Current Pharmaceutical Design - Volume 27, Issue 5, 2021

One of the beneficial effects of molecular hydrogen (H2, hydrogen gas) is neuroprotection and prevention of neurological disorders. It is important and useful if taking H2 every day can prevent or ameliorate the progression of neurodegenerative disorders, such as Parkinson’s disease or Alzheimer’s disease, both lacking specific therapeutic drugs. There are several mechanisms of how H2 protects neuronal damage. Anti-oxidative, anti-inflammatory, and the regulation of the endocrine system via stomach-brain connection seem to play an important role. At the cellular and tissue level, H2 appears to prevent the production of reactive oxygen species (ROS), and not only hydroxy radical (•OH) but also superoxide. In Parkinson’s disease model mice, chronic intake of H2 causes the release of ghrelin from the stomach. In Alzheimer’s disease model mice, sex-different neuroprotection is observed by chronic intake of H2. In female mice, declines of estrogen and estrogen receptor-β (ERβ) are prevented by H2, upregulating brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB). The question of how drinking H2 upregulates the release of ghrelin or attenuates the decline of estrogen remains to be investigated and the mechanism of how H2 modulates endocrine systems and the fundamental question of what or where is the target of H2 needs to be elucidated for a better understanding of the effects of H2.

This report reviews studies on the use of H2 in the ophthalmological field. In retinal diseases, particularly in a retinal ischemia-reperfusion injury, effects of H2 are remarkable in reducing retinal tissue damage. H2 treatment of corneal damage caused by alkali or UVB suppressed scar formation. The most unique application of H2 in the ophthalmological field appears to be its use in phacoemulsification cataract surgery. Ultrasound oscillation produces ·OH through the cavitation phenomenon in the anterior chamber of the eye, which induces oxidative insults in the corneal endothelium. Phacoemulsification using H2 dissolved in the irrigation solution significantly suppressed the corneal endothelial damage. The effect of H2 was direct and clear, as H2 instantly scavenges ·OH produced by ultrasound oscillation in the anterior chamber, thereby suppressing oxidative insults during the phacoemulsification procedure.

Molecular hydrogen (H2) was long regarded as non-functional in mammalian cells. We overturned the concept by demonstrating that H2 exhibits antioxidant effects and protects cells against oxidative stress. Subsequently, it has been revealed that H2 has multiple functions in addition to antioxidant effects, including antiinflammatory, anti-allergic functions, and as cell death and autophagy regulation. Additionally, H2 stimulates energy metabolism. As H2 does not readily react with most biomolecules without a catalyst, it is essential to identify the primary targets with which H2 reacts or interacts directly. As a first event, H2 may react directly with strong oxidants, such as hydroxyl radicals (•OH) in vivo. This review addresses the key issues related to this in vivo reaction. •OH may have a physiological role because it triggers a free radical chain reaction and may be involved in the regulation of Ca²⁺- or mitochondrial ATP-dependent K⁺-channeling. In the subsequent pathway, H2 suppressed a free radical chain reaction, leading to decreases in lipid peroxide and its end products. Derived from the peroxides, 4-hydroxy-2-nonenal functions as a mediator that up-regulates multiple functional PGC-1α. As the other direct target in vitro and in vivo, H2 intervenes in the free radical chain reaction to modify oxidized phospholipids, which may act as an antagonist of Ca²⁺-channels. The resulting suppression of Ca²⁺-signaling inactivates multiple functional NFAT and CREB transcription factors, which may explain H2 multi-functionality. This review also addresses the involvement of NFAT in the beneficial role of H2 in COVID-19, Alzheimer’s disease and advanced cancer. We discuss some unsolved issues of H2 action on lipopolysaccharide signaling, MAPK and NF-ΚB pathways and the Nrf2 paradox. Finally, as a novel idea for the direct targeting of H2, this review introduces the possibility that H2 causes structural changes in proteins via hydrate water changes.

