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Tyler W LeBaron,1,2 Ram B Singh,3 Ghizal Fatima,4 Kumar Kartikey,3 Jagdish P Sharma,3 Sergej M Ostojic,5,6 Anna Gvozdjakova,7 Branislav Kura,2 Mami Noda,8 Viliam Mojto,9 Mohammad Arif Niaz,10 Jan Slezak1 1Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic; 2Molecular Hydrogen Institute, Enoch, UT, USA; 3Hospital and Research Institute, Moradabad, India; 4Era Medical College, Lucknow, India; 5Applied Bioenergetics Lab, Faculty of Sport and PE, University of Novi Sad, Novi Sad, Serbia; 6Faculty of Health Sciences, University of Pécs, Pécs, Hungary; 7Medical Faculty, Pharmacobiochemical Laboratory of 3rd Medical Department, Comenius University Bratislava, Bratislava, Slovakia; 8Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; 9Third Internal Clinic, Faculty of Medicine, Comenius University, Bratislava, Slovakia; 10Center of Nutrition Research, International College of Nutrition, Moradabad, IndiaCorrespondence: Jan SlezakCentre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, Dúbravská Cesta 9, Bratislava 841 04, Slovak RepublicTel +421 903 620 181Email jan.slezak@savba.skPurpose: Metabolic syndrome is associated with several medical risk factors including dyslipidemia, hyperglycemia, and obesity, which has become a worldwide pandemic. The sequelae of this condition increase the risk of cardiovascular and neurological disease and increased mortality. Its pathophysiology is associated with redox dysregulation, excessive inflammation, and perturbation of cellular homeostasis. Molecular hydrogen (H2) may attenuate oxidative stress, improve cellular function, and reduce chronic inflammation. Pre-clinical and clinical studies have shown promising effects of H2-rich water (HRW) on specific features of metabolic syndrome, yet the effects of long-term, high-concentration HRW in this prevalent condition remain poorly addressed.Methods: We conducted a randomized, double-blinded, placebo-controlled trial in 60 subjects (30 men and 30 women) with metabolic syndrome. An initial observation period of one week was used to acquire baseline clinical data followed by randomization to either placebo or high-concentration HRW (> 5.5 millimoles of H2 per day) for 24 weeks.Results: Supplementation with high-concentration HRW significantly reduced blood cholesterol and glucose levels, attenuated serum hemoglobin A1c, and improved biomarkers of inflammation and redox homeostasis as compared to placebo (P < 0.05). Furthermore, H2 tended to promote a mild reduction in body mass index and waist-to-hip ratio.Conclusion: Our results give further credence that high-concentration HRW might have promising effects as a therapeutic modality for attenuating risk factors of metabolic syndrome.Keywords: metabolism, fasting blood glucose, cholesterol, inflammation, oxidative stress, hydrogen water

Molecular hydrogen (H 2 ) has antioxidant, anti-inflammatory, and anti-fibrotic effects. In a rat model simulating pulmonary fibrotic changes induced by monocrotaline-induced pulmonary hypertension (MPH), we had previously explored the impact of inhaled H 2 on lung inflammation and blood pressure. In this study, we further focused the biological effects of H 2 on mast cells (MCs) and the parameters of the fibrotic phenotype of the local tissue microenvironment. MPH resulted in a significantly increased number of MCs in both the pneumatic and respiratory parts of the lungs, an increased number of tryptase-positive MCs with increased expression of TGF-β, activated interaction with immunocompetent cells (macrophages and plasma cells) and fibroblasts, and increased MC colocalization with a fibrous component of the extracellular matrix of connective tissue. The alteration in the properties of the MC population occurred together with intensified collagen fibrillogenesis and an increase in the integral volume of collagen and elastic fibers of the extracellular matrix of the pulmonary connective tissue. The exposure of H 2 together with monocrotaline (MCT), despite individual differences between animals, tended to decrease the intrapulmonary MC population and the severity of the fibrotic phenotype of the local tissue microenvironment compared to changes in animals exposed to the MCT effect alone. In addition, the activity of collagen fibrillogenesis associated with MCs and the expression of TGF-β and tryptase in MCs decreased, accompanied by a reduction in the absolute and relative content of reticular and elastic fibers in the lung stroma. Thus, with MCT exposure, inhaled H 2 has antifibrotic effects involving MCs in the lungs of rats. This reveals the unknown development mechanisms of the biological effects of H 2 on the remodeling features of the extracellular matrix under inflammatory background conditions of the tissue microenvironment.

Objectives: To assess the impact of medium-term supplementation with dihydrogen and pyrroloquinoline quinone (PQQ) on mitochondrial biomarkers, brain metabolism, and cognition in elderly individuals diagnosed with mild cognitive impairment., Design: A parallel-group, randomized, placebo-controlled, double-blind experimental design, maintaining a 1:1 allocation ratio between the experimental group (receiving the dihydrogen-producing minerals and PQQ) and the control group (receiving the placebo) throughout the trial., Setting and Participants: Thirty-four elderly individuals with mild cognitive impairment (mean age 71.9 ± 3.8 years; 28 females) voluntarily provided written consent to participate in this trial. Participants were assigned in a double-blind parallel-group design to receive either a dihydrogen-PQQ mixture (Alpha Hope®, CalerieLife, Irvine, CA) or placebo twice daily for a 6-week intervention period., Methods: The primary endpoint was the change in serum brain-derived neurotrophic factor (BDNF) from baseline to the 6-week follow-up; secondary outcomes included cognitive function indices, specific metabolites in brain tissue, brain oxygenation, and the prevalence and severity of side effects. Interaction effects (time vs. intervention) were evaluated using two-way ANOVA with repeated measures and Friedman's 2-way ANOVA by ranks, for normally distributed data with homogeneous variances and non-homogeneous variances, respectively., Results: Dihydrogen-PQQ resulted in a significant elevation in serum BDNF levels at the six-week follow-up (P = 0.01); conversely, no changes in BDNF levels were observed in the placebo group throughout the study duration (P = 0.27). A non-significant trend in the impact of interventions on BDNF levels was observed (treatment vs. time interaction, P = 0.14), suggesting a tendency for dihydrogen-PQQ to upregulate BDNF levels compared to the placebo. A significant interaction effect was observed for the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores in the orientation domain (P = 0.03), indicating the superiority of dihydrogen-PQQ over placebo in enhancing this cognitive aspect. Cerebral oxygenation saturation exhibited a significant increase following the administration of the dihydrogen-PQQ mixture, from 48.4 ± 7.2% at baseline to 52.8 ± 6.6% at 6-week post-administration (P = 0.005). In addition, brain N-acetyl aspartate levels significantly increased at seven out of thirteen locations post-intervention in participants receiving the mixture (P ≤ 0.05)., Conclusions: Despite the limited number of participants included in the study for interpreting clinical parameters, the dihydrogen-PQQ mixture blend shows promise as a potential dietary intervention for enhancing mental orientation and brain metabolism in individuals with age-related mild cognitive decline., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Stem cell therapy has emerged as a promising avenue for regenerative medicine, offering the potential to treat a wide range of debilitating diseases and injuries. Among the various types of stem cells, mesenchymal stem cells (MSCs) have garnered significant attention due to their unique properties and therapeutic potential. In recent years, researchers have been exploring novel approaches to enhance the effectiveness of MSC-based therapies. One such approach that has gained traction is the priming of MSCs with molecular hydrogen (H 2 ). This article delves into the fascinating world of mesenchymal stem cell priming with molecular hydrogen and the potential benefits it holds for regenerative medicine.

