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Review Article

Direct Targets and Subsequent Pathways for Molecular Hydrogen to Exert Multiple Functions: Focusing on Interventions in Radical Reactions

Author(s): Shigeo Ohta*

Volume 27, Issue 5, 2021

Published on: 06 August, 2020

Page: [595 - 609] Pages: 15

DOI: 10.2174/1381612826666200806101137

open access plus

Abstract

Molecular hydrogen (H2) was long regarded as non-functional in mammalian cells. We overturned the concept by demonstrating that H2 exhibits antioxidant effects and protects cells against oxidative stress. Subsequently, it has been revealed that H2 has multiple functions in addition to antioxidant effects, including antiinflammatory, anti-allergic functions, and as cell death and autophagy regulation. Additionally, H2 stimulates energy metabolism. As H2 does not readily react with most biomolecules without a catalyst, it is essential to identify the primary targets with which H2 reacts or interacts directly. As a first event, H2 may react directly with strong oxidants, such as hydroxyl radicals (•OH) in vivo. This review addresses the key issues related to this in vivo reaction. •OH may have a physiological role because it triggers a free radical chain reaction and may be involved in the regulation of Ca2+- or mitochondrial ATP-dependent K+-channeling. In the subsequent pathway, H2 suppressed a free radical chain reaction, leading to decreases in lipid peroxide and its end products. Derived from the peroxides, 4-hydroxy-2-nonenal functions as a mediator that up-regulates multiple functional PGC-1α. As the other direct target in vitro and in vivo, H2 intervenes in the free radical chain reaction to modify oxidized phospholipids, which may act as an antagonist of Ca2+-channels. The resulting suppression of Ca2+-signaling inactivates multiple functional NFAT and CREB transcription factors, which may explain H2 multi-functionality. This review also addresses the involvement of NFAT in the beneficial role of H2 in COVID-19, Alzheimer’s disease and advanced cancer. We discuss some unsolved issues of H2 action on lipopolysaccharide signaling, MAPK and NF-κB pathways and the Nrf2 paradox. Finally, as a novel idea for the direct targeting of H2, this review introduces the possibility that H2 causes structural changes in proteins via hydrate water changes.

Keywords: Calcium signaling, free radical chain reaction, hydroxyl radical, 4-hydroxy-2-nonenal, inflammation, molecular hydrogen, mechanism, NFAT, oxidized phospholipid, PGC-1α.

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[1]
Yagi T, Higuchi Y. Studies on hydrogenase. Proc Jpn Acad, Ser B, Phys Biol Sci 2013; 89(1): 16-33.
[http://dx.doi.org/10.2183/pjab.89.16] [PMID: 23318679]
[2]
Fontecilla-Camps JC, Frey M, Garcin E, et al. Hydrogenase: a hydrogen-metabolizing enzyme. What do the crystal structures tell us about its mode of action? Biochimie 1997; 79(11): 661-6.
[http://dx.doi.org/10.1016/S0300-9084(97)83499-2] [PMID: 9479448]
[3]
Fritsch J, Lenz O, Friedrich B. Structure, function and biosynthesis of O2-tolerant hydrogenases. Nat Rev Microbiol 2013; 11(2): 106-14.
[http://dx.doi.org/10.1038/nrmicro2940] [PMID: 23321533]
[4]
Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 2007; 13(6): 688-94.
[http://dx.doi.org/10.1038/nm1577] [PMID: 17486089]
[5]
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.
[http://dx.doi.org/10.1186/2045-9912-1-18] [PMID: 22146365]
[6]
Ohta S. Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases. Biochim Biophys Acta 2012; 1820(5): 586-94.
[http://dx.doi.org/10.1016/j.bbagen.2011.05.006] [PMID: 21621588]
[7]
Ohta S. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des 2011; 17(22): 2241-52.
[http://dx.doi.org/10.2174/138161211797052664] [PMID: 21736547]
[8]
Ohta S. Molecular hydrogen as a novel antioxidant: overview of the advantages of hydrogen for medical applications. Methods Enzymol 2015; 555: 289-317.
[http://dx.doi.org/10.1016/bs.mie.2014.11.038] [PMID: 25747486]
[9]
Nicolson GL, de Mattos GF, Settineri R, et al. Clinical effects of hydrogen administration: from animal and human diseases to exercise medicine. Int J Clin Med 2016; 07(01): 32-76.
[http://dx.doi.org/10.4236/ijcm.2016.71005]
[10]
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.
[http://dx.doi.org/10.1152/jappl.1994.76.3.1113] [PMID: 8005852]
[11]
Lillo RS, Parker EC, Porter WR. Decompression comparison of helium and hydrogen in rats. J Appl Physiol 1997; 82(3): 892-901.
[http://dx.doi.org/10.1152/jappl.1997.82.3.892] [PMID: 9074979]
[12]
Cole AR, Raza A, Ahmed H, et al. Safety of inhaled hydrogen gas in healthy mice. Med Gas Res 2019; 9(3): 133-8.
[http://dx.doi.org/10.4103/2045-9912.266988] [PMID: 31552876]
[13]
Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther 2014; 144(1): 1-11.
[http://dx.doi.org/10.1016/j.pharmthera.2014.04.006] [PMID: 24769081]
[14]
Tao G, Song G, Qin S. Molecular hydrogen: current knowledge on mechanism in alleviating free radical damage and diseases. Acta Biochim Biophys Sin (Shanghai) 2019; 51(12): 1189-97.
[http://dx.doi.org/10.1093/abbs/gmz121] [PMID: 31738389]
[15]
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.
[http://dx.doi.org/10.1038/srep03273] [PMID: 24253616]
[16]
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 (Silver Spring) 2011; 19(7): 1396-403.
[http://dx.doi.org/10.1038/oby.2011.6] [PMID: 21293445]
[17]
Buchholz BM, Kaczorowski DJ, Sugimoto R, et al. Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am J Transplant 2008; 8(10): 2015-24.
[http://dx.doi.org/10.1111/j.1600-6143.2008.02359.x] [PMID: 18727697]
[18]
Ishibashi T. Molecular hydrogen: new antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Curr Pharm Des 2013; 19(35): 6375-81.
[http://dx.doi.org/10.2174/13816128113199990507] [PMID: 23859555]
[19]
Lloyd RV, Hanna PM, Mason RP. The origin of the hydroxyl radical oxygen in the Fenton reaction. Free Radic Biol Med 1997; 22(5): 885-8.
