Molecular Hydrogen Applicable Radioprotective Agent

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International Journal of Molecular Sciences Review Molecular Hydrogen as a Potential Clinically Applicable Radioprotective Agent Shin-ichi Hirano 1,* and Fumitake Satoh 1 , Yusuke Ichikawa 1, Bunpei Sato 1, Haru Yamamoto 2, Yoshiyasu Takefuji 3 􏰁􏰂􏰃 􏰅􏰆􏰇 􏰈􏰉􏰊􏰋􏰌􏰂􏰍 Citation: Hirano,S.-i.;Ichikawa,Y.; Sato, B.; Yamamoto, H.; Takefuji, Y.; Satoh, F. Molecular Hydrogen as a Potential Clinically Applicable Radioprotective Agent. Int. J. Mol. Sci. 2021,22,4566. https://doi.org/ 10.3390/ijms22094566 Academic Editor: Michael Hausmann Received: 24 March 2021 Accepted: 22 April 2021 Published: 27 April 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 2 3 * Correspondence: s_hirano@e-miz.co.jp; Tel.: +81-467-53-7511 Abstract: Although ionizing radiation (radiation) is commonly used for medical diagnosis and cancer treatment, radiation-induced damages cannot be avoided. Such damages can be classified into direct and indirect damages, caused by the direct absorption of radiation energy into DNA and by free radicals, such as hydroxyl radicals (•OH), generated in the process of water radiolysis. More specifically, radiation damage concerns not only direct damages to DNA, but also secondary damages to non-DNA targets, because low-dose radiation damage is mainly caused by these indirect effects. Molecular hydrogen (H2) has the potential to be a radioprotective agent because it can selectively scavenge •OH, a reactive oxygen species with strong oxidizing power. Animal experiments and clinical trials have reported that H2 exhibits a highly safe radioprotective effect. This paper reviews previously reported radioprotective effects of H2 and discusses the mechanisms of H2, not only as an antioxidant, but also in intracellular responses including anti-inflammation, anti-apoptosis, and the regulation of gene expression. In doing so, we demonstrate the prospects of H2 as a novel and clinically applicable radioprotective agent. Keywords: molecular hydrogen; radiation-induced damage; medical application; radioprotective agent; non-DNA target; intracellular response; oxidation; inflammation; apoptosis; gene expression 1. Introduction Ionizing radiation (radiation) is commonly used for medical diagnosis and cancer treatment. Amongst these uses, radiation therapy is known to be one of the most effective treatments for cancer. It is difficult to control radiation-induced damage with conventional radiation therapy; therefore, intensity-modulated radiation therapy (IMRT) has recently been used [1]. However, various radiation damages can also occur with IMRT. The harmful effects of radiation on the living body can be classified into direct and indirect effects. Direct effects are caused by the direct absorption of radiation energy into nucleic acids (DNA), proteins, and lipids [2–5]. Indirect effects are caused by free radicals, such as hydroxyl radicals (•OH), and molecular products generated in the process of water radiolysis [2–5]. In addition to the direct damage on DNA, secondary damages to non-DNA targets can- not be ignored because low-dose radiation damage is mainly caused by these indirect effects. Secondary damages include oxidation, inflammation, apoptosis, and effects on gene expression related to intracellular responses. Medical applications of H2 were first reported by Dole et al. in 1975 [6]. They reported that the inhalation of hyperbaric H2 caused a marked regression in squamous cell carcinoma in mice induced by UV radiation. With the exception of a few studies, however, H2 has not been extensively studied for medical applications. In 2007, Ohsawa et al. reported that the Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan; y_ichikawa@e-miz.co.jp (Y.I.); b_sato@e-miz.co.jp (B.S.); info@e-miz.co.jp (F.S.) Department of Molecular & Cell Biology, University of California, Berkeley, 3060 Valley Life Sciences Bldg #3140, Berkeley, CA 94720-3140, USA; haru.yamamoto@berkeley.edu Faculty of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa 252-0882, Japan; takefuji@keio.jp Int. J. Mol. Sci. 2021, 22, 4566. https://doi.org/10.3390/ijms22094566 https://www.mdpi.com/journal/ijms

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