The Molecular Biological Mechanism of Hydrogen Therapy and Its Application in Spinal Cord Injury

References

• Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: a possible treatment for cancer. Science. 1975;190(4210):152–154. doi:10.1126/science.1166304
   PubMed Web of Science ®Google Scholar
• 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):688–694. doi:10.1038/nm1577
   PubMed Web of Science ®Google Scholar
• Lu H, Chen W, Liu W, et al. Molecular hydrogen regulates PTEN-AKT-mTOR signaling via ROS to alleviate peritoneal dialysis-related peritoneal fibrosis. FASEB J. 2020;34(3):4134–4146. doi:10.1096/fj.201901981R
   PubMed Web of Science ®Google Scholar
• Liu B, Xue J, Zhang M, et al. Hydrogen inhalation alleviates nonalcoholic fatty liver disease in metabolic syndrome rats. Mol Med Rep. 2020;22(4):2860–2868. doi:10.3892/mmr.2020.11364
   PubMed Web of Science ®Google Scholar
• Ji H, Zhao Z, Liu Z, et al. Real-world effectiveness and safety of hydrogen inhalation in Chinese patients with Type 2 diabetes: a single-arm, retrospective study. Diabetes Metab Syndr Obes. 2023;16:2039–2050. doi:10.2147/DMSO.S412898
   PubMed Web of Science ®Google Scholar
• Abolfazli S, Ebrahimi N, Morabi E, et al. Hydrogen sulfide: physiological roles and therapeutic implications against COVID-19. Curr Med Chem. 2023;2023:1.
   Google Scholar
• Matei N, Camara R, Zhang JH. Emerging mechanisms and novel applications of hydrogen gas therapy. Med Gas Res. 2018;8(3):98–102. doi:10.4103/2045-9912.239959
   PubMed Web of Science ®Google Scholar
• Ohta S. Development of hydrogen medicine and biology: potential for various applications in diverse fields. Curr Pharm Des. 2021;27(5):583–584. doi:10.2174/138161282705210211144515
   PubMed Web of Science ®Google Scholar
• Hu X, Xu W, Ren Y, et al. Spinal cord injury: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023;8(1):245.
   PubMed Web of Science ®Google Scholar
• Pizzolato C, Gunduz MA, Palipana D, et al. Non-invasive approaches to functional recovery after spinal cord injury: therapeutic targets and multimodal device interventions. Exp Neurol. 2021;339:113612. doi:10.1016/j.expneurol.2021.113612
   PubMed Web of Science ®Google Scholar
• Huang H, Chen L, Moviglia G, et al. Advances and prospects of cell therapy for spinal cord injury patients. J Neurorestoratol. 2022;10(1):13–30. doi:10.26599/JNR.2022.9040007
   Web of Science ®Google Scholar
• Sharma HS, Chopp M, Chen L, et al. The 2021 yearbook of Neurorestoratology. J Neurorestoratol. 2022;10(3):100008. doi:10.1016/j.jnrt.2022.100008
   Web of Science ®Google Scholar
• Huang H, Bach JR, Sharma HS, et al. The 2022 yearbook of Neurorestoratology. J Neurorestoratol. 2023;11(2):100054. doi:10.1016/j.jnrt.2023.100054
   Web of Science ®Google Scholar
• Chan PH. Role of oxidants in ischemic brain damage. Stroke. 1996;27(6):1124–1129. doi:10.1161/01.STR.27.6.1124
   PubMed Web of Science ®Google Scholar
• Ren A, Liu R, Miao ZG, et al. Hydrogen-rich water regulates effects of ROS balance on morphology, growth and secondary metabolism via glutathione peroxidase in Ganoderma lucidum. Environ Microbiol. 2017;19(2):566–583. doi:10.1111/1462-2920.13498
   PubMed Web of Science ®Google Scholar
• Wu L, Li Z, Yao Y. Hydrogen peroxide preconditioning is of dual role in cardiac ischemia/reperfusion. Eur J Pharmacol. 2023;947:175684. doi:10.1016/j.ejphar.2023.175684
   PubMed Web of Science ®Google Scholar
• Chang Y, Han Q, Bao X, et al. Hyperbaric oxygen combined with hydrogen-rich saline protects against acute lung injury. Undersea Hyperb Med. 2023;50(2):155–165. doi:10.22462/01.01.2023.42
   PubMed Web of Science ®Google Scholar
• You IS, Sharma S, Fadriquela A, et al. Antioxidant properties of hydrogen gas attenuates oxidative stress in airway epithelial cells. Molecules. 2021;26(21). doi:10.3390/molecules26216375
   Web of Science ®Google Scholar
