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Open Access 01-12-2015 | Review

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

Authors: Masatoshi Ichihara, Sayaka Sobue, Mikako Ito, Masafumi Ito, Masaaki Hirayama, Kinji Ohno

Published in: Medical Gas Research | Issue 1/2015

Abstract

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.

Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13(6):688–94. doi:10.1038/nm1577.PubMedCrossRef

Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science. 1975;190(4210):152–4.PubMedCrossRef

Roberts BJ, Fife WP, Corbett TH, Schabel Jr FM. Response of five established solid transplantable mouse tumors and one mouse leukemia to hyperbaric hydrogen. Cancer Treat Rep. 1978;62(7):1077–9.PubMed

Abraini JH, Gardette-Chauffour MC, Martinez E, Rostain JC, Lemaire C. Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture. J Appl Physiol. 1994;76(3):1113–8.PubMed

Gharib B, Hanna S, Abdallahi OM, Lepidi H, Gardette B, De Reggi M. Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation. C R Acad Sci III. 2001;324(8):719–24.PubMedCrossRef

Shirahata S, Kabayama S, Nakano M, Miura T, Kusumoto K, Gotoh M, et al. Electrolyzed-reduced water scavenges active oxygen species and protects DNA from oxidative damage. Biochem Biophys Res Commun. 1997;234(1):269–74. doi:10.1006/bbrc.1997.6622.PubMedCrossRef

Li Y, Nishimura T, Teruya K, Maki T, Komatsu T, Hamasaki T, et al. Protective mechanism of reduced water against alloxan-induced pancreatic beta-cell damage: Scavenging effect against reactive oxygen species. Cytotechnology. 2002;40(1–3):139–49. doi:10.1023/A:1023936421448.PubMedCentralPubMedCrossRef

Huang KC, Yang CC, Lee KT, Chien CT. Reduced hemodialysis-induced oxidative stress in end-stage renal disease patients by electrolyzed reduced water. Kidney Int. 2003;64(2):704–14. doi:10.1046/j.1523-1755.2003.00118.x.PubMedCrossRef

Yanagihara T, Arai K, Miyamae K, Sato B, Shudo T, Yamada M, et al. Electrolyzed hydrogen-saturated water for drinking use elicits an antioxidative effect: a feeding test with rats. Biosci Biotechnol Biochem. 2005;69(10):1985–7.PubMedCrossRef

10.

Huang G, Zhou J, Zhan W, Xiong Y, Hu C, Li X, et al. The neuroprotective effects of intraperitoneal injection of hydrogen in rabbits with cardiac arrest. Resuscitation. 2013;84(5):690–5. doi:10.1016/j.resuscitation.2012.10.018.PubMedCrossRef

11.

Ito M, Hirayama M, Yamai K, Goto S, Ito M, Ichihara M, et al. Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Med Gas Res. 2012;2(1):15. doi:10.1186/2045-9912-2-15.PubMedCentralPubMedCrossRef

12.

Sobue S, Yamai K, Ito M, Ohno K, Ito M, Iwamoto T, et al. Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents. Mol Cell Biochem. 2015;403(1–2):231–41. doi:10.1007/s11010-015-2353-y.PubMedCrossRef

13.

Qiu X, Li H, Tang H, Jin Y, Li W, Sun Y, et al. Hydrogen inhalation ameliorates lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol. 2011;11(12):2130–7. doi:10.1016/j.intimp.2011.09.007.PubMedCrossRef

14.

Xie K, Yu Y, Huang Y, Zheng L, Li J, Chen H, et al. Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and apoptosis. Shock. 2012;37(5):548–55. doi:10.1097/SHK.0b013e31824ddc81.PubMed

15.

Hattori Y, Kotani T, Tsuda H, Mano Y, Tu L, Li H, et al. Maternal molecular hydrogen treatment attenuates lipopolysaccharide-induced rat fetal lung injury. Free Radic Res. 2015;49:1026–37. doi:10.3109/10715762.2015.1038257.PubMedCrossRef

16.

Zhang Y, Liu Y, Zhang J. Saturated hydrogen saline attenuates endotoxin-induced lung dysfunction. J Surg Res. 2015;198:41–9. doi:10.1016/j.jss.2015.04.055.PubMedCrossRef

17.

Hayashida K, Sano M, Ohsawa I, Shinmura K, Tamaki K, Kimura K, et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun. 2008;373(1):30–5. doi:10.1016/j.bbrc.2008.05.165.PubMedCrossRef

18.

Sakai K, Cho S, Shibata I, Yoshitomi O, Maekawa T, Sumikawa K. Inhalation of hydrogen gas protects against myocardial stunning and infarction in swine. Scand Cardiovasc J. 2012;46(3):183–9. doi:10.3109/14017431.2012.659676.PubMedCrossRef

19.

Yoshida A, Asanuma H, Sasaki H, Sanada S, Yamazaki S, Asano Y, et al. H(2) mediates cardioprotection via involvements of K(ATP) channels and permeability transition pores of mitochondria in dogs. Cardiovasc Drugs Ther. 2012;26(3):217–26. doi:10.1007/s10557-012-6381-5.PubMedCrossRef

20.

Shinbo T, Kokubo K, Sato Y, Hagiri S, Hataishi R, Hirose M, et al. Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart. Am J Physiol Heart Circ Physiol. 2013;305(4):H542–50. doi:10.1152/ajpheart.00844.2012.PubMedCrossRef

21.

Sun Q, Kang Z, Cai J, Liu W, Liu Y, Zhang JH, et al. Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp Biol Med (Maywood). 2009;234(10):1212–9. doi:10.3181/0812-RM-349.CrossRef

22.

Zhang Y, Sun Q, He B, Xiao J, Wang Z, Sun X. Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion. Int J Cardiol. 2011;148(1):91–5. doi:10.1016/j.ijcard.2010.08.058.PubMedCrossRef

23.

Jing L, Wang Y, Zhao XM, Zhao B, Han JJ, Qin SC, et al. Cardioprotective Effect of Hydrogen-rich Saline on Isoproterenol-induced Myocardial Infarction in Rats. Heart Lung Circ. 2015;24(6):602–10. doi:10.1016/j.hlc.2014.11.018.PubMedCrossRef

24.

Zhang G, Gao S, Li X, Zhang L, Tan H, Xu L, et al. Pharmacological postconditioning with lactic acid and hydrogen rich saline alleviates myocardial reperfusion injury in rats. Sci Rep. 2015;5:9858. doi:10.1038/srep09858.PubMedCentralPubMedCrossRef

25.

Ohno K, Ito M, Ichihara M, Ito M. Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxid Med Cell Longev. 2012;2012:353152. doi:10.1155/2012/353152.PubMedCentralPubMedCrossRef

26.

Itoh T, Fujita Y, Ito M, Masuda A, Ohno K, Ichihara M, et al. Molecular hydrogen suppresses FcepsilonRI-mediated signal transduction and prevents degranulation of mast cells. Biochem Biophys Res Commun. 2009;389(4):651–6. doi:10.1016/j.bbrc.2009.09.047.PubMedCrossRef

27.

Itoh T, Hamada N, Terazawa R, Ito M, Ohno K, Ichihara M, et al. Molecular hydrogen inhibits lipopolysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in macrophages. Biochem Biophys Res Commun. 2011;411(1):143–9. doi:10.1016/j.bbrc.2011.06.116.PubMedCrossRef

28.

Manaenko A, Lekic T, Ma Q, Zhang JH, Tang J. Hydrogen inhalation ameliorated mast cell-mediated brain injury after intracerebral hemorrhage in mice. Crit Care Med. 2013;41(5):1266–75. doi:10.1097/CCM.0b013e31827711c9.PubMedCentralPubMedCrossRef

29.

Chen Y, Jiang J, Miao H, Chen X, Sun X, Li Y. Hydrogen-rich saline attenuates vascular smooth muscle cell proliferation and neointimal hyperplasia by inhibiting reactive oxygen species production and inactivating the Ras-ERK1/2-MEK1/2 and Akt pathways. Int J Mol Med. 2013;31(3):597–606. doi:10.3892/ijmm.2013.1256.PubMed

30.

Cardinal JS, Zhan J, Wang Y, Sugimoto R, Tsung A, McCurry KR, et al. Oral hydrogen water prevents chronic allograft nephropathy in rats. Kidney Int. 2010;77(2):101–9. doi:10.1038/ki.2009.421.PubMedCrossRef

31.

Liu Q, Shen WF, Sun HY, Fan DF, Nakao A, Cai JM, et al. Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice. Liver Int. 2010;30(7):958–68. doi:10.1111/j.1478-3231.2010.02254.x.PubMedCrossRef

32.

Kasuyama K, Tomofuji T, Ekuni D, Tamaki N, Azuma T, Irie K, et al. Hydrogen-rich water attenuates experimental periodontitis in a rat model. J Clin Periodontol. 2011;38(12):1085–90. doi:10.1111/j.1600-051X.2011.01801.x.PubMedCrossRef

33.

Tanaka Y, Shigemura N, Kawamura T, Noda K, Isse K, Stolz DB, et al. Profiling molecular changes induced by hydrogen treatment of lung allografts prior to procurement. Biochem Biophys Res Commun. 2012;425(4):873–9. doi:10.1016/j.bbrc.2012.08.005.PubMedCentralPubMedCrossRef

34.

Sun Y, Shuang F, Chen DM, Zhou RB. Treatment of hydrogen molecule abates oxidative stress and alleviates bone loss induced by modeled microgravity in rats. Osteoporos Int. 2013;24(3):969–78. doi:10.1007/s00198-012-2028-4.PubMedCrossRef

35.

Xu XF, Zhang J. Saturated hydrogen saline attenuates endotoxin-induced acute liver dysfunction in rats. Physiol Res. 2013;62(4):395–403.PubMed

36.

Li DZ, Zhang QX, Dong XX, Li HD, Ma X. Treatment with hydrogen molecules prevents RANKL-induced osteoclast differentiation associated with inhibition of ROS formation and inactivation of MAPK, AKT and NF-kappa B pathways in murine RAW264.7 cells. J Bone Miner Metab. 2014;32(5):494–504. doi:10.1007/s00774-013-0530-1.PubMedCrossRef

37.

Guo SX, Fang Q, You CG, Jin YY, Wang XG, Hu XL, et al. Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation. J Transl Med. 2015;13:183. doi:10.1186/s12967-015-0548-3.PubMedCentralPubMedCrossRef

38.

Liu X, Chen Z, Mao N, Xie Y. The protective of hydrogen on stress-induced gastric ulceration. Int Immunopharmacol. 2012;13(2):197–203. doi:10.1016/j.intimp.2012.04.004.PubMedCrossRef

39.

Chen Q, Chen P, Zhou S, Yan X, Zhang J, Sun X, et al. Hydrogen-rich saline attenuated neuropathic pain by reducing oxidative stress. Can J Neurol Sci. 2013;40(6):857–63.PubMedCrossRef

40.

Wu F, Qiu Y, Ye G, Luo H, Jiang J, Yu F, et al. Treatment with hydrogen molecule attenuates cardiac dysfunction in streptozotocin-induced diabetic mice. Cardiovasc Pathol. 2015;24:294–303. doi:10.1016/j.carpath.2015.04.008.PubMedCrossRef

41.

Zhai Y, Zhou X, Dai Q, Fan Y, Huang X. Hydrogen-rich saline ameliorates lung injury associated with cecal ligation and puncture-induced sepsis in rats. Exp Mol Pathol. 2015;98(2):268–76. doi:10.1016/j.yexmp.2015.03.005.PubMedCrossRef

42.

Sun H, Chen L, Zhou W, Hu L, Li L, Tu Q, et al. The protective role of hydrogen-rich saline in experimental liver injury in mice. J Hepatol. 2011;54(3):471–80. doi:10.1016/j.jhep.2010.08.011.PubMedCrossRef

43.

Wang C, Li J, Liu Q, Yang R, Zhang JH, Cao YP, et al. Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-kappaB activation in a rat model of amyloid-beta-induced Alzheimer’s disease. Neurosci Lett. 2011;491(2):127–32. doi:10.1016/j.neulet.2011.01.022.PubMedCrossRef

44.

Iio A, Ito M, Itoh T, Terazawa R, Fujita Y, Nozawa Y, et al. Molecular hydrogen attenuates fatty acid uptake and lipid accumulation through downregulating CD36 expression in HepG2 cells. Med Gas Res. 2013;3(1):6. doi:10.1186/2045-9912-3-6.PubMedCentralPubMedCrossRef

45.

Shin MH, Park R, Nojima H, Kim HC, Kim YK, Chung JH. Atomic hydrogen surrounded by water molecules, H(H2O)m, modulates basal and UV-induced gene expressions in human skin in vivo. PLoS One. 2013;8(4):e61696. doi:10.1371/journal.pone.0061696.PubMedCentralPubMedCrossRef

46.

