Stroke is a major cause of mortality and morbidity worldwide. Effective treatments are limited. Molecular hydrogen is emerging as a novel medical gas with therapeutic potential for various neurological diseases, including stroke. We reviewed the experimental and clinical findings of the effects of molecular hydrogen therapy in stroke patients and models. The underlying neuroprotective mechanisms against stroke pathology were also discussed.
Huang L, Lenahan C, Boling W, Tang J, Zhang JH. Molecular Hydrogen Application in Stroke: Bench to Bedside. Curr Pharm Des. 2021;27(5):703-712.
Hydrogen gas (H2 ) has entered the world of experimental therapeutics approximately four and a half decades ago. Over the years, this simple molecule appears to drive more and more scientific attention perhaps due to a dualism of H2 affirmative features demonstrated in numerous in vitro, animal and human studies on one side, and stillpuzzling mechanism(s) of its biological activity on the other. Up to this point, H2 was scrutinized for more than 170 different disease models and pathologies, and many research groups across the world have lately started to dynamically investigate its conceivable performance-enhancing potential. We outlined here the studies indexed in leading research databases (PubMed, Web of Science, SCOPUS, JSTORE) that explored the effects of hydrogen on exercise performance, and also addressed important restraints, open questions, and windows of opportunities for forthcoming research and possible H2 enactment in exercise physiology. About two dozen trials have been identified in this domain, with most published during the past 5 years, while drinking hydrogen-rich water recognized as the most convenient method to deliver H2 in both animal and human studies. Either administered as an inhalational gas, enteral hydrogen-rich water, or intravenous hydrogen-rich saline, H2 seems to favorably affect various exercise performance outcomes and biomarkers of exercise-associated fatigue, inflammation, and oxidative stress. Not all studies have shown corroborative effects, and it appears that the gold-standard protocol for applying H2 in the field of exercise science does not exist at the moment, with studies markedly differ in the dose of H2 administered, the duration of a treatment, and the source of hydrogen. H2 is a newfangled and rather effective performance-enhancing agent yet its promising ergogenic potency has to be further validated and characterized in more well-controlled, appropriately sampled and long-term mechanistic trials. Also, appropriate regulation of hydrogen utilization in sport as an exotic medical gas may require distinctive legislative actions of relevant regulatory agencies in the future.
Ostojic SM. Hydrogen Gas as an Exotic Performance-Enhancing Agent: Challenges and Opportunities. Curr Pharm Des. 2020 Sep 22. doi: 10.2174/1381612826666200922155242.
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.
Kura B, Bagchi AK, Singal PK, et al. Molecular hydrogen: potential in mitigating oxidative-stress-induced radiation injury. Can J Physiol Pharmacol. 2019 Apr;97(4):287-292.
As an antioxidant, hydrogen-rich water has been widely studied in recent years. It is mild enough neither to disturb metabolic redox reactions nor to affect signaling reactive oxygen species. Therefore, there should be no or few adverse effects of H(2). Numerous studies in biology and medicine show that hydrogen-rich water has achieved good results in nervous system, digestive system, respiratory system, heart and kidney diseases. At present, there are few studies on the treatment of eye diseases with hydrogen-rich water. This review summarizes the research progress of hydrogen-rich water for eye diseases in the domestic and foreign literature.
Chen XX, Zhou XQ, Wei RL. Research progress of hydrogen-rich saline for eye diseases. Zhonghua Yan Ke Za Zhi. 2018 Aug 11;54(8):631-635.
Neonatal hypoxic ischemic encephalopathy (HIE) is an important cause of neonatal death and disability. At present, there is no unified standard and specialized treatment method for neonatal HIE. In clinical practice, the authors have found that a gap remains between preclinical medical research and clinical application in the treatment of neonatal HIE. To promote an organic combination of preclinical research and clinical application, the authors here propose the different phases as intervention targets, based on the pathophysiologic changes in phases I, II, and III of neonatal HIE; moreover, they suggest transformative medicine as a principle that may improve the therapeutic effect by blocking the progression of the disease to an irreversible stage. For instance, in phase I, mild hypothermia, free radical scavenger (erythropoietin, hydrogen-rich saline), excitatory amino acid receptor blocker, and neuroprotective agents should be administered to neonates with moderate/severe HIE; in phase II, following phase I treatment, anti-inflammatory agents, neuroprotective or nerve regeneration agents, and stem cell transplantation should be administered to patients; in phase III, anti-inflammatory agents, neuroprotective or nerve regeneration agents, and stem cell transplantation should be administered to patients. As soon as the patient’s condition has stabilized, acupuncture, massage, and rehabilitation training should be performed. Following further study of stem cells, stem cell transplantation is expected to become the most promising therapeutic candidate for treatment of severe neonatal HIE with its sequelae.
Wang Q, Lv H, Lu L, et al. Neonatal hypoxic-ischemic encephalopathy: emerging therapeutic strategies based on pathophysiologic phases of the injury. J Matern Fetal Neonatal Med. 2019 Nov;32(21):3685-3692.
Oxidative stress and neuroinflammation cause many neurological disorders. Recently, it has been reported that molecular hydrogen (H2) functions as an antioxidant and anti-inflammatory agent. The routes of H2 administration in animal model and human clinical studies are roughly classified into three types, inhalation of H2 gas, drinking H2-dissolved water, and injection of H2-dissolved saline. This review discusses some of the remarkable progress that has been made in the research of H2 use for neurological disorders, such as cerebrovascular diseases, neurodegenerative disorders, and neonatal brain disorders. Although most neurological disorders are currently incurable, these studies suggest the clinical potential of H2 administration for their prevention, treatment, and mitigation. Several of the potential effectors of H2 will also be discussed, including cell signaling molecules and hormones that are responsible for preventing oxidative stress and inflammation. Nevertheless, further investigation will be required to determine the direct target molecule of H2.
