randomly assigned (in a 1:1 ratio) to receive either hydrogen/oxygen mixture or oxygen therapy. Primary endpoint was the change from baseline in BCSS score at day 7. Adverse events (AEs) were recorded to evaluate safety. Results Change of BCSS score in Hydrogen/oxygen group was larger than that in Oxygen group (− 5.3 vs. − 2.4 point; difference: − 2.75 [95% CI − 3.27 to − 2.22], meeting criteria for superiority). Similar results were observed in other time points from day 2 through day 6. There was a significant reduction of Cough Assessment Test score in Hydrogen/oxygen group compared to control (− 11.00 vs. − 6.00, p < 0.001). Changes in pulmonary function, arterial blood gas and noninvasive oxygen saturation did not differ significantly between groups as well as other endpoints. AEs were reported in 34 (63.0%) patients in Hydrogen/oxygen group and 42 (77.8%) in Oxygen group. No death and equipment defects were reported during study period. Conclusions The trial demonstrated that hydrogen/oxygen therapy is superior to oxygen therapy in patient with AECOPD with acceptable safety and tolerability profile. Trial registration: Name of the registry: U.S National Library of Medicine Clinical Trials; Trial registration number: NCT04000451; Date of registration: June 27, 2019-Retrospectively registered; URL of trial registry record: https://www.clinicaltrials.gov/ct2/show/study/NCT04000451?term=04000451&draw=2&rank=1 .
... However, recent studies reversed this notion by representing that H2 reacts with extremely Reactive Oxygen Species (ROS) like hydroxyl radical (•OH) and peroxynitrite (ONOO) in cells. Basic and clinical research has revealed that molecular hydrogen demonstrates important medicinal properties with antioxidant, anti-inflammatory and anti-apoptopic protective effect on cells and organs [1][2][3][4][5]. To date, about two thousand scientific articles on the direction of hydrogen therapy have already been published on experimental animal models and human studies. ...
Article
Full-text available
Hydrogen was determined to have good efficacy for reducing key blood level biomarkers associated with liver injury suggesting the compound may provide novel option for the treatment of several liver diseases by decreasing of accumulation of toxins and reduction of levels of serum liver enzymes. The present pharmacological study was conducted to evaluate the effectiveness of a gastric hydrogen generating powder called "Aqua Active" (AA) in a rat model of liver injury, the Partial Bile Duct Ligation (PBDL), following administration of 0.2% AA formulated in rat pellets food for 14 days. The data indicate that treatment with AA at a dose of 150 mg/kg/day can effectively slow the progression of liver injury that is triggered by bile duct ligation in rats. At both 7 and 14 days post-PBDL surgery, treatment with AA exhibited reductions in ALT, AST, ALP, GGT and total bilirubin, most of which were statistically significant. At 7 days, the compound showed statistically significant decreases in ALP, GGT and total bilirubin levels. Although the values of some parameters decreased in the vehicle group by 14 days, additional reductions due to AA treatment were sustained for ALP, AST and for GGT and total bilirubin. GGT and total bilirubin level after 14 days of treatment compared to the vehicle-treated control group were observed to be highly significant (p<0.05). Thus AA, gastric hydrogen generating powder demonstrated a good efficacy for reducing key parameters associated with liver function in the PBDL model.
... H 2 gas is flammable at temperatures in excess of 527 • C and is known to explode in a rapid chain reaction with O 2 [110]. According to contemporary reports, H 2 should not exceed 4.6% in air and 4.1% by volume in pure oxygen gas [111]. Hydrogen, as a pure gas, is an explosion risk and therefore it is not safe, or practical, to store such a volatile gas in the clinical environment. ...
Article
Full-text available
Since the late 18th century, molecular hydrogen (H2) has been shown to be well tolerated, firstly in animals, and then in humans. However, although research into the beneficial effects of molecular hydrogen in both plant and mammalian physiology is gaining momentum, the idea of utilising this electrochemically neutral and non-polar diatomic compound for the benefit of health has yet to be widely accepted by regulatory bodies worldwide. Due to the precise mechanisms of H2 activity being as yet undefined, the lack of primary target identification, coupled with difficulties regarding administration methods (e.g., dosage and dosage frequencies, long-term effects of treatment, and the patient’s innate antioxidant profile), there is a requirement for H2 research to evidence how it can reasonably and most effectively be incorporated into medical practice. This review collates and assesses the current information regarding the many routes of molecular hydrogen administration in animals and humans, whilst evaluating how targeted delivery methods could be integrated into a modern healthcare system.
... Hydrogen gas (H 2 ) is a novel antioxidant, which was first reported by as being able to alleviate oxidative stress by suppressing hydroxyl radicals (•OH) and peroxynitrite (ONOO-) [12]. Hydrogen has been reported to possess antioxidative, anti-inflammation, and antiapoptosis effects [13] and demonstrated as a novel therapy for different diseases such as cerebral, myocardial, hepatic, renal, and intestinal diseases [14][15][16][17][18][19][20]. Especially, hydrogen inhalation can alleviate hypertoxic lung injury in rats [21] and protect mice against cigarette-induced chronic obstructive pulmonary disease (COPD) [22]. ...
Article
Full-text available
Acute respiratory distress syndrome (ARDS) causes uncontrolled pulmonary inflammation, resulting in high morbidity and mortality in severe cases. Given the antioxidative effect of molecular hydrogen, some recent studies suggest the potential use of molecular hydrogen as a biomedicine for the treatment of ARDS. In this study, we aimed to explore the protective effects of magnesium hydride (MgH2) on two types of ARDS models and its underlying mechanism in a lipopolysaccharide (LPS)-induced ARDS model of the A549 cell line. The results showed that LPS successfully induced oxidative stress, inflammatory reaction, apoptosis, and barrier breakdown in alveolar epithelial cells (AEC). MgH2 can exert an anti-inflammatory effect by down-regulating the expressions of inflammatory cytokines (IL-1β, IL-6, and TNF-α). In addition, MgH2 decreased oxidative stress by eliminating intracellular ROS, inhibited apoptosis by regulating the expressions of cytochrome c, Bax, and Bcl-2, and suppressed barrier breakdown by up-regulating the expression of ZO-1 and occludin. Mechanistically, the expressions of p-AKT, p-mTOR, p-P65, NLRP3, and cleaved-caspase-1 were decreased after MgH2 treatment, indicating that AKT/mTOR and NF-κB/NLRP3/IL-1β pathways participated in the protective effects of MgH2. Furthermore, the in vivo study also demonstrated that MgH2-treated mice had a better survival rate and weaker pathological damage. All these findings demonstrated that MgH2 could exert an ARDS-protective effect by regulating the AKT/mTOR and NF-κB/NLRP3/IL-1β pathways to suppress LPS-induced inflammatory reaction, oxidative stress injury, apoptosis, and barrier breakdown, which may provide a potential strategy for the prevention and treatment of ARDS.
... Gao et al. suggested that CaOx crystal could induce inflammatory reaction and oxidative stress through Akt, ERK1/2, and P38 MAPK pathways and affect amino acid metabolism and fatty acids β oxidation, resulting in kidney injury. Besides, according to a series of studies on the treatment of crystalline kidney injury, hydrogen-rich water (HRW), which has been used in the medical field, attracted our attention due to its activities of anti-oxidation, anti-inflammation, anti-fibrosis, and anti-apoptosis (12). The primary advantages of HRW are that it is a portable, easily administered, and safe means of delivering hydrogen. ...
... The search for a simple method to delay or halt the ageing process has been going on for centuries based on efficient anti-oxidant products. Growing evidence of the ability of hydrogen, either as a gas or solution, to scavenge and selectively inactivate ROS suggest that it could exert protective effects (20). Bathing every day for 3 months in waters containing molecular hydrogen (N=18) has been shown to decrease the oxidation-reduction potential (ORP) and increased the elasticity of human skin (21,22). ...
Article
Persistent oxidative stress plays an important role in a variety of pathologies, and the search for an effective and well tolerated antioxidant agent continues. Molecular hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. The non-specific mechanism of hydrogen as a therapeutic antioxidant gives it broad therapeutic potential across a wide range of medical applications, as has been shown by a substantial volume of preclinical data, as well as a growing body of clinical evidence. This review provides an overview of the therapeutic potential of hydrogen, in ageing and wellness applications as well as medical applications, including acute ischemia/reperfusion injury, inflammation and ulceration, metabolic disorders, neurodegenerative disorders, and cancer (anti-cancer effects, radiation toxicities, and side effects of cisplatin) with an emphasis on clinical data. Overall, this review shows that hydrogen is an effective antioxidant, anti-inflammatory and cytoprotective agent.