There are many situations of excessive production of reactive oxygen species (ROS) such as radiation, ischemia/reperfusion (I/R), and inflammation. ROS contribute to and arises from numerous cellular pathologies, diseases, and aging. ROS can cause direct deleterious effects by damaging proteins, lipids, and nucleic acids as well as exert detrimental effects on several cell signaling pathways. However, ROS are important in many cellular functions. The injurious effect of excessive ROS can hypothetically be mitigated by exogenous antioxidants, but clinically this intervention is often not favorable. In contrast, molecular hydrogen provides a variety of advantages for mitigating oxidative stress due to its unique physical and chemical properties. H2 may be superior to conventional antioxidants, since it can selectively reduce •OH radicals while preserving important ROS that are otherwise used for normal cellular signaling. Additionally, H2 exerts many biological effects, including antioxidation, anti-inflammation, anti-apoptosis, and anti-shock. H2 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 H2, plays a critical role in regulating cellular redox balance, metabolism, and inducing adaptive responses against cellular stress. H2 also influences the crosstalk among the regulatory mechanisms of autophagy and apoptosis, which involve MAPKs, p53, Nrf2, NF-ΚB, p38 MAPK, mTOR, etc. The pleiotropic effects of molecular hydrogen on various proteins, molecules and signaling pathways can at least partly explain its almost universal pluripotent therapeutic potential.

Aberrant redox-sensitive reactions and accumulation of oxidative damage can impair body functions and contribute to the development of various pathologies and aging. Although antioxidant substances have long been recognized as a measure of alleviating oxidative stress and restoring redox balance, the arsenal of effective means of preventing the development of various disorders, is still limited. There is an emerging field that utilizes molecular hydrogen (H2) as a scavenger of free radicals and reactive oxygen species (ROS). Among the remarkable characteristics of H2 is its ability to counteract the harmful effects of hydroxyl radical and peroxynitrite without affecting the activity of functionally important ROS, such as hydrogen peroxide and nitric oxide. The beneficial effects of H2 have been documented in numerous clinical studies and studies on animal models and cell cultures. However, the established scavenging activity of H2 can only partially explain its beneficial effects because the effects are achieved at very low concentrations of H2. Given the rate of H2 diffusion, such low concentrations may not be sufficient to scavenge continuously generated ROS. H2 can also act as a signaling molecule and induce defense responses. However, the exact targets and mechanism(s) by which H2 exerts these effects are unknown. Here, we analyzed both positive and negative effects of the endogenous H2, identified the redox-sensitive components of the pathways affected by molecular hydrogen, and also discussed the potential role of molecular hydrogen in regulating cellular redox.

Hydrogen therapy has recently received increasing attention as an emerging and promising therapeutic technology due to its selective antioxidant property and cell energy regulatory capability in vivo. To solve the low solubility issue of hydrogen, a variety of nanomaterials and devices for hydrogen supply have recently been developed, aiming to increase the concentration of hydrogen in the specific disease site and realize controlled hydrogen release and combined treatment. In this review, we mainly focus on the latest advances in using hydrogen-generating devices and nanomaterials for hydrogen therapy. These developments include sustained release of H2, controlled release of H2, versatile modalities of synergistic therapy, etc. Also, bio-safety issues and challenges are discussed to further promote the clinical applications of hydrogen therapy and the development of hydrogen medicine.

Background: Mounting evidence indicates that hydrogen gas (H²) is a versatile therapeutic agent, even at very low, non-combustible concentrations. The Chinese National Health and Medical Commission recently recommended the use of inhaled H² in addition to O² therapy in the treatment of COVID-19-associated pneumonia, and its effects extend to anti-tumor, anti-inflammatory and antioxidant actions. Summary: In this review, we have highlighted key findings from preclinical research and recent clinical studies demonstrating that H² reduces the organ damage caused by ischemia-reperfusion. We have also outlined the critical role this effect plays in a variety of medical emergencies, including myocardial infarction, hemorrhagic shock, and out-of-hospital cardiac arrest, as well as in organ transplantation. H² is compared with established treatments such as targeted temperature management, and we have also discussed its possible mechanisms of action, including the recently identified suppression of TNF-α-mediated endothelial glycocalyx degradation by inhaled H². In addition, our new method that enables H² gas to be easily transported to emergency settings and quickly injected into an organ preservation solution at the site of donor organ procurement have been described. Conclusion: H² is an easily administered, inexpensive and well-tolerated agent that is highly effective for a wide range of conditions in emergency medicine, as well as for preserving donated organs.

Because multicellular organisms do not have hydrogenase, H2 has been considered to be biologically inactive in these species, and enterobacteria to be largely responsible for the oxidation of H2 taken into the body. However, we showed previously that inhalation of H2 markedly suppresses brain injury induced by focal ischemia-reperfusion by buffering oxidative stress. Although the reaction constant of H2 with hydroxyl radical in aqueous solution is two to three orders of magnitude lower than that of conventional antioxidants, we showed that hydroxyl radical generated by the Fenton reaction reacts with H2 at room temperature without a catalyst. Suppression of hydroxyl radical by H2 has been applied in ophthalmic surgery. However, many of the anti- inflammatory and other therapeutic effects of H2 cannot be completely explained by its ability to scavenge reactive oxygen species. H2 administration is protective in several disease models, and preculture in the presence of H2 suppresses oxidative stress-induced cell death. Specifically, H2 administration induces mitochondrial oxidative stress and activates Nrf2; this phenomenon, in which mild mitochondrial stress leaves the cell less susceptible to subsequent perturbations, is called mitohormesis. Based on these findings, we conclude that crosstalk between antioxidative stress pathways and the anti-inflammatory response is the most important molecular mechanism involved in the protective function of H2, and that regulation of the immune system underlies H2 efficacy. For further medical applications of H2, it will be necessary to identify the biomolecule on which H2 first acts.