Background: Premenstrual syndrome (PMS) consists of psychiatric or somatic symptoms negatively affecting the daily life. PMS treatment can involve the use of complementary-alternative approaches. Hydrogen-rich water (HRW) has antioxidant and anti-inflammatory properties that may treat PMS. This study aimed to investigate the effect of drinking HRW on the severity of premenstrual symptoms and the quality of life of women who suffer from PMS., Methods: This study is a randomized controlled trial. Participants were randomized into two groups (intervention group=33, control group=32) using the block randomization method. Participants were requested to consume 1500-2000 mL of HRW daily in the intervention group and drink water in the placebo group. Participants began drinking either HRW or placebo water from day 16 of their menstrual cycle until day 2 of the following cycle for three menstrual cycles. The research data were collected using a Demographic Information Form, Premenstrual Syndrome Scale (PMSS), and Short form of the World Health Organization Quality of Life Questionnaire (WHOQOL- BREF)., Results: The intervention group had significantly lower mean scores than the control group in both the first and second follow-ups on the PMSS (P<0.05). In the first follow-up, the intervention group had significantly higher mean scores in the Physical Health and Psychological domains of the WHOQOL-BREF compared to the control group (P<0.05). Group × time interaction was significant for PMSS (F = 10.54, P<0.001). Group × time interaction was insignificant for WHOQOL- BREF (P>0.05)., Conclusions: The consumption of HRW reduces the severity of premenstrual symptoms and improves individuals' quality of life in physical and psychological domains., (© 2024. The Author(s).)

Study Objectives: Sleep loss contributes to various health issues and impairs neurological function. Molecular hydrogen has recently gained popularity as a nontoxic ergogenic and health promoter. The effect of molecular hydrogen on sleep and sleep-related neural systems remains unexplored. This study investigates the impact of hydrogen-rich water (HRW) on sleep behavior and neuronal activation in sleep-deprived mice., Methods: Adult C57BL/6J mice were implanted with electroencephalography (EEG) and electromyography (EMG) recording electrodes and given HRW (0.7-1.4 mM) or regular water for 7 days ad libitum. Sleep-wake cycles were recorded under baseline conditions and after acute sleep loss. Neuronal activation in sleep- and wake-related regions was assessed using cFos immunostaining., Results: HRW increased sleep consolidation in undisturbed mice and increased non-rapid-eye movement and rapid-eye-movement sleep amount in sleep-deprived mice. HRW also decreased the average amount of time for mice to fall asleep after light onset. Neuronal activation in the lateral septum, medial septum, ventrolateral preoptic area, and median preoptic area was significantly altered in all mice treated with HRW., Conclusions: HRW improves sleep consolidation and increases neuronal activation in sleep-related brain regions. It may serve as a simple, effective treatment to improve recovery after sleep loss., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Hydrogen has been shown to exhibit selective antioxidant properties against hydroxyl radicals, and exerts antioxidant and anti-inflammatory effects. The monocrotaline-induced model of pulmonary hypertension is suitable for studying substances with antioxidant activity because oxidative stress is induced by monocrotaline. On day 1, male Wistar rats were subcutaneously injected with a water-alcohol solution of monocrotaline or a control with an only water-alcohol solution. One group of monocrotaline-injected animals was placed in a plastic box that was constantly ventilated with atmospheric air containing 4% of molecular hydrogen, and the two groups of rats, injected with monocrotaline or vehicle, were placed in boxes ventilated with atmospheric air. After 21 days, hemodynamic parameters were measured under urethane narcosis. The results showed that, although hydrogen inhalation had no effect on the main markers of pulmonary hypertension induced by monocrotaline injection, there was a reduction in systemic blood pressure due to its systolic component, and a decrease in TGF-β expression, as well as a reduction in tryptase-containing mast cells.

Background: Although several studies have shown that the Coronavirus Disease 2019 (COVID-19) lockdown has had negative impacts on mental health and eating behaviors among the general population and athletes, few studies have examined the long-term effects on elite and sub-elite athletes. The present study aimed to investigate the long-term impact of COVID-19 lockdown on mental health and eating behaviors in elite versus sub-elite athletes two years into the pandemic. A cross-sectional comparative study was conducted between March and April 2022, involving athletes from 14 countries, using a convenient non-probabilistic and snowball sampling method. A total of 1420 athletes (24.5 ± 7.9 years old, 569 elites, 35% women, and 851 sub-elites, 45% women) completed an online survey-based questionnaire. The questionnaire included a sociodemographic survey, information about the COVID-19 pandemic, the Depression, Anxiety and Stress Scale-21 Items (DASS-21) for mental health assessment, and the Rapid Eating Assessment for Participants (REAP-S) for assessing eating behavior., Results: The results showed that compared to sub-elite athletes, elite athletes had lower scores on the DASS-21 (p = .001) and its subscales of depression (p = .003), anxiety (p = .007), and stress (p < .001), as well as a lower REAP-S score indicating lower diet quality (p = .013)., Conclusion: In conclusion, two years into the pandemic, elite athletes were likelier to have better mental health profiles than sub-elite athletes but surprisingly had lower diet quality., (© 2023. The Author(s).)