... Hydrogen gas is the lightest known gas. It is colorless and odorless, with only 1/14 of the density of air [9]. Hydrogen gas has strong reducibility and is mainly used as a reducing agent in various industrial reactions to provide electrons to oxidizing substances [10]. ...
Article
Full-text available
As a small-molecule reductant substance, hydrogen gas has an obvious antioxidant function. It can selectively neutralize hydroxyl radicals (•OH) and peroxynitrite (ONOO•) in cells, reducing oxidative stress damage. The purpose of this study was to investigate the effect of hydrogen gas (3%) on early chronic liver injury (CLI) induced by CCl4 and to preliminarily explore the protective mechanism of hydrogen gas on hepatocytes by observing the expression of uncoupling protein 2 (UCP2) in liver tissue. Here, 32 rats were divided into four groups: the control group, CCl4 group, H2 (hydrogen gas) group, and CCl4 + H2 group. The effect of hydrogen gas on early CLI was observed by serological tests, ELISA, hematoxylin and eosin staining, and oil red O staining. Immunohistochemical staining and Western blotting were used to observe the expression of UCP2 in liver tissues. We found that CCl4 can induce significant steatosis in hepatocytes. When the hydrogen gas was inhaled, hepatocyte steatosis was reduced, and the UCP2 expression level in liver tissue was increased. These results suggest that hydrogen gas might upregulate UCP2 expression levels, reduce the generation of intracellular oxygen free radicals, affect lipid metabolism in liver cells, and play a protective role in liver cells.
... H 2 administration for 9 days significantly elevated SOD-2, and increased the phosphorylation of Akt kinase at Ser473, a cell survival signaling molecule involved in the regulation of Nrf2 (111). Induction of this pathway by hydrogen results in the increase of various antioxidant enzymes such as catalase, superoxide dismutase, and heme oxygenase-1 (38,112,113). ...
Article
There are many situations of excessive production of reactive oxygen species (ROS) such as radiation, ischemia/reperfusion (I/R), and inflammation. ROS contribute to and arises from numerous cellular pathologies, diseases, and aging. ROS can cause direct deleterious effects by damaging proteins, lipids, and nucleic acids as well as exert detrimental effects on several cell signaling pathways. However, ROS are important in many cellular functions. The injurious effect of excessive ROS can hypothetically be mitigated by exogenous antioxidants, but clinically this intervention is often not favorable. In contrast, molecular hydrogen provides a variety of advantages for mitigating oxidative stress due to its unique physical and chemical properties. H2 may be superior to conventional antioxidants, since it can selectively reduce ●OH radicals while preserving important ROS that are otherwise used for normal cellular signaling. Additionally, H2 exerts many biological effects, including anti-oxidation, anti-inflammation, anti-apoptosis, and anti-shock. H2 accomplishes these effects by indirectly regulating signal transduction and gene expression, each of which involve multiple signaling pathways and crosstalk. The Keap1-Nrf2-ARE signaling pathway, which can be activated by H2 , plays a critical role in regulating cellular redox balance, metabolism, and inducing adaptive responses against cellular stress. H2 also influences the crosstalk among the regulatory mechanisms of autophagy and apoptosis, which involve MAPKs, p53, Nrf2, NF-κB, p38 MAPK, mTOR, etc. The pleiotropic effects of molecular hydrogen on various proteins, molecules and signaling pathways can at least partly explain its almost universal pluripotent therapeutic potential.
... Over the past few years, uses of H 2 have been largely anticipated as novel medical treatments [29]. H 2 has been employed in different forms to various disease models, and research on its curative effects has progressed rapidly [30,31]. In the present study, H 2 -induced ADSCs were con rmed to exhibit a high biocompatibility in vitro based on MTT and Live-Dead Cell Staining (Fig. 2). ...
Preprint
Full-text available
Purpose: This study aims to clarify the systems underlying regulation and regulatory roles of hydrogen in the myogenic differentiation of adipose mesenchymal stem cells (ADSCs). Materials and methods: In this study, ADSCs acted as an in vitro myogenic differentiating mode. First, the Alamar blue Staining and mitochondrial tracer technique were used to verify whether hydrogen could promote cell proliferation. In addition, this study assessed myogenic differentiating markers (e.g., Myogenin, Mhc and Myod protein expressions) based on the Western blotting assay, analysis on cellular morphological characteristics (e.g., Myotube number, length, diameter and maturation index), RT-PCR (Mhc and Myod mRNA expression) and Immunofluorescence analysis (Desmin, Myosin and β-actin protein expression). Lastly, to verify the myogenic differentiating system of hydrogen, Western blotting assay was performed to detect p38 and p-p38 proteins expressions. Results: Hydrogen can remarkably enhance the proliferation of ADSCs in vitro by increasing the number of single-cell mitochondria and by up-regulating the expression of myogenic biomarkers (e.g., Myod, Mhc and myotube formation). The expressions of both p38 and p-p38 were up-regulated by hydrogen. The differentiating ability was suppressed when the cells were cultivated in combination with SB203580 (p38 MAPK signal pathway inhibitor). Conclusions: The present study initially indicated that hydrogen can promote myogenic differentiation via the p38 MAPK pathway. Thus, the mentioned results present insights into myogenic differentiation and are likely to generate one potential alternative strategy for skeletal muscle related diseases.
Article
The accumulation of calcium nitrate [Ca(NO3)2] in the edible part of vegetables is one of the main reasons for the reduction of production and is harmful to human health, but so far, there is no effective method to solve environmentally problem. In this study, an environmentally friendly hydrogen-rich water (HRW) was used to study its effect on alleviating the growth inhibition of Brassica campestris spp. chinensis L. seedlings exposed to excessive Ca(NO3)2. The results of Chinese cabbage seedlings exposed to excessive Ca(NO3)2 showed that the nitrate content in edible parts of seedlings was reduced by exogenous HRW by promoting seedling growth, reducing oxidative stress, and reducing the excess of 80 mM Ca(NO3)2 which was toxic effects in the edible part of the seedlings. The conclusion was supported by the following results: (1) when Ca(NO3)2 was added excessively, HRW could effectively reduce the growth inhibition of Chinese cabbage seedlings by increasing root lengths and leaves and roots weights; (2) HRW inhibited the accumulation of the O2·−, H2O2, MDA and the conductivity of relative electrical under Ca(NO3)2 through increasing the activity of antioxidant enzymes (SOD, POD, CAT, APX); (3) HRW was processed by transporters (BcNRT1.5 and BcNRT1.8), which allowed more nitrates to be stored in the roots and reduces transport to the ground.
Article
In today's society, healthy skin and a beautiful appearance are considered the foundation of general well-being. The skin is the largest organ of the body and plays an important role in protecting it against various factors such as environmental, physical, chemical, and biological hazards. These factors include mediators that lead to oxidation reactions that produce reactive oxygen/nitrogen species and additional oxidants in the skin cells. An increase in oxidants beyond the antioxidant capacity of its defense system causes oxidative stress and chronic inflammation in the body. This response can cause further disruption of collagen fibers and hinder the functioning of skin cells that may result in the development of various skin diseases including psoriasis, atopic dermatitis and aging. In this review, we summarized the present information related to the role of oxidative stress in the pathogenesis of dermatological disorders, and its impact on physical beauty and the daily lives of patients. We also discussed how molecular hydrogen exhibits a therapeutic effect against skin diseases via its effects on oxidative stress. Furthermore, findings from this summary review indicate that molecular hydrogen might be an effective treatment modality for the prevention and treatment of skin-related illnesses.
Article
In today's society, healthy skin and a beautiful appearance are considered the foundation of general well-being. The skin is the largest organ of the body and plays an important role in protecting it against various factors such as environmental, physical, chemical, and biological hazards. These factors include mediators that lead to oxidation reactions that produce reactive oxygen/nitrogen species and additional oxidants in the skin cells. An increase in oxidants beyond the antioxidant capacity of its defense system causes oxidative stress and chronic inflammation in the body. This response can cause further disruption of collagen fibers and hinder the functioning of skin cells that may result in the development of various skin diseases including psoriasis, atopic dermatitis, and aging. In this review, we summarized the present information related to the role of oxidative stress in the pathogenesis of dermatological disorders and its impact on physical beauty and the daily lives of patients. We also discussed how molecular hydrogen exhibits a therapeutic effect against skin diseases via its effects on oxidative stress. Furthermore, findings from this summary review indicate that molecular hydrogen might be an effective treatment modality for the prevention and treatment of skin-related illnesses.