• Yan M, Yu Y, Mao X, et al. Hydrogen gas inhalation attenuates sepsis-induced liver injury in a FUNDC1-dependent manner. Int Immunopharmacol. 2019;71:61–67. doi:10.1016/j.intimp.2019.03.021
   PubMed Web of Science ®Google Scholar
• Du Y, Chen L, Qiao H, et al. Hydrogen-Rich Saline-A novel neuroprotective agent in a mouse model of experimental cerebral ischemia via the ROS-NLRP3 inflammasome signaling pathway in vivo and in vitro. Brain Sci. 2023;13(6). doi:10.3390/brainsci13060939
   Web of Science ®Google Scholar
• Zhang N, Deng C, Zhang X, Zhang J, Bai C. Inhalation of hydrogen gas attenuates airway inflammation and oxidative stress in allergic asthmatic mice. Asthma Res Pract. 2018;4:3. doi:10.1186/s40733-018-0040-y
   PubMedGoogle Scholar
• Wu DD, Jin S, Cheng RX, et al. Hydrogen sulfide functions as a micro-modulator bound at the copper active site of Cu/Zn-SOD to regulate the catalytic activity of the enzyme. Cell Rep. 2023;42(7):112750. doi:10.1016/j.celrep.2023.112750
   PubMed Web of Science ®Google Scholar
• Liu L, Xie K, Chen H, 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
   PubMed Web of Science ®Google Scholar
• 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;69:11–18. doi:10.1016/j.intimp.2019.01.022
   PubMed Web of Science ®Google Scholar
• Zhao C, Zhou X, Qiu J, et al. Exosomes derived from bone marrow mesenchymal stem cells inhibit complement activation in rats with spinal cord injury. Drug Des Devel Ther. 2019;13:3693–3704. doi:10.2147/DDDT.S209636
   PubMed Web of Science ®Google Scholar
• Bigford GE, Garshick E. Systemic inflammation after spinal cord injury: a review of biological evidence, related health risks, and potential therapies. Curr Opin Pharmacol. 2022;67:102303. doi:10.1016/j.coph.2022.102303
   PubMed Web of Science ®Google Scholar
• Wang ST, Bao C, He Y, et al. Hydrogen gas (XEN) inhalation ameliorates airway inflammation in asthma and COPD patients. QJM. 2020;113(12):870–875. doi:10.1093/qjmed/hcaa164
   PubMed Web of Science ®Google Scholar
• Shao A, Wu H, Hong Y, 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. 2016;53(5):3462–3476. doi:10.1007/s12035-015-9242-y
   PubMed Web of Science ®Google Scholar
• Li J, Dong Y, Chen H, 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;1486:103–111. doi:10.1016/j.brainres.2012.09.031
   PubMed Web of Science ®Google Scholar
• Liu H, Kang X, Ren P, et al. Hydrogen gas ameliorates acute alcoholic liver injury via anti-inflammatory and antioxidant effects and regulation of intestinal microbiota. Int Immunopharmacol. 2023;120:110252. doi:10.1016/j.intimp.2023.110252
   PubMed Web of Science ®Google Scholar
• Fujii Y, Shirai M, Inamori S, et al. Insufflation of hydrogen gas restrains the inflammatory response of cardiopulmonary bypass in a rat model. Artif Organs. 2013;37(2):136–141. doi:10.1111/j.1525-1594.2012.01535.x
   PubMed Web of Science ®Google Scholar
• Yin H, Feng Y, Duan Y, Ma S, Guo Z, Wei Y. Hydrogen gas alleviates lipopolysaccharide-induced acute lung injury and inflammatory response in mice. J Inflamm. 2022;19(1):16. doi:10.1186/s12950-022-00314-x
   Google Scholar
• Zhao P, Cai Z, Zhang X, et al. Hydrogen attenuates inflammation by inducing early M2 macrophage polarization in skin wound healing. Pharmaceuticals. 2023;16(6):885. doi:10.3390/ph16060885
   Web of Science ®Google Scholar
• 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):91–95. doi:10.1016/j.ijcard.2010.08.058
   PubMed Web of Science ®Google Scholar
• Yao L, Chen H, Wu Q, Xie K. Hydrogen-rich saline alleviates inflammation and apoptosis in myocardial I/R injury via PINK-mediated autophagy. Int J Mol Med. 2019;44(3):1048–1062. doi:10.3892/ijmm.2019.4264
   PubMed Web of Science ®Google Scholar
• Guo SX, Fang Q, You CG, 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
   PubMed Web of Science ®Google Scholar
• Wang C, Li J, Liu Q, 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):127–132. doi:10.1016/j.neulet.2011.01.022
   PubMed Web of Science ®Google Scholar