Sepsis is the main cause of death in critically ill patients with no effective treatment. Sepsis is lifethreatening organ dysfunction due to a dysregulated host response to infection. As a novel medical gas, molecular hydrogen (H2) has a therapeutic effect on many diseases, such as sepsis. H2 treatment exerts multiple biological effects, which can effectively improve multiple organ injuries caused by sepsis. However, the underlying molecular mechanisms of hydrogen involved in the treatment of sepsis remain elusive, which are likely related to anti-inflammation, anti-oxidation, anti-apoptosis, regulation of autophagy and multiple signaling pathways. This review can help better understand the progress of hydrogen in the treatment of sepsis, and provide a theoretical basis for the clinical application of hydrogen therapy in sepsis in the future.

Radiation-induced lung injury is characterized by an acute pneumonia phase followed by a fibrotic phase. At the time of irradiation, a rapid, short-lived burst of reactive oxygen species (ROS) such as hydroxyl radicals (•OH) occurs, but chronic radiation-induced lung injury may occur due to excess ROS such as H2O2, O2•−, ONOO−, and •OH. Molecular hydrogen (H2) is an efficient antioxidant that quickly diffuses cell membranes, reduces ROS such as •OH and ONOO−, and suppresses damage caused by oxidative stress in various organs. In 2011, through the evaluation of electron-spin resonance and fluorescent indicator signals, we had reported that H2 can eliminate •OH and can protect against oxidative stress-related apoptotic damage induced by irradiation of cultured lung epithelial cells. We had explored for the first time the radioprotective effects of H2 treatment on acute and chronic radiation-induced lung damage in mice by inhaled H2 gas (for acute) and imbibed H2-enriched water (for chronic). Thus, we had proposed that H2 be considered a potential radioprotective agent. Recent publications have shown that H2 directly neutralizes highly reactive oxidants and indirectly reduces oxidative stress by regulating the expression of various genes. By regulating gene expression, H2 functions as an anti-inflammatory and anti-apoptotic molecule and promotes energy metabolism. The increased evidence obtained from cultured cells or animal experiments reveal a putative place for H2 treatment and its radioprotective effect clinically. This review focuses on major scientific advances in the treatment of H2 as a new class of radioprotective agents.

Hypoxic-ischemic encephalopathy (HIE) remains to be a major cause of morbidity, mortality and severe neurodevelopmental disability in term neonates. Moderate whole body hypothermia is an established, effective neuroprotective therapy to reduce mortality and long-term disability associated with HIE, however, research for adjunct therapies is still warranted to complement the effect of hypothermia. In the last decade, molecular hydrogen emerged as a simple, available, inexpensive substance with advantageous pharmacokinetics to ameliorate hypoxic-ischemic cellular damage. The present review examines the preclinical studies employing hydrogen to combat the deleterious consequences of hypoxic-ischemic insults in rodent and piglet HIE models. Hydrogen exerted unequivocal neuroprotective actions shown by preserved neurovascular function, neuronal viability, and neurocognitive functions in virtually all model species and hypoxic-ischemic insult types tested. Administration of hydrogen started in most studies after the hypoxic-ischemic insult enhancing the translational value of the findings. Among the explored mechanisms of hydrogen-induced neuroprotection, antioxidant, anti- apoptotic and anti-inflammatory effects appeared to be dominant. Unfortunately, the additive neuroprotective effect of hydrogen and therapeutic hypothermia has not yet been demonstrated, thus such studies are warranted to promote the clinical testing of molecular hydrogen as an adjunct neuroprotective treatment of HIE.