Liu YQ, Liu YF, Ma XM, Xiao YD, Wang YB, Zhang MZ, et al. Hydrogen-rich saline attenuates skin ischemia/reperfusion induced apoptosis via regulating Bax/Bcl-2 ratio and ASK-1/JNK pathway. J Plast Reconstr Aesthet Surg. 2015;68(7):e147–56. doi:10.1016/j.bjps.2015.03.001.PubMedCrossRef

47.

Zhang JY, Song SD, Pang Q, Zhang RY, Wan Y, Yuan DW, et al. Hydrogen-rich water protects against acetaminophen-induced hepatotoxicity in mice. World J Gastroenterol. 2015;21(14):4195–209. doi:10.3748/wjg.v21.i14.4195.PubMedCentralPubMedCrossRef

48.

Hong Y, Shao A, Wang J, Chen S, Wu H, McBride DW, et al. Neuroprotective effect of hydrogen-rich saline against neurologic damage and apoptosis in early brain injury following subarachnoid hemorrhage: possible role of the Akt/GSK3beta signaling pathway. PLoS One. 2014;9(4):e96212. doi:10.1371/journal.pone.0096212.PubMedCentralPubMedCrossRef

49.

Guo SX, Jin YY, Fang Q, You CG, Wang XG, Hu XL, et al. Beneficial effects of hydrogen-rich saline on early burn-wound progression in rats. PLoS One. 2015;10(4):e0124897. doi:10.1371/journal.pone.0124897.PubMedCentralPubMedCrossRef

50.

Wei L, Ge L, Qin S, Shi Y, Du C, Du H, et al. Hydrogen-rich saline protects retina against glutamate-induced excitotoxic injury in guinea pig. Exp Eye Res. 2012;94(1):117–27. doi:10.1016/j.exer.2011.11.016.PubMedCrossRef

51.

Abe T, Li XK, Yazawa K, Hatayama N, Xie L, Sato B, et al. Hydrogen-rich University of Wisconsin solution attenuates renal cold ischemia-reperfusion injury. Transplantation. 2012;94(1):14–21. doi:10.1097/TP.0b013e318255f8be.PubMedCrossRef

52.

Noda K, Shigemura N, Tanaka Y, Kawamura T, Hyun Lim S, Kokubo K, et al. A novel method of preserving cardiac grafts using a hydrogen-rich water bath. J Heart Lung Transplant. 2013;32(2):241–50. doi:10.1016/j.healun.2012.11.004.PubMedCrossRef

53.

Huang CS, Kawamura T, Peng X, Tochigi N, Shigemura N, Billiar TR, et al. Hydrogen inhalation reduced epithelial apoptosis in ventilator-induced lung injury via a mechanism involving nuclear factor-kappa B activation. Biochem Biophys Res Commun. 2011;408(2):253–8. doi:10.1016/j.bbrc.2011.04.008.PubMedCrossRef

54.

Song G, Tian H, Liu J, Zhang H, Sun X, Qin S. H2 inhibits TNF-alpha-induced lectin-like oxidized LDL receptor-1 expression by inhibiting nuclear factor kappaB activation in endothelial cells. Biotechnol Lett. 2011;33(9):1715–22. doi:10.1007/s10529-011-0630-8.PubMedCrossRef

55.

Kubota M, Shimmura S, Kubota S, Miyashita H, Kato N, Noda K, et al. Hydrogen and N-acetyl-L-cysteine rescue oxidative stress-induced angiogenesis in a mouse corneal alkali-burn model. Invest Ophthalmol Vis Sci. 2011;52(1):427–33. doi:10.1167/iovs.10-6167.PubMedCrossRef

56.

Ji Q, Hui K, Zhang L, Sun X, Li W, Duan M. The effect of hydrogen-rich saline on the brain of rats with transient ischemia. J Surg Res. 2011;168(1):e95–101. doi:10.1016/j.jss.2011.01.057.PubMedCrossRef

57.

Shen L, Wang J, Liu K, Wang C, Wang C, Wu H, et al. Hydrogen-rich saline is cerebroprotective in a rat model of deep hypothermic circulatory arrest. Neurochem Res. 2011;36(8):1501–11. doi:10.1007/s11064-011-0476-4.PubMedCrossRef

58.

Qin ZX, Yu P, Qian DH, Song MB, Tan H, Yu Y, et al. Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-alpha/NF-kappaB pathway. Atherosclerosis. 2012;220(2):343–50. doi:10.1016/j.atherosclerosis.2011.11.002.PubMedCrossRef

59.

Song G, Tian H, Qin S, Sun X, Yao S, Zong C, et al. Hydrogen decreases athero-susceptibility in apolipoprotein B-containing lipoproteins and aorta of apolipoprotein E knockout mice. Atherosclerosis. 2012;221(1):55–65. doi:10.1016/j.atherosclerosis.2011.11.043.PubMedCrossRef

60.

Zheng H, Yu YS. Chronic hydrogen-rich saline treatment attenuates vascular dysfunction in spontaneous hypertensive rats. Biochem Pharmacol. 2012;83(9):1269–77. doi:10.1016/j.bcp.2012.01.031.PubMedCrossRef

61.

Hong Y, Guo S, Chen S, Sun C, Zhang J, Sun X. Beneficial effect of hydrogen-rich saline on cerebral vasospasm after experimental subarachnoid hemorrhage in rats. J Neurosci Res. 2012;90(8):1670–80. doi:10.1002/jnr.22739.PubMedCrossRef

62.

Guo JD, Li L, Shi YM, Wang HD, Hou SX. Hydrogen water consumption prevents osteopenia in ovariectomized rats. Br J Pharmacol. 2013;168(6):1412–20. doi:10.1111/bph.12036.PubMedCentralPubMedCrossRef

63.

Xiao M, Zhu T, Wang T, Wen FQ. Hydrogen-rich saline reduces airway remodeling via inactivation of NF-kappaB in a murine model of asthma. Eur Rev Med Pharmacol Sci. 2013;17(8):1033–43.PubMed

64.

Liu GD, Zhang H, Wang L, Han Q, Zhou SF, Liu P. Molecular hydrogen regulates the expression of miR-9, miR-21 and miR-199 in LPS-activated retinal microglia cells. Int J Ophthalmol. 2013;6(3):280–5. doi:10.3980/j.issn.2222-3959.2013.03.05.PubMedCentralPubMed

65.

Li FY, Zhu SX, Wang ZP, Wang H, Zhao Y, Chen GP. Consumption of hydrogen-rich water protects against ferric nitrilotriacetate-induced nephrotoxicity and early tumor promotional events in rats. Food Chem Toxicol. 2013;61:248–54. doi:10.1016/j.fct.2013.10.004.PubMedCrossRef

66.

Zhuang Z, Sun XJ, Zhang X, Liu HD, You WC, Ma CY, et al. Nuclear factor-kappaB/Bcl-XL pathway is involved in the protective effect of hydrogen-rich saline on the brain following experimental subarachnoid hemorrhage in rabbits. J Neurosci Res. 2013;91(12):1599–608. doi:10.1002/jnr.23281.PubMedCrossRef

67.

Tan YC, Xie F, Zhang HL, Zhu YL, Chen K, Tan HM, et al. Hydrogen-rich saline attenuates postoperative liver failure after major hepatectomy in rats. Clin Res Hepatol Gastroenterol. 2014;38(3):337–45. doi:10.1016/j.clinre.2013.11.007.PubMedCrossRef

68.

Zhang J, Wu Q, Song S, Wan Y, Zhang R, Tai M, et al. Effect of hydrogen-rich water on acute peritonitis of rat models. Int Immunopharmacol. 2014;21(1):94–101. doi:10.1016/j.intimp.2014.04.011.PubMedCrossRef

69.

Xin HG, Zhang BB, Wu ZQ, Hang XF, Xu WS, Ni W, et al. Consumption of hydrogen-rich water alleviates renal injury in spontaneous hypertensive rats. Mol Cell Biochem. 2014;392(1–2):117–24. doi:10.1007/s11010-014-2024-4.PubMedCrossRef

70.

Wang X, Yu P, Yong Y, Liu X, Jiang J, Liu D, et al. Hydrogen-rich saline resuscitation alleviates inflammation induced by severe burn with delayed resuscitation. Burns. 2015;41(2):379–85. doi:10.1016/j.burns.2014.07.012.PubMedCrossRef

71.

Zhang CB, Tang YC, Xu XJ, Guo SX, Wang HZ. Hydrogen gas inhalation protects against liver ischemia/reperfusion injury by activating the NF-kappaB signaling pathway. Exp Ther Med. 2015;9(6):2114–20. doi:10.3892/etm.2015.2385.PubMedCentralPubMed

72.

Shi Q, Liao KS, Zhao KL, Wang WX, Zuo T, Deng WH, et al. Hydrogen-rich saline attenuates acute renal injury in sodium taurocholate-induced severe acute pancreatitis by inhibiting ROS and NF-kappaB pathway. Mediators Inflamm. 2015;2015:685043. doi:10.1155/2015/685043.PubMedCentralPubMed

73.

Shao A, Wu H, Hong Y, Tu S, Sun X, Wu Q et al. Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-kappaB Pathway and NLRP3 Inflammasome. Mol Neurobiol. 2015. doi:10.1007/s12035-015-9242-y.

74.

Chen X, Liu Q, Wang D, Feng S, Zhao Y, Shi Y, et al. Protective Effects of Hydrogen-Rich Saline on Rats with Smoke Inhalation Injury. Oxid Med Cell Longev. 2015;2015:106836. doi:10.1155/2015/106836.PubMedCentralPubMed

75.

Kohama K, Yamashita H, Aoyama-Ishikawa M, Takahashi T, Billiar TR, Nishimura T, et al. Hydrogen inhalation protects against acute lung injury induced by hemorrhagic shock and resuscitation. Surgery. 2015;158(2):399–407. doi:10.1016/j.surg.2015.03.038.PubMedCrossRef

76.

Ren JD, Ma J, Hou J, Xiao WJ, Jin WH, Wu J, et al. Hydrogen-rich saline inhibits NLRP3 inflammasome activation and attenuates experimental acute pancreatitis in mice. Mediators Inflamm. 2014;2014:930894. doi:10.1155/2014/930894.PubMedCentralPubMed

77.

Liu FT, Xu SM, Xiang ZH, Li XN, Li J, Yuan HB, et al. Molecular hydrogen suppresses reactive astrogliosis related to oxidative injury during spinal cord injury in rats. CNS Neurosci Ther. 2014;20(8):778–86. doi:10.1111/cns.12258.PubMedCrossRef

78.

Kishimoto Y, Kato T, Ito M, Azuma Y, Fukasawa Y, Ohno K, et al. Hydrogen ameliorates pulmonary hypertension in rats by anti-inflammatory and antioxidant effects. J Thorac Cardiovasc Surg. 2015;150:645–54. doi:10.1016/j.jtcvs.2015.05.052.PubMedCrossRef

79.

Zhang L, Shu R, Wang C, Wang H, Li N, Wang G. Hydrogen-rich saline controls remifentanil-induced hypernociception and NMDA receptor NR1 subunit membrane trafficking through GSK-3beta in the DRG in rats. Brain Res Bull. 2014;106:47–55. doi:10.1016/j.brainresbull.2014.05.005.PubMedCrossRef

80.

Xie K, Wang W, Chen H, Han H, Liu D, Wang G, et al. Hydrogen-Rich Medium Attenuated Lipopolysaccharide-Induced Monocyte-Endothelial Cell Adhesion and Vascular Endothelial Permeability via Rho-Associated Coiled-Coil Protein Kinase. Shock. 2015;44(1):58–64. doi:10.1097/SHK.0000000000000365.PubMedCrossRef

81.

Spulber S, Edoff K, Hong L, Morisawa S, Shirahata S, Ceccatelli S. Molecular hydrogen reduces LPS-induced neuroinflammation and promotes recovery from sickness behaviour in mice. PLoS One. 2012;7(7):e42078. doi:10.1371/journal.pone.0042078.PubMedCentralPubMedCrossRef

82.

Kawamura T, Wakabayashi N, Shigemura N, Huang CS, Masutani K, Tanaka Y, et al. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. Am J Physiol Lung Cell Mol Physiol. 2013;304(10):L646–56. doi:10.1152/ajplung.00164.2012.PubMedCentralPubMedCrossRef

83.

Zhai X, Chen X, Shi J, Shi D, Ye Z, Liu W, et al. Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression. Free Radic Biol Med. 2013;65:731–41. doi:10.1016/j.freeradbiomed.2013.08.004.PubMedCrossRef

84.

Xie Q, Li XX, Zhang P, Li JC, Cheng Y, Feng YL, et al. Hydrogen gas protects against serum and glucose deprivationinduced myocardial injury in H9c2 cells through activation of the NFE2related factor 2/heme oxygenase 1 signaling pathway. Mol Med Rep. 2014;10(2):1143–9. doi:10.3892/mmr.2014.2283.PubMed

85.

Song G, Zong C, Zhang Z, Yu Y, Yao S, Jiao P, et al. Molecular Hydrogen stabilizes atherosclerotic plaque in low-density lipoprotein receptor knockout mice. Free Radic Biol Med. 2015;87:58–68. doi:10.1016/j.freeradbiomed.2015.06.018.PubMedCrossRef

86.