• Akagi J, Baba H. Hydrogen gas activates coenzyme Q10 to restore exhausted CD8(+) T cells, especially PD-1(+)Tim3(+)terminal CD8(+) T cells, leading to better nivolumab outcomes in patients with lung cancer. Oncol Lett. 2020;20(5):258. doi:10.3892/ol.2020.12121
   PubMed Web of Science ®Google Scholar
• LeBaron TW, Laher I, Kura B, Slezak J. Hydrogen gas: from clinical medicine to an emerging ergogenic molecule for sports athletes (1). Can J Physiol Pharmacol. 2019;97(9):797–807. doi:10.1139/cjpp-2019-0067
   PubMed Web of Science ®Google Scholar
• Dohi K, Kraemer BC, Erickson MA, 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
   PubMed Web of Science ®Google Scholar
• Li TT, Sun T, Wang YZ, Wan Q, Li WZ, Yang WC. Molecular hydrogen alleviates lung injury after traumatic brain injury: pyroptosis and apoptosis. Eur J Pharmacol. 2022;914:174664. doi:10.1016/j.ejphar.2021.174664
   PubMed Web of Science ®Google Scholar
• Li TT, Yang WC, Wang YZ, et al. Effects of a high concentration of hydrogen on neurological function after traumatic brain injury in diabetic rats. Brain Res. 2020;1730:146651. doi:10.1016/j.brainres.2020.146651
   PubMed Web of Science ®Google Scholar
• Chen X, Cui J, Zhai X, et al. Inhalation of hydrogen of different concentrations ameliorates spinal cord injury in mice by protecting spinal cord neurons from apoptosis, oxidative injury and mitochondrial structure damages. Cell Physiol Biochem. 2018;47(1):176–190. doi:10.1159/000489764
   PubMedGoogle Scholar
• Wang JL, Zhang QS, Zhu KD, et al. Hydrogen-rich saline injection into the subarachnoid cavity within 2 weeks promotes recovery after acute spinal cord injury. Neural Regen Res. 2015;10(6):958–964. doi:10.4103/1673-5374.158361
   PubMed Web of Science ®Google Scholar
• Qiu P, Liu Y, Chen K, Dong Y, Liu S, Zhang J. Hydrogen-rich saline regulates the polarization and apoptosis of alveolar macrophages and attenuates lung injury via suppression of autophagy in septic rats. Ann Transl Med. 2021;9(12):974. doi:10.21037/atm-21-2489
   PubMed Web of Science ®Google Scholar
• Jiang S, Fan Q, Xu M, et al. Hydrogen-rich saline protects intestinal epithelial tight junction barrier in rats with intestinal ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress-induced apoptosis pathway. J Pediatr Surg. 2020;55(12):2811–2819. doi:10.1016/j.jpedsurg.2020.01.061
   PubMed Web of Science ®Google Scholar
• Liu L, Yan Z, Wang Y, Meng J, Chen G. Suppression of autophagy facilitates hydrogen gas-mediated lung cancer cell apoptosis. Oncol Lett. 2020;20(4):112. doi:10.3892/ol.2020.11973
   PubMed Web of Science ®Google Scholar
• Wang L, Yin Z, Wang F, et al. Hydrogen exerts neuroprotection by activation of the miR-21/PI3K/AKT/GSK-3beta pathway in an in vitro model of traumatic brain injury. J Cell Mol Med. 2020;24(7):4061–4071. doi:10.1111/jcmm.15051
   PubMed Web of Science ®Google Scholar
• Wang H, Huo X, Chen H, et al. Hydrogen-rich saline activated autophagy via HIF-1alpha pathways in neuropathic pain model. Biomed Res Int. 2018;2018:4670834. doi:10.1155/2018/4670834
   PubMed Web of Science ®Google Scholar
• Zhuang X, Yu Y, Jiang Y, et al. Molecular hydrogen attenuates sepsis-induced neuroinflammation through regulation of microglia polarization through an mTOR-autophagy-dependent pathway. Int Immunopharmacol. 2020;81:106287. doi:10.1016/j.intimp.2020.106287
   PubMed Web of Science ®Google Scholar
• Gao Y, Yang H, Chi J, et al. Hydrogen gas attenuates myocardial ischemia reperfusion injury independent of postconditioning in rats by attenuating endoplasmic reticulum stress-induced autophagy. Cell Physiol Biochem. 2017;43(4):1503–1514. doi:10.1159/000481974
   PubMedGoogle Scholar
• Ma H, Chen H, Dong A, Wang Y, Bian Y, Xie K. 富氢液激活自噬减轻带状疱疹后神经痛大鼠痛敏并降低炎症因子的水平 [Hydrogen-rich saline attenuates hyperalgesia and reduces cytokines in rats with post-herpetic neuralgia via activating autophagy]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017;33(2):155–158. Chinese.
