pulmoПульмонологияPULMONOLOGIYA0869-01892541-9617Scientific and Practical Journal “PULMONOLOGIYA” LLC10.18093/0869-0189-2024-34-1-59-64pulmo-4401Research ArticleЛЕКЦИИLECTIONSМитохондрии как ключевая мишень воздействия молекулярного водородаMitochondria as a key target of molecular hydrogenhttps://orcid.org/0000-0002-4215-9963НестеровС. В.NesterovS. V.

Нестеров Семен Валерьевич – к. б. н., старший научный сотрудник Отделения биоэнергетики

123182, Москва, пл. Академика Курчатова, 1

Semen V. Nesterov, Candidate in Biology, Senior Researcher, Departmentof Bioenergetics

pl. Akademika  Kurchatova 1, Moscow, 123182

semen.v.nesterov@phystech.eduhttps://orcid.org/0000-0003-2286-4961РоговА. Г.RogovA. G.

Рогов Антон Геннадьевич – к. б. н., начальник лаборатории молекулярной биоэнергетики Отделения биоэнергетики

123182, Москва, пл. Академика Курчатова, 1

 

Anton G. Rogov, Candidate in Biology, Head of Molecular Bioenergetics Laboratory, Department of Bioenergetics

pl. Akademika  Kurchatova 1, Moscow, 123182

rogov_ag@nrcki.ruhttps://orcid.org/0000-0002-3247-3502ВасиловР. Г.VasilovR. G.

Василов Раиф Гаянович – д. б. н, профессор, заместитель руководителя по научной работе Отделения биоэнергетики

123182, Москва, пл. Академика Курчатова, 1

Raif G. Vasilov, Doctor in Biology, Professor, Deputy Head for Research,Department of Bioenergetics

pl. Akademika  Kurchatova 1, Moscow, 123182

Vasilov_RG@nrcki.ruФедеральное государственное бюджетное учреждение «Национальный исследовательский центр “Курчатовский институт”РоссияFederal State Budgetary Institution National Research Center “Kurchatov Institute”Russian Federation2024130120243415964Copyright © Нестеров С.В., Рогов А.Г., Василов Р.Г., 20242024Нестеров С.В., Рогов А.Г., Василов Р.Г.Nesterov S.V., Rogov A.G., Vasilov R.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.pulmonology.ru/pulm/article/view/4401

Целью работы явилась систематизация данных о биологически значимых эффектах молекулярного водорода для выявления механизмов его действия на организм. Проведен анализ литературных источников о действии молекулярного водорода, принимаемого в форме ингаляций, и обогащенной водородом воды на организм человека и лабораторных млекопитающих (крыс, мышей), а также модели клеточных систем в условиях in vitro. Предложен механизм, согласно которому, помимо ранее известного действия водорода по нейтрализации высокоактивных форм кислорода, существует также как минимум еще одна группа молекул, являющихся мишенью молекулярного водорода в организме, – это порфирины, входящие в состав гемопротеинов, в особенности цитохромов дыхательной цепи митохондрий. При высокой концентрации углекислоты, которая образуется в цикле трикарбоновых кислот в матриксе митохондрий, водород повреждает часть гемов в результате ковалентного присоединения к ним группы CO. При малых дозах водорода это вызывает умеренное снижение митохондриального потенциала и стимулирует адаптационный ответ организма, в т. ч. активацию фактора транскрипции Nrf2, экспрессию гемоксигеназы и ферментов антиоксидантной защиты, митофагию и обновление клеточной популяции митохондрий.

Заключение. Молекулярный водород является адаптогеном, вызывающим митохондриальный гормезис – обновление и усиление биоэнергетических и антиоксидантных систем организма.

The aim of the work was to systematize the data on the biologically significant effects of molecular hydrogen to uncover the mechanisms of its effect on the human body. The paper analyzes the literature on the effect of molecular hydrogen administered in the form of inhalation and hydrogenenriched water on the human body, on laboratory mammals (rats, mice), and on model cell systems in vitro. As a result, a mechanism has been proposed according to which, in addition to the already known effect of hydrogen in neutralizing highly reactive oxygen species, there is at least one other group of molecules that are the target of molecular hydrogen in the body. These are the porphyrins, which are part of the hemoproteins, in particularly the cytochromes of the mitochondrial respiratory chain. In the presence of high concentrations of carbon dioxide, which is formed in the tricarboxylic acid cycle in the mitochondrial matrix, hydrogen damages some of the hemes as a result of covalent binding of the CO group to them. At low doses of hydrogen, this causes a moderate decrease in mitochondrial potential and stimulates the adaptive response of the body, including activation of the transcription factor Nrf2, expression of the heme oxygenase and antioxidant defense enzymes, mitophagy, and renewal of the mitochondrial population in the cell.