Article
Prolonged intestinal cold storage causes considerable mucosal breakdown, which could bolster bacterial translocation and cause life‐threatening infection for the transplant recipient. The intestine has an intraluminal compartment, which could be a target for intervention, but has not yet been fully investigated. Hydrogen gas exerts organ protection and has used been recently in several clinical and basic research studies on topics including intestinal transplantation. In this study, we aimed to investigate the cytoprotective efficacy of intraluminally administered hydrogen‐rich saline on cold IR injury in intestinal transplantation. Isogeneic intestinal transplantation with 6 hours of cold ischemia was performed on Lewis rats. Hydrogen‐rich saline (H2 concentration at 5 ppm) or normal saline was intraluminally introduced immediately before preservation. Graft intestine was excised 3 hours after reperfusion and analyzed. Histopathological analysis of control grafts revealed blunting of the villi and erosion. These mucosal changes were notably attenuated by intraluminal hydrogen. Intestinal mucosa damage caused by IR injury led to considerable deterioration of gut barrier function 3 h post‐reperfusion. However, this decline in permeability was critically prevented by hydrogen treatment. IR‐induced upregulation of proinflammatory cytokine mRNAs such as IL‐6 was mitigated by hydrogen treatment. Western blot revealed that hydrogen treatment regulated loss of the transmembrane protein ZO‐1. Hydrogen‐rich saline intraluminally administered in the graft intestine modulated IR injury to transplanted intestine in rats. Successful abrogation of intestinal IR injury with a novel strategy using intraluminal hydrogen may be easily clinically applicable and will compellingly improve patient care after transplantation.
Article
Oxidative stress, as results of deregulated production and accumulation of reactive oxygen and nitrogen species, is a common hallmark in a multitude of human diseases. Enormous studies have demonstrated that such imbalance of redox homeostasis is implicated in both disease initiation and progress. The development of antioxidants to target overexpressed reactive oxygen and/or nitrogen species, which is referred to as antioxidant therapy, has thus represented an important therapeutic option for the oxidative stress relevant diseases. Over the past decade, antioxidative nanotechnologies have been emerging as an alternative strategy and have shown many unique advantages over conventional antioxidants (such as enzymes and small molecules), owing to their advantageous pharmacokinetics and biodistribution, stable antioxidative activity, and more importantly, intrinsic multiple radicals scavenging properties. This review provides a comprehensive and up-to-date overview on antioxidative nanomaterials in terms of the category, their antioxidative activities and underlying mechanisms, and the potential biomedical applications. In addition, the challenges in this exciting field and future perspectives are also discussed.
Article
Gas therapy is a new therapeutic method that has been developed in recent years and shows great clinical prospects for the treatment of tumours and cardiovascular, nerve, and immune system diseases. Therapeutic gases, including oxygen, hydrogen, nitric oxide, hydrogen sulfide, xenon, and other bioactive gases are involved in modulating cell signaling pathways and have important physiological functions with substantial therapeutic potential. However, their precise delivery remains a major challenge. Recently, researchers began to use ultrasound to trigger microbubbles that have encapsulated these gases for intravenous administration. This not only enhances the contrast of ultrasound imaging, but also precisely releases gases in the targeted area using ultrasound-targeted microbubble destruction. This article reviews the latest advances in the use of microbubbles to load therapeutic gases for the treatment of diseases.
Article
Hydrogen has important values in industrial manufacture, medical health care and diverse energy application areas. Among the many possible approaches, convenient and safe hydrogen production from water electrolysis has always been a preferred in‐situ hydrogen supply technology. So far, many of the electrodes thus involved are based on rigid metals or conductive items which may encounter inconvenience or insufficiency sometimes. In order to achieve targeted release of hydrogen, appropriate administration of suitable flexible hydrogen evolution electrodes is the key. In recent years, gallium‐based liquid metals have emerged in the field of flexible and biological electrodes. Starting from this point, liquid metal is proposed here as a transformable amorphous electrode for hydrogen evolution in electrolytic water which may help mold new conceptual electrolysis and energy utilization ways. The electrochemical performances and flexible behaviors lying behind are investigated and clarified. According to the experiments, the catalytic activity of the liquid metal itself generally is not remarkable, but it would be significantly improved after being composited with certain active materials such as nickel. Further, the controllability, flexibility, and adaptability of liquid metal‐based amorphous materials which are unmatched by other electrode materials were evaluated. Overall, the motions of such shape transformable liquid metal electrodes could be controlled by electric or magnetic fields, and their deformations are compliantly adaptive to different spaces. This might easily expand the area of hydrogen evolution and lead to multi‐site in‐situ hydrogen production. The present study demonstrates the value of liquid metals in flexible energy systems and opens up more application possibilities for the electrolytic hydrogen production. This article is protected by copyright. All rights reserved.
Article
Aberrant redox-sensitive reactions and accumulation of oxidative damage can impair body functions and contribute to the development of various pathologies and aging. Although antioxidant substances have long been recognized as a measure of alleviating oxidative stress and restoring redox balance, the arsenal of effective means of preventing the development of various disorders is still limited. There is an emerging field that utilizes molecular hydrogen (H2 ) as a scavenger of free radicals and reactive oxygen species (ROS). Among the remarkable characteristics of H2 is its ability to counteract harmful effects of hydroxyl radical and peroxynitrite without affecting activity of functionally important ROS, such as hydrogen peroxide and nitric oxide. The beneficial effects of H2 have been documented in numerous clinical studies and studies on animal models and cell cultures. However, the established scavenging activity of H2 can only partially explain its beneficial effects, because the effects are achieved at very low concentrations of H2 . Given the rate of H2 diffusion, such low concentrations may not be sufficient to scavenge continuously generated ROS. H2 can also act as a signaling molecule and induce defense responses. However, the exact targets and mechanism(s) by which H2 exerts these effects are unknown. Here we analyzed both positive and negative effects of the endogenous H2 , identified the redox-sensitive components of the pathways affected by molecular hydrogen, and also discussed a potential role of molecular hydrogen in regulating cellular redox.
Article
Purpose Oxidative damage and intestinal flora dysbiosis play important roles in the progression of chronic ulcerative colitis (UC). This study explored the effect and mechanism of molecular hydrogen in chronic UC. Materials and methods Male C57BL/6 mice (19.6 ± 0.4 g, 7 weeks) were randomly divided into 3 groups: normal control (NC) group, UC (Dextran Sulfate Sodium, DSS) group, and hydrogen-rich water (HRW, 0.8 ppm)-treated UC (DSS + HRW) group. Mice in the DSS treatment group were treated with DSS for the following 3 cycles to establish chronic UC model: the first 2 cycles consisted of 2.5% DSS for 5 days, followed by drinking water for 16 days, and a third cycle consisted of 2% DSS for 4 days, followed by drinking water for 10 days. The mice in the DSS + HRW group were administered HRW daily throughout the experiment. Results The mice in the DSS groups developed typical clinical signs of colitis. HRW treatment partially ameliorated colitis symptoms, improved histopathological changes, significantly increased glutathione (GSH) concentration and decreased TNF-α level. Notably, HRW treatment significantly inhibited the growth of Enterococcus faecalis, Clostridium perfringens and Bacteroides fragilis (P < 0.05 vs. DSS group), with the relative abundance that was close to the levels in the NC group. Microarray analysis revealed that 252 genes were significantly modified after HRW treatment compared with those in the DSS treatment alone group, and 17 genes were related to inflammation, including 9 interferon-stimulated genes (ISGs). Conclusions Hydrogen-rich water partially alleviates inflammation, oxidative stress and intestinal flora dysbiosis in DSS-induced chronic UC mice.