[http://dx.doi.org/10.1016/S0891-5849(96)00432-7] [PMID: 9119257]
[20]
Alluri H, Anasooya Shaji C, Davis ML, Tharakan B. Oxygen-glucose deprivation and reoxygenation as an in vitro ischemia-reperfusion injury model for studying blood-brain barrier dysfunction. J Vis Exp 2015; (99): e52699
[http://dx.doi.org/10.3791/52699] [PMID: 25992584]
[21]
Portal L, Martin V, Assaly R, et al. A model of hypoxia-reoxygenation on isolated adult mouse cardiomyocytes: characterization, comparison with ischemia-reperfusion, and application to the cardioprotective effect of regular treadmill exercise. J Cardiovasc Pharmacol Ther 2013; 18(4): 367-75.
[http://dx.doi.org/10.1177/1074248412475158] [PMID: 23406783]
[22]
Juretic H, Montalbo-Lomboy M, van Leeuwen JH, Cooper WJ, Grewell D. Hydroxyl radical formation in batch and continuous flow ultrasonic systems. Ultrason Sonochem 2015; 22: 600-6.
[http://dx.doi.org/10.1016/j.ultsonch.2014.07.003] [PMID: 25088186]
[23]
Shah NS, Khan JA, Nawaz S, Khan HM. Role of aqueous electron and hydroxyl radical in the removal of endosulfan from aqueous solution using gamma irradiation. J Hazard Mater 2014; 278: 40-8.
[http://dx.doi.org/10.1016/j.jhazmat.2014.05.073] [PMID: 24952221]
[24]
Takeshita K, Fujii K, Anzai K, Ozawa T. In vivo monitoring of hydroxyl radical generation caused by x-ray irradiation of rats using the spin trapping/EPR technique. Free Radic Biol Med 2004; 36(9): 1134-43.
[http://dx.doi.org/10.1016/j.freeradbiomed.2004.02.016] [PMID: 15082067]
[25]
Yu J, Yu Q, Liu Y, Zhang R, Xue L. Hydrogen gas alleviates oxygen toxicity by reducing hydroxyl radical levels in PC12 cells. PLoS One 2017; 12(3)e0173645
[http://dx.doi.org/10.1371/journal.pone.0173645] [PMID: 28362819]
[26]
Chen M, Zhang J, Chen Y, et al. Hydrogen protects lung from hypoxia/re-oxygenation injury by reducing hydroxyl radical production and inhibiting inflammatory responses. Sci Rep 2018; 8(1): 8004.
[http://dx.doi.org/10.1038/s41598-018-26335-2] [PMID: 29789753]
[27]
Chuai Y, Qian L, Sun X, Cai J. Molecular hydrogen and radiation protection. Free Radic Res 2012; 46(9): 1061-7.
[http://dx.doi.org/10.3109/10715762.2012.689429] [PMID: 22537465]
[28]
Zhang J, Hao H, Chen M, Wang H, Feng Z, Chen H. Hydrogen-rich water alleviates the toxicities of different stresses to mycelial growth in Hypsizygus marmoreus. AMB Express 2017; 7(1): 107.
[http://dx.doi.org/10.1186/s13568-017-0406-1] [PMID: 28565883]
[29]
Oharazawa H, Igarashi T, Yokota T, 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.
[http://dx.doi.org/10.1167/iovs.09-4089] [PMID: 19834032]
[30]
Igarashi T, Ohsawa I, Kobayashi M, et al. Hydrogen prevents corneal endothelial damage in phacoemulsification cataract surgery. Sci Rep 2016; 6: 31190.
[http://dx.doi.org/10.1038/srep31190] [PMID: 27498755]
[31]
Wan WL, Tian B, Lin YJ, et al. Photosynthesis-inspired H2 generation using a chlorophyll-loaded liposomal nanoplatform to detect and scavenge excess ROS. Nat Commun 2020; 11(1): 534.
[http://dx.doi.org/10.1038/s41467-020-14413-x] [PMID: 31988280]
[32]
Hyspler R, Ticha A, Schierbeek H, Galkin A, Zadak Z. The evaluation and quantitation of dihydrogen metabolism using deuterium isotope in rats. PLoS One 2015; 10(6)e0130687
[http://dx.doi.org/10.1371/journal.pone.0130687] [PMID: 26103048]
[33]
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.
[http://dx.doi.org/10.1007/978-1-4614-1566-4_36] [PMID: 22259109]
[34]
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.
[http://dx.doi.org/10.1007/978-1-4614-7411-1_42] [PMID: 23852510]
[35]
Shibata A, Sugano Y, Shimouchi A, et al. Decrease in exhaled hydrogen as marker of congestive heart failure. Open Heart 2018; 5(2)e000814
[http://dx.doi.org/10.1136/openhrt-2018-000814] [PMID: 30245836]
[36]
Buxton GV, Greenstock CL, Helman WP, Ross AB. Critical review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (•OH/•O-) in aqueous solution. J Phys Chem Ref Data 1988; 17(2): 513-886.
[http://dx.doi.org/10.1063/1.555805]
[37]
Wood KC, Gladwin MT. The hydrogen highway to reperfusion therapy. Nat Med 2007; 13(6): 673-4.
[http://dx.doi.org/10.1038/nm0607-673] [PMID: 17554332]
[38]
Enami S, Sakamoto Y, Colussi AJ. Fenton chemistry at aqueous interfaces. Proc Natl Acad Sci USA 2014; 111(2): 623-8.
[http://dx.doi.org/10.1073/pnas.1314885111] [PMID: 24379389]
[39]
Iuchi K, Nishimaki K, Kamimura N, Ohta S. Molecular hydrogen suppresses free-radical-induced cell death by mitigating fatty acid peroxidation and mitochondrial dysfunction. Can J Physiol Pharmacol 2019; 97(10): 999-1005.
[http://dx.doi.org/10.1139/cjpp-2018-0741] [PMID: 31295412]
[40]
Iuchi K, Imoto A, Kamimura N, et al. Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators. Sci Rep 2016; 6: 18971.
[http://dx.doi.org/10.1038/srep18971] [PMID: 26739257]
[41]
Chen X, Shen Q, Li Z, Wan W, Chen J, Zhang J. Metal-free H2 activation for highly selective hydrogenation of nitroaromatics using phosphorus-doped carbon nanotubes. ACS Appl Mater Interfaces 2020; 12(1): 654-66.
[http://dx.doi.org/10.1021/acsami.9b17582] [PMID: 31808342]
[42]
Loomis RA, Lester MI. OH-H2 entrance channel complexes. Annu Rev Phys Chem 1997; 48: 643-73.
[http://dx.doi.org/10.1146/annurev.physchem.48.1.643] [PMID: 15012452]
[43]
Henkel S, Sander W. Activation of molecular hydrogen by a singlet carbene through quantum mechanical tunneling. Angew Chem Int Ed Engl 2015; 54(15): 4603-7.