Conclusion. Molecular hydrogen is an adaptogen that causes mitochondrial hormesis – the renewal and strengthening of the body’s bioenergetic and antioxidant systems.

молекулярный водородмитохондриибиоэнергетикаантиоксидантактивные формы кислородамитофагияmolecular hydrogenmitochondriabioenergeticsantioxidantreactive oxygen speciesmitophagyРабота выполнена при поддержке Федерального государственного бюджетного учреждения «Национальный исследовательский центр “Курчатовский институт”» (тематический план 1 п. 4.1 «Структурные и функциональные исследования митохондрий, разработка потенциальных терапевтических средств»)ReferencesOhsawa 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.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.Mohd Noor M.N.Z., Alauddin A.S., Wong Y.H. 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.Mohd Noor M.N.Z., Alauddin A.S., Wong Y.H. 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.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.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.Wu C., Zou P., Feng S. et al. Molecular hydrogen: an emerging therapeutic medical gas for brain disorders. Mol. Neurobiol. 2023; 60 (4):1749–1765. DOI: 10.1007/s12035-022-03175-w.Wu C., Zou P., Feng S. et al. Molecular hydrogen: an emerging therapeutic medical gas for brain disorders. Mol. Neurobiol. 2023; 60 (4):1749–1765. DOI: 10.1007/s12035-022-03175-w.Li Y., Li G., Suo L., Zhang J. Recent advances in studies of molecular hydrogen in the treatment of pancreatitis. Life Sci. 2021; 264: 118641. DOI: 10.1016/j.lfs.2020.118641.Li Y., Li G., Suo L., Zhang J. Recent advances in studies of molecular hydrogen in the treatment of pancreatitis. Life Sci. 2021; 264: 118641. DOI: 10.1016/j.lfs.2020.118641.Hong C.T., Hu C.J., Lin H.Y., Wu D. Effects of concomitant use of hydrogen water and photobiomodulation on Parkinson disease: a pilot study. Medicine (Baltimore). 2021; 100 (4): e24191. DOI: 10.1097/MD.0000000000024191.Hong C.T., Hu C.J., Lin H.Y., Wu D. Effects of concomitant use of hydrogen water and photobiomodulation on Parkinson disease: a pilot study. Medicine (Baltimore). 2021; 100 (4): e24191. DOI: 10.1097/MD.0000000000024191.Botek M., Krejčí J., Valenta M. et al. Molecular hydrogen positively affects physical and respiratory function in acute post-COVID-19 patients: a new perspective in rehabilitation. Int. J. Environ. Res. Public Health. 2022; 19 (4): 1992. DOI: 10.3390/ijerph19041992.Botek M., Krejčí J., Valenta M. et al. Molecular hydrogen positively affects physical and respiratory function in acute post-COVID-19 patients: a new perspective in rehabilitation. Int. J. Environ. Res. Public Health. 2022; 19 (4): 1992. DOI: 10.3390/ijerph19041992.Kura B., Szantova M., LeBaron T.W. et al. Biological effects of hydrogen water on subjects with NAFLD: a randomized, placebo-controlled trial. Antioxidants (Basel). 2022; 11 (10): 1935. DOI: 10.3390/antiox11101935.Kura B., Szantova M., LeBaron T.W. et al. Biological effects of hydrogen water on subjects with NAFLD: a randomized, placebo-controlled trial. Antioxidants (Basel). 2022; 11 (10): 1935. DOI: 10.3390/antiox11101935.Singh R.B., Tarnava A., Fatima G. et al. Can hydrogen water enhance oxygen saturation in patients with chronic lung disease? A non-randomized, observational pilot study. Diseases. 2023; 11 (4): 127. DOI: 10.3390/diseases11040127.Singh R.B., Tarnava A., Fatima G. et al. Can hydrogen water enhance oxygen saturation in patients with chronic lung disease? A non-randomized, observational pilot study. Diseases. 