Li Y, Xie K, Chen H, Wang G, Yu Y. Hydrogen gas inhibits high-mobility group box 1 release in septic mice by upregulation of heme oxygenase 1. J Surg Res. 2015;196(1):136–48. doi:10.1016/j.jss.2015.02.042.PubMedCrossRef

87.

Li Y, Li Q, Chen H, Wang T, Liu L, Wang G, et al. Hydrogen Gas Alleviates the Intestinal Injury Caused by Severe Sepsis in Mice by Increasing the Expression of Heme Oxygenase-1. Shock. 2015;44(1):90–8. doi:10.1097/SHK.0000000000000382.PubMedCrossRef

88.

Kawamura T, Huang CS, Peng X, Masutani K, Shigemura N, Billiar TR, et al. The effect of donor treatment with hydrogen on lung allograft function in rats. Surgery. 2011;150(2):240–9. doi:10.1016/j.surg.2011.05.019.PubMedCrossRef

89.

Buchholz BM, Masutani K, Kawamura T, Peng X, Toyoda Y, Billiar TR, et al. Hydrogen-enriched preservation protects the isogeneic intestinal graft and amends recipient gastric function during transplantation. Transplantation. 2011;92(9):985–92. doi:10.1097/TP.0b013e318230159d.PubMed

90.

Chen HG, Xie KL, Han HZ, Wang WN, Liu DQ, Wang GL, et al. Heme oxygenase-1 mediates the anti-inflammatory effect of molecular hydrogen in LPS-stimulated RAW 264.7 macrophages. Int J Surg. 2013;11(10):1060–6. doi:10.1016/j.ijsu.2013.10.007.PubMedCrossRef

91.

Lin Y, Zhang W, Qi F, Cui W, Xie Y, Shen W. Hydrogen-rich water regulates cucumber adventitious root development in a heme oxygenase-1/carbon monoxide-dependent manner. J Plant Physiol. 2014;171(2):1–8. doi:10.1016/j.jplph.2013.08.009.PubMedCrossRef

92.

Chen Y, Chen H, Xie K, Liu L, Li Y, Yu Y, et al. H Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain. Inflammation. 2015;38:1835–46. doi:10.1007/s10753-015-0161-x.PubMedCrossRef

93.

Yu J, Zhang W, Zhang R, Ruan X, Ren P, Lu B. Lactulose accelerates liver regeneration in rats by inducing hydrogen. J Surg Res. 2015;195(1):128–35. doi:10.1016/j.jss.2015.01.034.PubMedCrossRef

94.

Wei R, Zhang R, Xie Y, Shen L, Chen F. Hydrogen Suppresses Hypoxia/Reoxygenation-Induced Cell Death in Hippocampal Neurons Through Reducing Oxidative Stress. Cell Physiol Biochem. 2015;36(2):585–98. doi:10.1159/000430122.PubMedCrossRef

95.

Matsumoto A, Yamafuji M, Tachibana T, Nakabeppu Y, Noda M, Nakaya H. Oral ‘hydrogen water’ induces neuroprotective ghrelin secretion in mice. Sci Rep. 2013;3:3273. doi:10.1038/srep03273.PubMedCentralPubMedCrossRef

96.

Yoritaka A, Takanashi M, Hirayama M, Nakahara T, Ohta S, Hattori N. Pilot study of H(2) therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial. Mov Disord. 2013;28(6):836–9. doi:10.1002/mds.25375.PubMedCrossRef

97.

Fujita K, Seike T, Yutsudo N, Ohno M, Yamada H, Yamaguchi H, et al. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. PLoS One. 2009;4(9):e7247. doi:10.1371/journal.pone.0007247.PubMedCentralPubMedCrossRef

98.

Fukuda K, Asoh S, Ishikawa M, Yamamoto Y, Ohsawa I, Ohta S. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem Biophys Res Commun. 2007;361(3):670–4. doi:10.1016/j.bbrc.2007.07.088.PubMedCrossRef

99.

Chen CH, Manaenko A, Zhan Y, Liu WW, Ostrowki RP, Tang J, et al. Hydrogen gas reduced acute hyperglycemia-enhanced hemorrhagic transformation in a focal ischemia rat model. Neuroscience. 2010;169(1):402–14. doi:10.1016/j.neuroscience.2010.04.043.PubMedCentralPubMedCrossRef

100.

Hugyecz M, Mracsko E, Hertelendy P, Farkas E, Domoki F, Bari F. Hydrogen supplemented air inhalation reduces changes of prooxidant enzyme and gap junction protein levels after transient global cerebral ischemia in the rat hippocampus. Brain Res. 2011;1404:31–8. doi:10.1016/j.brainres.2011.05.068.PubMedCrossRef

101.

Ono H, Nishijima Y, Adachi N, Tachibana S, Chitoku S, Mukaihara S, et al. Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study. Med Gas Res. 2011;1(1):12. doi:10.1186/2045-9912-1-12.PubMedCentralPubMedCrossRef

102.

Liu Y, Liu W, Sun X, Li R, Sun Q, Cai J, et al. Hydrogen saline offers neuroprotection by reducing oxidative stress in a focal cerebral ischemia-reperfusion rat model. Med Gas Res. 2011;1(1):15. doi:10.1186/2045-9912-1-15.PubMedCentralPubMedCrossRef

103.

Li J, Dong Y, Chen H, Han H, Yu Y, Wang G, et al. Protective effects of hydrogen-rich saline in a rat model of permanent focal cerebral ischemia via reducing oxidative stress and inflammatory cytokines. Brain Res. 2012;1486:103–11. doi:10.1016/j.brainres.2012.09.031.PubMedCrossRef

104.

Nagatani K, Wada K, Takeuchi S, Kobayashi H, Uozumi Y, Otani N, et al. Effect of hydrogen gas on the survival rate of mice following global cerebral ischemia. Shock. 2012;37(6):645–52. doi:10.1097/SHK.0b013e31824ed57c.PubMedCrossRef

105.

Ge P, Zhao J, Li S, Ding Y, Yang F, Luo Y. Inhalation of hydrogen gas attenuates cognitive impairment in transient cerebral ischemia via inhibition of oxidative stress. Neurol Res. 2012;34(2):187–94. doi:10.1179/1743132812Y.0000000002.PubMed

106.

Nagatani K, Nawashiro H, Takeuchi S, Tomura S, Otani N, Osada H, et al. Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: initial clinical studies. Med Gas Res. 2013;3(1):13. doi:10.1186/2045-9912-3-13.PubMedCentralPubMedCrossRef

107.

Olah O, Toth-Szuki V, Temesvari P, Bari F, Domoki F. Delayed neurovascular dysfunction is alleviated by hydrogen in asphyxiated newborn pigs. Neonatology. 2013;104(2):79–86. doi:10.1159/000348445.PubMedCrossRef

108.

Cui Y, Zhang H, Ji M, Jia M, Chen H, Yang J, et al. Hydrogen-rich saline attenuates neuronal ischemia--reperfusion injury by protecting mitochondrial function in rats. J Surg Res. 2014;192(2):564–72. doi:10.1016/j.jss.2014.05.060.PubMedCrossRef

109.

Han L, Tian R, Yan H, Pei L, Hou Z, Hao S, et al. Hydrogen-rich water protects against ischemic brain injury in rats by regulating calcium buffering proteins. Brain Res. 2015;1615:129–38. doi:10.1016/j.brainres.2015.04.038.PubMedCrossRef

110.

Takeuchi S, Nagatani K, Otani N, Nawashiro H, Sugawara T, Wada K, et al. Hydrogen improves neurological function through attenuation of blood–brain barrier disruption in spontaneously hypertensive stroke-prone rats. BMC Neurosci. 2015;16(1):22. doi:10.1186/s12868-015-0165-3.PubMedCentralPubMedCrossRef

111.

Zhuang Z, Zhou ML, You WC, Zhu L, Ma CY, Sun XJ, et al. Hydrogen-rich saline alleviates early brain injury via reducing oxidative stress and brain edema following experimental subarachnoid hemorrhage in rabbits. BMC Neurosci. 2012;13:47. doi:10.1186/1471-2202-13-47.PubMedCentralPubMedCrossRef

112.

Zhan Y, Chen C, Suzuki H, Hu Q, Zhi X, Zhang JH. Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats. Crit Care Med. 2012;40(4):1291–6. doi:10.1097/CCM.0b013e31823da96d.PubMedCentralPubMedCrossRef

113.

Takeuchi S, Mori K, Arimoto H, Fujii K, Nagatani K, Tomura S, et al. Effects of intravenous infusion of hydrogen-rich fluid combined with intra-cisternal infusion of magnesium sulfate in severe aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial. BMC Neurol. 2014;14:176. doi:10.1186/s12883-014-0176-1.PubMedCentralPubMedCrossRef

114.

Ji X, Liu W, Xie K, Liu W, Qu Y, Chao X, et al. Beneficial effects of hydrogen gas in a rat model of traumatic brain injury via reducing oxidative stress. Brain Res. 2010;1354:196–205. doi:10.1016/j.brainres.2010.07.038.PubMedCrossRef

115.

Eckermann JM, Chen W, Jadhav V, Hsu FP, Colohan AR, Tang J, et al. Hydrogen is neuroprotective against surgically induced brain injury. Med Gas Res. 2011;1(1):7. doi:10.1186/2045-9912-1-7.PubMedCentralPubMedCrossRef

116.

Hou Z, Luo W, Sun X, Hao S, Zhang Y, Xu F, et al. Hydrogen-rich saline protects against oxidative damage and cognitive deficits after mild traumatic brain injury. Brain Res Bull. 2012;88(6):560–5. doi:10.1016/j.brainresbull.2012.06.006.PubMedCrossRef

117.

Ji X, Tian Y, Xie K, Liu W, Qu Y, Fei Z. Protective effects of hydrogen-rich saline in a rat model of traumatic brain injury via reducing oxidative stress. J Surg Res. 2012;178(1):e9–16. doi:10.1016/j.jss.2011.12.038.PubMedCrossRef

118.

Dohi K, Kraemer BC, Erickson MA, McMillan PJ, Kovac A, Flachbartova Z, et al. Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS One. 2014;9(9):e108034. doi:10.1371/journal.pone.0108034.PubMedCentralPubMedCrossRef

119.

Fu Y, Ito M, Fujita Y, Ito M, Ichihara M, Masuda A, et al. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson’s disease. Neurosci Lett. 2009;453(2):81–5. doi:10.1016/j.neulet.2009.02.016.PubMedCrossRef

120.

Li J, Wang C, Zhang JH, Cai JM, Cao YP, Sun XJ. Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Res. 2010;1328:152–61. doi:10.1016/j.brainres.2010.02.046.PubMedCrossRef

121.

Nagata K, Nakashima-Kamimura N, Mikami T, Ohsawa I, Ohta S. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology. 2009;34(2):501–8. doi:10.1038/npp.2008.95.PubMedCrossRef

122.

Gu Y, Huang CS, Inoue T, Yamashita T, Ishida T, Kang KM, et al. Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. J Clin Biochem Nutr. 2010;46(3):269–76. doi:10.3164/jcbn.10-19.PubMedCentralPubMedCrossRef

123.

Liu L, Xie K, Chen H, Dong X, Li Y, Yu Y, et al. Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis. Brain Res. 2014;1589:78–92. doi:10.1016/j.brainres.2014.09.030.PubMedCrossRef

124.

Ueda Y, Nakajima A, Oikawa T. Hydrogen-related enhancement of in vivo antioxidant ability in the brain of rats fed coral calcium hydride. Neurochem Res. 2010;35(10):1510–5. doi:10.1007/s11064-010-0204-5.PubMedCrossRef

125.

Kashiwagi T, Yan H, Hamasaki T, Kinjo T, Nakamichi N, Teruya K, et al. Electrochemically reduced water protects neural cells from oxidative damage. Oxid Med Cell Longev. 2014;2014:869121. doi:10.1155/2014/869121.PubMedCentralPubMedCrossRef

126.

Huang Y, Xie K, Li J, Xu N, Gong G, Wang G, et al. Beneficial effects of hydrogen gas against spinal cord ischemia-reperfusion injury in rabbits. Brain Res. 2011;1378:125–36. doi:10.1016/j.brainres.2010.12.071.PubMedCrossRef

127.

Zhou L, Wang X, Xue W, Xie K, Huang Y, Chen H, et al. Beneficial effects of hydrogen-rich saline against spinal cord ischemia-reperfusion injury in rabbits. Brain Res. 2013;1517:150–60. doi:10.1016/j.brainres.2013.04.007.PubMedCrossRef

128.

Chen C, Chen Q, Mao Y, Xu S, Xia C, Shi X, et al. Hydrogen-rich saline protects against spinal cord injury in rats. Neurochem Res. 2010;35(7):1111–8. doi:10.1007/s11064-010-0162-y.PubMedCrossRef

129.