[http://dx.doi.org/10.1002/anie.201410501] [PMID: 25690272]
[44]
Meisner J, Kästner J. Reaction rates and kinetic isotope effects of H2 + OH → H2O + H. J Chem Phys 2016; 144(17)174303
[http://dx.doi.org/10.1063/1.4948319] [PMID: 27155636]
[45]
Hayashida K, Sano M, Kamimura N, et al. H(2) gas improves functional outcome after cardiac arrest to an extent comparable to therapeutic hypothermia in a rat model. J Am Heart Assoc 2012; 1(5)e003459
[http://dx.doi.org/10.1161/JAHA.112.003459] [PMID: 23316300]
[46]
Az-ma T, Saeki N, Yuge O. Cytosolic Ca2+ movements of endothelial cells exposed to reactive oxygen intermediates: role of hydroxyl radical-mediated redox alteration of cell-membrane Ca2+ channels. Br J Pharmacol 1999; 126(6): 1462-70.
[http://dx.doi.org/10.1038/sj.bjp.0702438] [PMID: 10217541]
[47]
Shirotani K, Katsura M, Higo A, et al. Suppression of Ca2+ influx through L-type voltage-dependent calcium channels by hydroxyl radical in mouse cerebral cortical neurons. Brain Res Mol Brain Res 2001; 92(1-2): 12-8.
[http://dx.doi.org/10.1016/S0169-328X(01)00128-0] [PMID: 11483237]
[48]
Kajimura M, Fukuda R, Bateman RM, Yamamoto T, Suematsu M. Interactions of multiple gas-transducing systems: hallmarks and uncertainties of CO, NO, and H2S gas biology. Antioxid Redox Signal 2010; 13(2): 157-92.
[http://dx.doi.org/10.1089/ars.2009.2657] [PMID: 19939208]
[49]
McCully JD, Levitsky S. The mitochondrial K(ATP) channel and cardioprotection. Ann Thorac Surg 2003; 75(2): S667-73.
[http://dx.doi.org/10.1016/S0003-4975(02)04689-1] [PMID: 12607710]
[50]
Li X, Mizuno R, Ono N, Ohhashi T. Glucose and glucose transporters regulate lymphatic pump activity through activation of the mitochondrial ATP-sensitive K+ channel. J Physiol Sci 2008; 58(4): 249-61.
[http://dx.doi.org/10.2170/physiolsci.RP004608] [PMID: 18597699]
[51]
Walewska A, Szewczyk A, Koprowski P. Gas signaling molecules and mitochondrial potassium channels. Int J Mol Sci 2018; 19(10)E3227
[http://dx.doi.org/10.3390/ijms19103227] [PMID: 30340432]
[52]
Tokube K, Kiyosue T, Arita M. Effects of hydroxyl radicals on KATP channels in guinea-pig ventricular myocytes. Pflugers Arch 1998; 437(1): 155-7.
[http://dx.doi.org/10.1007/s004240050760] [PMID: 9817800]
[53]
Maack C, Dabew ER, Hohl M, Schäfers HJ, Böhm M. Endogenous activation of mitochondrial KATP channels protects human failing myocardium from hydroxyl radical-induced stunning. Circ Res 2009; 105(8): 811-7.
[http://dx.doi.org/10.1161/CIRCRESAHA.109.206359] [PMID: 19729596]
[54]
Garlid AO, Jaburek M, Jacobs JP, Garlid KD. Mitochondrial reactive oxygen species: which ROS signals cardioprotection? Am J Physiol Heart Circ Physiol 2013; 305(7): H960-8.
[http://dx.doi.org/10.1152/ajpheart.00858.2012] [PMID: 23913710]
[55]
Sharma V, Wikström M. The role of the K-channel and the active-site tyrosine in the catalytic mechanism of cytochrome C oxidase. Biochim Biophys Acta 2016; 1857(8): 1111-5.
[http://dx.doi.org/10.1016/j.bbabio.2016.02.008] [PMID: 26898520]
[56]
Yoshida A, Asanuma H, Sasaki H, 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.
[http://dx.doi.org/10.1007/s10557-012-6381-5] [PMID: 22527618]
[57]
Jiao Y, Yu Y, Li B, et al. Protective effects of hydrogen rich saline against experimental diabetic peripheral neuropathy via activation of the mitochondrial ATP sensitive potassium channel channels in rats. Mol Med Rep 2020; 21(1): 282-90.https://www.spandidos-publications.com/10.3892/mmr.2019.10795
[PMID: 31746358]
[58]
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.
[http://dx.doi.org/10.1038/npp.2008.95] [PMID: 18563058]
[59]
Mikami T, Tano K, Lee H, et al. Drinking hydrogen water enhances endurance and relieves psychometric fatigue: a randomized, double-blind, placebo-controlled study. Can J Physiol Pharmacol 2019; 97(9): 857-62.
[http://dx.doi.org/10.1139/cjpp-2019-0059] [PMID: 31251888]
[60]
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.
[http://dx.doi.org/10.1016/j.bbrc.2007.07.088] [PMID: 17673169]
[61]
Hayashida K, Sano M, Ohsawa I, 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.
[http://dx.doi.org/10.1016/j.bbrc.2008.05.165] [PMID: 18541148]
[62]
Hayashida K, Sano M, Kamimura N, 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.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.011848] [PMID: 25366995]
[63]
Yamamoto R, Homma K, Suzuki S, Sano M, Sasaki J. Hydrogen gas distribution in organs after inhalation: Real-time monitoring of tissue hydrogen concentration in rat. Sci Rep 2019; 9(1): 1255.
[http://dx.doi.org/10.1038/s41598-018-38180-4] [PMID: 30718910]
[64]
Itoh T, Fujita Y, Ito 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.
[http://dx.doi.org/10.1016/j.bbrc.2009.09.047] [PMID: 19766097]
[65]
Wills ED. Mechanisms of lipid peroxide formation in tissues. Role of metals and haematin proteins in the catalysis of the oxidation unsaturated fatty acids. Biochim Biophys Acta 1965; 98: 238-51.
[http://dx.doi.org/10.1016/0005-2760(65)90118-9] [PMID: 14325327]
[66]
Tiwaskar HV, Suryakar AN, Ambekar JG, Makhija SJ. Alteration in the levels of serum lipid peroxide, cyclooxygenase activity and free fatty acids in bronchial asthma. Indian J Chest Dis Allied Sci 1986; 28(3): 122-5.
[PMID: 3110057]
[67]
Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014; 2014360438
[http://dx.doi.org/10.1155/2014/360438] [PMID: 24999379]
[68]
Wolpaw AJ, Stockwell BR. Multidimensional profiling in the investigation of small-molecule-induced cell death. Methods Enzymol 2014; 545: 265-302.
[http://dx.doi.org/10.1016/B978-0-12-801430-1.00011-1] [PMID: 25065894]
[69]
Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci 2016; 73(11-12): 2195-209.
[http://dx.doi.org/10.1007/s00018-016-2194-1] [PMID: 27048822]
[70]
Golstein P, Kroemer G. Cell death by necrosis: towards a molecular definition. Trends Biochem Sci 2007; 32(1): 37-43.