Iketani M, Ohsawa I. Molecular hydrogen as a neuroprotective agent. Curr Neuropharmacol. 2017;15(2):324-331.
Increased oxidative stress and pro-inflammatory conditions, commonly present in chronic dialysis patients, are thought to be enhanced during hemodialysis (HD) and to be associated with the excess morbidity and mortality seen in these patients. The hydrogen molecule (H2) has a unique biological capacity to act as an antioxidative and anti-inflammatory substance. In light of accumulating evidence from animal studies showing protective effects against organ damage during ischemia and inflammation, development of H2 treatments for HD patients has become a challenging clinical goal. An HD system utilizing a water electrolysis technique that renders large amounts of H2-enriched water has been developed. During HD with an H2-enriched solution (approximately 50 ppb H2), markers of increased oxidative stress (such as interleukin-6, myeloperoxidase, methemoglobin, increased lymphocyte apoptosis, and high blood pressure) are suppressed. These findings indicate that the use of an H2-enriched solution may prove to be a novel approach to ameliorate dialysis-related complications. This manuscript reviews the recent progress in H2research and the use of H2 in HD patients, including a description of a water electrolysis technique that delivers large amounts of H2-enriched water for use in clinical settings.
Nakayama M, Kabayama S, Ito S. The hydrogen molecule as antioxidant therapy: clinical application in hemodialysis and perspectives. Renal Replacement Therapy. 2016;2:23.
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterized by progressive photoreceptor apoptosis. Reactive oxygen species (ROS) have been recognized as critical initiators of the photoreceptor apoptosis in RP. Photoreceptor survival in RP mutants will not only require the inhibition of effectors of apoptotic machinery, but also the elimination of the initiating upstream signals, such as ROS. These cytotoxic ROS should be neutralized by the antioxidant defense system, otherwise they would interact with the macromolecules essential for photoreceptor survival. Hydrogen is a promising gaseous agent that has come to the forefront of therapeutic research over the last few years. It has been verified that hydrogen is capable of neutralizing the cytotoxic ROS selectively, rectifying abnormities in the apoptotic cascades, and attenuating the related inflammatory response. Hydrogen is so mild that it does not disturb the metabolic oxidation-reduction reactions or disrupt the physiologic ROS involved in cell signaling. Based on these findings, the authors hypothesize that hydrogen might be an effective therapeutic agent to slow or prevent photoreceptor degeneration in RP retinas. It is a logical step to test hydrogen for therapeutic use in multiple RP animal models, and ultimately in human RP patients.
Tao Y, Geng L, Wang L, et al. Use of hydrogen as a novel therapeutic strategy against photoreceptor degeneration in retinitis pigmentosa patients. Med Sci Monit. 2016 Mar 8;22:776-9.
Hydrogen, one of the most well-known natural molecules, has been used in numerous medical applications owing to its ability to selectively neutralize cytotoxic reactive oxygen species and ameliorate hazardous inflammations. Hydrogen can exert protective effects on various reactive oxygen species-related diseases, including the transplantation-induced intestinal graft injury, chronic inflammation, ischemia-reperfusion injuries, and so on. Especially in the eye, hydrogen has been used to counteract multiple ocular pathologies in the ophthalmological models. Herein, the ophthalmological utilizations of hydrogen are systematically reviewed and the underlying mechanisms of hydrogen-induced beneficial effects are discussed. It is our hope that the protective effects of hydrogen, as evidenced by these pioneering studies, would enrich our pharmacological knowledge about this natural element and cast light into the discovery of a novel therapeutic strategy against ocular diseases.
Tao Y, Geng L, Xu WW, et al. The potential utilizations of hydrogen as a promising therapeutic strategy against ocular diseases. Ther Clin Risk Manag. 2016 May 19;12:799-806.
Molecular hydrogen (dihydrogen; H2) has traditionally been described as a biologically inactive gas, with low capacity to react with most biomolecules. However, in the past two decades hydrogen emerged as a potent therapeutic agent, with antioxidant, anti-inflammatory and anti-apoptotic effects demonstrated in a plethora of animal disease models and human studies. Prominent effects of supplemental H2 in clinical environment are observed especially in oxidative stress-mediated disorders, including neurodegenerative, metabolic, inflammatory and skin diseases. Hydrogen can reach and react with cytotoxic reactive oxygen species (ROS) at the site of cellular damage, and protect tissues against acute and chronic oxidative injuries. In addition, treatment with H2 affected signal transduction and blood buffering capacity, suggesting that scavenging ROS might not be a unique mechanism of its action in vivo. Supplemental hydrogen has been involved in very promising results so far, yet several enigmas remain to be resolved regarding its role in health and disease. In particular, no answer has been provided why large quantities of gut-derived endogenous hydrogen have no systemic effects, while supplemental H2 demonstrates a prominent effect in much less amounts than that produced by intestinal bacteria. In this paper the authors discuss an alternative sites for endogenous H2 production in the human body that might be responsible for systemic effects of hydrogen, and its possible role in the pathogenesis of oxidative stress-related disorders.
Ostojic SM, Vojvodic-Ostojic A. Is melanin a source of bioactive molecular hydrogen? Pharmacol Res. 2016;103:177-9.
