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 H₂ 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 H₂ 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 H₂ may be useful for ROS/inflammation-induced cardiotoxicity and other conditions.

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 (H₂), an emerging novel medical gas, may complement. Herein, we systematically review the antioxidative, anti‐inflammatory, and antiapoptotic mechanisms of H₂. Its small molecular size and nonpolarity allow H₂ to rapidly diffuse through cell membranes and penetrate cellular organelles. H₂ has been demonstrated to suppress NF‐κB 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 H₂ 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.

Purpose: 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.

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. H₂may 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, H₂exerts many biological effects, including antioxidation, anti-inflammation, anti-apoptosis, and anti-shock. H₂accomplishes 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. H₂also 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.

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.

H₂ 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 H₂ administration. Beneficial exercise and H₂ 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 H₂, 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 H₂ in exercise medicine.