{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T01:22:44Z","timestamp":1789694564288,"version":"4.0.1"},"reference-count":82,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T00:00:00Z","timestamp":1619481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 (\u2022OH), 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 \u2022OH, 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.<\/jats:p>","DOI":"10.3390\/ijms22094566","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T06:19:11Z","timestamp":1619504351000},"page":"4566","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Molecular Hydrogen as a Potential Clinically Applicable Radioprotective Agent"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8610-8922","authenticated-orcid":false,"given":"Shin-ichi","family":"Hirano","sequence":"first","affiliation":[{"name":"Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Ichikawa","sequence":"additional","affiliation":[{"name":"Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bunpei","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haru","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Molecular &amp; Cell Biology, University of California, Berkeley, 3060 Valley Life Sciences Bldg #3140, Berkeley, CA 94720-3140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1826-742X","authenticated-orcid":false,"given":"Yoshiyasu","family":"Takefuji","sequence":"additional","affiliation":[{"name":"Faculty of Environment and Information Studies, Keio University, 5322 Endo, Fujisawa 252-0882, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumitake","family":"Satoh","sequence":"additional","affiliation":[{"name":"Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura, Kanagawa 247-0056, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"297","DOI":"10.21037\/tau.2017.12.16","article-title":"Intensity-modulated radiotherapy for prostate cancer","volume":"7","author":"Rao","year":"2018","journal-title":"Transl. Androl. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1089\/ars.2013.5635","article-title":"Hematopoietic stem cell injury induced by ionizing radiation","volume":"20","author":"Shao","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0079-6603(08)60611-X","article-title":"DNA damage produced by ionizing radiation in mammalian cells: Identities, mechanisms of formation, and reparability","volume":"35","author":"Ward","year":"1988","journal-title":"Prog. Nucleic Acid Res. Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3390\/w3010235","article-title":"Water radiolysis: Influence of oxide surfaces on H2 production under ionizing radiation","volume":"3","author":"Caer","year":"2011","journal-title":"Water"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nickoloff, J.A., Sharma, N., and Taylor, L. (2020). Clustered DNA double-strand breaks: Biological effects and relevance to cancer radiotherapy. Gene, 11.","DOI":"10.3390\/genes11010099"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1126\/science.1166304","article-title":"Hyperbaric hydrogen therapy: A possible treatment for cancer","volume":"190","author":"Dole","year":"1975","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/nm1577","article-title":"Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals","volume":"13","author":"Ohsawa","year":"2007","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1271\/bbb.69.1985","article-title":"Electrolyzed hydrogen-saturated water for drinking use elicits an antioxidative effect; a feeding test with rats","volume":"69","author":"Yanagihara","year":"2005","journal-title":"Biosci. Biotrechnol. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"47","DOI":"10.4103\/2045-9912.279983","article-title":"A \u201cphilosophical molecule,\u201d hydrogen may overcome senescence and intractable diseases","volume":"10","author":"Hirano","year":"2020","journal-title":"Med. Gas Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hirano, S.i., Ichikawa, Y., Sato, B., Satoh, F., and Takefuji, Y. (2020). Hydrogen is promising for medical applications. Clean. Technol., 2.","DOI":"10.3390\/cleantechnol2040033"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sato, T., Kinoshita, M., Yamamoto, T., Ito, M., Nishida, T., Takeuchi, M., Saitoh, D., Seki, S., and Mukai, Y. (2015). Treatment of irradiated mice with high-dose ascorbic acid reduced lethality. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117020"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1182\/blood-2003-05-1400","article-title":"Single administration of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and ineterleukin-3 in combination soon after irradiation prevents nonhuman primates from myelosuppression: Long-term follow-up of hematopoiesis","volume":"103","author":"Drouet","year":"2004","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1634\/stemcells.19-6-522","article-title":"Leridistim, a chimeric dual G-CSF and IL-3 receptor agonist, enhances multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression: Effect of schedule, dose, and route of administration","volume":"19","author":"Farese","year":"2001","journal-title":"Stem Cells"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1182\/blood-2002-06-1634","article-title":"Short-term injection of antiapoptotic cytokine combinations soon after lethal gamma-irradiation promotes survival","volume":"101","author":"Herodin","year":"2003","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1182\/blood.V95.3.837.003k08_837_845","article-title":"Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression","volume":"95","author":"MacVittie","year":"2000","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nuszkiewicz, J., Wanzniak, A., and Szewezyk-Golec, K. (2020). Inonizing radiation as a source of oxidative stress-The protective role of melatonin and Vitamin D. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165804"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/milmed\/167.suppl_1.87","article-title":"Prevention and treatments: Summary statement","volume":"167","author":"Seed","year":"2002","journal-title":"Milit. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1053\/j.seminoncol.2003.11.020","article-title":"Pilot study of subcutaneous amifostine in patients undergoing postoperative intensity modulated radiation therapy for head and neck cancer: Preliminary data","volume":"30","author":"Thorstad","year":"2003","journal-title":"Semin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"594","DOI":"10.3109\/09553002.2014.899450","article-title":"Radioprotection of hematopoietic progenitors by low dose amifostine prophylaxis","volume":"90","author":"Seed","year":"2014","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s13205-017-0925-0","article-title":"Appraised of biochemical classes of radioprotectors: Evidence, current status and guidelines for future development","volume":"7","author":"Mishra","year":"2017","journal-title":"3 Biotech"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8749090","DOI":"10.1155\/2019\/8749090","article-title":"Amifostine suppresses the side effects of radiation on BMSCs by promoting cell proliferation and reducing ROS production","volume":"2019","author":"Huang","year":"2019","journal-title":"Stem Cells Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/S0006-2952(98)00103-8","article-title":"Protective effects of the thiophosphate amifostine (WR2721) and a lazaroid (U83836E) on lipid peroxidation in endothelial cells during hypoxia\/reoxygenation","volume":"56","author":"Mertsch","year":"1998","journal-title":"Biochem. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/2045-9912-1-11","article-title":"Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors","volume":"1","author":"Kang","year":"2011","journal-title":"Med. Gas Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hirano, S.i., Aoki, Y., Li, X.K., Ichimaru, N., Takahara, S., and Takefuji, Y. (2021, March 22). Protective Effects of Hydrogen Gas Inhalation on Radiation-Induced Bone Marrow Damage in Cancer Patients: A Retrospective Observational Study. Available online: https:\/\/www.researchsquare.com\/article\/rs-16275\/v1.","DOI":"10.21203\/rs.3.rs-16275\/v1"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hirano, S.i., Aoki, Y., Li, X.K., Ichimaru, N., Takahara, S., and Takefuji, Y. (2021). Protective effects of hydrogen gas inhalation on radiation-induced bone marrow damage in cancer patients: A retrospective observational study. Med. Gas Res., 11. in press.","DOI":"10.21203\/rs.3.rs-16275\/v1"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"887","DOI":"10.7150\/ijbs.7220","article-title":"Hydrogen as a new class of radioprotective agent","volume":"9","author":"Qian","year":"2013","journal-title":"Int. J. Biol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110589","DOI":"10.1016\/j.biopha.2020.110589","article-title":"Molecular hydrogen: A potential radioprotective agent","volume":"130","author":"Hu","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S1383-5742(97)00035-5","article-title":"Analysis of a form of oxidative DNA damage, 8-hydroxy-2\u2032-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis","volume":"387","author":"Kasai","year":"1997","journal-title":"Mutat. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1093\/carcin\/11.9.1447","article-title":"The role of 8-hydroxyguanine in carcinogenesis","volume":"11","author":"Floyd","year":"1990","journal-title":"Carcinogenesis"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1021\/tx00036a006","article-title":"An immunochemical approach of identifying and characterizing protein targets of toxic reactive metabolites","volume":"6","author":"Pohl","year":"1993","journal-title":"Chem. Res. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/BF02790126","article-title":"Free radicals production and estimation of oxidative stress related to gamma irradiation","volume":"47","author":"Dubner","year":"1995","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2307\/3578167","article-title":"Structural changes in plasma membranes prepared from irradiated Chinese hamster V79 cells as revealed by Raman spectroscopy","volume":"126","author":"Verma","year":"1991","journal-title":"Radiat. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"580","DOI":"10.4103\/1673-5374.293153","article-title":"Effect of intensity-modulated radiation therapy on sciatic nerve injury caused by echinococcosis","volume":"16","author":"Xu","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13046-021-01883-0","article-title":"TP53 drives abscopal effects by secretion of senescence-associated molecular signals in non-small cell lung cancer","volume":"40","author":"Tesei","year":"2021","journal-title":"Int. Exp. Clin. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"624312","DOI":"10.3389\/fcell.2021.624312","article-title":"A perspective of epigenetic regulation in radiotherapy","volume":"9","author":"Peng","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1667\/RR15464.1","article-title":"Effect of hydrogen rich water on radiation-induced cognitive dysfunction in rats","volume":"193","author":"Liu","year":"2020","journal-title":"Radiat. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2298\/NTRP1001023Q","article-title":"Hydrogen-rich PBS protects cultured human cells from ionizing radiation-induced cellular damage","volume":"25","author":"Qian","year":"2010","journal-title":"Nucl. Technol. Radiat. Prot."