Since it was proposed in 2007, molecular hydrogen therapy has been widely concerned and researched. Many animal experiments were carried out in a variety of disease fields, such as cerebral infarction, ischemia reperfusion injury, Parkinson syndrome, type 2 diabetes mellitus, metabolic syndrome, chronic kidney disease, radiation injury, chronic hepatitis, rheumatoid arthritis, stress ulcer, acute sports injuries, mitochondrial and inflammatory disease, and acute erythema skin disease and other pathological processes or diseases. Molecular hydrogen therapy is pointed out as there is protective effect for sepsis patients, too. The impact of molecular hydrogen therapy against sepsis is shown from the aspects of basic vital signs, organ functions (brain, lung, liver, kidney, small intestine, etc.), survival rate, and so forth. Molecular hydrogen therapy is able to significantly reduce the release of inflammatory factors and oxidative stress injury. Thereby it can reduce damage of various organ functions from sepsis and improve survival rate. Molecular hydrogen therapy is a prospective method against sepsis.
Zheng Y, Zhu D. Molecular hydrogen therapy ameliorates organ damage induced by sepsis. Oxid Med Cell Longev. 2016;2016:5806057.
The medicinal value of hydrogen (H2) was ignored prior to research illustrating that inhalation of 2% H2 can significantly decrease the damage of cerebral ischemia/reperfusion caused by oxidative stress via selective elimination of hydroxyl freebase (OH) and peroxynitrite anion (ONOO-). Subsequently, there have been numerous experiments on H2. Most research and trials involving the mechanisms underlying H2 therapy show the effects of antioxygenation, anti-inflammation, and anti-apoptosis. Among quantities of diseases related with H2 therapy, the brain disease is a hotspot as brain tissue and cell damage are easier to be induced by oxidative stress and other stimulations. In this review, emphasis is on stroke, traumatic brain injuries, and degenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Taking into account the blood-brain barrier, penetrability, possible side effects, and the molecular properties of H2 within a single comprehensive review should contribute to advancing both clinical and non-clinical research and therapies. A systematic introduction of H2 therapy with regards to mechanisms and cerebral diseases both in animal and human subjects can make it easier to comprehend H2 therapy and therefore provide the basis for further clinical strategy.
Liu CL, Zhang K, Chen G. Hydrogen therapy: from mechanism to cerebral diseases. Med Gas Res. 2016 Apr 4;6(1):48-54.
In recent years, it has become evident that molecular hydrogen is a particularly effective treatment for various disease models such as ischemia-reperfusion injury; as a result, research on hydrogen has progressed rapidly. Hydrogen has been shown to be effective not only through intake as a gas, but also as a liquid medication taken orally, intravenously, or locally. Hydrogen’s effectiveness is thus multifaceted. Herein the authors review the recent research on hydrogen-rich water, and we examine the possibilities for its clinical application. Now that hydrogen is in the limelight as a gaseous signaling molecule due to its potential ability to inhibit oxidative stress signaling, new research developments are highly anticipated.
Iida A, Nosaka N, Yumoto T, Knaet al. The clinical application of hydrogen as a medical treatment. Acta Med Okayama. 2016 Oct;70(5):331-337.
Oxidative stress and neuroinflammation cause many neurological disorders. Recently, it was reported that molecular hydrogen (H2) functions as an antioxidant and anti-inflammatory agent. The routes of H2 administration in animal model and human clinical studies are roughly classified into three types, inhalation of H2 gas, drinking H2-dissolved water, and injection of H2-dissolved saline. This review discusses some of the remarkable progress that has been made in the research of H2 use for neurological disorders, such as cerebrovascular diseases, neurodegenerative disorders, and neonatal brain disorders. Although most neurological disorders are currently incurable, these studies suggest the clinical potential of H2 administration for their prevention, treatment, and mitigation. Several of the potential effectors of H2 will also be discussed, including cell signaling molecules and hormones that are responsible for preventing oxidative stress and inflammation. Nevertheless, further investigation will be required to determine the direct target molecule of H2.
Iketani M, Ohsawa I. Molecular Hydrogen as a Neuroprotective Agent. Curr Neuropharmacol. 2017;15(2):324-331.
Cataract is the leading cause of irreversible blindness worldwide. Increasing evidence indicates that oxidative stress is an important risk factor contributing to the development of cataract. Moreover, the enhancement of the antioxidant defense system may be beneficial to prevent or delay the cataractogenesis. The term oxidative stress has been defined as a disturbance in the equilibrium status of oxidant/antioxidant systems with progressive accumulation of reactive oxygen species (ROS) in intact cells. Superfluous ROS can damage proteins, lipids, polysaccharides, and nucleic acids within ocular tissues that are closely correlated with cataract formation. Therefore, prevention of oxidative stress damage by antioxidants might be considered as a viable means of medically offsetting the progression of this vision-impairing disease. Molecular hydrogen has recently been verified to have protective and therapeutic value as an antioxidant through its ability to selectively reduce cytotoxic ROS such as hydroxyl radical (OH). Hitherto, hydrogen has been used as a therapeutic element against multiple pathologies in both animal models and human patients. Unlike most well-known antioxidants, which are unable to successfully target organelles, hydrogen has advantageous distribution characteristics enabling it to penetrate biomembranes and diffuse into the cytosol, mitochondria, and nucleus. Consequently, the authors speculate that hydrogen might be an effective antioxidant to protect against lens damage, and it is important to further explore the biological mechanism underlying its potential therapeutic effects.
Qin L, Tao Y, Wang L et al. Hydrogen-rich saline as an innovative therapy for cataract: a hypothesis. Med Sci Monit. 2016 Sep 8;22:3191-5.