[http://dx.doi.org/10.1016/j.tibs.2006.11.001] [PMID: 17141506]
[71]
Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 2003; 4(7): 552-65.
[http://dx.doi.org/10.1038/nrm1150] [PMID: 12838338]
[72]
Wang H, Liu C, Zhao Y, Gao G. Mitochondria regulation in ferroptosis. Eur J Cell Biol 2020; 99(1)151058
[http://dx.doi.org/10.1016/j.ejcb.2019.151058] [PMID: 31810634]
[73]
Ono H, Nishijima Y, Ohta S, et al. Hydrogen gas inhalation treatment in acute cerebral infarction: a randomized controlled clinical study on safety and neuroprotection. J Stroke Cerebrovasc Dis 2017; 26(11): 2587-94.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.06.012] [PMID: 28669654]
[74]
Tamura T, Hayashida K, Sano M, et al. Feasibility and safety of hydrogen gas inhalation for post-cardiac arrest syndrome　- first-in-human pilot study. Circ J 2016; 80(8): 1870-3.
[http://dx.doi.org/10.1253/circj.CJ-16-0127] [PMID: 27334126]
[75]
Katsumata Y, Sano F, Abe T, et al. The effects of hydrogen gas inhalation on adverse left ventricular remodeling after percutaneous coronary intervention for st-elevated myocardial infarction　- first pilot study in humans. Circ J 2017; 81(7): 940-7.
[http://dx.doi.org/10.1253/circj.CJ-17-0105] [PMID: 28321000]
[76]
Schaur RJ, Siems W, Bresgen N, Eckl PM. 4-Hydroxy-nonenal-A bioactive lipid peroxidation product. Biomolecules 2015; 5(4): 2247-337.
[http://dx.doi.org/10.3390/biom5042247] [PMID: 26437435]
[77]
Kamimura N, Ichimiya H, Iuchi K, Ohta S. Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1α to enhance fatty acid metabolism. NPJ Aging Mech Dis 2016; 2(1): 16008.
[http://dx.doi.org/10.1038/npjamd.2016.8] [PMID: 28721265]
[78]
Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010; 91(1): 254S-7S.
[http://dx.doi.org/10.3945/ajcn.2009.28449B] [PMID: 19906798]
[79]
Kharitonenkov A, Shiyanova TL, Koester A, et al. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115(6): 1627-35.
[http://dx.doi.org/10.1172/JCI23606] [PMID: 15902306]
[80]
Fujita K, Seike T, Yutsudo N, 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
[http://dx.doi.org/10.1371/journal.pone.0007247] [PMID: 19789628]
[81]
Furukawa S, Fujita T, Shimabukuro M, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114(12): 1752-61.
[http://dx.doi.org/10.1172/JCI21625] [PMID: 15599400]
[82]
Monteiro R, Azevedo I. Chronic inflammation in obesity and the metabolic syndrome Mediators Inflamm 2010; 2010: 2010-289645.
[http://dx.doi.org/10.1155/2010/289645] [PMID: 20706689]
[83]
Tzivion G, Dobson M, Ramakrishnan G. FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta 2011; 1813(11): 1938-45.
[http://dx.doi.org/10.1016/j.bbamcr.2011.06.002] [PMID: 21708191]
[84]
Liang H, Ward WF. PGC-1alpha: a key regulator of energy metabolism. Adv Physiol Educ 2006; 30(4): 145-51.
[http://dx.doi.org/10.1152/advan.00052.2006] [PMID: 17108241]
[85]
Subbanagounder G, Leitinger N, Schwenke DC, et al. Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position. Arterioscler Thromb Vasc Biol 2000; 20(10): 2248-54.
[http://dx.doi.org/10.1161/01.ATV.20.10.2248] [PMID: 11031211]
[86]
Bochkov VN. Inflammatory profile of oxidized phospholipids. Thromb Haemost 2007; 97(3): 348-54.
[http://dx.doi.org/10.1160/TH06-08-0474] [PMID: 17334500]
[87]
Reis A, Spickett CM. Chemistry of phospholipid oxidation. Biochim Biophys Acta 2012; 1818(10): 2374-87.
[http://dx.doi.org/10.1016/j.bbamem.2012.02.002] [PMID: 22342938]
[88]
Johnstone SR, Ross J, Rizzo MJ, et al. Oxidized phospholipid species promote in vivo differential cx43 phosphorylation and vascular smooth muscle cell proliferation. Am J Pathol 2009; 175(2): 916-24.
[http://dx.doi.org/10.2353/ajpath.2009.090160] [PMID: 19608875]
[89]
Chu LH, Indramohan M, Ratsimandresy RA, et al. The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat Commun 2018; 9(1): 996.
[http://dx.doi.org/10.1038/s41467-018-03409-3] [PMID: 29520027]
[90]
Porter NA, Caldwell SE, Mills KA. Mechanisms of free radical oxidation of unsaturated lipids. Lipids 1995; 30(4): 277-90.
[http://dx.doi.org/10.1007/BF02536034] [PMID: 7609594]
[91]
Bochkov VN, Oskolkova OV, Birukov KG, Levonen AL, Binder CJ, Stöckl J. Generation and biological activities of oxidized phospholipids. Antioxid Redox Signal 2010; 12(8): 1009-59.
[http://dx.doi.org/10.1089/ars.2009.2597] [PMID: 19686040]
[92]
Song G, Li M, Sang H, 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.
[http://dx.doi.org/10.1194/jlr.M036640] [PMID: 23610159]
[93]
Song G, Lin Q, Zhao H, 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(7): 2724-33.
[http://dx.doi.org/10.1210/jc.2015-1321] [PMID: 25978109]
[94]
Kawai D, Takaki A, Nakatsuka A, et al. Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice. Hepatology 2012; 56(3): 912-21.
[http://dx.doi.org/10.1002/hep.25782] [PMID: 22505328]
[95]
Subbanagounder G, Deng Y, Borromeo C, Dooley AN, Berliner JA, Salomon RG. Hydroxy alkenal phospholipids regulate inflammatory functions of endothelial cells. Vascul Pharmacol 2002; 38(4): 201-9.
[http://dx.doi.org/10.1016/S1537-1891(02)00170-2] [PMID: 12449016]
[96]
Bochkov VN, Mechtcheriakova D, Lucerna M, et al. Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca(++)/NFAT. Blood 2002; 99(1): 199-206.
[http://dx.doi.org/10.1182/blood.V99.1.199] [PMID: 11756172]
[97]
Obinata H, Hattori T, Nakane S, Tatei K, Izumi T. Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A. J Biol Chem 2005; 280(49): 40676-83.
[http://dx.doi.org/10.1074/jbc.M507787200] [PMID: 16236715]
[98]
Nogueira JE, Passaglia P, Mota CMD, et al. Molecular hydrogen reduces acute exercise-induced inflammatory and oxidative stress status. Free Radic Biol Med 2018; 129: 186-93.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.09.028] [PMID: 30243702]
[99]
Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 2003; 17(18): 2205-32.