Article
Hydrogen-rich warm water (HW) has not been verified yet for skin anti-aging effects. Daily 10 min HW (dissolved hydrogen: 338–682 μg/mL, 41 °C) bathing and skin poultice with HW-impregnated towels for 11–61 days were demonstrated to improve wrinkle degrees (29 skin-loci) from 3.14 ± 0.52 to 1.52 ± 0.74 (p < 0.001) and blotch degrees (23 loci) from 3.48 ± 0.67 to 1.74 ± 0.86 (p < 0.001) in five healthy subjects (49–66 years old), by densito-/planimetrically evaluating with an Image-J software, and ranked into six hierarchies (0, 1–5). Meanwhile, skin oiliness was evaluated to increase for the oil-poor skins, but inversely decrease for excessively oily skins, suggesting the HW’s function as skin-oiliness modulation, with an appreciably negative correlation in prior oiliness contents versus change after HW application (r = −0.345, 23 loci). Skin moisture increased upon HW application, with a negative correlation (r = −0.090, 23 loci) in prior moisture contents versus post-HW-application moisture-changing rates, meaning that HW application compensated moisture for water-deficient skins (27.5–40% moisture), but not for wet skins (>41% moisture). Thus, the HW bath together with HW poultice exerted beneficial effects on skin appearances such as wrinkles, blotches and moisture/oiliness, some of which might ensue from enhanced antioxidant ability in blood, as was previously demonstrated for the HW bath.
Article
Background and Purpose Poor-grade subarachnoid hemorrhage still has a poor prognosis. This randomized controlled clinical trial evaluated intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy in patients with poor-grade subarachnoid hemorrhage. Methods Thirty-seven patients with poor-grade subarachnoid hemorrhage were randomized to Mg+H 2 , Mg, and control groups. Mg and Mg+H 2 groups received intracisternal magnesium sulfate infusion (2.5 mmol/L) at 20 mL/h for 14 days. Mg+H 2 group also received intravenous hydrogen-rich solution infusion for 14 days. Primary outcome measures were occurrence of delayed cerebral ischemia and cerebral vasospasm. Secondary outcome measures were modified Rankin Scale and Karnofsky performance status at 3 and 12 months, Barthel index at 12 months, and serum and cerebrospinal fluid malondialdehyde and neuron-specific enolase. Results Serum neuron-specific enolase levels were significantly lower in the Mg+H 2 group from days 3 to 14 than in the control group. Cerebrospinal fluid neuron-specific enolase levels were also significantly lower in the Mg+H 2 group from days 3 to 7 than in the control group. Incidences of cerebral vasospasm and delayed cerebral ischemia were significantly higher in the control group than in other groups. Modified Rankin Scale and Karnofsky performance status did not significantly differ between the three groups at 3 months. Modified Rankin Scale scores 0 to 2 were more common in the Mg and Mg+H 2 groups at 1 year. Barthel index was higher in the Mg+H 2 group than in the control group. Conclusions Intracisternal magnesium sulfate infusion started immediately after surgery reduces the incidence of cerebral vasospasm and delayed cerebral ischemia and improves clinical outcomes without complications in patients with poor-grade subarachnoid hemorrhage. Intracisternal magnesium sulfate infusion combined with intravenous hydrogen therapy decreases serum malondialdehyde and neuron-specific enolase and improves Barthel index, indicating hydrogen has additional effects. Registration URL: https://www.umin.ac.jp/ctr/index.htm . Unique identifier: UMIN000014696.
Article
The results of Cd (cadmium) concentration, Cd²⁺ fluorescent staining, NMT (non-invasive micro-test technology) analysis of Cd absorption revealed the remarkably positive role of HRW in reducing Cd uptake by root of pak choi seedlings. BcIRT1 (iron-regulated transporter 1) and BcZIP2 (zinc-regulated transporter protein 2) are the main Cd transporters in pak choi, but their roles in the process of HRW-reduced Cd uptake is still far from being answered. In this study, we specifically verified the function of IRT1 and ZIP2 in HRW-reduced Cd absorption in pak choi and Arabidopsis thaliana. Heterologous and homologous expression in Arabidopsis thaliana displayed that Cd concentrations in wild-type (Col-0) and transgenic A. thaliana of IRT1 and ZIP2 were significantly reduced by HRW, except for irt1- and zip2-mutant. NMT detection showed that HRW not only decreased Cd²⁺ influx in root of WT and transgenic lines, but also enhanced the competition between Zn and Cd. Taken together, the HRW-induced reduction of Cd accumulation in plants may be result from depressing the expression of BcIRT1 and BcZIP2 and affecting the preference of BcIRT1 and BcZIP2 in ion uptake.
Chapter
Hydrogen-rich water (HRW) supresses the development of the diseases caused by oxidative stress such as diabetes, cancer, arteriosclerosis, and neurodegenerative diseases. It also prevents the side effects caused by hemodialysis and anti-cancer drugs. The active species in this water are hydrogen molecules and atoms. The antioxidant, antiapoptic, and anti-inflammatory properties of HRW come from the presence of the active hydrogen atoms. They scavenge for reactive oxygen species (ROS), which cause oxidative stress-related diseases. The mechanism through which the scavenging of ROS occurs is not yet fully understood. Therefore, it is advisable to be cautious when administering HRW to patients.
Article
We analysed the effects of an experimental novel protocol of intensive hydrotherapy with hydrogen-rich water (HRW) on injury recovery in athletic men who suffered an acute ankle sprain (AAS) and compared it with a RICE protocol (rest, ice, compression, elevation). Professional athletes (age 23.7 ± 4.0 years; weight 78.6 ± 5.7 kg, height 182.5 ± 4.3 cm; professional experience 5.9 ± 3.9 years) who incurred AAS during a sport-related activity were randomly assigned immediately after the injury to either hydrogen group (n = 9) or a conventional RICE treatment group (n = 9). Hydrogen group received six 30-min ankle baths with HRW throughout the first 24 h post-injury, with hydrotherapy administered every 4 hours during the intervention period. RICE group stood off the injured leg, with ice packs administered for 20 min every 3 hours, with the injured ankle compressed with an elastic bandage for 24 hours and elevated at all possible times above the level of the heart. HRW was equivalent to RICE protocol to reduce ankle swelling (2.1 ± 0.9% vs. 1.6 ± 0.8%; P = 0.26), range of motion (2.4 ± 1.3 cm vs. 2.7 ± 0.8 cm; P = 0.60), and single-leg balance with eyes opened (18.4 ± 8.2 sec vs. 10.7 ± 8.0 sec; P = 0.06) and closed (5.6 ± 8.4 sec vs. 3.9 ± 4.2 sec; P = 0.59). This non-inferiority pilot trial supports the use of HRW as an effective choice in AAS management. However, more studies are needed to corroborate these findings in other soft tissue injuries.
Article
Full-text available
Social development is possible with agriculture. With the impact of environmental pollution, natural disasters, climate change, food security, and population growth, interdisciplinary "new agriculture" is becoming an important trend of modern agriculture. Hydrogen (H2) is the most common element on earth, making up more than 75% of the mass of the universe. Hydrogen gas is colorless, odorless, and tasteless and is considered a physiologically inert molecule and a potential source for clean energy in the future. Hydrogenated agriculture including mainly hydrogen-rich water (HRW) focuses on the molecular mechanisms underlying improved agricultural product quality. Studies have shown that H2 does not only affect plant growth and development but also affects the nutritional quality and shelf life of the fruit. Hydrogenated agriculture emerges as a promising technology for the sustainability of agricultural products in modern agricultural practices thanks to the different beneficial effects of H2 such as safety, nutritional and antioxidative properties, and high product productivity. In this review, the roles of H2 in plants, seed germination, seedling growth, root development, stomatal opening and closing, pre-harvest freshness, post-harvest freshness, and the changes caused by hydrogenated agriculture at various stages of the plant such as anthocyanin synthesis have been investigated.
Article
Full-text available
The incidence of dry eye disease is increasing worldwide because of the aging population and increasing use of information technology. Dry eye disease manifests as tear-layer instability and inflammation caused by osmotic hypersensitization in tear fluids; however, to our knowledge, no agent that treats both pathologies simultaneously is available. Molecular hydrogen (H2) is known to be effective against various diseases; therefore, we aimed to elucidate the effects of H2 on tear dynamics and the treatment of dry eye disease. We revealed that administering a persistent H2-generating supplement increased the human exhaled H2 concentration (p < 0.01) and improved tear stability (p < 0.01) and dry eye symptoms (p < 0.05) significantly. Furthermore, H2 significantly increased tear secretion in healthy mice (p < 0.05) and significantly suppressed tear reduction in a murine dry eye model (p = 0.007). H2 significantly and safely improved tear stability and dry eye symptoms in a small exploratory group of 10 human subjects, a subset of whom reported dry eye symptoms prior to treatment. Furthermore, it increased tear secretion rapidly in normal mice. Therefore, H2 may be a safe and effective new treatment for dry eye disease and thus larger trials are warranted.