Hydrogen, a therapeutic medical gas, can exert antioxidant activity via selectively reducing cytotoxic reactive oxygen species such as hydroxyl radicals. Hydrogen-rich saline is an alternative form of molecular hydrogen that has been widely used in many studies, including metabolic syndrome, cerebral, hepatic, myocardial ischemia/reperfusion, and liver injuries with obstructive jaundice, with beneficial results. Osteoradionecrosis of the jaw is a serious complication following radiotherapy for head and neck cancers. It has long been known that most radiation-induced symptoms are caused by free radicals generated by radiolysis of H2O, and the hydroxyl radical is the most reactive of these. Reducing the hydroxyl radical can distinctly improve the protection of cells from radiation damage. We hypothesized that hydrogen-rich saline might be an effective and specific method of managing and preventing osteoradionecrosis of the jaw.
Chen Y, Zong C, Guo Y, Tian L. Hydrogen-rich saline may be an effective and specific novel treatment for osteoradionecrosis of the jaw. Ther Clin Risk Manag. 2015 Oct 14;11:1581-5.
Molecular hydrogen (H2) is clinically administered; however, in some hospitals, H2 is given to patients without consideration of its safe use. In the present study, we prepared convenient and safe devices for the drinking of super-saturated H2 water, for intravenous drip infusion of H2-rich saline, and for the inhalation of H2 gas. In order to provide useful information for researchers using these devices, the changes in H2 concentration were studied. Our experimental results should contribute to the advance of non-clinical and clinical research in H2 medicine.
Kurokawa R, Seo T, Sato B, Hirano S, Sato F. Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation. Med Gas Res. 2015 Oct 26;5:13.
Therapeutic effects of molecular hydrogen for a wide range of disease models and human diseases have been investigated since 2007. A total of 321 original articles have been published from 2007 to June 2015. Most studies have been conducted in Japan, China, and the USA. About three-quarters of the articles show the effects in mice and rats. The number of clinical trials is increasing every year. In most diseases, the effect of hydrogen has been reported with hydrogen water or hydrogen gas, which was followed by confirmation of the effect with hydrogen-rich saline. Hydrogen water is mostly given ad libitum. Hydrogen gas of less than 4 % is given by inhalation. The effects have been reported in essentially all organs covering 31 disease categories that can be subdivided into 166 disease models, human diseases, treatment-associated pathologies, and pathophysiological conditions of plants with a predominance of oxidative stress-mediated diseases and inflammatory diseases. Specific extinctions of hydroxyl radical and peroxynitrite were initially presented, but the radical-scavenging effect of hydrogen cannot be held solely accountable for its drastic effects. Many authors have shown that the effects can be mediated by modulating activities and expressions of various molecules such as Lyn, ERK, p38, JNK, ASK1, Akt, GTP-Rac1, iNOS, Nox1, NF-κB p65, IκBα, STAT3, NFATc1, c-Fos, and ghrelin. Master regulator(s) that drive these modifications, however, remain to be elucidated and are currently being extensively investigated.
Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K. Beneficial biological effects and the underlying mechanisms of molecular hydrogen – comprehensive review of 321 original articles. Med Gas Res. 2015 Oct 19;5:12.
Molecular hydrogen (H2) can scavenge hydroxyl radical and diminish the toxicity of peroxynitrite; hence, it has interesting potential for antioxidant protection. Recently, a number of studies have explored the utility of inhaled hydrogen gas, or of hydrogen-saturated water, administered parenterally or orally, in rodent models of pathology and in clinical trials, oftentimes with very positive outcomes. The efficacy of orally ingested hydrogen-rich water (HW) has been particularly surprising, given that only transient and rather small increments in plasma hydrogen can be achieved by this method. A recent study in mice has discovered that orally administered HW provokes increased gastric production of the orexic hormone ghrelin, and that this ghrelin mediates the favorable impact of HW on a mouse model of Parkinson’s disease. The possibility that most of the benefits observed with HW in experimental studies are mediated by ghrelin merits consideration. Ghrelin is well known to function as an appetite stimulant and secretagogue for growth hormone, but it influences physiological function throughout the body via interaction with the widely express GHS-R1a receptor. Rodent and, to a more limited extent, clinical studies establish that ghrelin has versatile neuroprotective and cognitive enhancing activity, favorably impacts vascular health, exerts anti-inflammatory activity useful in autoimmune disorders, and is markedly hepatoprotective. The stimulatory impact of ghrelin on GH-IGF-I activity, while potentially beneficial in sarcopenia or cachectic disorders, does raise concerns regarding the long-term impact of ghrelin up-regulation on cancer risk. The impact of ingesting HW water on ghrelin production in humans needs to be evaluated; if HW does up-regulate ghrelin in humans, it may have versatile potential for prevention and control of a number of health disorders.
McCarty MF. Potential ghrelin-mediated benefits and risks of hydrogen water. Med Hypotheses. 2015;84(4):350-5.
This book provides a clearly structured introduction to hydrogen biology and medicine. Hydrogen is the one of the most abundant elements in the universe and has the simplest structure. In 2007, Japanese researchers found that the selective oxidation of hydrogen has a therapeutic effect on various diseases and injuries, sparking widespread interest in the biomedical field. In recent years, hundreds of peer-reviewed papers have been published internationally reporting the positive effects of hydrogen on many human diseases, including strokes, diabetes, Parkinson’s disease, Alzheimer’s disease and sepsis. The authors provide readers with a comprehensive overview of this subject, from its physical and chemical properties to its biological effects, as well as the problems and obstacles that exist.