Ge Y, Wu F, Sun X, Xiang Z, Yang L, Huang S, et al. Intrathecal infusion of hydrogen-rich normal saline attenuates neuropathic pain via inhibition of activation of spinal astrocytes and microglia in rats. PLoS One. 2014;9(5):e97436. doi:10.1371/journal.pone.0097436.PubMedCentralPubMedCrossRef

130.

Kawaguchi M, Satoh Y, Otsubo Y, Kazama T. Molecular hydrogen attenuates neuropathic pain in mice. PLoS One. 2014;9(6):e100352. doi:10.1371/journal.pone.0100352.PubMedCentralPubMedCrossRef

131.

Zhang L, Shu R, Wang H, Yu Y, Wang C, Yang M, et al. Hydrogen-rich saline prevents remifentanil-induced hyperalgesia and inhibits MnSOD nitration via regulation of NR2B-containing NMDA receptor in rats. Neuroscience. 2014;280:171–80. doi:10.1016/j.neuroscience.2014.09.024.PubMedCrossRef

132.

Shu RC, Zhang LL, Wang CY, Li N, Wang HY, Xie KL, et al. Spinal peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via enhancement of divalent metal transporter 1 without iron-responsive element-mediated iron accumulation in rats. Anesthesiology. 2015;122(4):908–20. doi:10.1097/ALN.0000000000000562.PubMedCrossRef

133.

Oharazawa H, Igarashi T, Yokota T, Fujii H, Suzuki H, Machide M, et al. Protection of the retina by rapid diffusion of hydrogen: administration of hydrogen-loaded eye drops in retinal ischemia-reperfusion injury. Invest Ophthalmol Vis Sci. 2010;51(1):487–92. doi:10.1167/iovs.09-4089.PubMedCrossRef

134.

Liu H, Hua N, Xie K, Zhao T, Yu Y. Hydrogen-rich saline reduces cell death through inhibition of DNA oxidative stress and overactivation of poly (ADP-ribose) polymerase-1 in retinal ischemia-reperfusion injury. Mol Med Rep. 2015;12(2):2495–502. doi:10.3892/mmr.2015.3731.PubMedCentralPubMed

135.

Xiao X, Cai J, Xu J, Wang R, Cai J, Liu Y, et al. Protective effects of hydrogen saline on diabetic retinopathy in a streptozotocin-induced diabetic rat model. J Ocul Pharmacol Ther. 2012;28(1):76–82. doi:10.1089/jop.2010.0129.PubMedCrossRef

136.

Feng Y, Wang R, Xu J, Sun J, Xu T, Gu Q, et al. Hydrogen-rich saline prevents early neurovascular dysfunction resulting from inhibition of oxidative stress in STZ-diabetic rats. Curr Eye Res. 2013;38(3):396–404. doi:10.3109/02713683.2012.748919.PubMedCrossRef

137.

Huang L, Zhao S, Zhang JH, Sun X. Hydrogen saline treatment attenuates hyperoxia-induced retinopathy by inhibition of oxidative stress and reduction of VEGF expression. Ophthalmic Res. 2012;47(3):122–7. doi:10.1159/000329600.PubMedCrossRef

138.

Feng M, Wang XH, Yang XB, Xiao Q, Jiang FG. Protective effect of saturated hydrogen saline against blue light-induced retinal damage in rats. Int J Ophthalmol. 2012;5(2):151–7. doi:10.3980/j.issn.2222-3959.2012.02.07.PubMedCentralPubMed

139.

Tian L, Zhang L, Xia F, An J, Sugita Y, Zhang Z. Hydrogen-rich saline ameliorates the retina against light-induced damage in rats. Med Gas Res. 2013;3(1):19. doi:10.1186/2045-9912-3-19.PubMedCentralPubMedCrossRef

140.

Yokota T, Kamimura N, Igarashi T, Takahashi H, Ohta S, Oharazawa H. Protective effect of molecular hydrogen against oxidative stress caused by peroxynitrite derived from nitric oxide in rat retina. Clin Experiment Ophthalmol. 2015;43:568–77. doi:10.1111/ceo.12525.PubMedCrossRef

141.

Sun JC, Xu T, Zuo Q, Wang RB, Qi AQ, Cao WL, et al. Hydrogen-rich saline promotes survival of retinal ganglion cells in a rat model of optic nerve crush. PLoS One. 2014;9(6):e99299. doi:10.1371/journal.pone.0099299.PubMedCentralPubMedCrossRef

142.

Yang CX, Yan H, Ding TB. Hydrogen saline prevents selenite-induced cataract in rats. Mol Vis. 2013;19:1684–93.PubMedCentralPubMed

143.

Kikkawa YS, Nakagawa T, Horie RT, Ito J. Hydrogen protects auditory hair cells from free radicals. Neuroreport. 2009;20(7):689–94. doi:10.1097/WNR.0b013e32832a5c68.PubMedCrossRef

144.

Taura A, Kikkawa YS, Nakagawa T, Ito J. Hydrogen protects vestibular hair cells from free radicals. Acta Otolaryngol Suppl. 2010;130(563):95–100. doi:10.3109/00016489.2010.486799.CrossRef

145.

Lin Y, Kashio A, Sakamoto T, Suzukawa K, Kakigi A, Yamasoba T. Hydrogen in drinking water attenuates noise-induced hearing loss in guinea pigs. Neurosci Lett. 2011;487(1):12–6. doi:10.1016/j.neulet.2010.09.064.PubMedCrossRef

146.

Zhou Y, Zheng H, Ruan F, Chen X, Zheng G, Kang M, et al. Hydrogen-rich saline alleviates experimental noise-induced hearing loss in guinea pigs. Neuroscience. 2012;209:47–53. doi:10.1016/j.neuroscience.2012.02.028.PubMedCrossRef

147.

Chen L, Yu N, Lu Y, Wu L, Chen D, Guo W, et al. Hydrogen-saturated saline protects intensive narrow band noise-induced hearing loss in guinea pigs through an antioxidant effect. PLoS One. 2014;9(6):e100774. doi:10.1371/journal.pone.0100774.PubMedCentralPubMedCrossRef

148.

Kurioka T, Matsunobu T, Satoh Y, Niwa K, Shiotani A. Inhaled hydrogen gas therapy for prevention of noise-induced hearing loss through reducing reactive oxygen species. Neurosci Res. 2014;89:69–74. doi:10.1016/j.neures.2014.08.009.PubMedCrossRef

149.

Qu J, Li X, Wang J, Mi W, Xie K, Qiu J. Inhalation of hydrogen gas attenuates cisplatin-induced ototoxicity via reducing oxidative stress. Int J Pediatr Otorhinolaryngol. 2012;76(1):111–5. doi:10.1016/j.ijporl.2011.10.014.PubMedCrossRef

150.

Kikkawa YS, Nakagawa T, Taniguchi M, Ito J. Hydrogen protects auditory hair cells from cisplatin-induced free radicals. Neurosci Lett. 2014;579:125–9. doi:10.1016/j.neulet.2014.07.025.PubMedCrossRef

151.

Qu J, Gan YN, Xie KL, Liu WB, Wang YF, Hei RY, et al. Inhalation of hydrogen gas attenuates ouabain-induced auditory neuropathy in gerbils. Acta Pharmacol Sin. 2012;33(4):445–51. doi:10.1038/aps.2011.190.PubMedCentralPubMedCrossRef

152.

Tomofuji T, Kawabata Y, Kasuyama K, Endo Y, Yoneda T, Yamane M, et al. Effects of hydrogen-rich water on aging periodontal tissues in rats. Sci Rep. 2014;4:5534. doi:10.1038/srep05534.PubMedCentralPubMedCrossRef

153.

Shi J, Yao F, Zhong C, Pan X, Yang Y, Lin Q. Hydrogen saline is protective for acute lung ischaemia/reperfusion injuries in rats. Heart Lung Circ. 2012;21(9):556–63. doi:10.1016/j.hlc.2012.05.782.PubMedCrossRef

154.

Li H, Zhou R, Liu J, Li Q, Zhang J, Mu J, et al. Hydrogen-rich saline attenuates lung ischemia-reperfusion injury in rabbits. J Surg Res. 2012;174(1):e11–6. doi:10.1016/j.jss.2011.10.001.PubMedCrossRef

155.

Zheng J, Liu K, Kang Z, Cai J, Liu W, Xu W, et al. Saturated hydrogen saline protects the lung against oxygen toxicity. Undersea Hyperb Med. 2010;37(3):185–92.PubMed

156.

Sun Q, Cai J, Liu S, Liu Y, Xu W, Tao H, et al. Hydrogen-rich saline provides protection against hyperoxic lung injury. J Surg Res. 2011;165(1):e43–9. doi:10.1016/j.jss.2010.09.024.PubMedCrossRef

157.

Huang CS, Kawamura T, Lee S, Tochigi N, Shigemura N, Buchholz BM, et al. Hydrogen inhalation ameliorates ventilator-induced lung injury. Crit Care. 2010;14(6):R234. doi:10.1186/cc9389.PubMedCentralPubMedCrossRef

158.

Liu H, Liang X, Wang D, Zhang H, Liu L, Chen H, et al. Combination therapy with nitric oxide and molecular hydrogen in a murine model of acute lung injury. Shock. 2015;43(5):504–11. doi:10.1097/SHK.0000000000000316.PubMedCrossRef

159.

Mao YF, Zheng XF, Cai JM, You XM, Deng XM, Zhang JH, et al. Hydrogen-rich saline reduces lung injury induced by intestinal ischemia/reperfusion in rats. Biochem Biophys Res Commun. 2009;381(4):602–5. doi:10.1016/j.bbrc.2009.02.105.PubMedCrossRef

160.

Fang Y, Fu XJ, Gu C, Xu P, Wang Y, Yu WR, et al. Hydrogen-rich saline protects against acute lung injury induced by extensive burn in rat model. J Burn Care Res. 2011;32(3):e82–91. doi:10.1097/BCR.0b013e318217f84f.PubMedCrossRef

161.

Liu S, Liu K, Sun Q, Liu W, Xu W, Denoble P, et al. Consumption of hydrogen water reduces paraquat-induced acute lung injury in rats. J Biomed Biotechnol. 2011;2011:305086. doi:10.1155/2011/305086.PubMedCentralPubMed

162.

Sato C, Kamijo Y, Yoshimura K, Nagaki T, Yamaya T, Asakuma S, et al. Effects of hydrogen water on paraquat-induced pulmonary fibrosis in mice. Kitasato Med J. 2015;45(1):9–16.

163.

Ning Y, Shang Y, Huang H, Zhang J, Dong Y, Xu W, et al. Attenuation of cigarette smoke-induced airway mucus production by hydrogen-rich saline in rats. PLoS One. 2013;8(12):e83429. doi:10.1371/journal.pone.0083429.PubMedCentralPubMedCrossRef

164.

He B, Zhang Y, Kang B, Xiao J, Xie B, Wang Z. Protection of oral hydrogen water as an antioxidant on pulmonary hypertension. Mol Biol Rep. 2013;40(9):5513–21. doi:10.1007/s11033-013-2653-9.PubMedCentralPubMedCrossRef

165.

Hayashi T, Yoshioka T, Hasegawa K, Miyamura M, Mori T, Ukimura A, et al. Inhalation of hydrogen gas attenuates left ventricular remodeling induced by intermittent hypoxia in mice. Am J Physiol Heart Circ Physiol. 2011;301(3):H1062–9. doi:10.1152/ajpheart.00150.2011.PubMedCrossRef

166.

Kato R, Nomura A, Sakamoto A, Yasuda Y, Amatani K, Nagai S, et al. Hydrogen gas attenuates embryonic gene expression and prevents left ventricular remodeling induced by intermittent hypoxia in cardiomyopathic hamsters. Am J Physiol Heart Circ Physiol. 2014;307(11):H1626–33. doi:10.1152/ajpheart.00228.2014.PubMedCrossRef

167.

Yu YS, Zheng H. Chronic hydrogen-rich saline treatment reduces oxidative stress and attenuates left ventricular hypertrophy in spontaneous hypertensive rats. Mol Cell Biochem. 2012;365(1–2):233–42. doi:10.1007/s11010-012-1264-4.PubMedCrossRef

168.

Zhang JY, Wu QF, Wan Y, Song SD, Xu J, Xu XS, et al. Protective role of hydrogen-rich water on aspirin-induced gastric mucosal damage in rats. World J Gastroenterol. 2014;20(6):1614–22. doi:10.3748/wjg.v20.i6.1614.PubMedCentralPubMedCrossRef

169.

Xue J, Shang G, Tanaka Y, Saihara Y, Hou L, Velasquez N, et al. Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water. BMC Complement Altern Med. 2014;14:81. doi:10.1186/1472-6882-14-81.PubMedCentralPubMedCrossRef

170.

Zheng X, Mao Y, Cai J, Li Y, Liu W, Sun P, et al. Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res. 2009;43(5):478–84. doi:10.1080/10715760902870603.PubMedCrossRef

171.

