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Emerging mechanisms and novel applications of h2 gas therapy

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Emerging mechanisms and novel applications of h2 gas therapy ( emerging-mechanisms-and-novel-applications-h2-gas-therapy )

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REViEW Emerging mechanisms and novel applications of hydrogen gas therapy Nathanael Matei1, Richard Camara1, John H. Zhang1, 2, 3, * 1 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA 2 Department of Anesthesiology, Loma Linda University, Loma Linda, CA, USA 3 Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USA *Correspondence to: John H. Zhang, MD, Johnzhang3910@yahoo.com. orcid: 0000-0002-4319-4285 (John H. Zhang) Clinical and pre-clinical studies have reported a broad range of applications for hydrogen gas therapy. Classically, conventional antioxidant therapy is limited because it neutralizes both the detrimental and protective effects of reactive oxygen species. As a weak reducing agent, hydrogen gas avoids this paradox by reacting with strong oxidants while leaving other beneficial oxidants reactive. This review gathers a promising list of hydrogen gas applications that merit further mechanistic investigation and additional therapeutic trials. Reports support the ability of hydrogen gas to downregulate the expression of pro-inflammatory cytokines and pro-apoptotic factors. Mechanistically, hy- drogen gas has been shown to downregulate miR-9 and miR-21, while upregulating miR-199 to reduce inflammatory injury. In angiogenic pathways, hydrogen’s inhibition of cyclic guanosine monophosphate-degrading phosphodiesterase led to higher levels of cyclic guanosine monophosphate, activation of protein kinase, and angiogenesis; next, as hydrogen gas increased the levels of intracellular calcium, stimulated vascular endothelial growth factor increased nitric oxide production. In conjunction, hydrogen gas opened adenosine triphosphate-sensitive potassium channel channels, which activate downstream mitogen-activated protein kinase pathways. Growing molecular mechanisms have discovered a plethora of downstream targets for hydrogen gas therapy that include autophagy (via the adenosine 5'-monophosphate-activated protein kinase/mammalian target of rapamycin pathway), histone modification, mitochondrial unfolded protein response, acute oxidative stress after exercise, and oxidative stress secondary to aging. In conclusion, evolving research has discovered novel molecular connections that will continue to widen applications for hydrogen therapy. Key words: hydrogen therapy; selective anti-oxidation, therapeutic applications; hydrogen pathway; anti-inflammation; anti-apoptosis; hydrogen gas; future directions doi: 10.4103/2045-9912.239959 How to cite this article: Matei N, Camara R, Zhang JH. Emerging mechanisms and novel applications of hydrogen gas therapy. Med Gas Res. 2018;8(3):98-102. Funding: This work was supported by the National Institutes of Health grant (NS081740 to JHZ). Abstract INtRODUCtiON Clinical and pre-clinical studies have reported a broad range of applications for hydrogen gas therapy. Molecular hydrogen is the smallest gas molecule that can cross cellular membranes and diffuse throughout the body; however, it requires proper safety measures at concentrations above 4% because of its combustible properties.1 The reaction constants of hydrogen with oxide radical ion (•O−) and hydroxyl radical (•OH) in water is in the order of 10−7 M/s, compared to other molecules that are in the orders of 10−9 to 10−10 M/s; however, with high collision rates, hydrogen may overcome the low reaction rate constants and be a therapeutic antioxidant.1,2 Classically, conventional antioxidant therapy was limited because it neu- tralized both the detrimental and protective effects of reactive oxygen species (ROS): strongly oxidizing ROS, e.g., •OH, which damage tissue and advantageous species, superoxide and hydrogen peroxide, which enhance endogenous protec- tive signal transduction pathways.3 As a weak reducing agent, hydrogen gas avoids this paradox by reacting with strong oxidants, e.g., •OH, while leaving other beneficial oxidants reactive.3 Hydrogen's unique reducing properties have been leveraged to treat a plethora of oxidative stress pathologies. Acute oxi- dative stress develops from vigorous exercise, inflammation, ischemia and reperfusion (I/R) injury, surgical bleeding, and tissue transplantation.4,5 The first report of the therapeutic ef- fects of hydrogen presented the regression of skin tumors in a mice model with squamous cell carcinoma.6 Studies have since broadened to include cardiovascular,7 nervous system,8 reproductive, metabolic,9 digestive,10 and respiratory diseases11 (Figure 1). While 12 L of endogenous hydrogen gas is produced daily by the intestinal flora, the mechanisms of low concentration hydrogen gas (1–4%) require further investigation,3 and although the mechanisms for hydrogen remain unclear, non-mechanistic studies have primarily focused on ischemic models. Molecular hydrogen behaves as an inert gas at body temperature and does not react with any biological compounds; therefore, with few side-effects and numerous publications on its biological and medical benefits, there is a promising potential for clinical use.12 In this review, we hope to elucidate some of the emerging mechanisms and novel applications of hydrogen gas therapy. Under aerobic conditions normal cellular functions produce ROS—e.g., superoxide radical, •OH and hydrogen peroxide.13 During ischemia, mitochondrial damage occurs, causing electrons to leak from the Krebs cycle and the electron transport chain; these electrons produce superoxide anion 98 © 2018 Medical Gas Research | Published by Wolters Kluwer - Medknow

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