Skeletal muscle atrophy is associated with poor quality of life and disability. Thus, finding a new strategy for the prevention and treatment of skeletal muscle atrophy is very crucial. This study aimed to investigate the therapeutic potential of hydrogen-rich water (HRW) on muscle atrophy in a unilateral hind limb immobilization model. Thirty-six male Balb/C mice were divided into control (without immobilization), atrophy, and atrophy + hydrogen-rich water (HRW). Unilateral hind limb immobilization was induced using a splint for 7 days (atrophy) and removed for 10 days (recovery). At the end of each phase, gastrocnemius and soleus muscle weight, limb grip strength, skeletal muscle histopathology, muscle fiber size, cross-section area (CSA), serum troponin I and skeletal muscle IL-6, TNF-α and Malondialdehyde (MDA), and mRNA expression of NF-κB, BAX and Beclin-1 were evaluated. Muscle weight and limb grip strength in the H 2 -treated group were significantly improved during the atrophy phase, and this improvement continued during the recovery period. Treatment by HRW increased CSA and muscle fiber size and reduced muscle fibrosis, serum troponin I, IL-6, TNF-α and MDA which was more prominent in the atrophy phase. These data suggest that HRW could improve muscle atrophy in an immobilized condition and could be considered a new strategy during rehabilitation.

Cardiac surgery-associated acute kidney injury is a common post-operative complication, mostly due to increasing oxidative stress. Recently, molecular hydrogen (H 2 gas) has also been applied to cardiac surgery due to its ability to reduce oxidative stress. We evaluated the potential effect of H 2 application on the kidney in an in vivo model of simulated heart transplantation. Pigs underwent cardiac surgery within 3 h while connected to extracorporeal circulation (ECC) and subsequent 60 min of spontaneous reperfusion of the heart. We used two experimental groups: T-pigs after transplantation and TH-pigs after transplantation treated with 4% H 2 mixed with air during inhalation of anesthesia and throughout oxygenation of blood in ECC. The levels of creatinine, urea and phosphorus were measured in plasma. Renal tissue samples were analyzed by Western blot method for protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap-1), and superoxide dismutase (SOD1). After cardiac surgery, selected plasma biomarkers were elevated. However, H 2 therapy was followed by the normalization of all these parameters. Our results suggest activation of Nrf2/Keap1 pathway as well as increased SOD1 protein expression in the group treated with H 2 . The administration of H 2 had a protective effect on the kidneys of pigs after cardiac surgery, especially in terms of normalization of plasma biomarkers to control levels., Competing Interests: No conflicts of interest, financial or otherwise, as declared by the authors.

Background: Recently, chronic lung diseases have been found to be associated with marked inflammation and oxidative stress, which leads to fibrosis in the lungs and chronic respiratory failure. This study aims to determine if hydrogen-rich water (HRW) can enhance oxygen saturation among patients with chronic lung diseases., Methods: Ten patients with chronic lung diseases due to COPD ( n = 7), bronchial asthma ( n = 2), and tuberculosis of the lung ( n = 1) with oxygen saturation of 90-95% were provided high-concentration (>5 mM) HRW using H 2 -producing tablets for 4 weeks. Oxygen saturation was measured via oximeter and blood pressure via digital automatic BP recorder., Results: HRW administration was associated with a significant increase in oxygen saturation (SpO 2 ) and decrease in TBARS, MDA, and diene conjugates, with an increase in vitamin E and nitrite levels, compared to baseline levels. Physical training carried out after HRW therapy appeared to increase exercise tolerance and decrease hypoxia, as well as delay the need for oxygen therapy., Conclusion: Treatment with HRW in patients with hypoxia from chronic lung diseases may decrease oxidative stress and improve oxygen saturation in some patients. HRW therapy may also provide increased exercise tolerance in patients with chronic hypoxia, but further research is needed.

Introduction: Despite the progress in the management of the pandemic caused by COVID-19, it is necessary to continue exploring and explaining how this situation affected the athlete population around the world to improve their circumstances and reduce the negative impact of changes in their lifestyle conditions that were necessitated due to the pandemic. The aim of this study was to analyze the moderating influence of physical activity (PA) and dietary habits on the impact of the COVID-19 pandemic experience on sleep quality in elite and amateur athletes., Materials and Methods: A total of 1,420 elite (40.1%) and amateur (59.9%) athletes (41% women; 59% men) from 14 different countries participated in a cross-sectional design study. Data were collected using a battery of questionnaires that identified sociodemographic data, sleep quality index, PA levels, dietary habits, and the athletes' perception of their experience during the COVID-19 pandemic. Means and standard deviations were calculated for each variable. The analysis of variances and the correlation between variables were carried out with non-parametric statistics. A simple moderation effect was calculated to analyze the interaction between PA or dietary habits on the perception of the COVID-19 experience effect on sleep quality in elite and amateur athletes., Results: The PA level of elite athletes was higher than amateur athletes during COVID-19 ( p < 0.001). However, the PA level of both categories of athletes was lower during COVID-19 than pre-COVID-19 ( p < 0.01). In addition, amateurs had a higher diet quality than elite athletes during the pandemic ( p = 0.014). The perception of the COVID-19 experience as controllable was significantly higher ( p = 0.020) among elite athletes. In addition, two moderating effects had significant interactions. For amateur athletes, the PA level moderated the effect of controllable COVID-19 experience on sleep quality [ F (3,777) = 3.05; p = 0.028], while for elite athletes, the same effect was moderated by dietary habits [ F (3,506) = 4.47, p = 0.004]., Conclusion: Elite athletes had different lifestyle behaviors compared to amateurs during the COVID-19 lockdown. Furthermore, the relevance of maintaining high levels of PA for amateurs and good quality dietary habits by elite athletes was noted by the moderating effect that both variables had on the influence of the controllable experience during the COVID-19 pandemic on sleep quality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Taheri, Irandoust, Reynoso-Sánchez, Muñoz-Helú, Cruz-Morales, Torres-Ramírez, Mirmoezzi, Youzbashi, Mirakhori, Dergaa, Vancini, Mataruna-Dos-Santos, Korinna Zazueta-Beltrán, Zouhal, Morales-Beltrán, Soylu, Molgado-Sifuentes, González-Hernández, Hernández-Cruz, Bojorquez Castro, Kurt, Trabelsi, Chtourou, Seghatoleslami, López-Camacho, Mendoza-Baldenebro, Torabi, Ben Saad, Washif, Strahler, Guimarães-Mataruna, Lebaron, Shaabani Ezdini, Rezaei, Moshtagh, Yagin, Gülü, Esmaeili, Müller, Ammar, Scoditti, Garbarino, Puce, Bragazzi and Nobari.)