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3109\/10715760903468758","article-title":"Radioprotective effect of hydrogen in cultured cells and mice","volume":"44","author":"Qian","year":"2010","journal-title":"Free Radic. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"BR144","DOI":"10.12659\/MSM.882616","article-title":"Hydrogen-rich saline protects immunocytes from radiation-induced apoptosis","volume":"18","author":"Yang","year":"2012","journal-title":"Med. Sci. Monit."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1111\/jcmm.12245","article-title":"Protective effect of hydrogen-rich saline against radiation-induced immune dysfunction","volume":"18","author":"Zhao","year":"2014","journal-title":"J. Cell Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"L415","DOI":"10.1152\/ajplung.00008.2011","article-title":"Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress","volume":"301","author":"Terasaki","year":"2011","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1269\/jrr.10093","article-title":"The potential cardioprotective effects of hydrogen in irradiated mice","volume":"51","author":"Qian","year":"2010","journal-title":"J. Radiat. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s11010-019-03512-z","article-title":"Regulation of microRNAs by molecular hydrogen contributes to the prevention of radiation-induced damage in the rat myocardium","volume":"457","author":"Kura","year":"2019","journal-title":"Mol. Cell Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e433","DOI":"10.1038\/emm.2017.246","article-title":"Hydrogen water ameliorates radiation-induced gastrointestinal toxicity via MyD88\u2032s effects on the gut microbiota","volume":"50","author":"Xiao","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"106517","DOI":"10.1016\/j.intimp.2020.106517","article-title":"Hydrogen attenuates radiation-induced intestinal damage by reducing oxidative stress and inflammatory response","volume":"84","author":"Qiu","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8241678","DOI":"10.1155\/2017\/8241678","article-title":"Hydrogen-rich water ameliorates total body irradiation-induced hematopoietic stem cell injury by reducing hydroxyl radical","volume":"3","author":"Zhang","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_47","first-page":"BR89","article-title":"Hydrogen-rich saline protects spermatogenesis and hematopoiesis in irradiated BALB\/c mice","volume":"18","author":"Cauai","year":"2012","journal-title":"Med. Sci. Monit."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1042\/BJ20111786","article-title":"Hydrogen-rich saline attenuates radiation-induced male germ cell loss in mice through reducing hydroxyl radicals","volume":"442","author":"Chuai","year":"2012","journal-title":"Biochem. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/bcpt.12016","article-title":"Protection by hydrogen against gamma ray-induced testicular damage in rats","volume":"112","author":"Jiang","year":"2013","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"182","DOI":"10.3109\/09546634.2012.762639","article-title":"Hydrogen protects rats from dermatitis caused by local radiation","volume":"25","author":"Mei","year":"2014","journal-title":"J. Dermatol. Treat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1093\/jrr\/rru067","article-title":"Protective effect of inhalation of hydrogen gas on radiation-induced dermatitis and skin injury in rats","volume":"55","author":"Watanabe","year":"2014","journal-title":"J. Radiat. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1093\/jrr\/rry074","article-title":"The healing effect of hydrogen-rich water on acute radiation-induced skin injury in rats","volume":"60","author":"Zhou","year":"2019","journal-title":"J. Radiat. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1016\/j.ijom.2020.04.011","article-title":"A study on the protective effect of molecular hydrogen on osteoradionecrosis of the jaw in rats","volume":"49","author":"Chen","year":"2020","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"297","DOI":"10.7150\/ijbs.7.297","article-title":"Hydrogen protects mice from radiation induced thymic lymphoma in BALB\/c mice","volume":"7","author":"Zhao","year":"2011","journal-title":"Int. J. Biol. Sci."},{"key":"ref_55","unstructured":"NERL Data (2021, April 12). Radiation Chemistry Data Center, Notre Dame Radiation Laboratory (n.d.), Available online: http:\/\/kinetics.nist.gov\/solution\/."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s40779-018-0156-7","article-title":"Radiation-induced inflammation and autoimmune disease","volume":"5","author":"Yahyapour","year":"2018","journal-title":"Millit. Med. Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Hirano, S.i., Ichikawa, Y., Sato, B., Yamamoto, H., Takefuji, Y., and Satoh, F. (2021). Potential therapeutic application of hydrogen in chronic inflammatory diseases: Possible inhibiting role on mitochondrial stress. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052549"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"G450","DOI":"10.1152\/ajpgi.00158.2020","article-title":"Hydrogen-rich water protects liver injury in nonalcoholic steatohepatitis through HO-1 enhancement via IL-10 and Sirt 1 signaling","volume":"320","author":"Li","year":"2021","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s00011-020-01347-9","article-title":"Hydrogen attenuates sepsis-associated encephalopathy by NRF2 mediated NLRP3 pathway inactivation","volume":"69","author":"Xie","year":"2015","journal-title":"Inflamm. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1097\/SHK.0000000000001594","article-title":"Hydrogen gas alleviates sepsis-induced brain injury by improving mitochondrial biogenesis through the activation of PGC-\u03b1 in mice","volume":"55","author":"Xie","year":"2021","journal-title":"Shock"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/2045-9912-1-12","article-title":"Improved brain MRI indices in the acute brain stem infarct sires treated with hydroxy radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study","volume":"1","author":"Ono","year":"2011","journal-title":"Med. Gas Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1269\/jrr.07061","article-title":"Free radical scavenger edaravone suppresses X-ray-induced apoptosis through p53 inhibition in MOLT-4 cells","volume":"48","author":"Sasano","year":"2007","journal-title":"J. Radiat. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1001\/jama.297.8.842","article-title":"Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis","volume":"297","author":"Bjelakovic","year":"2007","journal-title":"JAMA"},{"key":"ref_64","first-page":"301","article-title":"Hydrogen gas restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis","volume":"41","author":"Akagi","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1097\/SHK.0000000000001098","article-title":"Hydrogen-rich saline regulates intestinal barrier dysfunction, dysbiosis and bacterial translocation in a murine model of sepsis","volume":"50","author":"Ikeda","year":"2018","journal-title":"Shock"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1253\/circj.CJ-17-0105","article-title":"The effects of hydrogen gas inhalation on adverse left ventricular remodeling after percutaneous coronary intervention for ST-elevated myocardial infraction. First pilot study in humans","volume":"81","author":"Katsumata","year":"2017","journal-title":"Circ. J."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Takeuchi, S., Nagatani, K., Otani, N., Nawashiro, H., Sugawara, T., Wada, K., and Mori, K. (2015). Hydrogen improves neurological function through attenuation of blood-brain barrier disruption in spontaneously hypertensive stroke-prone rats. BMC Neurosci., 16.","DOI":"10.1186\/s12868-015-0165-3"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/jdi.12674","article-title":"Subcutaneous injection of hydrogen gas is a novel effective treatment for type 2 diabetes","volume":"9","author":"Zhang","year":"2018","journal-title":"J. Diabetes Investig."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"140","DOI":"10.3164\/jcbn.09-100","article-title":"Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome: An open label pilot study","volume":"46","author":"Nakao","year":"2010","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5485","DOI":"10.1038\/srep05485","article-title":"Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes","volume":"4","author":"Liu","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1038\/s41598-018-38180-4","article-title":"Hydrogen gas distribution in organs after inhalation: Real-time monitoring of tissue hydrogen concentration in rat","volume":"9","author":"Yamamoto","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1002\/mds.25375","article-title":"Pilot study of H2 therapy in Parkinson\u2019s disease. A randomized double-blind placebo-controlled trial","volume":"28","author":"Yoritaka","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1016\/j.jstrokecerebrovasdis.2017.06.012","article-title":"Hydrogen gas inhalation treatment in acute cerebral infarction: A randomized clinical study on safety and neuroprotection","volume":"26","author":"Ono","year":"2017","journal-title":"J. Stroke Cerebrovasc."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/2045-9912-2-27","article-title":"Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: An open-label pilot study","volume":"2","author":"Ishibashi","year":"2012","journal-title":"Med. Gas Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.intimp.2014.06.001","article-title":"Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: A randomized, double-blind placebo-controlled pilot study","volume":"21","author":"Ishibashi","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"482","DOI":"10.2174\/1567205014666171106145017","article-title":"Effects of molecular hydrogen assessed by an animal model and a randomized clinical study on mild cognitive impairment","volume":"15","author":"Nishimaki","year":"2017","journal-title":"Curr. Alzheimer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"8645","DOI":"10.2147\/OTT.S227217","article-title":"A gallbladder carcinoma patient with pseudo-progressive remission after hydrogen inhalation","volume":"12","author":"Chen","year":"2019","journal-title":"Onco Targets Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"133","DOI":"10.4103\/2045-9912.266988","article-title":"Safety of inhaled hydrogen gas in healthy mice","volume":"9","author":"Cole","year":"2019","journal-title":"Med. Gas Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1056\/NEJM196907172810303","article-title":"Production and excretion of hydrogen gas in man","volume":"281","author":"Levitt","year":"1969","journal-title":"N. Engl. J. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3931","DOI":"10.1007\/s00216-013-7606-6","article-title":"Medical applications of breath hydrogen measurements","volume":"406","author":"Shin","year":"2014","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_81","first-page":"101","article-title":"Increased concentrations of breath hydrogen gas in Japanese centenarians","volume":"10","author":"Aoki","year":"2013","journal-title":"Anti-Aging Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/978-1-4614-1566-4_36","article-title":"Estimation of molecular hydrogen consumption in the human whole body after the ingestion of hydrogen-rich water","volume":"737","author":"Shimouchi","year":"2012","journal-title":"Adv. Exp. Med. 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