Molecular hydrogen (dihydrogen, H(2)) acts as a therapeutic antioxidant by selectively reducing hydroxyl radicals (•OH) and peroxynitrite (ONOO-). It has been well-known that ionising radiation (IR) causes oxidative damage and consequent apoptosis mainly due to the production of •OH that follows radiolysis of H(2)O. Authors reported the protective effect of H(2) in irradiated cells and mice for the first time, and this effect is well repeated in other laboratories in different experimental animal models. A randomised, placebo-controlled investigation also showed consumption of H(2) can improve the quality of life of patients treated with radiotherapy for liver tumours. These encouraging results suggested that H(2) has a potential as a radioprotective agent with efficacy and non-toxicity.
Chuai Y, Qian L, Sun X, Cai J. Molecular hydrogen and radiation protection. Free Radic Res. 2012 Sep;46(9):1061-7.
Inhalation of hydrogen gas has been proven to be an effective treatment for ischemia-reperfusion injury by selectively reducing hydroxyl and peroxynitrite radicals. There has been considerable evidence of hydrogen’s protective effect against diseases related to oxidative injury, such as the ischemia-reperfusion injury of the brain, liver and heart. More and more studies suggest that radical oxygen species (ROS) play an important role in the development of diabetic erectile dysfunction (ED) and antioxidants can markedly decrease the production of ROS and improve the erectile function. Authors hypothesize that hydrogen therapy may be a promising, safe and effective treatment for diabetic ED by reducing the production of ROS.
Chen J, Zhang B, Li M, Qi T, Chen Z, Sun X, et al. Hydrogen therapy may be a promising, safe and effective treatment for diabetic erectile dysfunction: a hypothesis. Alternative Medicine Studies 2011; 1(1): e11.
It is well known that most of the ionizing radiation-induced damage is caused by hydroxyl radicals (·OH) follows radiolysis of H2O. Molecular hydrogen (H2) has antioxidant activities by selectively reducing ·OH and peroxynitrite(ONOO-). Authors firstly hypothesized and demonstrated the radioprotective effect of H2 in vitro and in vivo, which was also repeated on different experimental animal models by different departments. A randomized, placebo-controlled study showed that consumption of hydrogen-rich water reduces the biological reaction to radiation-induced oxidative stress without compromising anti-tumor effects. These encouraging results suggested that H2 represents a potentially novel preventative strategy for radiation-induced oxidative injuries. H2 is explosive. Therefore, administration of hydrogen-rich solution (physiological saline/pure water/other solutions saturated with H2) may be more practical in daily life and more suitable for daily consumption. This review focuses on major scientific and clinical advances of hydrogen-rich solution/H2 as a new class of radioprotective agent.
Qian L, Shen J, Chuai Y, Cai J. Hydrogen as a New Class of Radioprotective Agent. Int J Biol Sci. 2013 Sep 14;9(9):887-894.
Hydrogen gas is a bioactive molecule that has a diversity of effects, including anti-apoptotic, anti-inflammatory and anti-oxidative properties; these overlap with the process of neuroprogression in major psychiatric disorders. Specifically, both bipolar disorder and schizophrenia are associated with increased oxidative and inflammatory stress. Moreover, lithium which is commonly administered for treating bipolar disorder has effects on oxidative stress and apoptotic pathways, as do valproate and some atypical antipsychotics for treating schizophrenia. Molecular hydrogen has been studied pre-clinically in animal models for the treatment of some medical conditions including hypoxia and neurodegenerative disorders, and there are intriguing clinical findings in neurological disorders including Parkinson’s disease. Therefore, it is hypothesized that administration of hydrogen molecule may have potential as a novel therapy for bipolar disorder, schizophrenia, and other concurrent disorders characterized by oxidative, inflammatory and apoptotic dysregulation.
Ghanizadeh A, Berk M. Molecular hydrogen: an overview of its neurobiological effects and therapeutic potential for bipolar disorder and schizophrenia. Med Gas Res. 2013 Jun 6;3(1):11.
Allogeneic haematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of haematological malignant and non-malignant haematologic diseases. However, acute graft-versus-host disease (aGVHD) is a kind of severe complication of HSCT limiting its application. Cytokines such as tumour necrosis factor-α (TNF-α), IL-6 play an extremely important role in the formation and development of aGVHD. Besides, the oxidation phenomena and/or the formation of free radicals have been suggested to be causally related to various haematological disorders including aGVHD. Reactive oxygen species (ROS), such as hydroxyl radicals, play an important role in the formation and development of aGVHD. Hydrogen has been reported to have the ability to inhibit levels of cytokines such as TNF, IL-6 in vivo. Recent studies provided evidence that hydrogen inhalation can selectively reduce cytotoxic oxygen radicals and exert antioxidant effects. Therefore, authors suggested that hydrogen may have therapeutic effects on aGVHD. This hypothesis entails many experimentally testable predictions. Authors propose the experimental study by detecting complete blood counts (CBC) and Clinic signs of aGVHD mice. They also propose to detect the levels of TNF-α, IL-2, IL-1β, IL-6 which play important roles in the pathogenesis of aGVHD. To discover potential mechanisms of the therapeutic effects of hydrogen on the aGVHD model, authors will examine gene-expression profiles. This study will open a new therapeutic avenue combining the field of therapeutic medical gases and aGVHD. This theory is original and probably of importance, because therapeutic medical gases have never been used for aGVHD previously.
Qian L, Shen J. Hydrogen therapy may be an effective and specific novel treatment for Acute Graft-versus-host disease (GVHD). J Cell Mol Med. 2013 Aug;17(8):1059-63.