The anti-inflammatory and anti-apoptotic effects of molecular hydrogen, delivered as hydrogen-rich saline (HRS), on spinal cord injury was investigated. Four-month-old male Sprague Dawley rats ( n = 24) were classified into four groups: (1) control-laminectomy only at T7-T10; (2) spinal injury-dura left intact, Tator and Rivlin clip compression model applied to the spinal cord for 1 min, no treatment given; (3) HRS group-applied intraperitoneally (i.p.) for seven days; and (4) spinal injury-HRS administered i.p. for seven days after laminectomy at T7-T10 level, leaving the dura intact and applying the Tator and Rivlin clip compression model to the spinal cord for 1 min. Levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured in blood taken at day seven from all groups, and hematoxylin-eosin (H & E) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) were used to stain the tissue samples. IL-6 and TNF-α levels were significantly lower in the group treated with HRS following the spinal cord injury compared to the group whose spinal cord was damaged. A decrease in apoptosis was also observed. The anti-inflammatory and anti-apoptotic effect of IL-6 may be a clinically useful adjuvant therapy after spinal cord injury.

It is known that molecular hydrogen is a relatively stable, ubiquitous gas that is a minor component of the atmosphere. At the same time, in recent decades molecular hydrogen has been shown to have diverse biological effects. By the end of 2022, more than 2000 articles have been published in the field of hydrogen medicine, many of which are original studies. Despite the existence of several review articles on the biology of molecular hydrogen, many aspects of the research direction remain unsystematic. Therefore, the purpose of this review was to systematize ideas about the nature, characteristics, and mechanisms of the influence of molecular hydrogen on various types of cells, including stem cells. The historical aspects of the discovery of the biological activity of molecular hydrogen are presented. The ways of administering molecular hydrogen into the body are described. The molecular, cellular, tissue, and systemic effects of hydrogen are also reviewed. Specifically, the effect of hydrogen on various types of cells, including stem cells, is addressed. The existing literature indicates that the molecular and cellular effects of hydrogen qualify it to be a potentially effective agent in regenerative medicine.

Numerous benefits have been attributed to alkaline-electrolyzed-reduced water (ERW). Sometimes these claims are associated with easily debunked concepts. The observed benefits have been conjectured to be due to the intrinsic properties of ERW (e.g., negative oxidation-reduction potential (ORP), alkaline pH, H 2 gas), as well enigmatic characteristics (e.g., altered water structure, microclusters, free electrons, active hydrogen, mineral hydrides). The associated pseudoscientific marketing has contributed to the reluctance of mainstream science to accept ERW as having biological effects. Finally, through many in vitro and in vivo studies, each one of these propositions was examined and refuted one-by-one until it was conclusively demonstrated that H 2 was the exclusive agent responsible for both the negative ORP and the observed therapeutic effects of ERW. This article briefly apprised the history of ERW and comprehensively reviewed the sequential research demonstrating the importance of H 2 . We illustrated that the effects of ERW could be readily explained by the known biological effects of H 2 and by utilizing conventional chemistry without requiring any metaphysical conjecture (e.g., microclustering, free electrons, etc.) or reliance on implausible notions (e.g., alkaline water neutralizes acidic waste). The H 2 concentration of ERW should be measured to ensure it is comparable to those used in clinical studies.

Many studies demonstrate the safety of alkaline-electrolyzed-reduced water (ERW); however, several animal studies have reported significant tissue damage and hyperkalemia after drinking ERW. The mechanism responsible for these results remains unknown but may be due to electrode degradation associated with the production of higher pH, in which platinum nanoparticles and other metals that have harmful effects may leach into the water. Clinical studies have reported that, when ERW exceeds pH 9.8, some people develop dangerous hyperkalemia. Accordingly, regulations on ERW mandate that the pH of ERW should not exceed 9.8. It is recommended that those with impaired kidney function refrain from using ERW without medical supervision. Other potential safety concerns include impaired growth, reduced mineral, vitamin, and nutrient absorption, harmful bacterial overgrowth, and damage to the mucosal lining causing excessive thirst. Since the concentration of H 2 in ERW may be well below therapeutic levels, users are encouraged to frequently measure the H 2 concentration with accurate methods, avoiding ORP or ORP-based H 2 meters. Importantly, although, there have been many people that have used high-pH ERW without any issues, additional safety research on ERW is warranted, and ERW users should follow recommendations to not ingest ERW above 9.8 pH.

Non-alcoholic fatty liver disease (NAFLD) is a liver pathology affecting around 25% of the population worldwide. Excess oxidative stress, inflammation and aberrant cellular signaling can lead to this hepatic dysfunction and eventual carcinoma. Molecular hydrogen has been recognized for its selective antioxidant properties and ability to attenuate inflammation and regulate cellular function. We administered hydrogen-rich water (HRW) to 30 subjects with NAFLD in a randomized, double-blinded, placebo-controlled manner for eight weeks. Phenotypically, we observed beneficial trends (p > 0.05) in decreased weight (≈1 kg) and body mass index in the HRW group. HRW was well-tolerated, with no significant changes in liver enzymes and a trend of improved lipid profile and reduced lactate dehydrogenase levels. HRW tended to non-significantly decrease levels of nuclear factor kappa B, heat shock protein 70 and matrix metalloproteinase-9. Interestingly, there was a mild, albeit non-significant, tendency of increased levels of 8-hydroxy-2’-deoxyguanosine and malondialdehyde in the HRW group. This mild increase may be indicative of the hormetic effects of molecular hydrogen that occurred prior to the significant clinical improvements reported in previous longer-term studies. The favorable trends in this study in conjunction with previous animal and clinical findings suggest that HRW may serve as an important adjuvant therapy for promoting and maintaining optimal health and wellness. Longer term studies focused on prevention, maintenance, or treatment of NAFLD and early stages of NASH are warranted.

Molecular hydrogen ameliorates pathological states in a variety of human diseases, animal models, and cell models, but the effects of hydrogen on cancer have been rarely reported. In addition, the molecular mechanisms underlying the effects of hydrogen remain mostly unelucidated. We found that hydrogen enhances proliferation of four out of seven human cancer cell lines (the responders). The proliferation-promoting effects were not correlated with basal levels of cellular reactive oxygen species. Expression profiling of the seven cells showed that the responders have higher gene expression of mitochondrial electron transport chain (ETC) molecules than the non-responders. In addition, the responders have higher mitochondrial mass, higher mitochondrial superoxide, higher mitochondrial membrane potential, and higher mitochondrial spare respiratory capacity than the non-responders. In the responders, hydrogen provoked mitochondrial unfolded protein response (mtUPR). Suppression of cell proliferation by rotenone, an inhibitor of mitochondrial ETC complex I, was rescued by hydrogen in the responders. Hydrogen triggers mtUPR and induces cell proliferation in cancer cells that have high basal and spare mitochondrial ETC activities.

Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the world. Tumor removal remains the preferred frontline treatment; however, effective non-surgical interventions remain a high priority. 5-fluorouracil (5-FU) is a widely used chemotherapy agent, and molecular hydrogen (H 2 ) has been recognized for its antioxidant and anti-inflammatory effects, with research also suggesting its potential anti-tumor effects. Therefore, H 2 dissolved in water [hydrogen-rich water (HRW)], with or without 5-FU, may present itself as a novel therapeutic for CRC., Aim: To investigate the effects of HRW, with or without 5-FU, as a novel therapeutic for CRC., Methods: CRC was induced in the left flank of inbred Balb/c mice. A total of 24 mice bearing tumors were randomly divided into four groups ( n = 6 per group) and treated as follows: (1) Control group; (2) 5-FU group that received intraperitoneal injection of 5-FU (5 mg/kg) every other day; (3) H 2 group that received HRW, created and delivered via dissolving the H 2 -generating tablet in the animals' drinking water, with 200 μL also delivered by oral gavage; and (4) The combination group, H 2 (administered in same way as for group three) combined with 5-FU administered same way as group two., Results: Administration of HRW + 5-FU significantly improved tumor weight, tumor size, collagen content and fibrosis as compared to the CRC control group. Specifically, HRW attenuated oxidative stress (OS) and potentiated antioxidant activity (AA), whereas 5-FU treatment exacerbated OS and blunted AA. The combination of HRW + 5-FU significantly reduced tumor weight and size, as well as reduced collagen deposition and the degree of fibrosis, while further increasing OS and decreasing AA compared to administration of 5-FU alone., Conclusion: Administration of HRW, with or without 5-FU, may serve as a therapeutic for treating CRC., Competing Interests: Conflict-of-interest statement: Tarnava A is involved in commercial entities with interest in the marketing of hydrogen-rich water; LeBaron TW has received travel reimbursement, honoraria, and speaking and consultancy fees from various academic and commercial entities regarding molecular hydrogen. All other authors report no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Despite being trialed in other regions of the world, the use of molecular hydrogen (H 2 ) 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 H 2 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 Fe 3+ 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 H 2 in agriculture will only be adopted if the benefits outweigh the production and application costs. HRW is safe and relatively easy to use. If H 2 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.

COVID-19 is a widespread global pandemic with nearly 185 million confirmed cases and about four million deaths. It is caused by an infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which primarily affects the alveolar type II pneumocytes. The infection induces pathological responses including increased inflammation, oxidative stress, and apoptosis. This situation results in impaired gas exchange, hypoxia, and other sequelae that lead to multisystem organ failure and death. As summarized in this article, many interventions and therapeutics have been proposed and investigated to combat the viral infection-induced inflammation and oxidative stress that contributes to the etiology and pathogenesis of COVID-19. However, these methods have not significantly improved treatment outcomes. This may partly be attributable to their inability at restoring redox and inflammatory homeostasis, for which molecular hydrogen (H 2 ), an emerging novel medical gas, may complement. Herein, we systematically review the antioxidative, anti-inflammatory, and antiapoptotic mechanisms of H 2 . Its small molecular size and nonpolarity allow H 2 to rapidly diffuse through cell membranes and penetrate cellular organelles. H 2 has been demonstrated to suppress NF- κ B inflammatory signaling and induce the Nrf2/Keap1 antioxidant pathway, as well as to improve mitochondrial function and enhance cellular bioenergetics. Many preclinical and clinical studies have demonstrated the beneficial effects of H 2 in varying diseases, including COVID-19. However, the exact mechanisms, primary modes of action, and its true clinical effects remain to be delineated and verified. Accordingly, additional mechanistic and clinical research into this novel medical gas to combat COVID-19 complications is warranted., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Duried Alwazeer et al.)

Traumatic brain injuries (TBIs) are a leading cause of death and disability. Sports-related TBIs are estimated to be more than several million per year. The pathophysiology of TBIs involves high levels of inflammation, oxidative stress, dysregulation of ion homeostasis, mitochondrial dysfunction, and apoptosis. There is also a reduction in cerebral blood flow, leading to hypoxia and reduced removal of metabolic waste, which further exacerbates the injury. There is currently no recognized effective medical treatment or intervention for TBIs, which may in part be due to the difficulty of drug delivery through the blood-brain barrier. Molecular hydrogen has recently emerged as a neuroprotective medical gas against cerebral infarction and neurodegenerative diseases including TBIs. Its small molecular size and nonpolar nature allow it to easily diffuse through the blood-brain barrier, cell membranes and subcellular compartments. Hydrogen has been shown to exert selective anti-inflammatory, antioxidant, and anti-apoptotic effects by regulating various transcription factors and protein phosphorylation cascades. Nitric oxide is another well-recognized medical gas that plays divergent roles in protecting from and in the recovery of TBIs, as well as in contributing to their pathophysiology and injury. Excessive activation of inducible nitric oxide synthase leads to excess inflammation and oxidative/nitrosative damage as well as a paradoxical nitric oxide depletion in the locations it is needed. Hydrogen regulates nitric oxide production and metabolism, which enhances its benefits while reducing its harms. A novel H 2 -infused, nitric oxide producing beverage, Hydro Shot, may have important neuroprotective benefits for TBIs. We report preliminary indications that Hydro Shot may be a meaningful adjuvant treatment for TBIs., Competing Interests: MLM is a scientific advisor to the company. TWL reports personal fees from medical/academic conferences including travel reimbursement, honoraria, and speaking and consultancy fees from various academic and commercial entities regarding molecular hydrogen. All other authors report no conflict of interest., (© 2021 The Author(s). Published by IMR Press.)