[http://dx.doi.org/10.1101/gad.1102703] [PMID: 12975316]
[100]
Musson RE, Cobbaert CM, Smit NP. Molecular diagnostics of calcineurin-related pathologies. Clin Chem 2012; 58(3): 511-22.
[http://dx.doi.org/10.1373/clinchem.2011.167296] [PMID: 22015374]
[101]
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.
[http://dx.doi.org/10.1007/s00774-013-0530-1] [PMID: 24196871]
[102]
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.
[http://dx.doi.org/10.1007/s11033-013-2653-9] [PMID: 23955545]
[103]
Kishimoto Y, Kato T, Ito M, et al. Hydrogen ameliorates pulmonary hypertension in rats by anti-inflammatory and antioxidant effects. J Thorac Cardiovasc Surg 2015; 150(3): 645-54.https://www.jtcvs.org/article/S0022-5223(15)00864-8/fulltext
[PMID: 26095621.]
[104]
Negishi-Koga T, Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev 2009; 231(1): 241-56.
[http://dx.doi.org/10.1111/j.1600-065X.2009.00821.x] [PMID: 19754901]
[105]
Ramiro-Diaz JM, Nitta CH, Maston LD, et al. NFAT is required for spontaneous pulmonary hypertension in superoxide dismutase 1 knockout mice. Am J Physiol Lung Cell Mol Physiol 2013; 304(9): L613-25.
[http://dx.doi.org/10.1152/ajplung.00408.2012] [PMID: 23475768]
[106]
Obasanjo-Blackshire K, Mesquita R, Jabr RI, et al. Calcineurin regulates NFAT-dependent iNOS expression and protection of cardiomyocytes: co-operation with Src tyrosine kinase. Cardiovasc Res 2006; 71(4): 672-83.
[http://dx.doi.org/10.1016/j.cardiores.2006.05.026] [PMID: 16828070]
[107]
He J, Xiong S, Zhang J, et al. Protective effects of hydrogen-rich saline on ulcerative colitis rat model. J Surg Res 2013; 185(1): 174-81.
[http://dx.doi.org/10.1016/j.jss.2013.05.047] [PMID: 23773716]
[108]
Luo J, Sun L, Lin X, et al. A calcineurin- and NFAT-dependent pathway is involved in α-synuclein-induced degeneration of midbrain dopaminergic neurons. Hum Mol Genet 2014; 23(24): 6567-74.
[http://dx.doi.org/10.1093/hmg/ddu377] [PMID: 25051958]
[109]
Itoh T, Hamada N, Terazawa R, et al. Molecular hydrogen inhibits lipopolysaccharide/interferon γ-induced nitric oxide production through modulation of signal transduction in macrophages. Biochem Biophys Res Commun 2011; 411(1): 143-9.
[http://dx.doi.org/10.1016/j.bbrc.2011.06.116] [PMID: 21723254]
[110]
Kawamura T, Huang CS, Peng X, et al. The effect of donor treatment with hydrogen on lung allograft function in rats. Surgery 2011; 150(2): 240-9.
[http://dx.doi.org/10.1016/j.surg.2011.05.019] [PMID: 21801961]
[111]
Cardinal JS, Zhan J, Wang Y, et al. Oral hydrogen water prevents chronic allograft nephropathy in rats. Kidney Int 2010; 77(2): 101-9.
[http://dx.doi.org/10.1038/ki.2009.421] [PMID: 19907413]
[112]
Motojima H, Villareal MO, Iijima R, Han J, Isoda H. Acteoside inhibits type I allergy through the down-regulation of Ca/NFAT and JNK MAPK signaling pathways in basophilic cells. J Nat Med 2013; 67(4): 790-8.
[http://dx.doi.org/10.1007/s11418-013-0753-4] [PMID: 23494816]
[113]
Sakai T, Sato B, Hara K, 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.https://www.dovepress.com/consumption-of-water-containing-over-35-mg-of-dissolved-hydrogen-could-peer-reviewed-article-VHRM
[PMID: 25378931]
[114]
Guan WJ, Wei CH, Chen AL, et al. Hydrogen/oxygen mixed gas inhalation improves disease severity and dyspnea in patients with Coronavirus disease 2019 in a recent multicenter, open-label clinical trial. J Thorac Dis 2020; 12(6): 3448-52.https://jtd.amegroups.com/article/view/40994/html
[PMID: 32642277]
[115]
Liu LD, Wu XY, Tao BD, Wang N, Zhang J. Protective effect and mechanism of hydrogen treatment on lung epithelial barrier dysfunction in rats with sepsis. Genet Mol Res 2016; 15(1)
[http://dx.doi.org/10.4238/gmr.15016050] [PMID: 26909920]
[116]
Xie K, Liu L, Yu Y, Wang G. Hydrogen gas presents a promising therapeutic strategy for sepsis. BioMed Res Int 2014; 2014807635
[http://dx.doi.org/10.1155/2014/807635] [PMID: 24829918]
[117]
Qiu P, Liu Y, Zhang J. Recent advances in studies of molecular hydrogen against sepsis. Int J Biol Sci 2019; 15(6): 1261-75.
[http://dx.doi.org/10.7150/ijbs.30741] [PMID: 31223285]
[118]
Varga V, Németh J, Oláh O, et al. Molecular hydrogen alleviates asphyxia-induced neuronal cyclooxygenase-2 expression in newborn pigs. Acta Pharmacol Sin 2018; 39(8): 1273-83.
[http://dx.doi.org/10.1038/aps.2017.148] [PMID: 29565041]
[119]
Huang CS, Kawamura T, Lee S, et al. Hydrogen inhalation ameliorates ventilator-induced lung injury. Crit Care 2010; 14(6): R234.
[http://dx.doi.org/10.1186/cc9389] [PMID: 21184683]
[120]
Huang CS, Kawamura T, Peng X, 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.
[http://dx.doi.org/10.1016/j.bbrc.2011.04.008] [PMID: 21473852]
[121]
Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement 2016; 12(6): 719-32.
[http://dx.doi.org/10.1016/j.jalz.2016.02.010] [PMID: 27179961]
[122]
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.
[http://dx.doi.org/10.1016/j.brainres.2010.02.046] [PMID: 20171955]
[123]
Tan X, Shen F, Dong WL, Yang Y, Chen G. The role of hydrogen in Alzheimer’s disease. Med Gas Res 2019; 8(4): 176-80.http://www.medgasres.com/article.asp?issn=2045-9912;year=2018;volume=8;issue=4;spage=176;epage=180;aulast=Tan
[PMID: 30713672]
[124]
Zhang L, Zhao P, Yue C, et al. Sustained release of bioactive hydrogen by Pd hydride nanoparticles overcomes Alzheimer’s disease. Biomaterials 2019; 197: 393-404.