Hydrogen is a major component of interstellar space and the fuel that sustains the stars. However, it is seldom regarded as a therapeutic gas. A recent study provided evidence that hydrogen inhalation exerted antioxidant and anti-apoptotic effects and protected the brain against ischemia-reperfusion injury by selectively reducing hydroxyl radical and peroxynitrite. It has been known that the mechanisms underlying the brain injury after acute carbon monoxide poisoning are interwoven with multiple factors including oxidative stress, free radicals, and neuronal nitric oxide synthase as well as abnormal inflammatory responses. Studies have shown that free radical scavengers can improve the neural damage. Based on the findings abovementioned, we hypothesize that hydrogen therapy may be an effective, simple, economic and novel strategy in the treatment of acute carbon monoxide poisoning.
Shen M, He J, Cai J, Sun Q, Sun X, Huo Z. Hydrogen as a novel and effective treatment of acute carbon monoxide poisoning. Med Hypotheses. 2010 Aug;75(2):235-7.
Aplastic anemia (AA) is a rare bone marrow failure disorder with high mortality rate, which is characterized by pancytopenia and an associated increase in the risk of hemorrhage, infection, organ dysfunction and death. The oxidation phenomenon and/or the formation of free radicals have been suggested to be causally related to various hematological disorders, including aplastic anemia. TNF-α, IL-6, and IL-2 also play important roles in the pathogenesis of AA. Recent studies have provided evidence that hydrogen inhalation can selectively reduce cytotoxic oxygen radicals and exert antioxidant effects. It was also reported that hydrogen could suppress the levels of TNF-α and IL-6. Based on these findings, we hypothesize that hydrogen therapy may be an effective, simple, economic and novel strategy in the treatment of aplastic anemia.
Qian L, Shen J, Cai J. Hydrogen therapy may be an effective and specific novel treatment for aplastic anemia. Med Sci Monit. 2012 Jun;18(6):HY19-22.
Hydrogen is the most abundant chemical element in the universe, however, it is seldom regarded as a therapeutic gas. Recent studies show that inhaled hydrogen gas (H(2)) has antioxidant and antiapoptotic activities that protect the brain against ischemia-reperfusion injury and stroke by selectively reducing hydroxyl and peroxynitrite radicals. It is also well known that more than a half of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals. Studies have show that reducing hydroxyl radicals can significantly improve the protection of cells from radiation damage. In like manner, we hypothesize that hydrogen therapy may be an effective, specific and unique treatment for acute radiation syndrome.
Liu C, Cui J, Sun Q, Cai J. Hydrogen therapy may be an effective and specific novel treatment for acute radiation syndrome. Med Hypotheses. 2010 Jan;74(1):145-6.
Hydrogen is a colorless, odorless, tasteless and flammable gas. Hydrogen is considered a physiologically inert gas and is often used in deep-sea diving medicine. In mammals, endogenous hydrogen is produced as a result of the fermentation of non-digestible carbohydrates by intestinal bacteria and it is absorbed into the systemic circulation. Recent evidence indicates that hydrogen is a potent anti-oxidative, anti-apoptotic and anti-inflammatory agent and so may have potential medical application. The present review evaluates the concept of ‘hydrogen resuscitation’, based on knowledge that hydrogen treatment effectively protects cells, tissues and organs against oxidative injury and help them recover from dysfunction. Hydrogen therapy can be delivered by inhalation, the administration of hydrogen-enriched fluid or by approaches that affect endogenous hydrogen production. Studies have shown that hydrogen resuscitation has cytoprotective effects in different cell types and disease models including ischemia-reperfusion injury, inflammation, toxicity, trauma, metabolic disease, etc. The underlying mechanism may be the selective elimination of hydroxyl radicals, although other mechanisms may also be involved (e.g. hydrogen functioning as a gaseous signaling molecule). Hydrogen resuscitation may have several potential advantages over current pharmacological therapies for the oxidative injuries. However, more work is needed to identify the precise mechanism underlying the actions of hydrogen and to validate its therapeutic potential in the clinical setting.
Zheng XF, Sun XJ, Xia ZF. Hydrogen resuscitation, a new cytoprotective approach. Clin Exp Pharmacol Physiol. 2001 March;38(3):155-163.
Effects of molecular hydrogen on various diseases have been documented for 63 disease models and human diseases in the past four and a half years. Most studies have been performed on rodents including two models of Parkinson’s disease and three models of Alzheimer’s disease. Prominent effects are observed especially in oxidative stress-mediated diseases including neonatal cerebral hypoxia; Parkinson’s disease; ischemia/reperfusion of spinal cord, heart, lung, liver, kidney, and intestine; transplantation of lung, heart, kidney, and intestine. Six human diseases have been studied to date: diabetes mellitus type 2, metabolic syndrome, hemodialysis, inflammatory and mitochondrial myopathies, brain stem infarction, and radiation-induced adverse effects. Two enigmas, however, remain to be solved. First, no dose-response effect is observed. Rodents and humans are able to take a small amount of hydrogen by drinking hydrogen-rich water, but marked effects are observed. Second, intestinal bacteria in humans and rodents produce a large amount of hydrogen, but an addition of a small amount of hydrogen exhibits marked effects. Further studies are required to elucidate molecular bases of prominent hydrogen effects and to determine the optimal frequency, amount, and method of hydrogen administration for each human disease.
Ohno K, Ito M, Ichihara M, Ito M. Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxid Med Cell Longev. 2012;2012:353152.
Studies on molecular hydrogen have evolved tremendously from its humble beginnings and have continued to change throughout the years. Hydrogen is extremely unique since it has the capability to act at the cellular level. Hydrogen is qualified to cross the blood brain barrier, to enter the mitochondria, and even has the ability to translocate to the nucleus under certain conditions. Once in these ideal locations of the cell, previous studies have shown that hydrogen exerts antioxidant, anti-apoptotic, anti-inflammatory, and cytoprotective properties that are beneficial to the cell. Hydrogen is most commonly applied as a gas, water, saline, and can be applied in a variety of other mediums. There are also few side effects involving hydrogen, thus making hydrogen a perfect medical gas candidate for the convention of novel therapeutic strategies against cardiovascular, cerebrovascular, cancer, metabolic, and respiratory diseases and disorders. Although hydrogen appears to be faultless at times, there still are several deficiencies or snares that need to be investigated by future studies. This review article seeks to delve and comprehensively analyze the research and experiments that alludes to molecular hydrogen being a novel therapeutic treatment that medicine desperately needs.