Article
The relevance of research on molecular hydrogen in the world has increased significantly, since it turned out to be an extremely unique reagent, since it has the ability to act at the cellular level. Hydrogen is able to cross the blood-brain barrier, penetrate into mitochondria and other areas of cells, where it exhibits antioxidant, anti-apoptotic, anti-inflammatory and cytoprotective properties. The aim of the scientific review is to theoretically substantiate the current state of the use of molecular hydrogen and hydrogen water in environmentally friendly and sports medicine. For this, evidence has been provided regarding the effect of consumption of molecular hydrogen and hydrogen water on changes in physiological and biochemical parameters, taking into account the oxidative stress caused by exercise. In addition, this review highlights possible future directions in this area of research.
Preprint
Full-text available
We investigated effects of molecular hydrogen (H2) supplementation on acid-base status, pulmonary gas exchange responses, and local muscle oxygenation during incremental exercise. Eighteen healthy, trained subjects in a randomized, double-blind, crossover design received H2-rich calcium powder (HCP) (1500 mg/day, containing 2.544 µg/day of H2) or H2-depleted placebo (1500 mg/day) for 3 consecutive days. They performed cycling incremental exercise starting at 20-watts work rate, increasing by 20 watts/2 min until exhaustion. Breath-by-breath pulmonary ventilation (VE) and CO2 output (VCO2) were measured and muscle deoxygenation (deoxy[Hb + Mb]) was determined via time-resolved-NIRS in the vastus lateralis (VL) and rectus femoris (RF). Blood gases' pH, lactate, and HCO3− concentrations were measured at rest and 120-, 200-, and 240-watt work rates. At rest, the HCP group had significantly lower VE, VCO2, and higher HCO3−, PCO2 versus placebo. During exercise, a significant pH decrease and greater HCO3− continued until 240-watts work rate in HCP. The VE was significantly lower in HCP versus placebo, but HCP did not affect the gas exchange status of VCO2 or oxygen uptake (VO2). HCP increased absolute values of deoxy[Hb + Mb] at the RF but not VL. Thus, HCP-induced hypoventilation would lead to lower pH and secondarily impaired balance between O2 delivery and utilization in the local RF during exercise, suggesting that HCP supplementation, which increases the at-rest antioxidant potential, affects the lower ventilation and pH status during incremental exercise. HPC induced a significantly lower O2 delivery/utilization ratio in the RF but not the VL, which may be because these regions possess inherently different vascular/metabolic control properties, perhaps related to fiber-type composition.
Article
Full-text available
Birth asphyxia can cause moderate to severe brain injury. It is unclear to what degree apoptotic or necrotic mechanisms of cell death account for damage after neonatal hypoxia-ischemia (HI). In a 7-d-old rat HI model, we determined the contributions of apoptosis and necrosis to neuronal injury in adjacent Nissl-stained, hematoxylin and eosin-stained, and terminal deoxynucleotidyl transferase-mediated UTP nick end-labeled sections. We found an apoptotic-necrotic continuum in the morphology of injured neurons in all regions examined. Eosinophilic necrotic neurons, typical in adult models, were rarely observed in neonatal HI. Electron microscopic analysis showed "classic" apoptotic and necrotic neurons and "hybrid" cells with intermediate characteristics. The time course of apoptotic injury varied regionally. In CA3, dentate gyrus, medial habenula, and laterodorsal thalamus, the density of apoptotic cells was highest at 24-72 hr after HI and then declined. In contrast, densities remained elevated from 12 hr to 7 d after HI in most cortical areas and in the basal ganglia. Temporal and regional patterns of neuronal death were compared with expression of caspase-3, a cysteine protease involved in the execution phase of apoptosis. Immunocytochemical and Western blot analyses showed increased caspase-3 expression in damaged hemispheres 24 hr to 7 d after HI. A p17 peptide fragment, which results from the proteolytic activation of the caspase-3 precursor, was detected in hippocampus, thalamus, and striatum but not in cerebral cortex. The continued expression of activated caspase-3 and the persistence of cells with an apoptotic morphology for days after HI suggests a prolonged role for apoptosis in neonatal hypoxic ischemic brain injury.
Article
Full-text available
This paper presents a composition method for stack-attributed tree transducers. Stackattributed tree transducers extend attributed tree transducers with a pushdown stack device for attribute values. Stack-attributed tree transducers are more powerful than attributed tree transducers due to the stack mechanism. We extend the existing composition method for attributed tree transducers to the composition method for stack-attributed tree transducers. The composition method is proved to be correct and to enjoy a closure property.
Article
Full-text available
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 objective of this study was to examine the effectiveness of hydrogen rich water (1.5-2 L/day) in an open label, 8-week study on 20 subjects with potential metabolic syndrome. Hydrogen rich water was produced, by placing a metallic magnesium stick into drinking water (hydrogen concentration; 0.55-0.65 mM), by the following chemical reaction; Mg + 2H(2)O --> Mg (OH)(2) + H(2). 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 hydrogen rich water represents a potentially novel therapeutic and preventive strategy for metabolic syndrome. The portable magnesium stick was a safe, easy and effective method of delivering hydrogen rich water for daily consumption by participants in the study.
Article
Full-text available
Background: Small intestinal bacterial overgrowth (SIBO) is a condition in which excessive levels of bacteria, mainly the colonic-type species are present in the small intestine. Recent data suggest that SIBO may contribute to the pathophysiology of Irritable bowel syndrome (IBS). The purpose of this study was to identify potential predictors of SIBO in patients with IBS. Methods: Adults with IBS based on Rome II criteria who had predominance of bloating and flatulence underwent a glucose breath test (GBT) to determine the presence of SIBO. Breath samples were obtained at baseline and at 30, 45, 60, 75 and 90 minutes after ingestion of 50 g of glucose dissolved in 150 mL of water. Results of the glucose breath test, which measures hydrogen and methane levels in the breath, were considered positive for SIBO if 1) the hydrogen or methane peak was >20 ppm when the baseline was <10 ppm, or 2) the hydrogen or methane peak increased by 12 ppm when baseline was >or=10 ppm. Results: Ninety-eight patients were identified who underwent a GBT (mean age, 49 y; 78% female). Thirty-five patients (36%) had a positive GBT result suggestive of SIBO. A positive GBT result was more likely in patients >55 years of age (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.4-9.0) and in females (OR, 4.0; 95% CI, 1.1-14.5). Hydrogen was detected more frequently in patients with diarrhea-predominant IBS (OR, 8; 95% CI, 1.4-45), and methane was the main gas detected in patients with constipation-predominant IBS (OR, 8; 95% CI, 1.3-44). There was no significant correlation between the presence of SIBO and the predominant bowel pattern or concurrent use of tegaserod, proton pump inhibitors, or opiate analgesics. Conclusions: Small intestinal bacterial overgrowth was present in a sizeable percentage of patients with IBS with predominance of bloating and flatulence. Older age and female sex were predictors of SIBO in patients with IBS. Identification of possible predictors of SIBO in patients with IBS could aid in the development of successful treatment plans.
Article
Full-text available
It has been demonstrated that hydrogen can selectively reduce hydroxyl and peroxynitrite in vitro. Since most of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals, this study was designed to test the hypothesis that hydrogen may be an effective radioprotective agent. This paper demonstrates that treating cells with hydrogen before irradiation could significantly inhibit ionizing irradiation(IR)-induced Human Lymphocyte AHH-1 cells apoptosis and increase cells viability in vitro. This paper also shows that hydrogen can protect gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde (MDA) intestinal 8-hydroxydeoxyguanosine (8-OHDG) levels and increase plasma endogenous antioxidants in vivo. It is suggested that hydrogen has a potential as an effective and safe radioprotective agent.