[http://dx.doi.org/10.1016/j.biomaterials.2019.01.037] [PMID: 30703744]
[125]
Nishimaki K, Asada T, Ohsawa I, et al. Effects of molecular hydrogen assessed by an animal model and a randomized clinical study on mild cognitive impairment. Curr Alzheimer Res 2018; 15(5): 482-92.
[http://dx.doi.org/10.2174/1567205014666171106145017] [PMID: 29110615]
[126]
Ono H, Nishijima Y, Sakamoto M, et al. Pilot study on therapeutic inhalation of hydrogen gas for improving patients with Alzheimer’s disease assessed by cognitive subscale scores and magnetic resonance diffusion tensor imaging. J Alzheimers Neuro Disorder 2018; 1(11): 004.https://bioaccent.org/alzheimers-neurological/alzheimers-neurological04.pdf
[127]
Abdul HM, Sama MA, Furman JL, et al. Cognitive decline in Alzheimer’s disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci 2009; 29(41): 12957-69.
[http://dx.doi.org/10.1523/JNEUROSCI.1064-09.2009] [PMID: 19828810]
[128]
Hudry E, Wu HY, Arbel-Ornath M, et al. Inhibition of the NFAT pathway alleviates amyloid β neurotoxicity in a mouse model of Alzheimer’s disease. J Neurosci 2012; 32(9): 3176-92.
[http://dx.doi.org/10.1523/JNEUROSCI.6439-11.2012] [PMID: 22378890]
[129]
Taglialatela G, Rastellini C, Cicalese L. Reduced incidence of dementia in solid organ transplant patients treated with calcineurin inhibitors. J Alzheimers Dis 2015; 47(2): 329-33.
[http://dx.doi.org/10.3233/JAD-150065] [PMID: 26401556]
[130]
Chen JB, Kong XF, Lv YY, et al. “Real world survey” of hydrogen-controlled cancer: a follow-up report of 82 advanced cancer patients. Med Gas Res 2019; 9(3): 115-21.http://www.medgasres.com/article.asp?issn=2045-9912;year=2019;volume=9;issue=3;spage=115;epage=121;aulast=Chen
[PMID: 31552873]
[131]
Akagi J, Baba H. Hydrogen gas restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis. Oncol Rep 2019; 41(1): 301-11.https://www.spandidos-publications.com/10.3892/or.2018.6841
[PMID: 30542740]
[132]
Chen JB, Pan ZB, Du DM, et al. Hydrogen gas therapy induced shrinkage of metastatic gallbladder cancer: A case report. World J Clin Cases 2019; 7(15): 2065-74.
[http://dx.doi.org/10.12998/wjcc.v7.i15.2065] [PMID: 31423439]
[133]
Chen J, Mu F, Lu T, Du D, Xu K. Brain metastases completely disappear in non-small cell lung cancer using hydrogen gas inhalation: A Case Report. OncoTargets Ther 2019; 12: 11145-51.
[http://dx.doi.org/10.2147/OTT.S235195] [PMID: 31908482 ]
[134]
Chen JB, Kong XF, Mu F, et al. Hydrogen therapy can be used to control tumor progression and alleviate the adverse events of medications in patients with advanced non-small cell lung cancer. Med Gas Res 2020; 10(2): 75-80.http://www.medgasres.com/article.asp?issn=2045-9912;year=2020; volume=10;issue=2;spage=75;epage=80;aulast=Chen
[PMID: 32541132]
[135]
Iwai Y, Hamanishi J, Chamoto K, Honjo T. Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 2017; 24(1): 26.
[http://dx.doi.org/10.1186/s12929-017-0329-9] [PMID: 28376884]
[136]
Chamoto K, Chowdhury PS, Kumar A, et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci USA 2017; 114(5): E761-70.
[http://dx.doi.org/10.1073/pnas.1620433114] [PMID: 28096382]
[137]
Kumar A, Chamoto K, Chowdhury PS, Honjo T. Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy. eLife 2020; 9: 9.
[http://dx.doi.org/10.7554/eLife.52330] [PMID: 32122466]
[138]
Erridge C, Kennedy S, Spickett CM, Webb DJ. Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4: roles for CD14, LPS-binding protein, and MD2 as targets for specificity of inhibition. J Biol Chem 2008; 283(36): 24748-59.
[http://dx.doi.org/10.1074/jbc.M800352200] [PMID: 18559343]
[139]
Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine 2008; 42(2): 145-51.
[http://dx.doi.org/10.1016/j.cyto.2008.01.006] [PMID: 18304834]
[140]
Bochkov V, Gesslbauer B, Mauerhofer C, Philippova M, Erne P, Oskolkova OV. Pleiotropic effects of oxidized phospholipids. Free Radic Biol Med 2017; 111: 6-24.
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.12.034] [PMID: 28027924]
[141]
Kadl A, Sharma PR, Chen W, et al. Oxidized phospholipid-induced inflammation is mediated by Toll-like receptor 2. Free Radic Biol Med 2011; 51(10): 1903-9.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.08.026] [PMID: 21925592]
[142]
Oskolkova OV, Afonyushkin T, Preinerstorfer B, et al. Oxidized phospholipids are more potent antagonists of lipopolysaccharide than inducers of inflammation. J Immunol 2010; 185(12): 7706-12.
[http://dx.doi.org/10.4049/jimmunol.0903594] [PMID: 21068406]
[143]
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
[http://dx.doi.org/10.1371/journal.pone.0042078] [PMID: 22860058]
[144]
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.
[http://dx.doi.org/10.1186/1476-9255-9-2] [PMID: 22296736]
[145]
Chen HG, Xie KL, Han HZ, 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.
[http://dx.doi.org/10.1016/j.ijsu.2013.10.007] [PMID: 24148794]
[146]
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.
[http://dx.doi.org/10.3980/j.issn.2222-3959.2013.03.05] [PMID: 23826519]
[147]
Saramago EA, Borges GS, Singolani-Jr CG, et al. Molecular hydrogen potentiates hypothermia and prevents hypotension and fever in LPS-induced systemic inflammation. Brain Behav Immun 2019; 75: 119-28.
[http://dx.doi.org/10.1016/j.bbi.2018.09.027] [PMID: 30261305]
[148]
Wang Y, Zhang J, Bo J, Wang X, Zhu J. Hydrogen-rich saline ameliorated LPS-induced acute lung injury via autophagy inhibition through the ROS/AMPK/mTOR pathway in mice. Exp Biol Med (Maywood) 2019; 244(9): 721-7.
[http://dx.doi.org/10.1177/1535370219847941] [PMID: 31042074]
[149]
Tan S, Long Z, Hou X, et al. H2 Protects Against Lipopolysaccharide-Induced Cardiac Dysfunction via Blocking TLR4-Mediated Cytokines Expression. Front Pharmacol 2019; 10: 865.