   PubMedGoogle Scholar
• Mu G, Li Q, Lu B, Yu X. Amelioration of nerve demyelination by hydrogen-producing silicon-based agent in neuropathic pain rats. Int Immunopharmacol. 2023;117:110033. doi:10.1016/j.intimp.2023.110033
   PubMed Web of Science ®Google Scholar
• Luo N, Lin H, Zhang L, et al. Effect of hydrogen on AM pyroptosis induced by severe burns in rats. J Pers Med. 2023;13(3). doi:10.3390/jpm13030377
   Web of Science ®Google Scholar
• Zou R, Nie C, Pan S, et al. Co-administration of hydrogen and metformin exerts cardioprotective effects by inhibiting pyroptosis and fibrosis in diabetic cardiomyopathy. Free Radic Biol Med. 2022;183:35–50. doi:10.1016/j.freeradbiomed.2022.03.010
   PubMed Web of Science ®Google Scholar
• Ma J, Dong S, Lu H, et al. The hydrogen storage nanomaterial MgH(2) improves irradiation-induced male fertility impairment by suppressing oxidative stress. Biomater Res. 2022;26(1):20. doi:10.1186/s40824-022-00266-6
   PubMedGoogle Scholar
• Zhang CS, Han Q, Song ZW, Jia HY, Shao TP, Chen YP. Hydrogen gas post-conditioning attenuates early neuronal pyroptosis in a rat model of subarachnoid hemorrhage through the mitoK(ATP) signaling pathway. Exp Ther Med. 2021;22(2):836. doi:10.3892/etm.2021.10268
   PubMed Web of Science ®Google Scholar
• Yu M, Qin C, Li P, et al. Hydrogen gas alleviates sepsis-induced neuroinflammation and cognitive impairment through regulation of DNMT1 and DNMT3a-mediated BDNF promoter IV methylation in mice. Int Immunopharmacol. 2021;95:107583. doi:10.1016/j.intimp.2021.107583
   PubMed Web of Science ®Google Scholar
• Zanini D, Todorovic N, Korovljev D, et al. The effects of 6-month hydrogen-rich water intake on molecular and phenotypic biomarkers of aging in older adults aged 70 years and over: a randomized controlled pilot trial. Exp Gerontol. 2021;155:111574. doi:10.1016/j.exger.2021.111574
   PubMed Web of Science ®Google Scholar
• Nieto-Diaz M, Esteban FJ, Reigada D, et al. MicroRNA dysregulation in spinal cord injury: causes, consequences and therapeutics. Front Cell Neurosci. 2014;8:53. doi:10.3389/fncel.2014.00053
   PubMed Web of Science ®Google Scholar
• Wang L, Zhao C, Wu S, et al. Hydrogen gas treatment improves the neurological outcome after traumatic brain injury via increasing miR-21 expression. Shock. 2018;50(3):308–315. doi:10.1097/SHK.0000000000001018
   PubMed Web of Science ®Google Scholar
• 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):280–285. doi:10.3980/j.issn.2222-3959.2013.03.05
   PubMed Web of Science ®Google Scholar
• Yao W, Lin X, Han X, et al. MicroRNA files in the prevention of intestinal ischemia/reperfusion injury by hydrogen rich saline. Biosci Rep. 2020;40(1). doi:10.1042/BSR20191043
   Google Scholar
• Tonelli C, Chio IIC, Tuveson DA. Transcriptional Regulation by Nrf2. Antioxid Redox Signal. 2018;29(17):1727–1745. doi:10.1089/ars.2017.7342
   PubMed Web of Science ®Google Scholar
• Sun R, Zhao N, Wang Y, et al. High concentration of hydrogen gas alleviates Lipopolysaccharide-induced lung injury via activating Nrf2 signaling pathway in mice. Int Immunopharmacol. 2021;101(Pt B):108198. doi:10.1016/j.intimp.2021.108198
   PubMedGoogle Scholar
• Fang W, Tang L, Wang G, et al. Molecular hydrogen protects human melanocytes from oxidative stress by activating Nrf2 signaling. J Invest Dermatol. 2020;140(11):2230–41 e9. doi:10.1016/j.jid.2019.03.1165