Article
Full-text available
Retinal ischemia-reperfusion (I/R) injury by transient elevation of intraocular pressure (IOP) is known to induce neuronal damage through the generation of reactive oxygen species. Study results have indicated that molecular hydrogen (H(2)) is an efficient antioxidant gas that selectively reduces the hydroxyl radical (*OH) and suppresses oxidative stress-induced injury in several organs. This study was conducted to explore the neuroprotective effect of H(2)-loaded eye drops on retinal I/R injury. Retinal ischemia was induced in rats by raising IOP for 60 minutes. H(2)-loaded eye drops were prepared by dissolving H(2) gas into a saline to saturated level and administered to the ocular surface continuously during the ischemia and/or reperfusion periods. One day after I/R injury, apoptotic cells in the retina were quantified, and oxidative stress was evaluated by markers such as 4-hydroxynonenal and 8-hydroxy-2-deoxyguanosine. Seven days after I/R injury, retinal damage was quantified by measuring the thickness of the retina. When H(2)-loaded eye drops were continuously administered, H(2) concentration in the vitreous body immediately increased and I/R-induced *OH level decreased. The drops reduced the number of retinal apoptotic and oxidative stress marker-positive cells and prevented retinal thinning with an accompanying activation of Müller glia, astrocytes, and microglia. The drops improved the recovery of retinal thickness by >70%. H(2) has no known toxic effects on the human body. Thus, the results suggest that H(2)-loaded eye drops are a highly useful neuroprotective and antioxidative therapeutic treatment for acute retinal I/R injury.
Article
Full-text available
It has been shown that molecular hydrogen (H(2)) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H(2)-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration-dependency of H(2) showed that H(2) as low as 0.08 ppm had almost the same effect as saturated H(2) water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H(2)-containing water, whereas production of superoxide (O(2)*(-)) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H(2) in drinking water can reduce oxidative stress in the brain. Thus, drinking H(2)-containing water may be useful in daily life to prevent or minimize the risk of life style-related oxidative stress and neurodegeneration.
Article
Full-text available
While it is well established that stroke and cerebral hypoperfusion are risk factors for Alzheimer's disease (AD), the molecular link between ischemia/hypoxia and amyloid precursor protein (APP) processing has only been recently established. Here we review the role of the release of reactive oxygen species (ROS) by the mitochondrial electron chain in response to hypoxia, providing evidence that hypoxia fosters the amyloidogenic APP processing through a biphasic mechanism that up-regulates Beta-secretase activity, which involves an early release of ROS and an activation of HIF-1Alpha.
Article
Full-text available
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. We have reported that molecular hydrogen (H(2)) acts as an efficient antioxidant (Ohsawa et al. in Nat Med 13:688-694, 2007). Here we show that hydrogen efficiently mitigates the side effects of cisplatin by reducing oxidative stress. Mice were administered cisplatin followed by inhaling hydrogen gas (1% H(2) in air). Furthermore, instead of inhaling hydrogen gas, we examined whether drinking water containing hydrogen (hydrogen water; 0.8 mM H(2) 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. Inhalation of hydrogen gas improved mortality and body-weight loss caused by cisplatin, and alleviated nephrotoxicity. Hydrogen was detected in blood when hydrogen water was placed in the stomach of a rat. Consuming hydrogen water ad libitum also reduced oxidative stress, mortality, and body-weight loss induced by cisplatin in mice. Hydrogen water improved metamorphosis accompanying decreased apoptosis in the kidney, and nephrotoxicity as assessed by serum creatinine and BUN levels. Despite its protective effects against cisplatin-induced toxicity, hydrogen did not impair anti-tumor activity of cisplatin against cancer cell lines in vitro and tumor-bearing mice in vivo. Hydrogen has potential for improving the quality of life of patients during chemotherapy by efficiently mitigating the side effects of cisplatin.
Article
Full-text available
Respiratory muscle weakness resulting from both diaphragmatic contractile dysfunction and atrophy has been hypothesized to contribute to the weaning difficulties associated with prolonged mechanical ventilation (MV). While it is clear that oxidative injury contributes to MV-induced diaphragmatic weakness, the source(s) of oxidants in the diaphragm during MV remain unknown. These experiments tested the hypothesis that xanthine oxidase (XO) contributes to MV-induced oxidant production in the rat diaphragm and that oxypurinol, a XO inhibitor, would attenuate MV-induced diaphragmatic oxidative stress, contractile dysfunction, and atrophy. Adult female Sprague-Dawley rats were randomly assigned to one of six experimental groups: 1) control, 2) control with oxypurinol, 3) 12 h of MV, 4) 12 h of MV with oxypurinol, 5) 18 h of MV, or 6) 18 h of MV with oxypurinol. XO activity was significantly elevated in the diaphragm after MV, and oxypurinol administration inhibited this activity and provided protection against MV-induced oxidative stress and contractile dysfunction. Specifically, oxypurinol treatment partially attenuated both protein oxidation and lipid peroxidation in the diaphragm during MV. Further, XO inhibition retarded MV-induced diaphragmatic contractile dysfunction at stimulation frequencies >60 Hz. Collectively, these results suggest that oxidant production by XO contributes to MV-induced oxidative injury and contractile dysfunction in the diaphragm. Nonetheless, the failure of XO inhibition to completely prevent MV-induced diaphragmatic oxidative damage suggests that other sources of oxidant production are active in the diaphragm during prolonged MV.
Article
The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)1 identified the metabolic syndrome as a multiplex risk factor for cardiovascular disease (CVD) that is deserving of more clinical attention. The cardiovascular community has responded with heightened awareness and interest. ATP III criteria for metabolic syndrome differ somewhat from those of other organizations. Consequently, the National Heart, Lung, and Blood Institute, in collaboration with the American Heart Association, convened a conference to examine scientific issues related to definition of the metabolic syndrome. The scientific evidence related to definition was reviewed and considered from several perspectives: (1) major clinical outcomes, (2) metabolic components, (3) pathogenesis, (4) clinical criteria for diagnosis, (5) risk for clinical outcomes, and (6) therapeutic interventions. ATP III viewed CVD as the primary clinical outcome of metabolic syndrome. Most individuals who develop CVD have multiple risk factors. In 1988, Reaven2 noted that several risk factors (eg, dyslipidemia, hypertension, hyperglycemia) commonly cluster together. This clustering he called Syndrome X , and he recognized it as a multiplex risk factor for CVD. Reaven and subsequently others postulated that insulin resistance underlies Syndrome X (hence the commonly used term insulin resistance syndrome ). Other researchers use the term metabolic syndrome for this clustering of metabolic risk factors. ATP III used this alternative term. It avoids the implication that insulin resistance is the primary or only cause of associated risk factors. Although ATP III identified CVD as the primary clinical outcome of the metabolic syndrome, most people with this syndrome have insulin resistance, which confers increased risk for type 2 diabetes. When diabetes becomes clinically apparent, CVD risk rises sharply. Beyond CVD and type 2 diabetes, individuals with metabolic syndrome seemingly are susceptible to other conditions, notably polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disturbances, and some …
Article
Context The Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) highlights the importance of treating patients with the metabolic syndrome to prevent cardiovascular disease. Limited information is available about the prevalence of the metabolic syndrome in the United States, however.Objective To estimate the prevalence of the metabolic syndrome in the United States as defined by the ATP III report.Design, Setting, and Participants Analysis of data on 8814 men and women aged 20 years or older from the Third National Health and Nutrition Examination Survey (1988-1994), a cross-sectional health survey of a nationally representative sample of the noninstitutionalized civilian US population.Main Outcome Measures Prevalence of the metabolic syndrome as defined by ATP III (≥3 of the following abnormalities): waist circumference greater than 102 cm in men and 88 cm in women; serum triglycerides level of at least 150 mg/dL (1.69 mmol/L); high-density lipoprotein cholesterol level of less than 40 mg/dL (1.04 mmol/L) in men and 50 mg/dL (1.29 mmol/L) in women; blood pressure of at least 130/85 mm Hg; or serum glucose level of at least 110 mg/dL (6.1 mmol/L).Results The unadjusted and age-adjusted prevalences of the metabolic syndrome were 21.8% and 23.7%, respectively. The prevalence increased from 6.7% among participants aged 20 through 29 years to 43.5% and 42.0% for participants aged 60 through 69 years and aged at least 70 years, respectively. Mexican Americans had the highest age-adjusted prevalence of the metabolic syndrome (31.9%). The age-adjusted prevalence was similar for men (24.0%) and women (23.4%). However, among African Americans, women had about a 57% higher prevalence than men did and among Mexican Americans, women had about a 26% higher prevalence than men did. Using 2000 census data, about 47 million US residents have the metabolic syndrome.Conclusions These results from a representative sample of US adults show that the metabolic syndrome is highly prevalent. The large numbers of US residents with the metabolic syndrome may have important implications for the health care sector.