Chen H, Sun YP, Hu PF, Liu WW, Xiang HG, Li Y, et al. The effects of hydrogen-rich saline on the contractile and structural changes of intestine induced by ischemia-reperfusion in rats. J Surg Res. 2011;167(2):316–22. doi:10.1016/j.jss.2009.07.045.PubMedCrossRef

172.

Kajiya M, Silva MJ, Sato K, Ouhara K, Kawai T. Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate. Biochem Biophys Res Commun. 2009;386(1):11–5. doi:10.1016/j.bbrc.2009.05.117.PubMedCrossRef

173.

He J, Xiong S, Zhang J, Wang J, Sun A, Mei X, et al. Protective effects of hydrogen-rich saline on ulcerative colitis rat model. J Surg Res. 2013;185(1):174–81. doi:10.1016/j.jss.2013.05.047.PubMedCrossRef

174.

Chen X, Zhai X, Shi J, Liu WW, Tao H, Sun X, et al. Lactulose mediates suppression of dextran sodium sulfate-induced colon inflammation by increasing hydrogen production. Dig Dis Sci. 2013;58(6):1560–8. doi:10.1007/s10620-013-2563-7.PubMedCrossRef

175.

Sheng Q, Lv Z, Cai W, Song H, Qian L, Wang X. Protective effects of hydrogen-rich saline on necrotizing enterocolitis in neonatal rats. J Pediatr Surg. 2013;48(8):1697–706. doi:10.1016/j.jpedsurg.2012.11.038.PubMedCrossRef

176.

Nishimura N, Tanabe H, Sasaki Y, Makita Y, Ohata M, Yokoyama S, et al. Pectin and high-amylose maize starch increase caecal hydrogen production and relieve hepatic ischaemia-reperfusion injury in rats. Br J Nutr. 2012;107(4):485–92. doi:10.1017/S0007114511003229.PubMedCrossRef

177.

Liu Y, Yang L, Tao K, Vizcaychipi MP, Lloyd DM, Sun X, et al. Protective effects of hydrogen enriched saline on liver ischemia reperfusion injury by reducing oxidative stress and HMGB1 release. BMC Gastroenterol. 2014;14:12. doi:10.1186/1471-230X-14-12.PubMedCentralPubMedCrossRef

178.

Matsuno N, Watanabe R, Kimura M, Iwata S, Fujiyama M, Kono S, et al. Beneficial effects of hydrogen gas on porcine liver reperfusion injury with use of total vascular exclusion and active venous bypass. Transplant Proc. 2014;46(4):1104–6. doi:10.1016/j.transproceed.2013.11.134.PubMedCrossRef

179.

Xia C, Liu W, Zeng D, Zhu L, Sun X, Sun X. Effect of hydrogen-rich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis B. Clin Transl Sci. 2013;6(5):372–5. doi:10.1111/cts.12076.PubMedCrossRef

180.

Kawai D, Takaki A, Nakatsuka A, Wada J, Tamaki N, Yasunaka T, et al. Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. Hepatology. 2012;56(3):912–21. doi:10.1002/hep.25782.PubMedCrossRef

181.

Xiang L, Tan JW, Huang LJ, Jia L, Liu YQ, Zhao YQ, et al. Inhalation of hydrogen gas reduces liver injury during major hepatotectomy in swine. World J Gastroenterol. 2012;18(37):5197–204. doi:10.3748/wjg.v18.i37.5197.PubMedCentralPubMed

182.

Kajiya M, Sato K, Silva MJ, Ouhara K, Do PM, Shanmugam KT, et al. Hydrogen from intestinal bacteria is protective for Concanavalin A-induced hepatitis. Biochem Biophys Res Commun. 2009;386(2):316–21. doi:10.1016/j.bbrc.2009.06.024.PubMedCrossRef

183.

Lee PC, Yang YY, Huang CS, Hsieh SL, Lee KC, Hsieh YC, et al. Concomitant inhibition of oxidative stress and angiogenesis by chronic hydrogen-rich saline and N-acetylcysteine treatments improves systemic, splanchnic and hepatic hemodynamics of cirrhotic rats. Hepatol Res. 2015;45(5):578–88. doi:10.1111/hepr.12379.PubMedCrossRef

184.

Koyama Y, Taura K, Hatano E, Tanabe K, Yamamoto G, Nakamura K, et al. Effects of oral intake of hydrogen water on liver fibrogenesis in mice. Hepatol Res. 2014;44(6):663–77. doi:10.1111/hepr.12165.PubMedCrossRef

185.

Chen H, Sun YP, Li Y, Liu WW, Xiang HG, Fan LY, et al. Hydrogen-rich saline ameliorates the severity of l-arginine-induced acute pancreatitis in rats. Biochem Biophys Res Commun. 2010;393(2):308–13. doi:10.1016/j.bbrc.2010.02.005.PubMedCrossRef

186.

Ren J, Luo Z, Tian F, Wang Q, Li K, Wang C. Hydrogen-rich saline reduces the oxidative stress and relieves the severity of trauma-induced acute pancreatitis in rats. J Trauma Acute Care Surg. 2012;72(6):1555–61. doi:10.1097/TA.0b013e31824a7913.PubMedCrossRef

187.

Zhang DQ, Feng H, Chen WC. Effects of hydrogen-rich saline on taurocholate-induced acute pancreatitis in rat. Evid Based Complement Alternat Med. 2013;2013:731932. doi:10.1155/2013/731932.PubMedCentralPubMed

188.

Zhu WJ, Nakayama M, Mori T, Nakayama K, Katoh J, Murata Y, et al. Intake of water with high levels of dissolved hydrogen (H2) suppresses ischemia-induced cardio-renal injury in Dahl salt-sensitive rats. Nephrol Dial Transplant. 2011;26(7):2112–8. doi:10.1093/ndt/gfq727.PubMedCrossRef

189.

Shingu C, Koga H, Hagiwara S, Matsumoto S, Goto K, Yokoi I, et al. Hydrogen-rich saline solution attenuates renal ischemia-reperfusion injury. J Anesth. 2010;24(4):569–74. doi:10.1007/s00540-010-0942-1.PubMedCrossRef

190.

Wang F, Yu G, Liu SY, Li JB, Wang JF, Bo LL, et al. Hydrogen-rich saline protects against renal ischemia/reperfusion injury in rats. J Surg Res. 2011;167(2):e339–44. doi:10.1016/j.jss.2010.11.005.PubMedCrossRef

191.

Xu B, Zhang YB, Li ZZ, Yang MW, Wang S, Jiang DP. Hydrogen-rich saline ameliorates renal injury induced by unilateral ureteral obstruction in rats. Int Immunopharmacol. 2013;17(2):447–52. doi:10.1016/j.intimp.2013.06.033.PubMedCrossRef

192.

Gu H, Yang M, Zhao X, Zhao B, Sun X, Gao X. Pretreatment with hydrogen-rich saline reduces the damage caused by glycerol-induced rhabdomyolysis and acute kidney injury in rats. J Surg Res. 2014;188(1):243–9. doi:10.1016/j.jss.2013.12.007.PubMedCrossRef

193.

Liu W, Dong XS, Sun YQ, Liu Z. A novel fluid resuscitation protocol: provide more protection on acute kidney injury during septic shock in rats. Int J Clin Exp Med. 2014;7(4):919–26.PubMedCentralPubMed

194.

Homma K, Yoshida T, Yamashita M, Hayashida K, Hayashi M, Hori S. Inhalation of Hydrogen Gas Is Beneficial for Preventing Contrast-Induced Acute Kidney Injury in Rats. Nephron Exp Nephrol. 2015. doi:10.1159/000369068.

195.

Nakashima-Kamimura N, Mori T, Ohsawa I, Asoh S, Ohta S. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol. 2009;64(4):753–61. doi:10.1007/s00280-008-0924-2.PubMedCrossRef

196.

Kitamura A, Kobayashi S, Matsushita T, Fujinawa H, Murase K. Experimental verification of protective effect of hydrogen-rich water against cisplatin-induced nephrotoxicity in rats using dynamic contrast-enhanced CT. Br J Radiol. 2010;83(990):509–14. doi:10.1259/bjr/25604811.PubMedCentralPubMedCrossRef

197.

Matsushita T, Kusakabe Y, Kitamura A, Okada S, Murase K. Investigation of protective effect of hydrogen-rich water against cisplatin-induced nephrotoxicity in rats using blood oxygenation level-dependent magnetic resonance imaging. Jpn J Radiol. 2011;29(7):503–12. doi:10.1007/s11604-011-0588-4.PubMedCrossRef

198.

Matsushita T, Kusakabe Y, Kitamura A, Okada S, Murase K. Protective effect of hydrogen-rich water against gentamicin-induced nephrotoxicity in rats using blood oxygenation level-dependent MR imaging. Magn Reson Med Sci. 2011;10(3):169–76.PubMedCrossRef

199.

Katakura M, Hashimoto M, Tanabe Y, Shido O. Hydrogen-rich water inhibits glucose and alpha,beta -dicarbonyl compound-induced reactive oxygen species production in the SHR.Cg-Leprcp/NDmcr rat kidney. Med Gas Res. 2012;2(1):18. doi:10.1186/2045-9912-2-18.PubMedCentralPubMedCrossRef

200.

Peng Z, Chen W, Wang L, Ye Z, Gao S, Sun X, et al. Inhalation of hydrogen gas ameliorates glyoxylate-induced calcium oxalate deposition and renal oxidative stress in mice. Int J Clin Exp Pathol. 2015;8(3):2680–9.PubMedCentralPubMed

201.

Matsumoto S, Ueda T, Kakizaki H. Effect of supplementation with hydrogen-rich water in patients with interstitial cystitis/painful bladder syndrome. Urology. 2013;81(2):226–30. doi:10.1016/j.urology.2012.10.026.PubMedCrossRef

202.

Lee JW, Kim JI, Lee YA, Lee DH, Song CS, Cho YJ, et al. Inhaled hydrogen gas therapy for prevention of testicular ischemia/reperfusion injury in rats. J Pediatr Surg. 2012;47(4):736–42. doi:10.1016/j.jpedsurg.2011.09.035.PubMedCrossRef

203.

Jiang D, Wu D, Zhang Y, Xu B, Sun X, Li Z. Protective effects of hydrogen rich saline solution on experimental testicular ischemia-reperfusion injury in rats. J Urol. 2012;187(6):2249–53. doi:10.1016/j.juro.2012.01.029.PubMedCrossRef

204.

Fan M, Xu X, He X, Chen L, Qian L, Liu J, et al. Protective effects of hydrogen-rich saline against erectile dysfunction in a streptozotocin induced diabetic rat model. J Urol. 2013;190(1):350–6. doi:10.1016/j.juro.2012.12.001.PubMedCrossRef

205.

Li S, Lu D, Zhang Y, Zhang Y. Long-term treatment of hydrogen-rich saline abates testicular oxidative stress induced by nicotine in mice. J Assist Reprod Genet. 2014;31(1):109–14. doi:10.1007/s10815-013-0102-2.PubMedCentralPubMedCrossRef

206.

Chen S, Jiang W. Effect of hydrogen injected subcutaneously on testicular tissues of rats exposed to cigarette smoke. Int J Clin Exp Med. 2015;8(4):5565–70.PubMedCentralPubMed

207.

Zhao L, Wang YB, Qin SR, Ma XM, Sun XJ, Wang ML, et al. Protective effect of hydrogen-rich saline on ischemia/reperfusion injury in rat skin flap. J Zhejiang Univ Sci B. 2013;14(5):382–91. doi:10.1631/jzus.B1200317.PubMedCentralPubMedCrossRef

208.

Yoon KS, Huang XZ, Yoon YS, Kim SK, Song SB, Chang BS, et al. Histological study on the effect of electrolyzed reduced water-bathing on UVB radiation-induced skin injury in hairless mice. Biol Pharm Bull. 2011;34(11):1671–7.PubMedCrossRef

209.

Guo Z, Zhou B, Li W, Sun X, Luo D. Hydrogen-rich saline protects against ultraviolet B radiation injury in rats. J Biomed Res. 2012;26(5):365–71. doi:10.7555/JBR.26.20110037.PubMedCentralPubMedCrossRef

210.

Kato S, Saitoh Y, Iwai K, Miwa N. Hydrogen-rich electrolyzed warm water represses wrinkle formation against UVA ray together with type-I collagen production and oxidative-stress diminishment in fibroblasts and cell-injury prevention in keratinocytes. J Photochem Photobiol B. 2012;106:24–33. doi:10.1016/j.jphotobiol.2011.09.006.PubMedCrossRef

211.

Ignacio RM, Yoon Y-S, Sajo MEJ, Kim C-S, Kim D-H, Kim S-K, et al. The balneotherapy effect of hydrogen reduced water on UVB-mediated skin injury in hairless mice. Mol Cell Toxicol. 2013;9(1):15–21. doi:10.1007/s13273-013-0003-6.CrossRef

212.