   PubMed Web of Science ®Google Scholar
• 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–L656. doi:10.1152/ajplung.00164.2012
   PubMed Web of Science ®Google Scholar
• Yu Y, Feng J, Lian N, et al. Hydrogen gas alleviates blood-brain barrier impairment and cognitive dysfunction of septic mice in an Nrf2-dependent pathway. Int Immunopharmacol. 2020;85:106585. doi:10.1016/j.intimp.2020.106585
   PubMed Web of Science ®Google Scholar
• Saha S, Buttari B, Panieri E, Profumo E, Saso L. An overview of Nrf2 Signaling pathway and its role in inflammation. Molecules. 2020;25(22):1.
   Web of Science ®Google Scholar
• Liu FT, Xu SM, Xiang ZH, et al. Molecular hydrogen suppresses reactive astrogliosis related to oxidative injury during spinal cord injury in rats. CNS Neurosci Ther. 2014;20(8):778–786. doi:10.1111/cns.12258
   PubMed Web of Science ®Google Scholar
• Bains M, Hall ED. Antioxidant therapies in traumatic brain and spinal cord injury. Biochim Biophys Acta. 2012;1822(5):675–684. doi:10.1016/j.bbadis.2011.10.017
   PubMed Web of Science ®Google Scholar
• An P, Zhao XC, Liu MJ, You YQ, Li JY. Gender-based differences in neuroprotective effects of hydrogen gas against intracerebral hemorrhage-induced depression. Neurochem Int. 2022;153:105276. doi:10.1016/j.neuint.2022.105276
   PubMed Web of Science ®Google Scholar
• Huang P, Wei S, Huang W, et al. Hydrogen gas inhalation enhances alveolar macrophage phagocytosis in an ovalbumin-induced asthma model. Int Immunopharmacol. 2019;74:105646. doi:10.1016/j.intimp.2019.05.031
   PubMed Web of Science ®Google Scholar
• Lu W, Li D, Hu J, et al. Hydrogen gas inhalation protects against cigarette smoke-induced COPD development in mice. J Thorac Dis. 2018;10(6):3232–3243. doi:10.21037/jtd.2018.05.93
   PubMed Web of Science ®Google Scholar
• Shi Y, Wang G, Li J, Yu W. Hydrogen gas attenuates sevoflurane neurotoxicity through inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells signaling and proinflammatory cytokine release in neonatal rats. Neuroreport. 2017;28(17):1170–1175. doi:10.1097/WNR.0000000000000899
   PubMed Web of Science ®Google Scholar
• Song JH, Jia HY, Shao TP, Liu ZB, Zhao YP. Hydrogen gas post-conditioning alleviates cognitive dysfunction and anxiety-like behavior in a rat model of subarachnoid hemorrhage. Exp Ther Med. 2021;22(4):1121. doi:10.3892/etm.2021.10555
   PubMed Web of Science ®Google Scholar
• Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296(5573):1655–1657. doi:10.1126/science.296.5573.1655
   PubMed Web of Science ®Google Scholar
• Ke H, Liu D, Li T, et al. Hydrogen-Rich Saline Regulates Microglial Phagocytosis and Restores Behavioral Deficits Following Hypoxia-Ischemia Injury in Neonatal Mice via the Akt Pathway. Drug Des Devel Ther. 2020;14:3827–3839. doi:10.2147/DDDT.S264684
   PubMed Web of Science ®Google Scholar
• Chen K, Wang N, Diao Y, et al. Hydrogen-rich saline attenuates brain injury induced by cardiopulmonary bypass and inhibits microvascular endothelial cell apoptosis Via the PI3K/Akt/GSK3beta signaling pathway in rats. Cell Physiol Biochem. 2017;43(4):1634–1647. doi:10.1159/000484024
   PubMedGoogle Scholar
• 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):651–656. doi:10.1016/j.bbrc.2009.09.047
   PubMed Web of Science ®Google Scholar