2023; 11 (4): 127. DOI: 10.3390/diseases11040127.Sumbalová Z., Kucharská J., Rausová Z. et al. The effect of adjuvant therapy with molecular hydrogen on endogenous coenzyme Q10 levels and platelet mitochondrial bioenergetics in patients with non-alcoholic fatty liver disease. Int. J. Mol. Sci. 2023; 24 (15): 12477. DOI: 10.3390/ijms241512477.Sumbalová Z., Kucharská J., Rausová Z. et al. The effect of adjuvant therapy with molecular hydrogen on endogenous coenzyme Q10 levels and platelet mitochondrial bioenergetics in patients with non-alcoholic fatty liver disease. Int. J. Mol. Sci. 2023; 24 (15): 12477. DOI: 10.3390/ijms241512477.LeBaron T.W., Larson A.J., Ohta S. et al. Acute supplementation with molecular hydrogen benefits submaximal exercise indices: randomized, double-blinded, placebo-controlled crossover pilot study. J. Lifestyle Med. 2019; 9 (1): 36–43. DOI: 10.15280/jlm.2019.9.1.36.LeBaron T.W., Larson A.J., Ohta S. et al. Acute supplementation with molecular hydrogen benefits submaximal exercise indices: randomized, double-blinded, placebo-controlled crossover pilot study. J. Lifestyle Med. 2019; 9 (1): 36–43. DOI: 10.15280/jlm.2019.9.1.36.Joli J., Buck P., Zipfel S., Stengel A. Post-COVID-19 fatigue: a systematic review. Front. Psychiatry. 2022; 13: 947973. DOI: 10.3389/fpsyt.2022.947973.Joli J., Buck P., Zipfel S., Stengel A. Post-COVID-19 fatigue: a systematic review. Front. Psychiatry. 2022; 13: 947973. DOI: 10.3389/fpsyt.2022.947973.Johnsen H.M., Filtvedt W., Hiorth M., Klaveness J. Silicon nanoparticles for oral administration of molecular hydrogen. Int. J. Pharm. 2022; 629: 122371. DOI: 10.1016/j.ijpharm.2022.122371.Johnsen H.M., Filtvedt W., Hiorth M., Klaveness J. Silicon nanoparticles for oral administration of molecular hydrogen. Int. J. Pharm. 2022; 629: 122371. DOI: 10.1016/j.ijpharm.2022.122371.Hancock J.T., Russell G. Downstream signalling from molecular hydrogen. Plants (Basel). 2021; 10 (2): 367. DOI: 10.3390/plants10020367.Hancock J.T., Russell G. Downstream signalling from molecular hydrogen. Plants (Basel). 2021; 10 (2): 367. DOI: 10.3390/plants10020367.Chen H.G., Xie K.L., Han H.Z. 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): 1060–1066. DOI: 10.1016/j.ijsu.2013.10.007.Chen H.G., Xie K.L., Han H.Z. 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): 1060–1066. DOI: 10.1016/j.ijsu.2013.10.007.Li Y., Li Q., Chen H. 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): 90–98. DOI: 10.1097/SHK.0000000000000382.Li Y., Li Q., Chen H. 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): 90–98. DOI: 10.1097/SHK.0000000000000382.Li Y., Xie K., Chen H. et al. Hydrogen gas inhibits high-mobility group box 1 release in septic mice by upregulation of heme oxygenase 1. J. Surg. Res. 2015; 196 (1): 136–148. DOI: 10.1016/j.jss.2015.02.042.Li Y., Xie K., Chen H. et al. Hydrogen gas inhibits high-mobility group box 1 release in septic mice by upregulation of heme oxygenase 1. J. Surg. Res. 2015; 196 (1): 136–148. DOI: 10.1016/j.jss.2015.02.042.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): 364–370. DOI: 10.1097/SHK.0000000000000856.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): 364–370. DOI: 10.1097/SHK.0000000000000856.Zhang Y., Dong A., Xie K., Yu Y. Protective effects of hydrogen on myocardial mitochondrial functions in septic mice. BioMed. Res. Int. 2020; 2020: 1568209. DOI: 10.1155/2020/1568209.Zhang Y., Dong A., Xie K., Yu Y. Protective effects of hydrogen on myocardial mitochondrial functions in septic mice. BioMed. Res. Int. 2020; 2020: 1568209. DOI: 10.1155/2020/1568209.Chen H., Mao X., Meng X. et al. Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy‑mediated NLRP3 inflammasome inactivation in sepsis. Int. J. Mol. Med. 2019; 44 (4): 1309–1324. DOI: 10.3892/ijmm.2019.4311.Chen H., Mao X., Meng X. et al. Hydrogen alleviates mitochondrial dysfunction and organ damage via autophagy‑mediated NLRP3 inflammasome inactivation in sepsis. Int. J. Mol. Med. 2019; 44 (4): 1309–1324. DOI: 10.3892/ijmm.2019.4311.Dumbuya J.S., Li S., Liang L. et al. Effects of hydrogen-rich saline in neuroinflammation and mitochondrial dysfunction in rat model of sepsis-associated encephalopathy. J. Transl. Med. 2022; 20 (1): 546. DOI: 10.1186/s12967-022-03746-4.Dumbuya J.S., Li S., Liang L. et al. Effects of hydrogen-rich saline in neuroinflammation and mitochondrial dysfunction in rat model of sepsis-associated encephalopathy. J. Transl. Med. 2022; 20 (1): 546. DOI: 10.1186/s12967-022-03746-4.Ren J.D., Wu X.B., Jiang R. et al. Molecular hydrogen inhibits lipopolysaccharide-triggered NLRP3 inflammasome activation in macrophages by targeting the mitochondrial reactive oxygen species. Biochim. Biophys Acta. 2016; 1863 (1): 50–55. DOI: 10.1016/j.bbamcr.2015.10.012.Ren J.D., Wu X.B., Jiang R. et al. Molecular hydrogen inhibits lipopolysaccharide-triggered NLRP3 inflammasome activation in macrophages by targeting the mitochondrial reactive oxygen species. Biochim. Biophys Acta. 2016; 1863 (1): 50–55. DOI: 10.1016/j.bbamcr.2015.10.012.Nie C., Ding X., Rong A. et al. Hydrogen gas inhalation alleviates myocardial ischemia-reperfusion injury by the inhibition of oxidative stress and NLRP3-mediated pyroptosis in rats. Life Sci. 2021; 272: 119248. DOI: 10.1016/j.lfs.2021.119248.Nie C., Ding X., Rong A. et al. Hydrogen gas inhalation alleviates myocardial ischemia-reperfusion injury by the inhibition of oxidative stress and NLRP3-mediated pyroptosis in rats. Life Sci. 2021; 272: 119248. DOI: 10.1016/j.lfs.2021.119248.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): 586–594. DOI: 10.1016/j.bbagen.2011.05.006.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): 586–594. DOI: 10.1016/j.bbagen.2011.05.006.Ostojic S.M. Targeting molecular hydrogen to mitochondria: barriers and gateways. Pharmacol. Res. 2015; 94: 51–53. DOI: 10.1016/j.phrs.2015.02.004.Ostojic S.M. Targeting molecular hydrogen to mitochondria: barriers and gateways. Pharmacol. Res. 2015; 94: 51–53. DOI: 10.1016/j.phrs.2015.02.004.Chen L.G., Zhang Y.Q., Wu Z.Z. et al. Peanut arachidin-1 enhances Nrf2-mediated protective mechanisms against TNF-α-induced ICAM-1 expression and NF-κB activation in endothelial cells. Int. J. Mol. Med. 2018; 41 (1): 541–547. DOI: 10.3892/ijmm.2017.3238.Chen L.G., Zhang Y.Q., Wu Z.Z. et al. Peanut arachidin-1 enhances Nrf2-mediated protective mechanisms against TNF-α-induced ICAM-1 expression and NF-κB activation in endothelial cells. Int. J. Mol. Med. 2018; 41 (1): 541–547. DOI: 10.3892/ijmm.2017.3238.Saha S., Buttari B., Panieri E. et al. An overview of Nrf2 signaling pathway and its role in inflammation. Molecules. 2020; 25 (22): 5474. DOI: 10.3390/molecules25225474.Saha S., Buttari B., Panieri E. et al. An overview of Nrf2 signaling pathway and its role in inflammation. Molecules. 2020; 25 (22): 5474. DOI: 10.3390/molecules25225474.Nguyen T., Nioi P., Pickett C.B. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J. Biol. Chem. 2009; 284 (20): 13291–13295. DOI: 10.1074/jbc.R900010200.Nguyen T., Nioi P., Pickett C.B. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J. Biol. Chem. 2009; 284 (20): 13291–13295. DOI: 10.1074/jbc.R900010200.Ishihara G., Kawamoto K., Komori N., Ishibashi T. Molecular hydrogen suppresses superoxide generation in the mitochondrial complex I and reduced mitochondrial membrane potential. Biochem. Biophys. Res. Commun. 2020; 522 (4): 965–970. DOI: 10.1016/j.bbrc.2019.11.135.Ishihara G., Kawamoto K., Komori N., Ishibashi T. Molecular hydrogen suppresses superoxide generation in the mitochondrial complex I and reduced mitochondrial membrane potential. Biochem. Biophys. Res. Commun. 