Ono H, Nishijima Y, Adachi N, Sakamoto M, Kudo Y, Nakazawa J, et al. Hydrogen(H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers. Med Gas Res. 2012;2(1):14. doi:10.1186/2045-9912-2-14.PubMedCentralPubMedCrossRef

213.

Ignacio RM, Kwak HS, Yun YU, Sajo ME, Yoon YS, Kim CS, et al. The Drinking Effect of Hydrogen Water on Atopic Dermatitis Induced by Dermatophagoides farinae Allergen in NC/Nga Mice. Evid Based Complement Alternat Med. 2013;2013:538673. doi:10.1155/2013/538673.PubMedCentralPubMedCrossRef

214.

Yoon YS, Sajo ME, Ignacio RM, Kim SK, Kim CS, Lee KJ. Positive Effects of hydrogen water on 2,4-dinitrochlorobenzene-induced atopic dermatitis in NC/Nga mice. Biol Pharm Bull. 2014;37(9):1480–5.PubMedCrossRef

215.

Ishibashi T, Ichikawa M, Sato B, Shibata S, Hara Y, Naritomi Y, et al. Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. Mol Med Rep. 2015;12(2):2757–64. doi:10.3892/mmr.2015.3707.PubMed

216.

Li Q, Kato S, Matsuoka D, Tanaka H, Miwa N. Hydrogen water intake via tube-feeding for patients with pressure ulcer and its reconstructive effects on normal human skin cells in vitro. Med Gas Res. 2013;3(1):20. doi:10.1186/2045-9912-3-20.PubMedCentralPubMedCrossRef

217.

Yu W, Chiu Y, Lee C, Yoshioka T, Yu H. Hydrogen-enriched water restoration of impaired calcium propagation by arsenic in primary keratinocytes. J Asian Earth Sci. 2013;77:342–8. doi:10.1016/j.jseaes.2013.07.007.CrossRef

218.

Ishibashi T, Sato B, Rikitake M, Seo T, Kurokawa R, Hara Y, et al. 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. Med Gas Res. 2012;2(1):27. doi:10.1186/2045-9912-2-27.PubMedCentralPubMedCrossRef

219.

Ishibashi T, Sato B, Shibata S, Sakai T, Hara Y, Naritomi Y, et al. Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: a randomized, double-blind, placebo-controlled pilot study. Int Immunopharmacol. 2014;21(2):468–73. doi:10.1016/j.intimp.2014.06.001.PubMedCrossRef

220.

Cai WW, Zhang MH, Yu YS, Cai JH. Treatment with hydrogen molecule alleviates TNFalpha-induced cell injury in osteoblast. Mol Cell Biochem. 2013;373(1–2):1–9. doi:10.1007/s11010-012-1450-4.PubMedCrossRef

221.

Hanaoka T, Kamimura N, Yokota T, Takai S, Ohta S. Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide. Med Gas Res. 2011;1(1):18. doi:10.1186/2045-9912-1-18.PubMedCentralPubMedCrossRef

222.

Huang T, Wang W, Tu C, Yang Z, Bramwell D, Sun X. Hydrogen-rich saline attenuates ischemia-reperfusion injury in skeletal muscle. J Surg Res. 2015;194(2):471–80. doi:10.1016/j.jss.2014.12.016.PubMedCrossRef

223.

Ito M, Ibi T, Sahashi K, Ichihara M, Ito M, Ohno K. Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Med Gas Res. 2011;1(1):24. doi:10.1186/2045-9912-1-24.PubMedCentralPubMedCrossRef

224.

Aoki K, Nakao A, Adachi T, Matsui Y, Miyakawa S. Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes. Med Gas Res. 2012;2(1):12. doi:10.1186/2045-9912-2-12.PubMedCentralPubMedCrossRef

225.

Ostojic SM, Vukomanovic B, Calleja-Gonzalez J, Hoffman JR. Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries. Postgrad Med. 2014;126(5):187–95. doi:10.3810/pgm.2014.09.2813.PubMedCrossRef

226.

Ohsawa I, Nishimaki K, Yamagata K, Ishikawa M, Ohta S. Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochem Biophys Res Commun. 2008;377(4):1195–8. doi:10.1016/j.bbrc.2008.10.156.PubMedCrossRef

227.

Ekuni D, Tomofuji T, Endo Y, Kasuyama K, Irie K, Azuma T, et al. Hydrogen-rich water prevents lipid deposition in the descending aorta in a rat periodontitis model. Arch Oral Biol. 2012;57(12):1615–22. doi:10.1016/j.archoralbio.2012.04.013.PubMedCrossRef

228.

Jiang H, Yu P, Qian DH, Qin ZX, Sun XJ, Yu J, et al. Hydrogen-rich medium suppresses the generation of reactive oxygen species, elevates the Bcl-2/Bax ratio and inhibits advanced glycation end product-induced apoptosis. Int J Mol Med. 2013;31(6):1381–7. doi:10.3892/ijmm.2013.1334.PubMed

229.

Sun Q, Kawamura T, Masutani K, Peng X, Sun Q, Stolz DB, et al. Oral intake of hydrogen-rich water inhibits intimal hyperplasia in arterialized vein grafts in rats. Cardiovasc Res. 2012;94(1):144–53. doi:10.1093/cvr/cvs024.PubMedCentralPubMedCrossRef

230.

Sakai T, Sato B, Hara K, Hara Y, Naritomi Y, Koyanagi S, et al. Consumption of water containing over 3.5 mg of dissolved hydrogen could improve vascular endothelial function. Vasc Health Risk Manag. 2014;10:591–7. doi:10.2147/VHRM.S68844.PubMedCentralPubMed

231.

Zhao S, Mei K, Qian L, Yang Y, Liu W, Huang Y, et al. Therapeutic effects of hydrogen-rich solution on aplastic anemia in vivo. Cell Physiol Biochem. 2013;32(3):549–60. doi:10.1159/000354459.PubMedCrossRef

232.

Kawasaki H, Guan J, Tamama K. Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials. Biochem Biophys Res Commun. 2010;397(3):608–13. doi:10.1016/j.bbrc.2010.06.009.PubMedCrossRef

233.

Tanikawa R, Takahashi I, Okubo N, Ono M, Okumura T, Ishibashi G, et al. Relationship between Exhaled Hydrogen and Human Neutrophil Function in the Japanese General Population. Hirosaki Medical Journal. 2015;65:138–46.

234.

Takeuchi S, Wada K, Nagatani K, Osada H, Otani N, Nawashiro H. Hydrogen may inhibit collagen-induced platelet aggregation: an ex vivo and in vivo study. Intern Med. 2012;51(11):1309–13.PubMedCrossRef

235.

Kato S, Hokama R, Okayasu H, Saitoh Y, Iwai K, Miwa N. Colloidal platinum in hydrogen-rich water exhibits radical-scavenging activity and improves blood fluidity. J Nanosci Nanotechnol. 2012;12(5):4019–27.PubMedCrossRef

236.

Kajiyama S, Hasegawa G, Asano M, Hosoda H, Fukui M, Nakamura N, et al. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res. 2008;28(3):137–43. doi:10.1016/j.nutres.2008.01.008.PubMedCrossRef

237.

Kamimura N, Nishimaki K, Ohsawa I, Ohta S. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity. 2011;19(7):1396–403. doi:10.1038/oby.2011.6.PubMedCrossRef

238.

Li Y, Hamasaki T, Nakamichi N, Kashiwagi T, Komatsu T, Ye J, et al. Suppressive effects of electrolyzed reduced water on alloxan-induced apoptosis and type 1 diabetes mellitus. Cytotechnology. 2011;63(2):119–31. doi:10.1007/s10616-010-9317-6.PubMedCentralPubMedCrossRef

239.

Yu P, Wang Z, Sun X, Chen X, Zeng S, Chen L, et al. Hydrogen-rich medium protects human skin fibroblasts from high glucose or mannitol induced oxidative damage. Biochem Biophys Res Commun. 2011;409(2):350–5. doi:10.1016/j.bbrc.2011.05.024.PubMedCrossRef

240.

Wang QJ, Zha XJ, Kang ZM, Xu MJ, Huang Q, Zou DJ. Therapeutic effects of hydrogen saturated saline on rat diabetic model and insulin resistant model via reduction of oxidative stress. Chin Med J (Engl). 2012;125(9):1633–7. doi:10.3760/cma.j.issn.0366-6999.2012.09.020.

241.

Amitani H, Asakawa A, Cheng K, Amitani M, Kaimoto K, Nakano M, et al. Hydrogen improves glycemic control in type1 diabetic animal model by promoting glucose uptake into skeletal muscle. PLoS One. 2013;8(1):e53913. doi:10.1371/journal.pone.0053913.PubMedCentralPubMedCrossRef

242.

Zong C, Song G, Yao S, Li L, Yu Y, Feng L, et al. Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet-fed hamsters. Metabolism. 2012;61(6):794–800. doi:10.1016/j.metabol.2011.10.014.PubMedCrossRef

243.

Song G, Li M, Sang H, Zhang L, Li X, Yao S, et al. Hydrogen-rich water decreases serum LDL-cholesterol levels and improves HDL function in patients with potential metabolic syndrome. J Lipid Res. 2013;54(7):1884–93. doi:10.1194/jlr.M036640.PubMedCentralPubMedCrossRef

244.

Song G, Lin Q, Zhao H, Liu M, Ye F, Sun Y, et al. Hydrogen activates ATP-binding cassette transporter A1-dependent efflux ex vivo and improves high-density lipoprotein function in patients with hypercholesterolemia: a double-blinded, randomized and placebo-controlled trial. J Clin Endocrinol Metab. 2015;100:2724–33. doi:10.1210/jc.2015-1321.PubMedCrossRef

245.

Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N. Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr. 2010;46(2):140–9. doi:10.3164/jcbn.09-100.PubMedCentralPubMedCrossRef

246.

Hashimoto M, Katakura M, Nabika T, Tanabe Y, Hossain S, Tsuchikura S, et al. Effects of hydrogen-rich water on abnormalities in a SHR.Cg-Leprcp/NDmcr rat - a metabolic syndrome rat model. Med Gas Res. 2011;1(1):26. doi:10.1186/2045-9912-1-26.PubMedCentralPubMedCrossRef

247.

Nishimura N, Tanabe H, Adachi M, Yamamoto T, Fukushima M. Colonic hydrogen generated from fructan diffuses into the abdominal cavity and reduces adipose mRNA abundance of cytokines in rats. J Nutr. 2013;143(12):1943–9. doi:10.3945/jn.113.183004.PubMedCrossRef

248.

Nakai Y, Sato B, Ushiama S, Okada S, Abe K, Arai S. Hepatic oxidoreduction-related genes are upregulated by administration of hydrogen-saturated drinking water. Biosci Biotechnol Biochem. 2011;75(4):774–6. doi:10.1271/bbb.100819.PubMedCrossRef

249.

Ostojic SM. Serum alkalinization and hydrogen-rich water in healthy men. Mayo Clin Proc. 2012;87(5):501–2. doi:10.1016/j.mayocp.2012.02.008.PubMedCentralPubMedCrossRef

250.

Ostojic SM, Stojanovic MD. Hydrogen-rich water affected blood alkalinity in physically active men. Res Sports Med. 2014;22(1):49–60. doi:10.1080/15438627.2013.852092.PubMedCrossRef

251.

Xie K, Yu Y, Pei Y, Hou L, Chen S, Xiong L, et al. Protective effects of hydrogen gas on murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. Shock. 2010;34(1):90–7. doi:10.1097/SHK.0b013e3181cdc4ae.PubMedCrossRef

252.

Zhou J, Chen Y, Huang GQ, Li J, Wu GM, Liu L, et al. Hydrogen-rich saline reverses oxidative stress, cognitive impairment, and mortality in rats submitted to sepsis by cecal ligation and puncture. J Surg Res. 2012;178(1):390–400. doi:10.1016/j.jss.2012.01.041.PubMedCrossRef

253.

Xie K, Fu W, Xing W, Li A, Chen H, Han H, et al. Combination therapy with molecular hydrogen and hyperoxia in a murine model of polymicrobial sepsis. Shock. 2012;38(6):656–63. doi:10.1097/SHK.0b013e3182758646.PubMed

254.

Li GM, Ji MH, Sun XJ, Zeng QT, Tian M, Fan YX, et al. Effects of hydrogen-rich saline treatment on polymicrobial sepsis. J Surg Res. 2013;181(2):279–86. doi:10.1016/j.jss.2012.06.058.PubMedCrossRef

255.

Liu W, Shan LP, Dong XS, Liu XW, Ma T, Liu Z. Combined early fluid resuscitation and hydrogen inhalation attenuates lung and intestine injury. World J Gastroenterol. 2013;19(4):492–502. doi:10.3748/wjg.v19.i4.492.PubMedCentralPubMedCrossRef

256.

Yu Y, Wang WN, Han HZ, Xie KL, Wang GL, Yu YH. Protective effects of hydrogen-rich medium on lipopolysaccharide-induced monocytic adhesion and vascular endothelial permeability through regulation of vascular endothelial cadherin. Genet Mol Res. 2015;14(2):6202–12. doi:10.4238/2015.June.9.6.PubMedCrossRef

257.