• Yang M, Dong Y, He Q, et al. Hydrogen: a novel option in human disease treatment. Oxid Med Cell Longev. 2020;2020:8384742. doi:10.1155/2020/8384742
   PubMed Web of Science ®Google Scholar
• Sauer H, Wartenberg M, Hescheler J. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem. 2001;11(4):173–186. doi:10.1159/000047804
   PubMed Web of Science ®Google Scholar
• Fernandes VS, Ribeiro AS, Martinez P, et al. Hydrogen sulfide plays a key role in the inhibitory neurotransmission to the pig intravesical ureter. PLoS One. 2014;9(11):e113580. doi:10.1371/journal.pone.0113580
   PubMed Web of Science ®Google Scholar
• Xue JL, Liu BY, Zhao M, et al. Inhalation of 4% and 67% hydrogen ameliorates oxidative stress, inflammation, apoptosis, and necroptosis in a rat model of glycerol-induced acute kidney injury. Med Gas Res. 2023;13(2):78–88. doi:10.4103/2045-9912.345169
   PubMed Web of Science ®Google Scholar
• Johnsen HM, Hiorth M, Klaveness J. Molecular hydrogen therapy-A review on clinical studies and outcomes. Molecules. 2023;28(23):7785. doi:10.3390/molecules28237785
   PubMed Web of Science ®Google Scholar
• Zhou Z-Q, Zhong C-H, Su Z-Q, et al. Breathing Hydrogen-Oxygen Mixture Decreases Inspiratory Effort in Patients with Tracheal Stenosis. Respiration. 2019;97(1):42–51. doi:10.1159/000492031
   PubMed Web of Science ®Google Scholar
• Zheng ZG, Sun WZ, Hu JY, et al. Hydrogen/oxygen therapy for the treatment of an acute exacerbation of chronic obstructive pulmonary disease: results of a multicenter, randomized, double-blind, parallel-group controlled trial. Respir Res. 2021;22(1):149. doi:10.1186/s12931-021-01740-w
   PubMed Web of Science ®Google Scholar
• Cheng D, Long J, Zhao L, Liu J. Hydrogen: a Rising star in gas medicine as a mitochondria-targeting nutrient via activating Keap1-Nrf2 antioxidant system. Antioxidants. 2023;12(12):1.
   Web of Science ®Google Scholar
• Zhang Y, Tan S, Xu J, Wang T. Hydrogen therapy in cardiovascular and metabolic diseases: from bench to bedside. Cell Physiol Biochem. 2018;47(1):1–10. doi:10.1159/000489737
   PubMed Web of Science ®Google Scholar
• Li H, Luo Y, Yang P, Liu J. Hydrogen as a complementary therapy against ischemic stroke: a review of the evidence. J Neurol Sci. 2019;396:240–246. doi:10.1016/j.jns.2018.11.004
   PubMed Web of Science ®Google Scholar
• Ramanathan D, Huang L, Wilson T, Boling W. Molecular hydrogen therapy for neurological diseases: a review of current evidence. Med Gas Res. 2023;13(3):94–98. doi:10.4103/2045-9912.359677
   PubMed Web of Science ®Google Scholar
• Zhang Q, Piao C, Xu J, et al. Comparative study on protective effect of hydrogen rich saline and adipose-derived stem cells on hepatic ischemia-reperfusion and hepatectomy injury in swine. Biomed Pharmacother. 2019;120:109453. doi:10.1016/j.biopha.2019.109453
   PubMed Web of Science ®Google Scholar
• Tao G, Liu F, Jin Z, et al. A strategy of local hydrogen capture and catalytic hydrogenation for enhanced therapy of chronic liver diseases. Theranostics. 2023;13(8):2455–2470. doi:10.7150/thno.80494
   PubMed Web of Science ®Google Scholar
• Ostojic SM. Should hydrogen therapy be included in a musculoskeletal medicine routine? F1000Res. 2016;5:2659. doi:10.12688/f1000research.9758.1
   PubMedGoogle Scholar
• Yuan T, Zhao JN, Bao NR. Hydrogen applications: advances in the field of medical therapy. Med Gas Res. 2023;13(3):99–107.
