Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine

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. We and others 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.

/pdf/beneficial-biological-effects-and-the-underlying-mechanisms-2nopjec0j6.pdf

Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles -

// Li Ge 1 , Ming Yang 2 , Na-Na Yang 3 , Xin-Xin Yin 2 and Wen-Gang Song 4 1 Department of Histology and Embryology, School of Basic Medical Sciences, Taishan Medical University, Tai-an City 271000, Shandong Province, PR China 2 Department of Clinical Medicine, Taishan Medical University, Tai-an City 271000, Shandong Province, PR China 3 Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Institute of Atherosclerosis, Taishan Medical University, Tai-an City 271000, Shandong Province, PR China 4 Department of medical immunology, School of Basic Medical Sciences, Taishan Medical University, Tai-an City 271000, Shandong Province, PR China Correspondence to: Wen-Gang Song, email: s.com@163.com Keywords: molecular hydrogen, selective anti-oxidation, gaseous signal modulator, preventive and therapeutic applications Received: April 27, 2017      Accepted: August 26, 2017      Published: September 21, 2017 ABSTRACT Since the 2007 discovery that molecular hydrogen (H 2 ) has selective antioxidant properties, multiple studies have shown that H 2 has beneficial effects in diverse animal models and human disease. This review discusses H 2 biological effects and potential mechanisms of action in various diseases, including metabolic syndrome, organ injury, and cancer; describes effective H 2 delivery approaches; and summarizes recent progress toward H 2 applications in human medicine. We also discuss remaining questions in H 2 therapy, and conclude with an appeal for a greater role for H 2 in the prevention and treatment of human ailments that are currently major global health burdens. This review makes a case for supporting hydrogen medicine in human disease prevention and therapy.

/pdf/molecular-hydrogen-a-preventive-and-therapeutic-medical-gas-1r1zrsk2gh.pdf

Molecular hydrogen: a preventive and therapeutic medical gas for various diseases

Molecular hydrogen (H2) was believed to be inert and nonfunctional in mammalian cells. We overturned this concept by demonstrating that H2 reacts with highly reactive oxidants such as hydroxyl radical ((•)OH) and peroxynitrite (ONOO(-)) inside cells. H2 has several advantages exhibiting marked effects for medical applications: it is mild enough neither to disturb metabolic redox reactions nor to affect signaling by reactive oxygen species. Therefore, it should have no or little adverse effects. H2 can be monitored with an H2-specific electrode or by gas chromatography. H2 rapidly diffuses into tissues and cells to exhibit efficient effects. Thus, we proposed the potential of H2 for preventive and therapeutic applications. There are several methods to ingest or consume H2: inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-dissolved saline (H2-saline), taking an H2 bath, or dropping H2-saline onto the eyes. Recent publications revealed that, in addition to the direct neutralization of highly reactive oxidants, H2 indirectly reduces oxidative stress by regulating the expression of various genes. Moreover, by regulating gene expression, H2 functions as an anti-inflammatory, antiallergic, and antiapoptotic molecule, and stimulates energy metabolism. In addition to growing evidence obtained by model animal experiments, extensive clinical examinations were performed or are under way. Since most drugs specifically act on their specific targets, H2 seems to differ from conventional pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has potential for clinical applications for many diseases.

Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical applications.

This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.

Cardiac purinergic signalling in health and disease

Background Exogenously administered hydrogen exerts cytoprotective effects through anti-oxidant, anti-inflammatory, and anti-apoptotic mechanisms in various disease settings, including organ transplantation. Our objective in this study was to evaluate the efficacy of a novel cold storage device equipped with a hydrogen-rich water bath. Methods The study used an established rat heterotopic transplantation model. Syngeneic heart grafts from elderly donors (60- to 70-week-old Lewis rats) or allografts from adult donors (12-week-old Brown Norway rats) were exposed to prolonged cold preservation. The cardiac grafts were stored in plastic bags containing Celsior, which were immersed in the cold water bath equipped with an electrolyzer to saturate the water with hydrogen. The cardiac grafts then were heterotopically engrafted into Lewis rat recipients. Results In both experimental settings, serum troponin I and creatine phosphokinase were markedly elevated 3 hours after reperfusion in the control grafts without hydrogen treatment. The grafts exhibited prominent inflammatory responses, including neutrophil infiltration and the upregulation of messenger RNAs for pro-inflammatory cytokines and chemokines. Myocardial injury and inflammatory events were significantly attenuated by organ storage in the hydrogen-rich water bath. The grafts stored using the hydrogen-rich water bath also exhibited less mitochondrial damage and a higher adenosine triphosphate content. Conclusions Hydrogen delivery to cardiac grafts during cold preservation using a novel hydrogen-supplemented water bath efficiently ameliorated myocardial injury due to cold ischemia and reperfusion. This new device to saturate organs with hydrogen during cold storage merits further investigation for possible therapeutic and preventative use during transplantation.

A novel method of preserving cardiac grafts using a hydrogen-rich water bath.

OBJECTIVES: Advanced donor age is one of the risk factors for graft failure and is the leading cause of early death after heart transplantation. Better myocardial preservation methods should reduce graft failure. The purpose of this study was to determine if adenosine, which is known to enhance cardioplegic protection, enhances myocardial preservation during heart transplantation using older donors. METHODS: We used a rat heterotopic heart transplantation model with Lewis rats that were at least 60 weeks old as donors. We injected saline (control) or adenosine (0.1 or 0.2 mg/kg) before cardioplegia, perfused with cold Celsior and stored the hearts in Celsior for 6 h at 4°C. The grafts were transplanted into syngenic, 12–16-week old recipients, and blood and tissue were collected 3 h after reperfusion. RESULTS: Bolus injection of adenosine led to faster mechanical arrest after perfusion with Celsior and faster reanimation after reperfusion compared with controls. Adenosine treatment significantly reduced myocardial injury, as indicated by serum troponin I and creatine phosphokinase levels. The mRNAs for inflammatory cytokines were markedly increased in the control grafts, but were less upregulated in the grafts treated with adenosine. The grafts treated with adenosine also exhibited less mitochondrial damage, fewer infiltrating cells and a higher adenosine triphosphate content. CONCLUSIONS: Adenosine injection prior to perfusion of cardioplegia significantly reduced cold ischaemia/reperfusion injury in cardiac grafts from older donors and improved the stores of cellular energy after reperfusion. This procurement protocol may be clinically feasible and should be considered in the clinical setting, particularly for older donors.

Adenosine injection prior to cardioplegia enhances preservation of senescent hearts in rat heterotopic heart transplantation

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A novel method of preserving cardiac grafts using a hydrogen-rich water bath.

Adenosine injection prior to cardioplegia enhances preservation of senescent hearts in rat heterotopic heart transplantation