Xie K, Yu Y, Zhang Z, Liu W, Pei Y, Xiong L, et al. Hydrogen gas improves survival rate and organ damage in zymosan-induced generalized inflammation model. Shock. 2010;34(5):495–501. doi:10.1097/SHK.0b013e3181def9aa.PubMedCrossRef

258.

Xu Z, Zhou J, Cai J, Zhu Z, Sun X, Jiang C. Anti-inflammation effects of hydrogen saline in LPS activated macrophages and carrageenan induced paw oedema. J Inflamm (Lond). 2012;9:2. doi:10.1186/1476-9255-9-2.CrossRef

259.

Fujii Y, Shirai M, Inamori S, Shimouchi A, Sonobe T, Tsuchimochi H, et al. Insufflation of hydrogen gas restrains the inflammatory response of cardiopulmonary bypass in a rat model. Artif Organs. 2013;37(2):136–41. doi:10.1111/j.1525-1594.2012.01535.x.PubMedCrossRef

260.

Cai J, Kang Z, Liu WW, Luo X, Qiang S, Zhang JH, et al. Hydrogen therapy reduces apoptosis in neonatal hypoxia-ischemia rat model. Neurosci Lett. 2008;441(2):167–72. doi:10.1016/j.neulet.2008.05.077.PubMedCrossRef

261.

Cai J, Kang Z, Liu K, Liu W, Li R, Zhang JH, et al. Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res. 2009;1256:129–37. doi:10.1016/j.brainres.2008.11.048.PubMedCrossRef

262.

Domoki F, Olah O, Zimmermann A, Nemeth I, Toth-Szuki V, Hugyecz M, et al. Hydrogen is neuroprotective and preserves cerebrovascular reactivity in asphyxiated newborn pigs. Pediatr Res. 2010;68(5):387–92. doi:10.1203/PDR.0b013e3181f2e81c.PubMed

263.

Mano Y, Kotani T, Ito M, Nagai T, Ichinohashi Y, Yamada K, et al. Maternal molecular hydrogen administration ameliorates rat fetal hippocampal damage caused by in utero ischemia-reperfusion. Free Radic Biol Med. 2014;69:324–30. doi:10.1016/j.freeradbiomed.2014.01.037.PubMedCrossRef

264.

Yang X, Guo L, Sun X, Chen X, Tong X. Protective effects of hydrogen-rich saline in preeclampsia rat model. Placenta. 2011;32(9):681–6. doi:10.1016/j.placenta.2011.06.020.PubMedCrossRef

265.

Guan Z, Li HF, Guo LL, Yang X. Effects of vitamin C, vitamin E, and molecular hydrogen on the placental function in trophoblast cells. Arch Gynecol Obstet. 2015;292(2):337–42. doi:10.1007/s00404-015-3647-8.PubMedCrossRef

266.

Saitoh Y, Okayasu H, Xiao L, Harata Y, Miwa N. Neutral pH hydrogen-enriched electrolyzed water achieves tumor-preferential clonal growth inhibition over normal cells and tumor invasion inhibition concurrently with intracellular oxidant repression. Oncol Res. 2008;17(6):247–55.PubMedCrossRef

267.

Zhao L, Zhou C, Zhang J, Gao F, Li B, Chuai Y, et al. Hydrogen protects mice from radiation induced thymic lymphoma in BALB/c mice. Int J Biol Sci. 2011;7(3):297–300.PubMedCentralPubMedCrossRef

268.

Ye J, Li Y, Hamasaki T, Nakamichi N, Komatsu T, Kashiwagi T, et al. Inhibitory effect of electrolyzed reduced water on tumor angiogenesis. Biol Pharm Bull. 2008;31(1):19–26.PubMedCrossRef

269.

Runtuwene J, Amitani H, Amitani M, Asakawa A, Cheng KC, Inui A. Hydrogen-water enhances 5-fluorouracil-induced inhibition of colon cancer. PeerJ. 2015;3:e859. doi:10.7717/peerj.859.PubMedCentralPubMedCrossRef

270.

Qian L, Cao F, Cui J, Wang Y, Huang Y, Chuai Y, et al. The potential cardioprotective effects of hydrogen in irradiated mice. J Radiat Res. 2010;51(6):741–7. doi:10.1269/jrr.10093.PubMedCrossRef

271.

Terasaki Y, Ohsawa I, Terasaki M, Takahashi M, Kunugi S, Dedong K, et al. Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. Am J Physiol Lung Cell Mol Physiol. 2011;301(4):L415–26. doi:10.1152/ajplung.00008.2011.PubMedCrossRef

272.

Jiang Z, Xu B, Yang M, Li Z, Zhang Y, Jiang D. Protection by hydrogen against gamma ray-induced testicular damage in rats. Basic Clin Pharmacol Toxicol. 2013;112(3):186–91. doi:10.1111/bcpt.12016.PubMedCrossRef

273.

Mei K, Zhao S, Qian L, Li B, Ni J, Cai J. Hydrogen protects rats from dermatitis caused by local radiation. J Dermatolog Treat. 2014;25(2):182–8. doi:10.3109/09546634.2012.762639.PubMedCrossRef

274.

Watanabe S, Fujita M, Ishihara M, Tachibana S, Yamamoto Y, Kaji T, et al. Protective effect of inhalation of hydrogen gas on radiation-induced dermatitis and skin injury in rats. J Radiat Res. 2014;55(6):1107–13. doi:10.1093/jrr/rru067.PubMedCentralPubMedCrossRef

275.

Qian L, Cao F, Cui J, Huang Y, Zhou X, Liu S, et al. Radioprotective effect of hydrogen in cultured cells and mice. Free Radic Res. 2010;44(3):275–82. doi:10.3109/10715760903468758.PubMedCrossRef

276.

Qian L, Li B, Cao F, Huang Y, Liu S, Cai J, et al. Hydrogen-rich PBS protects cultured human cells from ionizing radiation-induced cellular damage. Nucl Technol Radiat Prot. 2010;25(1):23–9. doi:10.2298/ntrp1001023q.CrossRef

277.

Chuai Y, Gao F, Li B, Zhao L, Qian L, Cao F, et al. Hydrogen-rich saline attenuates radiation-induced male germ cell loss in mice through reducing hydroxyl radicals. Biochem J. 2012;442(1):49–56. doi:10.1042/BJ20111786.PubMedCrossRef

278.

Yang Y, Li B, Liu C, Chuai Y, Lei J, Gao F, et al. Hydrogen-rich saline protects immunocytes from radiation-induced apoptosis. Med Sci Monit. 2012;18(4):BR144–8.PubMedCentralPubMedCrossRef

279.

Chuai Y, Shen J, Qian L, Wang Y, Huang Y, Gao F, et al. Hydrogen-rich saline protects spermatogenesis and hematopoiesis in irradiated BALB/c mice. Med Sci Monit. 2012;18(3):BR89–94.PubMedCentralPubMedCrossRef

280.

Yang Y, Gao F, Zhang H, Hunag Y, Zhang P, Liu C, et al. Molecular hydrogen protects human lymphocyte AHH-1 cells against 12C6+ heavy ion radiation. Int J Radiat Biol. 2013;89(12):1003–8. doi:10.3109/09553002.2013.817704.PubMedCrossRef

281.

Kang KM, Kang YN, Choi IB, Gu Y, Kawamura T, Toyoda Y, et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Med Gas Res. 2011;1(1):11. doi:10.1186/2045-9912-1-11.PubMedCentralPubMedCrossRef

282.

Zhao S, Yang Y, Liu W, Xuan Z, Wu S, Yu S, et al. Protective effect of hydrogen-rich saline against radiation-induced immune dysfunction. J Cell Mol Med. 2014;18(5):938–46. doi:10.1111/jcmm.12245.PubMedCentralPubMedCrossRef

283.

Sun Q, Cai J, Zhou J, Tao H, Zhang JH, Zhang W, et al. Hydrogen-rich saline reduces delayed neurologic sequelae in experimental carbon monoxide toxicity. Crit Care Med. 2011;39(4):765–9. doi:10.1097/CCM.0b013e318206bf44.PubMedCrossRef

284.

Wang W, Li Y, Ren J, Xia F, Li J, Zhang Z. Hydrogen rich saline reduces immune-mediated brain injury in rats with acute carbon monoxide poisoning. Neurol Res. 2012;34(10):1007–15. doi:10.1179/1743132812Y.0000000106.PubMedCrossRef

285.

Shen MH, Cai JM, Sun Q, Zhang DW, Huo ZL, He J, et al. Neuroprotective effect of hydrogen-rich saline in acute carbon monoxide poisoning. CNS Neurosci Ther. 2013;19(5):361–3. doi:10.1111/cns.12094.PubMedCrossRef

286.

Wang W, Tian L, Li Y, Wang X, Xia F, Li L, et al. Effects of hydrogen-rich saline on rats with acute carbon monoxide poisoning. J Emerg Med. 2013;44(1):107–15. doi:10.1016/j.jemermed.2012.01.065.PubMedCrossRef

287.

Yonamine R, Satoh Y, Kodama M, Araki Y, Kazama T. Coadministration of hydrogen gas as part of the carrier gas mixture suppresses neuronal apoptosis and subsequent behavioral deficits caused by neonatal exposure to sevoflurane in mice. Anesthesiology. 2013;118(1):105–13. doi:10.1097/ALN.0b013e318275146d.PubMedCrossRef

288.

Takaenoki Y, Satoh Y, Araki Y, Kodama M, Yonamine R, Yufune S, et al. Neonatal exposure to sevoflurane in mice causes deficits in maternal behavior later in adulthood. Anesthesiology. 2014;120(2):403–15. doi:10.1097/ALN.0000435846.28299.e7.PubMedCrossRef

289.

Wu S, Zhu L, Yang J, Fan Z, Dong Y, Luan R, et al. Hydrogen-containing saline attenuates doxorubicin-induced heart failure in rats. Pharmazie. 2014;69(8):633–6.PubMed

290.

Yoon YS, Kim DH, Kim SK, Song SB, Uh Y, Jin D, et al. The melamine excretion effect of the electrolyzed reduced water in melamine-fed mice. Food Chem Toxicol. 2011;49(8):1814–9. doi:10.1016/j.fct.2011.04.033.PubMedCrossRef

291.

Wang T, Zhao L, Liu M, Xie F, Ma X, Zhao P, et al. Oral intake of hydrogen-rich water ameliorated chlorpyrifos-induced neurotoxicity in rats. Toxicol Appl Pharmacol. 2014;280(1):169–76. doi:10.1016/j.taap.2014.06.011.PubMedCrossRef

292.

Nakao A, Kaczorowski DJ, Wang Y, Cardinal JS, Buchholz BM, Sugimoto R, et al. Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. J Heart Lung Transplant. 2010;29(5):544–53. doi:10.1016/j.healun.2009.10.011.PubMedCrossRef

293.

Tan M, Sun X, Guo L, Su C, Sun X, Xu Z. Hydrogen as additive of HTK solution fortifies myocardial preservation in grafts with prolonged cold ischemia. Int J Cardiol. 2013;167(2):383–90. doi:10.1016/j.ijcard.2011.12.109.PubMedCrossRef

294.

Noda K, Tanaka Y, Shigemura N, Kawamura T, Wang Y, Masutani K, et al. Hydrogen-supplemented drinking water protects cardiac allografts from inflammation-associated deterioration. Transpl Int. 2012;25(12):1213–22. doi:10.1111/j.1432-2277.2012.01542.x.PubMedCrossRef

295.

Kawamura T, Huang CS, Tochigi N, Lee S, Shigemura N, Billiar TR, et al. Inhaled hydrogen gas therapy for prevention of lung transplant-induced ischemia/reperfusion injury in rats. Transplantation. 2010;90(12):1344–51. doi:10.1097/TP.0b013e3181fe1357.PubMedCrossRef

296.

Zhou H, Fu Z, Wei Y, Liu J, Cui X, Yang W, et al. Hydrogen inhalation decreases lung graft injury in brain-dead donor rats. J Heart Lung Transplant. 2013;32(2):251–8. doi:10.1016/j.healun.2012.11.007.PubMedCrossRef

297.

Noda K, Shigemura N, Tanaka Y, Bhama J, D’Cunha J, Kobayashi H, et al. Hydrogen preconditioning during ex vivo lung perfusion improves the quality of lung grafts in rats. Transplantation. 2014;98(5):499–506. doi:10.1097/TP.0000000000000254.PubMedCrossRef

298.

Haam S, Lee S, Paik HC, Park MS, Song JH, Lim BJ, et al. The effects of hydrogen gas inhalation during ex vivo lung perfusion on donor lungs obtained after cardiac deathdagger. Eur J Cardiothorac Surg. 2015;48:542–7. doi:10.1093/ejcts/ezv057.PubMedCrossRef

299.