   PubMed Web of Science ®Google Scholar
• Meng J, Yu P, Jiang H, et al. Molecular hydrogen decelerates rheumatoid arthritis progression through inhibition of oxidative stress. Am J Transl Res. 2016;8(10):4472–4477.
   PubMed Web of Science ®Google Scholar
• Otsuka M, Arai K, Yoshida T, Hayashi A. Inhibition of retinal ischemia-reperfusion injury in rats by inhalation of low-concentration hydrogen gas. Graefes Arch Clin Exp Ophthalmol. 2024;262(3):823–833. doi:10.1007/s00417-023-06262-3
   PubMed Web of Science ®Google Scholar
• Mohd Noor MNZ, Alauddin AS, Wong YH, et al. A systematic review of molecular hydrogen therapy in cancer management. Asian Pac J Cancer Prev. 2023;24(1):37–47. doi:10.31557/APJCP.2023.24.1.37
   PubMedGoogle Scholar
• National Health Commission & National Administration of Traditional Chinese Medicine. Diagnosis and treatment protocol for novel coronavirus pneumonia (Trial Version 7). Chin Med J. 2020;133(9):1087–1095. doi:10.1097/CM9.0000000000000819
   PubMed Web of Science ®Google Scholar
• Perveen I, Bukhari B, Najeeb M, et al. Hydrogen therapy and its future prospects for ameliorating COVID-19: clinical applications, efficacy, and modality. Biomedicines. 2023;11(7). doi:10.3390/biomedicines11071892
   Web of Science ®Google Scholar
• Luo S, Wu J, Qiu Y, et al. Hydrogen promotes the effectiveness of bone mesenchymal stem cell transplantation in rats with spinal cord injury. Stem Cells Int. 2023;2023:8227382. doi:10.1155/2023/8227382
   PubMed Web of Science ®Google Scholar
• Wang R, Wu X, Tian Z, et al. Sustained release of hydrogen sulfide from anisotropic ferrofluid hydrogel for the repair of spinal cord injury. Bioact Mater. 2023;23:118–128. doi:10.1016/j.bioactmat.2022.10.020
   PubMed Web of Science ®Google Scholar
• Kimura A, Suehiro K, Mukai A, et al. Protective effects of hydrogen gas against spinal cord ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2022;164(6):e269–e83. doi:10.1016/j.jtcvs.2021.04.077
   PubMed Web of Science ®Google Scholar
• Huang Y, Xie K, Li J, et al. Beneficial effects of hydrogen gas against spinal cord ischemia-reperfusion injury in rabbits. Brain Res. 2011;1378:125–136. doi:10.1016/j.brainres.2010.12.071
   PubMed Web of Science ®Google Scholar
• Zhou L, Wang X, Xue W, et al. Beneficial effects of hydrogen-rich saline against spinal cord ischemia-reperfusion injury in rabbits. Brain Res. 2013;1517:150–160. doi:10.1016/j.brainres.2013.04.007
   PubMed Web of Science ®Google Scholar
• Li Q, Zhang H, Jia Z, et al. Hydrogen enriched saline alleviates morphine tolerance via inhibiting neuroinflammation, GLT-1, GS nitration and NMDA receptor trafficking and functioning in the spinal cord of rats. Neurosci Lett. 2021;755:135847. doi:10.1016/j.neulet.2021.135847
   PubMed Web of Science ®Google Scholar
• Huang Y, Xiao FM, Tang WJ, et al. Hydrogen inhalation promotes recovery of a patient in persistent vegetative state from intracerebral hemorrhage: a case report and literature review. World J Clin Cases. 2022;10(4):1311–1319. doi:10.12998/wjcc.v10.i4.1311
   PubMed Web of Science ®Google Scholar
• Du J, Li J, Li R, Yan X. High concentration of hydrogen ameliorates lipopolysaccharide-induced acute lung injury in a sirt1-dependent manner. Respir Physiol Neurobiol. 2022;296:103808. doi:10.1016/j.resp.2021.103808
   PubMed Web of Science ®Google Scholar
• Camara R, Huang L, Zhang JH. The production of high dose hydrogen gas by the AMS-H-01 for treatment of disease. Med Gas Res. 2016;6(3):164–166. doi:10.4103/2045-9912.191362
   PubMedGoogle Scholar