Colitis is an inflammatory condition of the bowels associated with abdominal pain, diarrhea, fatigue, and fever. Its etiology is multifactorial but related to the overproduction of inflammatory and oxidative mediators. There is currently no cure for this disease, and drugs used to manage it often have deleterious side effects. H 2 is recognized as having anti-inflammatory and antioxidant effects, which may qualify it as a novel therapeutic for colitis. We induced an acute model of colitis in mice by administering dextran sulfate sodium (DSS) in drinking water for seven days. Mice were divided into five groups (n=6); normal, colitis, H 2 -treated colitis, sulfasalazine-treated colitis, and H 2 plus sulfasalazine-treated colitis. From days three to ten, mice were given H 2 , sulfasalazine, or both. H 2 was administered via dissolving a hydrogen-generating tablet in water to make hydrogen-rich water (HRW), which was ingested ad libitum and via oral gavage (200 μL). The Disease Activity Index (DAI), histological changes, and markers of inflammation and oxidative stress were assessed. HRW and sulfasalazine significantly improved bodyweight, DAI, mucosal damage, crypt loss, and spleen weight compared to control. Both treatments significantly decreased inflammation (high-sensitive C-reactive protein) and restored redox balance (total thiol, superoxide dismutase, catalase activity). There was a trend for the combination treatment to be more effective than either HRW or sulfasalazine alone. Furthermore, HRW tended to be as effective as, and often more effective than, sulfasalazine. HRW may serve as a therapeutic for ameliorating DSS-induced colitis in mice., (Copyright © 2021 LeBaron et al.)

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. H 2 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, H 2 exerts many biological effects, including antioxidation, anti-inflammation, anti-apoptosis, and anti-shock. H 2 accomplishes these effects by indirectly regulating signal transduction and gene expression, each of which involves multiple signaling pathways and crosstalk. The Keap1-Nrf2-ARE signaling pathway, which can be activated by H 2 , plays a critical role in regulating cellular redox balance, metabolism, and inducing adaptive responses against cellular stress. H 2 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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.

Background and Aims: While non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common liver disease worldwide, its treatment remains elusive. Since metabolic impairment plays a major role in NAFLD pathogenesis, any pharmaceuticals, such as molecular hydrogen (H 2 ), that advance lipid and glucose metabolism could be appropriate to tackle this complex condition. The aim of this study was to analyze the effects of 28-day hydrogen-rich water intake on liver fat deposition, body composition and lab chemistry profiles in overweight patients suffering from mild-to-moderate NAFLD., Methods: Twelve overweight outpatients with NAFLD (age 56.2 ± 10.0 years; body mass index 37.7 ± 5.3 kg/m 2 ; 7 women and 5 men) voluntarily participated in this double-blind, placebo-controlled, crossover trial. All patients were allocated to receive either 1 L per day of hydrogen-rich water (HRW) or placebo water for 28 days. The study was registered at ClinicalTrials.gov (ID NCT03625362)., Results: Dual-echo MRI revealed that HRW significantly reduced liver fat accumulation in individual liver regions-of-interest at 28-day follow-up, as compared to placebo administration (P < 0.05). Baseline liver fat content was reduced from 284.0 ± 118.1 mM to 256.5 ± 108.3 mM after hydrogen treatment at 28-day follow-up (percent change 2.9%; 95% CI from 0.5 to 5.5). Serum aspartate transaminase levels dropped by 10.0% (95% CI; from -23.2 to 3.4) after hydrogen treatment at 28-day follow-up. No significant differences were observed between treatment groups in either weight or body composition among participants., Conclusions: Although preliminary, the results of this trial perhaps nominate HRW as an adjuvant treatment for mild-to-moderate NAFLD. These observations provide a rationale for further clinical trials to establish safety and efficacy of molecular hydrogen in NAFLD., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

H 2 has been clinically demonstrated to provide antioxidant and anti-inflammatory effects, which makes it an attractive agent in exercise medicine. Although exercise provides a multiplicity of benefits including decreased risk of disease, it can also have detrimental effects. For example, chronic high-intensity exercise in elite athletes, or sporadic bouts of exercise (i.e., noxious exercise) in untrained individuals, result in similar pathological factors such as inflammation, oxidation, and cellular damage that arise from and result in disease. Paradoxically, exercise-induced pro-inflammatory cytokines and reactive oxygen species largely mediate the benefits of exercise. Ingestion of conventional antioxidants and anti-inflammatories often impairs exercise-induced training adaptations. Disease and noxious forms of exercise promote redox dysregulation and chronic inflammation, changes that are mitigated by H 2 administration. Beneficial exercise and H 2 administration promote cytoprotective hormesis, mitochondrial biogenesis, ATP production, increased NAD + /NADH ratio, cytoprotective phase II enzymes, heat-shock proteins, sirtuins, etc. We review the biomedical effects of exercise and those of H 2 , and we propose that hydrogen may act as an exercise mimetic and redox adaptogen, potentiate the benefits from beneficial exercise, and reduce the harm from noxious exercise. However, more research is warranted to elucidate the potential ergogenic and therapeutic effects of H 2 in exercise medicine.

Acute physical exercise increases reactive oxygen species in skeletal muscle, leading to tissue damage and fatigue. Molecular hydrogen (H 2 ) acts as a therapeutic antioxidant directly or indirectly by inducing antioxidative enzymes. Here, we examined the effects of drinking H 2 water (H 2 -infused water) on psychometric fatigue and endurance capacity in a randomized, double-blind, placebo-controlled fashion. In Experiment 1, all participants drank only placebo water in the first cycle ergometer exercise session, and for comparison they drank either H 2 water or placebo water 30 min before exercise in the second examination. In these healthy non-trained participants ( n = 99), psychometric fatigue judged by visual analogue scales was significantly decreased in the H 2 group after mild exercise. When each group was divided into 2 subgroups, the subgroup with higher visual analogue scale values was more sensitive to the effect of H 2 . In Experiment 2, trained participants ( n = 60) were subjected to moderate exercise by cycle ergometer in a similar way as in Experiment 1, but exercise was performed 10 min after drinking H 2 water. Endurance and fatigue were significantly improved in the H 2 group as judged by maximal oxygen consumption and Borg's scale, respectively. Taken together, drinking H 2 water just before exercise exhibited anti-fatigue and endurance effects.