Article
We studied the role of reactive oxygen intermediates (ROls) in experimental liver metastasis induced in mice by the inoculation of COLON 26-M5 murine colon cancer cells, a highly metastatic variant of COLON 26 cells, and the effect of ROIs on the invasive capacity of the cells in an in vitro chemo-invasion assay model using reconstituted basement membrane matrigel. We also measured the release of ROIs from cells using electron spin resonance (ESR) spectrometry. Hydroxyl radicals (.OH) were constitutively released from the cells. This release was augmented by pre-treatment with phorbol 12-myristate 13-acetate (PMA). In experimental liver metastasis in CDF1 mice, the administration of recombinant human superoxide dismu-tase (r-hSOD) significantly increased the number of metastatic nodules, while administration of catalase significantly inhibited metastasis formation. In vitro pre-treatment of cells with PMA significantly increased the number of metastatic nodules. Invasive capacity of the cells was markedly augmented by pre-treatment with PMA. PMA-induced augmentation was significantly inhibited by the simultaneous addition of r-hSOD to the assay. Catalase had no significant effect. Our findings suggest that ROIs play an important role in tumor invasion and metastasis, and that hydrogen peroxide (H2O2) may contribute to the retention or extravasation of circulating tumor cells. Furthermore, the superoxide anion (O2-) released by tumor cells may play an important role in basement membrane degradation.
Article
The pathogenesis of chronic rejection likely involves an interplay between immunogenic and nonimmunogenic factors. The objective of this study was to determine the influence of cold ischemic preservation injury on the rate of progression to chronic rejection in the Lewis to F344 cardiac allograft model. To induce an ischemic injury, donor hearts were stored for 3 hr at 4 degrees C in University of Wisconsin solution before transplantation. Allografts were excised at 1, 7, and 90 days after transplantation or at rejection. Vasculopathy was graded for degree of intimal thickening based on the involvement of vascular perimeter and luminal compromise. The degree of vessel injury in ischemic injured allografts at 90 days was significantly greater than in nonischemic injured allografts (2.8+/-0.4 vs. 1.6+/-0.5, P<0.05). Ischemic injury in syngeneic grafts did not induce a vasculopathy. Immunoperoxidase staining with R73 (anti-T cell) and ED1 (anti-macrophage) monoclonal antibodies revealed that, in ischemic injured allografts at 90 days after transplantation, the infiltrate was composed predominantly of T cells and macrophages. Additionally, ischemic injured allografts excised at 7 days after transplantation showed cellular infiltrates composed of R73-positive T cells and rare interleukin-2 receptor-positive cells, which was not observed in nonischemic allografts or ischemic syngeneic grafts. The progression to chronic vasculopathy in this model is principally an immunologic process, which is accelerated by an ischemic insult to the allograft. The vascular injury is mediated in part by T cells and macrophages.
Article
By its antioxidant effect, molecular hydrogen gas (H2) was reported to protect organs from tissue damage induced by ischemia reperfusion. To evaluate its anti-inflammatory effects, we established a mouse model of human inflammatory bowel disease (IBD) by supplying mice with water containing (1) dextran sodium sulfate (DSS) (5%), (2) DSS (5%) and H2, or (3) H2 only ad libitum up to 7 days. At day-7, DSS-induced pathogenic outcomes including, loss of body weight, increase of colitis score, pathogenic shortening of colon length, elevated level of IL-12, TNF-α and IL-1β in colon lesion, were significantly suppressed by the addition of H2 to DSS solution. Histological analysis also revealed that the DSS-mediated colonic tissue destruction accompanied by macrophage infiltration was remarkably suppressed by H2. Therefore, the present study indicated that H2 can prevent the development of DSS-induced colitis in mice.
Article
It is well known that some intestinal bacteria, such as Escherichia coli, can produce a remarkable amount of molecular hydrogen (H2). Although the antioxidant effects of H2 are well documented, the present study examined whether H2 released from intestinally colonized bacteria could affect Concanavalin A (ConA)-induced mouse hepatitis. Systemic antibiotics significantly decreased the level of H2 in both liver and intestines along with suppression of intestinal bacteria. As determined by the levels of AST, ALT, TNF-α and IFN-γ in serum, suppression of intestinal bacterial flora by antibiotics increased the severity of ConA-induced hepatitis, while reconstitution of intestinal flora with H2-producing E. coli, but not H2-deficient mutant E. coli, down-regulated the ConA-induced liver inflammation. Furthermore, in vitro production of both TNF-α and IFN-γ by ConA-stimulated spleen lymphocytes was significantly inhibited by the introduction of H2. These results indicate that H2 released from intestinal bacteria can suppress inflammation induced in liver by ConA.
Article
Oxidative stress is implicated in atherogenesis; however most clinical trials with dietary antioxidants failed to show marked success in preventing atherosclerotic diseases. We have found that hydrogen (dihydrogen; H2) acts as an effective antioxidant to reduce oxidative stress [I. Ohsawa, M. Ishikawa, K. Takahashi, M. Watanabe, K. Nishimaki, K. Yamagata, K. Katsura, Y. Katayama, S, Asoh, S. Ohta, Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals, Nat. Med. 13 (2007) 688–694]. Here, we investigated whether drinking H2-dissolved water at a saturated level (H2–water) ad libitum prevents arteriosclerosis using an apolipoprotein E knockout mouse (apoE−/−), a model of the spontaneous development of atherosclerosis. ApoE−/− mice drank H2–water ad libitum from 2 to 6 month old throughout the whole period. Atherosclerotic lesions were significantly reduced by ad libitum drinking of H2–water (p = 0.0069) as judged by Oil-Red-O staining series of sections of aorta. The oxidative stress level of aorta was decreased. Accumulation of macrophages in atherosclerotic lesions was confirmed. Thus, consumption of H2-dissolved water has the potential to prevent arteriosclerosis.
Article
Protective effect of hydrogen (H(2)) gas on cardiac ischemia-reperfusion (I/R) injury has been demonstrated previously. This study was designed to test the hypothesis that hydrogen-rich saline (saline saturated with molecular hydrogen), which is easy to use, induces cardioprotection against ischemia (30 min) and reperfusion (24 h) injury in rats. Adult male Sprague-Dawley rats underwent 30-min occlusion of the left anterior descending (LAD) coronary artery and 24-h reperfusion. Intraperitoneal injection of hydrogen-rich saline before reperfusion significantly decreased plasma and myocardium malondialdehyde (MDA) concentration, decreased cardiac cell apoptosis, and myocardial 8-hydroxydeoxyguanosine (8-OHdG) in area at risk zones (AAR), suppressed the activity of caspase-3, and reduced infarct size. The heart function parameters including left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), +(dP/dt)(max) and -(dP/dt)(max) were also significantly improved 24 h after reperfusion. It is concluded that hydrogen-rich saline is a novel, simple, safe, and effective method to attenuate myocardial I/R injury.
Article
Protective effect of hydrogen (H(2)) gas on cardiac ischemia-reperfusion (I/R) injury has been demonstrated previously. This study was designed to test the hypothesis that hydrogen-rich saline (saline saturated with molecular hydrogen), which is easy to use, induces cardioprotection against ischemia (30 min) and reperfusion (24 h) injury in rats. Adult male Sprague-Dawley rats underwent 30-min occlusion of the left anterior descending (LAD) coronary artery and 24-h reperfusion. Intraperitoneal injection of hydrogen-rich saline before reperfusion significantly decreased plasma and myocardium malondialdehyde (MDA) concentration, decreased cardiac cell apoptosis, and myocardial 8-hydroxydeoxyguanosine (8-OHdG) in area at risk zones (AAR), suppressed the activity of caspase-3, and reduced infarct size. The heart function parameters including left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVDP), +(dP/dt)(max) and -(dP/dt)(max) were also significantly improved 24 h after reperfusion. It is concluded that hydrogen-rich saline is a novel, simple, safe, and effective method to attenuate myocardial I/R injury. Exp Biol Med 234:1212-1219, 2009
Article
Hydrogen has been reported to selectively reduce the hydroxyl radical, the most cytotoxic of reactive oxygen species. In this study we investigated the effects of hydrogen-rich saline on the prevention of lung injury induced by intestinal ischemia/reperfusion (I/R) in rats. Male Sprague-Dawley rats (n=30, 200-220g) were divided randomly into three experimental groups: sham operated, intestinal I/R plus saline treatment (5ml/kg, i.v.), and intestinal I/R plus hydrogen-rich saline treatment (5ml/kg, i.v.) groups. Intestinal I/R was produced by 90min of intestinal ischemia followed by a 4h of reperfusion. Hydrogen-rich saline treatment decreased the neutrophil infiltration, the lipid membrane peroxidation, NF-kappaB activation and the pro-inflammatory cytokine interleukin IL-1beta and TNF-alpha in the lung tissues compared with those in saline-treated rat. Hydrogen-rich saline attenuates lung injury induced by intestinal I/R.