• He Y, Shi JZ, Zhang RJ, et al. Effects of hydrogen gas inhalation on endometriosis in rats. Reprod Sci. 2017;24(2):324–331. doi:10.1177/1933719116655622
   PubMed Web of Science ®Google Scholar
• Asada R, Saitoh Y, Miwa N. Effects of hydrogen-rich water bath on visceral fat and skin blotch, with boiling-resistant hydrogen bubbles. Med Gas Res. 2019;9(2):68–73. doi:10.4103/2045-9912.260647
   PubMed Web of Science ®Google Scholar
• Kawamura M, Imamura R, Kobayashi Y, et al. Oral administration of si-based agent attenuates oxidative stress and ischemia-reperfusion injury in a rat model: a novel hydrogen administration method. Front Med Lausanne. 2020;7:95. doi:10.3389/fmed.2020.00095
   PubMed Web of Science ®Google Scholar
• Kayabas M, Sahin L, Makav M, et al. Protective effect of hydrogen-rich saline on spinal cord damage in rats. Pharmaceuticals. 2023;16(4). doi:10.3390/ph16040527
   Web of Science ®Google Scholar
• Ge L, Wei LH, Du CQ, et al. Hydrogen-rich saline attenuates spinal cord hemisection-induced testicular injury in rats. Oncotarget. 2017;8(26):42314–42331. doi:10.18632/oncotarget.15876
   PubMedGoogle Scholar
• Chen C, Chen Q, Mao Y, et al. Hydrogen-rich saline protects against spinal cord injury in rats. Neurochem Res. 2010;35(7):1111–1118. doi:10.1007/s11064-010-0162-y
   PubMed Web of Science ®Google Scholar
• Benjamin S, Au TY. A potential clinical application of hydrogen-rich saline in patients with traumatic brain injury. J Pediatr Surg. 2022;57(12):1032. doi:10.1016/j.jpedsurg.2022.06.007
   PubMedGoogle Scholar
• Tamura T, Suzuki M, Homma K, Sano M, Group HIS. Efficacy of inhaled hydrogen on neurological outcome following brain ischaemia during post-cardiac arrest care (HYBRID II): a multi-centre, randomised, double-blind, placebo-controlled trial. EClinicalMedicine. 2023;58:101907. doi:10.1016/j.eclinm.2023.101907
   PubMedGoogle Scholar
• 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):482–492. doi:10.2174/1567205014666171106145017
   PubMed Web of Science ®Google Scholar
• Ono H, Nishijima Y, Ohta S. Therapeutic inhalation of hydrogen gas for alzheimer’s disease patients and subsequent long-term follow-up as a disease-modifying treatment: an open label pilot study. Pharmaceuticals. 2023;16(3). doi:10.3390/ph16030434
   Web of Science ®Google Scholar
• Nagatani K, Nawashiro H, Takeuchi S, et al. Safety of intravenous administration of hydrogen-enriched fluid in patients with acute cerebral ischemia: initial clinical studies. Med Gas Res. 2013;3:13. doi:10.1186/2045-9912-3-13
   PubMedGoogle Scholar
• Yokoyama K, Sakamaki A, Takahashi K, et al. Hydrogen-producing small intestinal bacterial overgrowth is associated with hepatic encephalopathy and liver function. PLoS One. 2022;17(2):e0264459. doi:10.1371/journal.pone.0264459
   PubMed Web of Science ®Google Scholar
• Hammer HF, Fox MR, Keller J, et al. European guideline on indications, performance, and clinical impact of hydrogen and methane breath tests in adult and pediatric patients: European Association for gastroenterology, endoscopy and nutrition, European society of neurogastroenterology and motility, and European society for paediatric gastroenterology hepatology and nutrition consensus. United Eur Gastroenterol J. 2022;10(1):15–40. doi:10.1002/ueg2.12133
   PubMed Web of Science ®Google Scholar
• He J, Liu F, Xu T, et al. The role of hydrogen therapy in Alzheimer’s disease management: insights into mechanisms, administration routes, and future challenges. Biomed Pharmacother. 2023;168:115807. doi:10.1016/j.biopha.2023.115807
   PubMed Web of Science ®Google Scholar