Dixon BJ, Tang J, Zhang JH. The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance. Med Gas Res. 2013 May 16;3(1):10.
Hydrogen gas (H2), a colorless, tasteless, odorless, non-irritating and highly flammable diatomic gas, has been used in medical applications to prevent decomposition sickness in deep divers. For a long time, H2 was thought to be a “biologically inert gas” which could not react with biomolecules under normal pressure. In 2007, Ohsawa et al. first reported that inhalation of H2 markedly suppressed brain injury induced by ischemia-reperfusion, which made the antioxidant properties of H2 drew wide attention (Ohsawa et al., 2007). Soon afterwards H2 was found to be effective for many other diseases, including hepatic and cardiac hypoxia-ischemia injury, inflammation injury caused by small intestine transplantation, neonatal hypoxia–ischemia injury, and lung allograft, (Fukuda et al., 2007; Buchholz et al., 2008; Cai et al., 2008; Hayashida et al., 2008; Kawamura et al., 2011;). Besides, other ways to administrate H2, such as drinking H2-saturated water, intraperitoneal and intravenous injection of H2-saturated saline (first developed by our group), have also been proved to be effective to many disorders related with oxidative stress, such as cerebral hypoxia-ischemia injury, human typeⅡ diabetes, nephrotoxicity induced by cisplatin, Parkinson’s disease and atherosclerosis in apolipoprotein (Cai et al., 2009; Chen et al., 2009; Mao et al., 2009; Sun et al., 2009; Zheng et al., 2009; Oharazawa et al., 2010). Up to now, H2 has been proved to be effective to various disease models. Considering the unique antioxidant properties of H2, we believe it is important to review the medical researches of this novel antioxidant in this chapter. The aim of this chapter is to summarize research findings and mechanisms concerning the therapeutic potential of H2.
Liu S, Sun X, Tao H. Hydrogen: from a biologically inert gas to a unique antioxidant. In: Molecular Mechanisms and Biological Effects (Ed. Volodymyr Lushchak). Rijeka: InTech, 2012.
In the past few years many initial and subsequent clinical studies have demonstrated that hydrogen can act as an important physiological regulatory factor to cells and organs on the antioxidant, anti-inflammatory, anti-apoptotic and other protective effects. So far several delivery methods applied in these studies have proved to be available and convenient, including inhalation, drinking hydrogen-dissolved water and injection with hydrogen-saturated saline. This study reviews recent studies on the protectiveness of hydrogen and discusses the possible mechanisms including antioxidant ability as a gaseous signaling molecule, anti-cancer capability and others. It also tries to reveal whether endogenous hydrogen has an important role in the protective system. Nevertheless, there are still many remaining questions in the domain of hydrogen medicine and much work needs to be carried out in the future.
Zhang JY, Liu C, Zhou L, Qu K, Wang R, Tai MH, et al. A review of hydrogen as a new medical therapy. Hepatogastroenterology. 2012 Jun;59(116):1026-32.
Mitochondria are the major source of oxidative stress. Acute oxidative stress causes serious damage to tissues, and persistent oxidative stress is one of the causes of many common diseases, cancer and the aging process; however, there has been little success in developing an effective antioxidant with no side effect. We have reported that molecular hydrogen has potential as an effective antioxidant for medical applications [Ohsawa et al., Nat. Med. 13 (2007) 688-694]. We review the recent progress toward therapeutic and preventive applications of hydrogen. Since we published the first paper in Nature Medicine, effects of hydrogen have been reported in more than 38 diseases, physiological states and clinical tests in leading biological/medical journals. Based on this cumulative knowledge, the beneficial biological effects of hydrogen have been confirmed. There are several ways to intake or consume hydrogen, including inhaling hydrogen gas, drinking hydrogen-dissolved water, taking a hydrogen bath, injecting hydrogen-dissolved saline, dropping hydrogen-dissolved saline into the eyes, and increasing the production of intestinal hydrogen by bacteria. Hydrogen has many advantages for therapeutic and preventive applications, and shows not only anti-oxidative stress effects, but also has various anti-inflammatory and anti-allergic effects. Preliminary clinical trials show that drinking hydrogen-dissolved water seems to improve the pathology of mitochondrial disorders. Hydrogen has biological benefits toward preventive and therapeutic applications; however, the molecular mechanisms underlying the marked effects of small amounts of hydrogen remain elusive. Hydrogen is a novel antioxidant with great potential for actual medical applications.
Ohta S. Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases. Biochim Biophys Acta. 2012 May;1820(5):586-94.
Oxidative stress in the central nervous system is strongly associated with neuronal cell death in the pathogenesis of several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. In order to overcome the oxidative damage, there are some protective signaling pathways related to transcriptional upregulation of antioxidant enzymes, such as heme oxygenase-1 (HO-1) and superoxide dismutase (SOD)-1/-2. Their expression is regulated by several transcription factors and/or cofactors like nuclear factor-erythroid 2 (NF-E2) related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). These antioxidant enzymes are associated with, and in some cases, prevent neuronal death in animal models of neurodegenerative diseases. They are activated by endogenous mediators and phytochemicals, and also by several gases such as carbon monoxide (CO), hydrogen sulphide (H(2)S), and hydrogen (H(2)). These might thereby protect the brain from severe oxidative damage and resultant neurodegenerative diseases. In this paper, we discuss how the expression levels of these antioxidant enzymes are regulated. We also introduce recent advances in the therapeutic uses of medical gases against neurodegenerative diseases.