In 2007, Ohsawa and colleagues reported that molecular hydrogen (H2) gas significantly reduced the infarct volume size in a rat model of cerebral infarction, which was, at least, partially due to scavenging hydroxyl radicals. Since then, multiple studies have shown that H2 has not only anti-oxidative but also anti-inflammatory and anti-apoptotic properties, which has ignited interest in the clinical use of H2 in diverse diseases. A growing body of studies has indicated that H2 affects both mental and physical conditions. Mental disorders are characterized by disordered mood, thoughts, and behaviors that affect the ability to function in daily life. However, there is no sure way to prevent mental disorders. Although antidepressant and antianxiety drugs relieve symptoms of depression and anxiety, they have efficacy limitations and are accompanied by a wide range of side effects. While mental disorders are generally thought to be caused by a variety of genetic and/or environmental factors, recent progress has shown that these disorders are strongly associated with increased oxidative and inflammatory stress. Thus, H2 has received much attention as a novel therapy for the prevention and treatment of mental disorders. This review summarizes the recent progress in the use of H2 for the treatment of mental disorders and other related diseases. We also discuss the potential mechanisms of the biomedical effects of H2 and conclude that H2 could offer relief to people suffering from mental disorders.

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.

Atherosclerotic cardiovascular and cerebrovascular diseases are among the leading causes of morbidity and mortality worldwide. Given our recent understanding of its role as a small-molecule antioxidant and anti- inflammatory agent, hydrogen may play an important role in preventing and treating atherosclerotic cardiovascular and cerebrovascular disease. In the past decade, more than 50 publications in the English language literature considered the role of hydrogen as an anti-atherosclerotic agent. In this review, we summarized the pathophysiological characteristics and risk factors associated with atherosclerosis (AS) and the laboratory research data that focuses on hydrogen to prevent and treat this condition, including the responses observed in both animal models and human studies. We will also consider the molecular mechanisms underlying the efficacy of hydrogen molecules with respect to atherosclerotic disease. Future studies might include clinical trials with larger sample populations as well as experiments designed to explore the molecular mechanisms associated with hydrogen treatment in greater depth.

Background: 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 scientific attention, perhaps due to a dualism of H2 affirmative features demonstrated in numerous in vitro, animal and human studies on one side, and still puzzling 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. Methods: 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 of the trials 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. Results: 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 treatment, and the source of hydrogen. Conclusion: 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 longterm 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.

Physical exercise-induced oxidative stress and inflammation may be beneficial when exercise is a regular activity, but it is rather harmful when exercise is exhaustive and performed by unaccustomed organisms. Molecular hydrogen (H2) has recently appeared as a potent antioxidant and anti-inflammatory molecule in numerous pathological conditions. However, its role is relatively unknown under physiological conditions such as physical exercise. Therefore, this review summarizes the current knowledge of the H2, reducing oxidative stress and inflammation in physical exercise, reporting data from both animal and human studies.

In today’s society, healthy skin and a beautiful appearance are considered the foundation of general well-being. The skin is the largest organ of the body and plays an important role in protecting it against various hazards such as environmental, physical, chemical, and biological hazards. These factors include mediators that lead to oxidation reactions that produce reactive oxygen/nitrogen species and additional oxidants in the skin cells. An increase in oxidants beyond the antioxidant capacity of its defense system causes oxidative stress and chronic inflammation in the body. This response can cause further disruption of collagen fibers and hinder the functioning of skin cells that may result in the development of various skin diseases including psoriasis, atopic dermatitis, and aging. In this review, we summarized the present information related to the role of oxidative stress in the pathogenesis of dermatological disorders, and its impact on physical beauty and the daily lives of patients. We also discussed how molecular hydrogen exhibits a therapeutic effect against skin diseases via its effects on oxidative stress. Furthermore, findings from this summary review indicate that molecular hydrogen might be an effective treatment modality for the prevention and treatment of skin-related illnesses.

The emerging field of hydrogen biology has to date mainly been applied in medicine. However, hydrogen biology can also enable positive outcomes in agriculture. Agriculture faces significant challenges resulting from a growing population, climate change, natural disasters, environmental pollution, and food safety issues. In fact, hydrogen agriculture is a practical application of hydrogen biology, which may assist in addressing many of these challenges. It has been demonstrated that hydrogen gas (H2) may enhance plant tolerance towards abiotic and biotic stresses, regulate plant growth and development, increase nutritional values, prolong the shelf life, and decrease the nitrite accumulation during the storage of vegetables, as well as increase the resilience of livestock to pathogens. Our field trials show that H2 may have a promising potential to increase yield and improve the quality of agricultural products. This review aims to elucidate mechanisms for a novel agricultural application of H2 in China. Future development of hydrogen agriculture is proposed as well. Obviously, hydrogen agriculture belongs to a low carbon economy, and has great potential to provide “safe, tasty, healthy, and high-yield” agricultural products so that it may improve the sustainability of agriculture.