Liu R, Fang X, Meng C, Xing J, Liu J, Yang W, et al. Lung inflation with hydrogen during the cold ischemia phase decreases lung graft injury in rats. Exp Biol Med (Maywood). 2015;240:1214–22. doi:10.1177/1535370214563895.CrossRef

300.

Buchholz BM, Kaczorowski DJ, Sugimoto R, Yang R, Wang Y, Billiar TR, et al. Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am J Transplant. 2008;8(10):2015–24. doi:10.1111/j.1600-6143.2008.02359.x.PubMedCrossRef

301.

Shigeta T, Sakamoto S, Li XK, Cai S, Liu C, Kurokawa R, et al. Luminal injection of hydrogen-rich solution attenuates intestinal ischemia-reperfusion injury in rats. Transplantation. 2015;99(3):500–7. doi:10.1097/TP.0000000000000510.PubMedCrossRef

302.

Luo ZL, Cheng L, Ren JD, Fang C, Xiang K, Xu HT, et al. Hydrogen-rich saline protects against ischemia/reperfusion injury in grafts after pancreas transplantations by reducing oxidative stress in rats. Mediators Inflamm. 2015;2015:281985. doi:10.1155/2015/281985.PubMedCentralPubMed

303.

Yamada T, Uchida K, Onuma K, Kuzuno J, Ujihira M, Inoue G, et al. Hydrogen supplementation of preservation solution improves viability of osteochondral grafts. ScientificWorldJournal. 2014;2014:109876. doi:10.1155/2014/109876.PubMedCentralPubMedCrossRef

304.

Qian L, Mei K, Shen J, Cai J. Administration of hydrogen-rich saline protects mice from lethal acute graft-versus-host disease (aGVHD). Transplantation. 2013;95(5):658–62. doi:10.1097/TP.0b013e31827e6b23.PubMedCrossRef

305.

Yuan L, Chen X, Qian L, Shen J, Cai J. Administration of hydrogen-rich saline in mice with allogeneic hematopoietic stem-cell transplantation. Med Sci Monit. 2015;21:749–54. doi:10.12659/MSM.891338.PubMedCentralPubMedCrossRef

306.

Hayashida K, Sano M, Kamimura N, Yokota T, Suzuki M, Ohta S, et al. Hydrogen inhalation during normoxic resuscitation improves neurological outcome in a rat model of cardiac arrest independently of targeted temperature management. Circulation. 2014;130(24):2173–80. doi:10.1161/CIRCULATIONAHA.114.011848.PubMedCrossRef

307.

Huo TT, Zeng Y, Liu XN, Sun L, Han HZ, Chen HG, et al. Hydrogen-rich saline improves survival and neurological outcome after cardiac arrest and cardiopulmonary resuscitation in rats. Anesth Analg. 2014;119(2):368–80. doi:10.1213/ANE.0000000000000303.PubMedCrossRef

308.

Du Z, Jia H, Liu J, Zhao X, Wang Y, Sun X. Protective effects of hydrogen-rich saline in uncontrolled hemorrhagic shock. Exp Ther Med. 2014;7(5):1253–8. doi:10.3892/etm.2014.1572.PubMedCentralPubMed

309.

Du Z, Jia H, Liu J, Zhao X, Xu W. Effects of three hydrogen-rich liquids on hemorrhagic shock in rats. J Surg Res. 2015;193(1):377–82. doi:10.1016/j.jss.2014.06.051.PubMedCrossRef

310.

Nakayama M, Kabayama S, Nakano H, Zhu WJ, Terawaki H, Nakayama K, et al. Biological effects of electrolyzed water in hemodialysis. Nephron Clin Pract. 2009;112(1):c9–15. doi:10.1159/000210569.PubMedCrossRef

311.

Nakayama M, Nakano H, Hamada H, Itami N, Nakazawa R, Ito S. A novel bioactive haemodialysis system using dissolved dihydrogen (H2) produced by water electrolysis: a clinical trial. Nephrol Dial Transplant. 2010;25(9):3026–33. doi:10.1093/ndt/gfq196.PubMedCrossRef

312.

Terawaki H, Zhu WJ, Matsuyama Y, Terada T, Takahashi Y, Sakurai K, et al. Effect of a hydrogen (H2)-enriched solution on the albumin redox of hemodialysis patients. Hemodial Int. 2014;18(2):459–66. doi:10.1111/hdi.12112.PubMedCrossRef

313.

Tange Y, Takesawa S, Yoshitake S. Dialysate with high dissolved hydrogen facilitates dissociation of indoxyl sulfate from albumin. Nephrourol Mon. 2015;7(2):e26847. doi:10.5812/numonthly.26847.PubMedCentralPubMed

314.

Terawaki H, Hayashi Y, Zhu WJ, Matsuyama Y, Terada T, Kabayama S, et al. Transperitoneal administration of dissolved hydrogen for peritoneal dialysis patients: a novel approach to suppress oxidative stress in the peritoneal cavity. Med Gas Res. 2013;3(1):14. doi:10.1186/2045-9912-3-14.PubMedCentralPubMedCrossRef

315.

Terawaki H, Nakano H, Zhu WJ, Nakayama M. Successful treatment of encapsulating peritoneal sclerosis by hemodialysis and peritoneal lavage using dialysate containing dissolved hydrogen. Perit Dial Int. 2015;35(1):107–12. doi:10.3747/pdi.2013.00255.PubMedPubMedCentralCrossRef

316.

Yan H, Tian H, Kinjo T, Hamasaki T, Tomimatsu K, Nakamichi N, et al. Extension of the lifespan of Caenorhabditis elegans by the use of electrolyzed reduced water. Biosci Biotechnol Biochem. 2010;74(10):2011–5. doi:10.1271/bbb.100250.PubMedCrossRef

317.

Nakata K, Yamashita N, Noda Y, Ohsawa I. Stimulation of human damaged sperm motility with hydrogen molecule. Med Gas Res. 2015;5(1):2. doi:10.1186/s13618-014-0023-x.PubMedCentralPubMedCrossRef

318.

Ni XX, Cai ZY, Fan DF, Liu Y, Zhang RJ, Liu SL, et al. Protective effect of hydrogen-rich saline on decompression sickness in rats. Aviat Space Environ Med. 2011;82(6):604–9. doi:10.3357/asem.2964.2011.PubMedCrossRef

319.

Saitoh Y, Harata Y, Mizuhashi F, Nakajima M, Miwa N. Biological safety of neutral-pH hydrogen-enriched electrolyzed water upon mutagenicity, genotoxicity and subchronic oral toxicity. Toxicol Ind Health. 2010;26(4):203–16. doi:10.1177/0748233710362989.PubMedCrossRef

320.

Chen M, Cui W, Zhu K, Xie Y, Zhang C, Shen W. Hydrogen-rich water alleviates aluminum-induced inhibition of root elongation in alfalfa via decreasing nitric oxide production. J Hazard Mater. 2014;267:40–7. doi:10.1016/j.jhazmat.2013.12.029.PubMedCrossRef

321.

Xie Y, Mao Y, Lai D, Zhang W, Shen W. H(2) enhances arabidopsis salt tolerance by manipulating ZAT10/12-mediated antioxidant defence and controlling sodium exclusion. PLoS One. 2012;7(11):e49800. doi:10.1371/journal.pone.0049800.PubMedCentralPubMedCrossRef

322.

Xu S, Zhu S, Jiang Y, Wang N, Wang R, Shen W, et al. Hydrogen-rich water alleviates salt stress in rice during seed germination. Plant Soil. 2013;370(1–2):47–57. doi:10.1007/s11104-013-1614-3.CrossRef

323.

Hu H, Li P, Wang Y, Gu R. Hydrogen-rich water delays postharvest ripening and senescence of kiwifruit. Food Chem. 2014;156:100–9. doi:10.1016/j.foodchem.2014.01.067.PubMedCrossRef

324.

Xie Y, Mao Y, Zhang W, Lai D, Wang Q, Shen W. Reactive Oxygen Species-Dependent Nitric Oxide Production Contributes to Hydrogen-Promoted Stomatal Closure in Arabidopsis. Plant Physiol. 2014;165(2):759–73. doi:10.1104/pp. 114.237925.PubMedCentralPubMedCrossRef

325.

Su N, Wu Q, Liu Y, Cai J, Shen W, Xia K, et al. Hydrogen-rich water reestablishes ROS homeostasis but exerts differential effects on anthocyanin synthesis in two varieties of radish sprouts under UV-A irradiation. J Agric Food Chem. 2014;62(27):6454–62. doi:10.1021/jf5019593.PubMedCrossRef

326.

Zhang X, Zhao X, Wang Z, Shen W, Xu X. Protective effects of hydrogen-rich water on the photosynthetic apparatus of maize seedlings (Zea mays L.) as a result of an increase in antioxidant enzyme activities under high light stress. Plant Growth Regul. 2015;77:43–56.CrossRef

327.

Zeng J, Zhang M, Sun X. Molecular hydrogen is involved in phytohormone signaling and stress responses in plants. PLoS One. 2013;8(8):e71038. doi:10.1371/journal.pone.0071038.PubMedCentralPubMedCrossRef

328.

Jin Q, Zhu K, Cui W, Xie Y, Han B, Shen W. Hydrogen gas acts as a novel bioactive molecule in enhancing plant tolerance to paraquat-induced oxidative stress via the modulation of heme oxygenase-1 signalling system. Plant Cell Environ. 2013;36(5):956–69. doi:10.1111/pce.12029.PubMedCrossRef

329.

Cui W, Gao C, Fang P, Lin G, Shen W. Alleviation of cadmium toxicity in Medicago sativa by hydrogen-rich water. J Hazard Mater. 2013;260:715–24. doi:10.1016/j.jhazmat.2013.06.032.PubMedCrossRef

330.

Wu Q, Su N, Cai J, Shen Z, Cui J. Hydrogen-rich water enhances cadmium tolerance in Chinese cabbage by reducing cadmium uptake and increasing antioxidant capacities. J Plant Physiol. 2015;175:174–82. doi:10.1016/j.jplph.2014.09.017.PubMedCrossRef

331.

Cui W, Fang P, Zhu K, Mao Y, Gao C, Xie Y, et al. Hydrogen-rich water confers plant tolerance to mercury toxicity in alfalfa seedlings. Ecotoxicol Environ Saf. 2014;105:103–11. doi:10.1016/j.ecoenv.2014.04.009.PubMedCrossRef

332.

Sato Y, Kajiyama S, Amano A, Kondo Y, Sasaki T, Handa S, et al. Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochem Biophys Res Commun. 2008;375(3):346–50. doi:10.1016/j.bbrc.2008.08.020.PubMedCrossRef

333.

Ono H, Nishijima Y, Adachi N, Sakamoto M, Kudo Y, Kaneko K, et al. A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. Med Gas Res. 2012;2(1):21. doi:10.1186/2045-9912-2-21.PubMedCentralPubMedCrossRef

334.

Seo T, Kurokawa R, Sato B. A convenient method for determining the concentration of hydrogen in water: use of methylene blue with colloidal platinum. Med Gas Res. 2012;2:1. doi:10.1186/2045-9912-2-1.PubMedCentralPubMedCrossRef

335.

Shimouchi A, Nose K, Shirai M, Kondo T. Estimation of molecular hydrogen consumption in the human whole body after the ingestion of hydrogen-rich water. Adv Exp Med Biol. 2012;737:245–50. doi:10.1007/978-1-4614-1566-4_36.PubMedCrossRef

336.

Shimouchi A, Nose K, Mizukami T, Che DC, Shirai M. Molecular hydrogen consumption in the human body during the inhalation of hydrogen gas. Adv Exp Med Biol. 2013;789:315–21. doi:10.1007/978-1-4614-7411-1_42.PubMedCrossRef

337.

Liu C, Kurokawa R, Fujino M, Hirano S, Sato B, Li XK. Estimation of the hydrogen concentration in rat tissue using an airtight tube following the administration of hydrogen via various routes. Sci Rep. 2014;4:5485. doi:10.1038/srep05485.PubMedCentralPubMed

338.

Penders J, Kissner R, Koppenol WH. ONOOH does not react with H2: Potential beneficial effects of H2 as an antioxidant by selective reaction with hydroxyl radicals and peroxynitrite. Free Radic Biol Med. 2014;75:191–4. doi:10.1016/j.freeradbiomed.2014.07.025.PubMedCrossRef

339.

Kato S, Matsuoka D, Miwa N. Antioxidant activities of nano-bubble hydrogen-dissolved water assessed by ESR and 2,2′-bipyridyl methods. Mater Sci Eng C Mater Biol Appl. 2015;53:7–10. doi:10.1016/j.msec.2015.03.064.PubMedCrossRef

Title: Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles -
Authors: Masatoshi Ichihara
Sayaka Sobue
Mikako Ito
Masafumi Ito
Masaaki Hirayama
Kinji Ohno
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Medical Gas Research / Issue 1/2015
Electronic ISSN: 2045-9912
DOI: https://doi.org/10.1186/s13618-015-0035-1

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