Fujita K, Yamafuji M, Nakabeppu Y, Noda M. Therapeutic approach to neurodegenerative diseases by medical gases: focusing on redox signaling and related antioxidant enzymes. Oxid Med Cell Longev. 2012;2012:324256.
The protective effect of hydrogen (H2) on ROS-induced diseases has been proved by many researches, which demonstrated that through eliminating •OH and •ONOO–, H2 could effectively attenuate lipid and DNA peroxidation, improve cellular antioxidant capacity, and then protect cells against oxidant damage. Most of free radicals in human body are ROS, including O2•–,•OH, H2O2, NO•,•ONOO–, and so on. Under normal circumstances cells are able to maintain an adequate homeostasis between the formation and removal of ROS through particular enzymatic pathways or antioxidants. But under some pathological conditions, the balance is disturbed, leading to oxidative stress and various diseases, such as chronic obstructive pulmonary disease (COPD). Studies have shown that ROS played a pivotal role in the development of COPD and some antioxidants were effective in the protection against the damaging effects of oxidative stress. Therefore, we hypothesize that owing to its peculiarity to eliminate toxic ROS, hydrogen therapy may be a novel and effective treatment for COPD.
Liu SL, Liu K,Sun Q, Liu WW, Tao HY, Sun XJ. Hydrogen therapy may be a novel and effective treatment for COPD. Front Pharmacol. 2011; 2: 19.
Regulation of cellular redox balances is important for the homeostasis of human health. Thus, many important human diseases, such as inflammation, diabetes, glaucoma, cancers, ischemia and neurodegenerative diseases, have been investigated in the field of reactive oxygen species (ROS) and oxidative stress. To overcome the harmful effect of oxidative stress and ROS, one can directly eliminate them by medical gases such as carbon monoxide (CO), hydrogen sulphide (H(2)S), and molecular hydrogen (H(2)), or one can induce ROS-resistant proteins and antioxidant enzymes to antagonize oxidative stresses. This article reviews the molecular mechanisms how these medical gasses work as antioxidants, and how ROS resistant proteins are produced in the physiological context. Targeted therapeutic modalities to scavenge or prevent ROS might be applied in the prevention and treatment of ROS-related diseases in the near future.
Noda M, Fujita K, Lee CH, Yoshioka T. The principle and the potential approach to ROS-dependent cytotoxicity by non-pharmaceutical therapies: optimal use of medical gases with antioxidant properties. Curr Pharm Des. 2011;17(22):2253-63.
Persistent oxidative stress is one of the major causes of most lifestyle-related diseases, cancer and the aging process. Acute oxidative stress directly causes serious damage to tissues. Despite the clinical importance of oxidative damage, antioxidants have been of limited therapeutic success. We have proposed that molecular hydrogen (H(2)) has potential as a “novel” antioxidant in preventive and therapeutic applications [Ohsawa et al., Nat Med. 2007: 13; 688-94]. H(2) has a number of advantages as a potential antioxidant: H(2) rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect reactive oxygen species (ROS) that function in cell signaling, thereby, there should be little adverse effects of consuming H(2). There are several methods to ingest or consume H(2), including inhaling hydrogen gas, drinking H(2)-dissolved water (hydrogen water), taking a hydrogen bath, injecting H(2)- dissolved saline (hydrogen saline), dropping hydrogen saline onto the eye, and increasing the production of intestinal H(2) by bacteria. Since the publication of the first H(2) paper in Nature Medicine in 2007, the biological effects of H(2) have been confirmed by the publication of more than 38 diseases, physiological states and clinical tests in leading biological/medical journals, and several groups have started clinical examinations. Moreover, H(2) shows not only effects against oxidative stress, but also various anti-inflammatory and antiallergic effects. H(2) regulates various gene expressions and protein-phosphorylations, though the molecular mechanisms underlying the marked effects of very small amounts of H(2) remain elusive.
Ohta S. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des. 2011;17(22):2241-52.
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.
Huang CS, Kawamura T, Toyoda Y, Nakao A. Recent advances in hydrogen research as a therapeutic medical gas. Free Radic Res. 2010 Sep;44(9):971-82.
Oxidative stress is implicated in the pathogenesis of many diseases; however, currently used antioxidants have a high toxicity that constrains administration to a narrow window of therapeutic dosage. There is a clear need for more effective and safer antioxidants. Diatomic hydrogen (H(2)) was proposed as a novel antioxidant that selectively reduces levels of toxic reactive-oxygen species. Recently, many studies have reported that H(2) (inhaled or orally ingested, typically as approximately 0.8 mM H(2)-saturated water), can exert beneficial effects in diverse animal models of ischaemia-reperfusion injury, and inflammatory and neurological disease. In the clinic, oral administration of H(2)-saturated water is reported to improve lipid and glucose metabolism in subjects with diabetes or impaired glucose tolerance; promising results have also been obtained in reducing inflammation in haemodialysis patients and treating metabolic syndrome. These studies suggest H(2) has selective antioxidant properties, and can exert antiapoptotic, antiinflammatory and antiallergy effects. This review summarizes recent research findings and mechanisms concerning the therapeutic potential of H(2).
Hong Y, Chen S, Zhang JM. Hydrogen as a selective antioxidant: a review of clinical and experimental studies. J Int Med Res. 2010;38(6):1893-903.