Article
Background: Hydrogen has been considered as a novel antioxidant that prevents injuries resulted from ischemia-reperfusion (I/R) injury in various tissues. The study was designed to determine the effect of hydrogen-rich saline on the smooth muscle contractile response to KCl, and on epithelial proliferation and apoptosis of intestine subjected to I/R. Methods: Intestinal I/R injury was induced in Sprague-Dawley rats using bulldog clamps in superior mesenteric artery by 45 min ischemia followed by 1 h reperfusion. Rats were divided randomly into four groups: sham-operated, I/R, I/R plus saline treatment, and I/R plus hydrogen-rich saline treatment groups. Hydrogen-rich saline (>0.6 mM, 6 mL/kg) or saline (6 mL/kg) was administered, respectively, via tail vein 30 min prior to reperfusion. Following reperfusion, segments of terminal jejunum were rapidly taken and transferred into isolated organ bath and responses to KCl were recorded. Samples of terminal jejunum were also taken for measuring malondialdehyde and myeloperoxidase. Apoptosis in intestinal epithelium was determined with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL). Expression and distribution of proliferating cell nuclear antigen (PCNA) were detected with immunohistochemistry. Results: Hydrogen-rich saline treatment significantly attenuated the severity of intestinal I/R injury, with inhibiting of I/R-induced apoptosis, and promoting enterocytes proliferation. Moreover, Hydrogen-rich saline treatment significantly limited the neutrophil infiltration, lipid oxidation, and ameliorated the decreased contractility response to KCl in the intestine subjected to I/R. Conclusions: These results suggest that hydrogen treatment has a protective effect against intestinal contractile dysfunction and damage induced by intestinal I/R. This protective effect is possibly due to its ability to inhibit I/R-induced oxidative stress, apoptosis, and to promote epithelial cell proliferation.
Article
Hypoxia-ischemia (HI) brain injury is a major cause of neuronal cell death especially apoptosis in the perinatal period. This study was designated to examine the effect of hydrogen therapy on apoptosis in an established neonatal HI rat pup model. Seven-day-old rat pups were subjected to left common carotid artery ligation and then 90 min hypoxia (8% oxygen at 37 C). Immediately after HI insult, pups were placed into a chamber filled with 2% H(2) for 30 min, 60 min, or 120 min, respectively. 24 h after 2% H2 therapy, the pups were decapitated and brain injury was assessed by 2,3,5-triphenyltetrazoliumchloride (TTC), Nissl, and TUNEL staining, as well as caspase-3, caspase-12 activities in the cortex and hippocampus. H(2) treatment in a duration-dependent manner significantly reduced the number of positive TUNEL cells and suppressed caspase-3 and -12 activities. These results indicated H(2) administration after HI appeared to provide brain protection via inhibition of neuronal apoptosis. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
Article
Hydrogen selectively reduces levels of hydroxyl radicals and alleviates acute oxidative stress in many models. Hydrogen-rich saline provides a high concentration of hydrogen that can be easily and safely applied. In this study, we investigated the effects of hydrogen-rich saline on the prevention of liver injury induced by obstructive jaundice in rats. Male Sprague-Dawley rats (n=56) were divided randomly into four experimental groups: sham operated, bile duct ligation (BDL) plus saline treatment [5 ml/kg, intraperitoneal (i.p.)], BDL plus low-dose hydrogen-rich saline treatment (5 ml/kg, i.p.) and BDL plus high-dose hydrogen-rich saline treatment (10 ml/kg, i.p.). The liver damage was evaluated microscopically 10 days after BDL. Serum alanine aminotransferase and aspartate aminotransferase levels, tissue malondialdehyde content, myeloperoxidase activity, tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and high-mobility group box 1 levels were all increased significantly by BDL. Hydrogen-rich saline reduced levels of these markers and relieved morphological liver injury. Additionally, hydrogen-rich saline markedly increased the activities of anti-oxidant enzymes superoxide dismutase and catalase and downregulated extracellular signal-regulated protein kinase (ERK)1/2 activation. Hydrogen-rich saline attenuates BDL-induced liver damage, possibly by the reduction of inflammation and oxidative stress and the inhibition of the ERK1/2 pathway.
Article
In the present study, we examined the mechanisms of hydrogen-rich saline, a reported therapeutic antioxidant, in the treatment of acute spinal cord contusion injury. Male Sprague-Dawley rats were used to produce a standardized model of contuses spinal cord injury (125 kdyn force). Hydrogen-rich saline was injected intraperitoneally (5 ml/kg) immediately, and at 24 and 48 h after injury. All rats were sacrificed at 72 h after spinal cord injury (SCI). Apoptotic cell death, oxidative stress, inflammation, level of Brain derived neurotrophic factor (BDNF) were evaluated. In addition, locomotor behavior was assessed using the Basso, Beattice and Bresnahan (BBB) scale. We observed that administration of hydrogen-rich saline decreased the number of apoptotic cells, suppressed oxidative stress, and improved locomotor functions. Hydrogen-rich saline increased the release of BDNF. In conclusion, hydrogen-rich saline reduced acute spinal cord contusion injury, possibly by reduction of oxidative stress and elevation of BDNF.
Article
Hydrogen-dissolved water has been suggested to be effective for alleviating the oxidative stress. In the present study, neutral-pH hydrogen-enriched electrolyzed water (NHE-water; dissolved hydrogen: 0.90-1.14 parts per million [ppm]; oxido-reduced potential: -150 approximately -80 mV), which was prepared with a water-electrolysis apparatus equipped with a non-diaphragm cell and a highly compressed activated-carbon block, was evaluated for the mutagenic and genotoxic potentials, at concentrations up to 100% dose/plate, and for the subchronic toxicity. NHE-water did not induce reverse mutations in Salmonella typhimurium strains TA100, TA1535, TA98 and TA1537, and Escherichia coli strain WP2uvrA, in either the absence or presence of rat liver S9 for exogenous metabolic activation. Similarly, NHE-water did not induce chromosome aberrations in Chinese hamster lung fibroblast cells (CHL/IU), in short-term (6-hour) tests, with or without rat liver S9, or in a continuous treatment (24-hour) test. To evaluate the subchronic toxicity, Crj:CD(SD) specific pathogen free (SPF)-rats were administered with NHE-water at a dose of 20 mL/kg/day for 28 days via intragastric infusion. NHE-water-related toxic changes were not seen in terms of any items such as clinical symptoms, body weight, food consumption, urinalysis, hematology, blood chemistry, necropsy, each organ weight and histopathology. Thus, the no-observable-adverse-effect level (NOAEL) for NHE-water was estimated to be greater than 20 mL/kg/day under the conditions examined, demonstrating the consistency with the expected safety for a human with a body weight of 60 kg to drink the NHE-water up to at least 1.2 L/day.
Article
This study is to examine if hydrogen-rich saline reduced amyloid beta (Abeta) induced neural inflammation, and learning and memory deficits in a rat model. S-D male rats (n=84, 280-330g) were divided into three groups, sham-operated, Abeta1-42 injected and Abeta1-42 plus hydrogen-rich saline-treated animals. Hydrogen-rich saline (5ml/kg, i.p., daily) was injected for 14days after intracerebroventricular injection of Abeta1-42. The levels of MDA, IL-6 and TNF-alpha were assessed by biochemical and ELISA analysis. Morris Water Maze and open field task were used to assess the memory dysfunction and motor dysfunction, respectively. LTP were used to detect the electrophysiology changes, HNE and GFAP immunohistochemistry were used to assess the oxidative stress and glial cell activation. After Abeta1-42 injection, the levels of MDA, IL-6, and TNF-alpha were increased in brain tissues and hydrogen-rich saline treatment suppressed MDA, IL-6, and TNF-alpha concentration. Hydrogen-rich saline treatment improved Morris Water Maze and enhanced LTP in hippocampus blocked by Abeta1-42. Furthermore, hydrogen-rich saline treatment also decreased the immunoreactivitiy of HNE and GFAP in hippocampus induced by Abeta1-42. In conclusion, hydrogen-rich saline prevented Abeta-induced neuroinflammation and oxidative stress, which may contribute to the improvement of memory dysfunction in this rat model.