[http://dx.doi.org/10.3389/fphar.2019.00865] [PMID: 31440160]
[150]
Minematsu H, Shin MJ, Celil Aydemir AB, et al. Nuclear presence of nuclear factor of activated T cells (NFAT) c3 and c4 is required for Toll-like receptor-activated innate inflammatory response of monocytes/macrophages. Cell Signal 2011; 23(11): 1785-93.
[http://dx.doi.org/10.1016/j.cellsig.2011.06.013] [PMID: 21726630]
[151]
Iketani M, Ohshiro J, Urushibara T, et al. Preadministration of hydrogen-rich water protects against lipopolysaccharide-induced sepsis and attenuates liver injury. Shock 2017; 48(1): 85-93.
[http://dx.doi.org/10.1097/SHK.0000000000000810] [PMID: 27918369]
[152]
Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 2011; 75(1): 50-83.
[http://dx.doi.org/10.1128/MMBR.00031-10] [PMID: 21372320]
[153]
Wang P, Zhao M, Chen Z, et al. Hydrogen gas attenuates hypoxic-ischemic brain injury via regulation of the mapk/ho-1/pgc-1a pathway in neonatal rats. Oxid Med Cell Longev 2020; 20206978784
[http://dx.doi.org/10.1155/2020/6978784] [PMID: 32104537]
[154]
Han B, Zhou H, Jia G, et al. MAPKs and Hsc70 are critical to the protective effect of molecular hydrogen during the early phase of acute pancreatitis. FEBS J 2016; 283(4): 738-56.
[http://dx.doi.org/10.1111/febs.13629] [PMID: 26683671]
[155]
Li D, Ai Y. Hydrogen saline suppresses neuronal cell apoptosis and inhibits the p38 mitogen activated protein kinase caspase 3 signaling pathway following cerebral ischemia reperfusion injury. Mol Med Rep 2017; 16(4): 5321-5.
[http://dx.doi.org/10.3892/mmr.2017.7294] [PMID: 28849153]
[156]
Shi Q, Chen C, Deng WH, et al. Hydrogen-rich saline attenuates acute hepatic injury in acute necrotizing pancreatitis by inhibiting inflammation and apoptosis, involving JNK and p38 mitogen-activated protein kinase-dependent reactive oxygen species. Pancreas 2016; 45(10): 1424-31.
[http://dx.doi.org/10.1097/MPA.0000000000000678] [PMID: 27518466]
[157]
Zhang YX, Xu JT, You XC, et al. Inhibitory effects of hydrogen on proliferation and migration of vascular smooth muscle cells via down-regulation of mitogen/activated protein kinase and ezrin-radixin-moesin signaling pathways. Chin J Physiol 2016; 59(1): 46-55.
[http://dx.doi.org/10.4077/CJP.2016.BAE365] [PMID: 26875562]
[158]
Park YM. CD36, a scavenger receptor implicated in atherosclerosis. Exp Mol Med 2014; 46e99
[http://dx.doi.org/10.1038/emm.2014.38] [PMID: 24903227]
[159]
Silverstein RL, Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Sci Signal 2009; 2(72): re3.
[http://dx.doi.org/10.1126/scisignal.272re3] [PMID: 19471024]
[160]
Mitchell JP, Carmody RJ. NF-κB and the Transcriptional control of Inflammation. Int Rev Cell Mol Biol 2018; 335: 41-84.
[http://dx.doi.org/10.1016/bs.ircmb.2017.07.007] [PMID: 29305014]
[161]
Bading H. Nuclear calcium signalling in the regulation of brain function. Nat Rev Neurosci 2013; 14(9): 593-608.
[http://dx.doi.org/10.1038/nrn3531] [PMID: 23942469]
[162]
Wu G, Pan L, Sun J, Chen G, Wang S. Hydrogen gas protects against ovariectomy-induced osteoporosis by inhibiting NF-κB activation. Menopause 2019; 26(7): 785-92.
[http://dx.doi.org/10.1097/GME.0000000000001310] [PMID: 31083022]
[163]
Qin ZX, Yu P, Qian DH, et al. Hydrogen-rich saline prevents neointima formation after carotid balloon injury by suppressing ROS and the TNF-α/NF-κB pathway. Atherosclerosis 2012; 220(2): 343-50.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.11.002] [PMID: 22153150]
[164]
Wang C, Li J, Liu Q, et al. Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer’s disease. Neurosci Lett 2011; 491(2): 127-32.
[http://dx.doi.org/10.1016/j.neulet.2011.01.022] [PMID: 21238541]
[165]
Shi Q, Liao KS, Zhao KL, et al. Hydrogen-rich saline attenuates acute renal injury in sodium taurocholate-induced severe acute pancreatitis by inhibiting ROS and NF-κB pathway. Mediators Inflamm 2015; 2015685043
[http://dx.doi.org/10.1155/2015/685043] [PMID: 25878401]
[166]
Xiao M, Zhu T, Wang T, Wen FQ. Hydrogen-rich saline reduces airway remodeling via inactivation of NF-κB in a murine model of asthma. Eur Rev Med Pharmacol Sci 2013; 17(8): 1033-43.
[PMID: 23661516]
[167]
L’Episcopo F, Tirolo C, Testa N, et al. Aging-induced Nrf2-ARE pathway disruption in the subventricular zone drives neurogenic impairment in parkinsonian mice via PI3K-Wnt/β-catenin dysregulation. J Neurosci 2013; 33(4): 1462-85.
[http://dx.doi.org/10.1523/JNEUROSCI.3206-12.2013] [PMID: 23345222]
[168]
Sobue S, Yamai K, Ito M, 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.
[http://dx.doi.org/10.1007/s11010-015-2353-y] [PMID: 25707580]
[169]
Saha RN, Jana M, Pahan K. MAPK p38 regulates transcriptional activity of NF-kappaB in primary human astrocytes via acetylation of p65. J Immunol 2007; 179(10): 7101-9.
[http://dx.doi.org/10.4049/jimmunol.179.10.7101] [PMID: 17982102]
[170]
Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 2013; 53: 401-26.
[http://dx.doi.org/10.1146/annurev-pharmtox-011112-140320] [PMID: 23294312]
[171]
Bellezza I, Giambanco I, Minelli A, Donato R. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res 2018; 1865(5): 721-33.
[http://dx.doi.org/10.1016/j.bbamcr.2018.02.010] [PMID: 29499228]
[172]
Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Activators and inhibitors of NRF2: A review of their potential for clinical development. Oxid Med Cell Longev 2019; 20199372182
[http://dx.doi.org/10.1155/2019/9372182] [PMID: 31396308]
[173]
Kawamura T, Wakabayashi N, Shigemura N, 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.