microRNAs (miRNAs) constitute a large class of post-transcriptional regulators of gene expression. It has been estimated that miRNAs regulate up to 30% of the protein-coding genes in humans. They are implicated in many physiological and pathological processes, including those involved in radiation-induced heart damage. Biomedical studies indicate that molecular hydrogen has potential as a radioprotective agent due to its antioxidant, anti-inflammatory, and signal-modulating effects. However, the impact of molecular hydrogen on the expression of miRNAs in the heart after irradiation has not been investigated. This study aimed to explore the involvement of miRNA-1, -15b, and -21 in the protective action of molecular hydrogen on rat myocardium damaged by irradiation. The results showed that the levels of malondialdehyde (MDA) and tumor necrosis factor alpha (TNF-α) increased in the rat myocardium after irradiation. Treatment with molecular hydrogen-rich water (HRW) reduced these values to the level of non-irradiated controls. miRNA-1 is known to be involved in cardiac hypertrophy, and was significantly decreased in the rat myocardium after irradiation. Application of HRW attenuated this decrease in all evaluated time periods. miRNA-15b is considered to be anti-fibrotic, anti-hypertrophic, and anti-oxidative. Irradiation downregulated miRNA-15b, whereas administration of HRW restored these values. miRNA-21 is connected with cardiac fibrosis. We observed significant increase in miRNA-21 expression in the irradiated rat hearts. Molecular hydrogen lowered myocardial miRNA-21 levels after irradiation. This study revealed for the first time that the protective effects of molecular hydrogen on irradiation-induced heart damage may be mediated by regulating miRNA-1, -15b, and -21.

Cardiovascular diseases are the most common causes of morbidity and mortality worldwide. Redox dysregulation and a dyshomeostasis of inflammation arise from, and result in, cellular aberrations and pathological conditions, which lead to cardiovascular diseases. Despite years of intensive research, there is still no safe and effective method for their prevention and treatment. Recently, molecular hydrogen has been investigated in preclinical and clinical studies on various diseases associated with oxidative and inflammatory stress such as radiation-induced heart disease, ischemia-reperfusion injury, myocardial and brain infarction, storage of the heart, heart transplantation, etc. Hydrogen is primarily administered via inhalation, drinking hydrogen-rich water, or injection of hydrogen-rich saline. It favorably modulates signal transduction and gene expression resulting in suppression of proinflammatory cytokines, excess ROS production, and in the activation of the Nrf2 antioxidant transcription factor. Although H 2 appears to be an important biological molecule with anti-oxidant, anti-inflammatory, and anti-apoptotic effects, the exact mechanisms of action remain elusive. There is no reported clinical toxicity; however, some data suggests that H 2 has a mild hormetic-like effect, which likely mediate some of its benefits. The mechanistic data, coupled with the pre-clinical and clinical studies, suggest that H 2 may be useful for ROS/inflammation-induced cardiotoxicity and other conditions.

Background: Glioblastoma (GBM) is the most common type of primary malignant brain tumor. Molecular hydrogen has been considered a preventive and therapeutic medical gas in many diseases including cancer. In our study, we sought to assess the potential role of molecular hydrogen on GBM., Methods: The in vivo studies were performed using a rat orthotopic glioma model and a mouse subcutaneous xenograft model. Animals inhaled hydrogen gas (67%) 1 h two times per day. MR imaging studies were performed to determine the tumor volume. Immunohistochemistry (IHC), immunofluorescence staining, and flow cytometry analysis were conducted to determine the expression of surface markers. Sphere formation assay was performed to assess the cancer stem cell self-renewal capacity. Assays for cell migration, invasion, and colony formation were conducted., Results: The in vivo study showed that hydrogen inhalation could effectively suppress GBM tumor growth and prolong the survival of mice with GBM. IHC and immunofluorescence staining demonstrated that hydrogen treatment markedly downregulated the expression of markers involved in stemness (CD133, Nestin), proliferation (ki67), and angiogenesis (CD34) and also upregulated GFAP expression, a marker of differentiation. Similar results were obtained in the in vitro studies. The sphere-forming ability of glioma cells was also suppressed by hydrogen treatment. Moreover, hydrogen treatment also suppressed the migration, invasion, and colony-forming ability of glioma cells., Conclusions: Together, these results indicated that molecular hydrogen may serve as a potential anti-tumor agent in the treatment of GBM.

Uncontrolled production of oxygen and nitrogen radicals results in oxidative and nitrosative stresses that impair cellular functions and have been regarded as causative common denominators of many pathological processes. In this review, we report on the beneficial effects of molecular hydrogen in scavenging radicals in an artificial system of • OH formation. As a proof of principle, we also demonstrate that in rat hearts in vivo, administration of molecular hydrogen led to a significant increase in superoxide dismutase as well as pAKT, a cell survival signaling molecule. Irradiation of the rats caused a significant increase in lipid peroxidation, which was mitigated by pre-treatment of the animals with molecular hydrogen. The nuclear factor erythroid 2-related factor 2 is regarded as an important regulator of oxyradical homeostasis, as well as it supports the functional integrity of cells, particularly under conditions of oxidative stress. We suggest that the beneficial effects of molecular hydrogen may be through the activation of nuclear factor erythroid 2-related factor 2 pathway that promotes innate antioxidants and reduction of apoptosis, as well as inflammation.

Hyposmia is one of the earliest and the most common symptoms in Parkinson's disease (PD). The benefits of hydrogen water on motor deficits have been reported in animal PD models and PD patients, but the effects of hydrogen gas on PD patients have not been studied. We evaluated the effect of inhalation of hydrogen gas on olfactory function, non-motor symptoms, activities of daily living, and urinary 8-hydroxy-2'-deoxyguanine (8-OHdG) levels by a randomized, double-blinded, placebo-controlled, crossover trial with an 8-week washout period in 20 patients with PD. Patients inhaled either ~1.2-1.4% hydrogen-air mixture or placebo for 10 minutes twice a day for 4 weeks. Inhalation of low dose hydrogen did not significantly influence the PD clinical parameters, but it did increase urinary 8-OHdG levels by 16%. This increase in 8-OHdG is markedly less than the over 300% increase in diabetes, and is more comparable to the increase after a bout of strenuous exercise. Although increased reactive oxygen species is often associated with toxicity and disease, they also play essential roles in mediating cytoprotective cellular adaptations in a process known as hormesis. Increases of oxidative stress by hydrogen have been previously reported, along with its ability to activate the Nrf2, NF-κB pathways, and heat shock responses. Although we did not observe any beneficial effect of hydrogen in our short trial, we propose that the increased 8-OHdG and other reported stress responses from hydrogen may indicate that its beneficial effects are partly or largely mediated by hormetic mechanisms. The study was approved by the ethics review committee of Nagoya University Graduate School of Medicine (approval number 2015-0295). The clinical trial was registered at the University Hospital Medical Information Network (identifier UMIN000019082)., Competing Interests: Conflicts of interest There is no conflict of interest.