[http://dx.doi.org/10.1152/ajplung.00164.2012] [PMID: 23475767]
[174]
Yu Y, Yang Y, Bian Y, et al. Hydrogen gas protects against intestinal injury in wild type but not NRF2 knockout mice with severe sepsis by regulating HO-1 and HMGB1 release. Shock 2017; 48(3): 364-70.
[http://dx.doi.org/10.1097/SHK.0000000000000856] [PMID: 28234792]
[175]
Zhai X, Chen X, Shi J, 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.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.08.004] [PMID: 23954468]
[176]
Chen H, Xie K, Han H, et al. Molecular hydrogen protects mice against polymicrobial sepsis by ameliorating endothelial dysfunction via an Nrf2/HO-1 signaling pathway. Int Immunopharmacol 2015; 28(1): 643-54.
[http://dx.doi.org/10.1016/j.intimp.2015.07.034] [PMID: 26253656]
[177]
Yu J, Zhang W, Zhang R, et al. Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic cholangiocytes by activating Nrf2 expression. Toxicol Lett 2015; 238(3): 11-9.
[http://dx.doi.org/10.1016/j.toxlet.2015.08.010] [PMID: 26276082]
[178]
Tamaki N, Orihuela-Campos RC, Fukui M, Ito HO. Hydrogen-rich water intake accelerates oral palatal wound healing via activation of the Nrf2/antioxidant defense pathways in a rat model. Oxid Med Cell Longev 2016; 20165679040
[http://dx.doi.org/10.1155/2016/5679040] [PMID: 26798423]
[179]
Diao M, Zhang S, Wu L, et al. Hydrogen gas inhalation attenuates seawater instillation-induced acute lung injury via the Nrf2 pathway in rabbits. Inflammation 2016; 39(6): 2029-39.
[http://dx.doi.org/10.1007/s10753-016-0440-1] [PMID: 27596008]
[180]
Yuan J, Wang D, Liu Y, et al. Hydrogen-rich water attenuates oxidative stress in rats with traumatic brain injury via Nrf2 pathway. J Surg Res 2018; 228: 238-46.
[http://dx.doi.org/10.1016/j.jss.2018.03.024] [PMID: 29907217]
[181]
Liu Y, Dong F, Guo R, et al. Hydrogen-rich saline ameliorates experimental autoimmune encephalomyelitis in C57BL/6 Mice Via the Nrf2-ARE signaling pathway. Inflammation 2019; 42(2): 586-97.
[http://dx.doi.org/10.1007/s10753-018-0915-3] [PMID: 30343391]
[182]
Yu Y, Yang Y, Yang M, Wang C, Xie K, Yu Y. Hydrogen gas reduces HMGB1 release in lung tissues of septic mice in an Nrf2/HO-1-dependent pathway. Int Immunopharmacol 2019; 69: 11-8.
[http://dx.doi.org/10.1016/j.intimp.2019.01.022] [PMID: 30660872]
[183]
Wang X, Wang J. High-content hydrogen water-induced downregulation of miR-136 alleviates non-alcoholic fatty liver disease by regulating Nrf2 via targeting MEG3. Biol Chem 2018; 399(4): 397-406.
[http://dx.doi.org/10.1515/hsz-2017-0303] [PMID: 29261513]
[184]
Murakami Y, Ito M, Ohsawa I. Molecular hydrogen protects against oxidative stress-induced SH-SY5Y neuroblastoma cell death through the process of mitohormesis. PLoS One 2017; 12(5)e0176992
[http://dx.doi.org/10.1371/journal.pone.0176992] [PMID: 28467497]
[185]
Fang W, Wang G, Tang L, et al. Hydrogen gas inhalation protects against cutaneous ischaemia/reperfusion injury in a mouse model of pressure ulcer. J Cell Mol Med 2018; 22(9): 4243-52.
[http://dx.doi.org/10.1111/jcmm.13704] [PMID: 29921037]
[186]
Andrukhiv A, Costa AD, West IC, Garlid KD. Opening mitoKATP increases superoxide generation from complex I of the electron transport chain. Am J Physiol Heart Circ Physiol 2006; 291(5): H2067-74.
[http://dx.doi.org/10.1152/ajpheart.00272.2006] [PMID: 16798828]
[187]
Zhang J, Bao X, Zhang M, et al. MitoQ ameliorates testis injury from oxidative attack by repairing mitochondria and promoting the Keap1-Nrf2 pathway. Toxicol Appl Pharmacol 2019; 370: 78-92.
[http://dx.doi.org/10.1016/j.taap.2019.03.001] [PMID: 30836114]
[188]
Huang T, Xie Z, Wang J, Li M, Jing N, Li L. Nuclear factor of activated T cells (NFAT) proteins repress canonical Wnt signaling via its interaction with Dishevelled (Dvl) protein and participate in regulating neural progenitor cell proliferation and differentiation. J Biol Chem 2011; 286(43): 37399-405.
[http://dx.doi.org/10.1074/jbc.M111.251165] [PMID: 21880741]
[189]
Wang Q, Zhou Y, Rychahou P, Liu C, Weiss HL, Evers BM. NFAT5 represses canonical Wnt signaling via inhibition of β-catenin acetylation and participates in regulating intestinal cell differentiation. Cell Death Dis 2013; 4e671
[http://dx.doi.org/10.1038/cddis.2013.202] [PMID: 23764852]
[190]
Fromigué O, Haÿ E, Barbara A, Marie PJ. Essential role of nuclear factor of activated T cells (NFAT)-mediated Wnt signaling in osteoblast differentiation induced by strontium ranelate. J Biol Chem 2010; 285(33): 25251-8.
[http://dx.doi.org/10.1074/jbc.M110.110502] [PMID: 20554534]
[191]
Rada P, Rojo AI, Offergeld A, et al. WNT-3A regulates an Axin1/NRF2 complex that regulates antioxidant metabolism in hepatocytes. Antioxid Redox Signal 2015; 22(7): 555-71.
[http://dx.doi.org/10.1089/ars.2014.6040] [PMID: 25336178]
[192]
Tian D, Shi Y, Chen D, Liu Q, Fan F. The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling. Int J Oncol 2017; 51(2): 545-54.
[http://dx.doi.org/10.3892/ijo.2017.4042] [PMID: 28627706]
[193]
Fang W, Tang L, Wang G, et al. Molecular hydrogen protects human melanocytes from oxidative stress by activating nrf2 signaling. J Invest Dermatol 2020. Epub ahead of print
[http://dx.doi.org/10.1016/j.jid.2019.03.1165] [PMID: 32234461]
[194]
Cheng J, Tang C, Li X, Hu J, Lü J. Hydrogen molecules can modulate enzymatic activity and structural properties of pepsin in vitro. Colloids Surf B Biointerfaces 2020; 189110856
[http://dx.doi.org/10.1016/j.colsurfb.2020.110856] [PMID: 32087530]

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