Background: Clinical studies have reported hydrogen-rich water (HRW) to have therapeutic and ergogenic effects. The aim of this study was to determine the effect of acute supplementation with HRW on exercise performance as measured by VO 2 , respiratory exchange ratio (RER), heart rate (HR), and respiratory rate (RR)., Methods: Baseline levels of all exercise indices were determined in nineteen (4 female, 23.4 ± 9.1 yr; 15 male, 30.5 ± 6.8 yr) healthy subjects using a graded treadmill exercise test to exhaustion. Each subject was examined two additional times in a randomized double-blinded, placebo-controlled crossover fashion. Subjects received either HRW or placebo, which was consumed the day before and the day of the testing. HRW was delivered using the hydrogen-producing tablets, DrinkHRW (5 mg of H 2 ). All data was analyzed with SPSS using pairwise comparisons with Bonferroni adjustment., Results: HRW supplementation did not influence maximal or minimal indices of exercise performance (VO 2 , RER, HR and RR) (p < 0.05). However, HRW significantly decreased average exercising RR and HR (p < 0.05). HRW decreased exercising HR during minutes 1-9 of the graded exercise test (121 ± 26 bpm) compared to placebo (126 ± 26 bpm) and baseline (124 ± 27 bpm) (p < 0.001) without substantially influencing VO 2 ., Conclusion: Acute supplementation of DrinkHRW tablets may benefit submaximal aerobic exercise performance by lowering exercising HR. Further studies are needed to determine the influence and practical significance of HRW on varying exercise intensities as well as optimal dosing protocols and the effects of chronic use.

Aim: To identify the effect of hydrogen-rich water (HRW) and electrolyzed-alkaline water (EAW) on high-fat-induced non-alcoholic fatty acid disease in mice., Methods: Mice were divided into four groups: (1) Regular diet (RD)/regular water (RW); (2) high-fat diet (HFD)/RW; (3) RD/EAW; and (4) HFD/EAW. Weight and body composition were measured. After twelve weeks, animals were sacrificed, and livers were processed for histology and reverse-transcriptase polymerase chain reaction. A similar experiment was performed using HRW to determine the influence and importance of molecular hydrogen (H 2 ) in EAW. Finally, we compared the response of hepatocytes isolated from mice drinking HRW or RW to palmitate overload., Results: EAW had several properties important to the study: (1) pH = 11; (2) oxidation-reduction potential of -495 mV; and (3) H 2 = 0.2 mg/L. However, in contrast to other studies, there were no differences between the groups drinking EAW or RW in either the RD or HFD groups. We hypothesized that the null result was due to low H 2 concentrations. Therefore, we evaluated the effects of RW and low and high HRW concentrations (L-HRW = 0.3 mg H 2 /L and H-HRW = 0.8 mg H 2 /L, respectively) in mice fed an HFD. Compared to RW and L-HRW, H-HRW resulted in a lower increase in fat mass (46% vs 61%), an increase in lean body mass (42% vs 28%), and a decrease in hepatic lipid accumulation ( P < 0.01). Lastly, exposure of hepatocytes isolated from mice drinking H-HRW to palmitate overload demonstrated a protective effect from H 2 by reducing hepatocyte lipid accumulation in comparison to mice drinking regular water., Conclusion: H 2 is the therapeutic agent in electrolyzed-alkaline water and attenuates HFD-induced nonalcoholic fatty liver disease in mice., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest.

Due to its anti-inflammatory and anti-oxidative effects, recent research has demonstrated that molecular hydrogen can serve as a new medical approach for depression, anxiety and traumatic brain injury. However, its potential effects on neurodevelopmental diseases, such as autism are still elusive. The present study aims to investigate the potential effects of hydrogen-rich water (HRW) administration on valproic acid (VPA)-induced autistic-like behavioral deficits, and the associated underlying mechanism in adolescent mice offspring. Pregnant ICR mice were randomly divided into five groups ( n = 6). One group was injected with saline (NAV group) and provided hydrogen-free water. The other four groups were injected with VPA (600 mg/kg, intraperitoneally, i.p.) on pregnant day (PND) 12.5. One group was provided with hydrogen-free water (VEH group) and the other three groups were provided HRW at different segments, postnatal day 1 (PND 1) to PND 21 (PHV group), PND 13 to PND 21 (PVS group) or from PND 13 to postnatal day 42 (PVL group). Behavioral tests, including open field, novelty suppressed feeding (NSF), hot plate, social interaction (SI) and contextual fear memory tests were conducted between postnatal day 35-42. We found that HRW administration significantly reversed the autistic-like behaviors induced by maternal VPA exposure in the adolescent offspring of both male and female adolescent offspring. Furthermore, HRW administration significantly reversed the alternation of serum levels of interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), but without any effects on the BDNF levels in maternal VPA-exposed mice offspring. These data suggest the need for additional research on HRW as a potential preventive strategy for autism and related disorders. Lay Summary : Maternal VPA injection induces autistic-like behavioral deficits in adolescent mice offspring. HRW administration ameliorates autistic-like behavioral deficits. HRW administration reverses the alternation of serum levels of IL-6 and TNF-α induced by VPA.

SuHeXiang (SHX) has been used to treat a wide range of diseases, including those related to the central nervous system. However, the effects of SHX on mood disorders are still elusive. This study aimed to investigate the effects of SHX essential oil on stress-induced depression of mice. In an acute stress-induced depression model, mice inhaled vehicle (1% Tween 80) for 10 min or 10% SHX for 10 or 30 min once daily for 12 continuous days. In the chronic mild stress (CMS)-induced depression model, mice were exposed to a 28-d CMS treatment. Tail suspension test (TST), forced swimming test (FST), sucrose preference test (SPT), open field test (OFT), and novelty suppressed feeding (NSF) test were conducted. In addition, serum levels of angiogenin (ANG), thrombopoietin (TPO), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated by enzyme-linked immunosorbent assay (ELISA) assays. The results showed that in mice exposed to acute stress, repeated SHX inhalation exerted significant antidepressant and anxiolytic activities, and also reduced the serum levels of ANG, TPO, IL-6, and TNF-α. It also significantly reversed the depressive and anxiety-like behaviors, and reduced the serum levels of ANG and TPO in mice exposed to CMS. This is the first report to show that SHX inhalation could produce significant antidepressant and anxiolytic-like effects. These effects might be mediated by SHX ability to modulate the inflammatory response, and reduce dysfunction of vascular genesis and thrombosis. These results support further exploration for developing SHX inhalation as a novel therapeutic strategy for depression and stress-related disorders.