2020; 522 (4): 965–970. DOI: 10.1016/j.bbrc.2019.11.135.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. DOI: 10.1371/journal.pone.0176992.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. DOI: 10.1371/journal.pone.0176992.Yang Y.X., Fei W.Y., Liu M.S. et al. Molecular hydrogen promotes adipose-derived stem cell myogenic differentiation via regulation of mitochondria. Curr. Stem Cell Res. Ther. 2023; 18 (6): 864–875. DOI: 10.2174/1574888X17666220926115240.Yang Y.X., Fei W.Y., Liu M.S. et al. Molecular hydrogen promotes adipose-derived stem cell myogenic differentiation via regulation of mitochondria. Curr. Stem Cell Res. Ther. 2023; 18 (6): 864–875. DOI: 10.2174/1574888X17666220926115240.Hasegawa T., Ito M., Hasegawa S. et al. Molecular hydrogen enhances proliferation of cancer cells that exhibit potent mitochondrial unfolded protein response. Int. J. Mol. Sci. 2022; 23 (5): 2888. DOI: 10.3390/ijms23052888.Hasegawa T., Ito M., Hasegawa S. et al. Molecular hydrogen enhances proliferation of cancer cells that exhibit potent mitochondrial unfolded protein response. Int. J. Mol. Sci. 2022; 23 (5): 2888. DOI: 10.3390/ijms23052888.Tran H.C., Van Aken O. Mitochondrial unfolded protein-related responses across kingdoms: similar problems, different regulators. Mitochondrion. 2020; 53: 166–177. DOI: 10.1016/j.mito.2020.05.009.Tran H.C., Van Aken O. Mitochondrial unfolded protein-related responses across kingdoms: similar problems, different regulators. Mitochondrion. 2020; 53: 166–177. DOI: 10.1016/j.mito.2020.05.009.Suárez-Rivero J.M., Pastor-Maldonado C.J., Povea-Cabello S. et al. Activation of the mitochondrial unfolded protein response: a new therapeutic target? Biomedicines. 2022; 10 (7): 1611. DOI: 10.3390/biomedicines10071611.Suárez-Rivero J.M., Pastor-Maldonado C.J., Povea-Cabello S. et al. Activation of the mitochondrial unfolded protein response: a new therapeutic target? Biomedicines. 2022; 10 (7): 1611. DOI: 10.3390/biomedicines10071611.Gvozdjáková A., Kucharská J., Kura B. et al. A new insight into the molecular hydrogen effect on coenzyme Q and mitochondrial function of rats. Can. J. Physiol. Pharmacol. 2020; 98 (1): 29–34. DOI: 10.1139/cjpp-2019-0281.Gvozdjáková A., Kucharská J., Kura B. et al. A new insight into the molecular hydrogen effect on coenzyme Q and mitochondrial function of rats. Can. J. Physiol. Pharmacol. 2020; 98 (1): 29–34. DOI: 10.1139/cjpp-2019-0281.Jin Z., Zhao P., Gong W. et al. Fe-porphyrin: a redox-related biosensor of hydrogen molecule. Nano Res. 2023; 16 (2): 2020–2025. DOI: 10.1007/s12274-022-4860-y.Jin Z., Zhao P., Gong W. et al. Fe-porphyrin: a redox-related biosensor of hydrogen molecule. Nano Res. 2023; 16 (2): 2020–2025. DOI: 10.1007/s12274-022-4860-y.Zheng X., Chen W., Gong F. et al. The Role and Mechanism of pyroptosis and potential therapeutic targets in sepsis: a review. Front. Immunol. 2021; 12: 711939. DOI: 10.3389/fimmu.2021.711939.Zheng X., Chen W., Gong F. et al. The Role and Mechanism of pyroptosis and potential therapeutic targets in sepsis: a review. Front. Immunol. 2021; 12: 711939. DOI: 10.3389/fimmu.2021.711939.Нестеров С.В., Ягужинский Л.С., Подопригора Г.И., Нарциссов Я.Р. Автокаталитический цикл в патогенезе сахарного диабета: биохимические и патофизиологические аспекты метаболической терапии с помощью натуральных аминокислот на примере глицина. Сахарный диабет. 2018; 21 (4): 283–292. DOI: 10.14341/DM9529.Nesterov S.V., Yaguzhinsky L.S., Podoprigora G.I., Nartsissov Ya.R. [Autocatalytic cycle in the pathogenesis of diabetes mellitus: biochemical and pathophysiological aspects of metabolic therapy with natural amino acids on the example of glycine]. Sakharnyy diabet. 2018; 21 (4): 283–292. DOI: 10.14341/DM9529 (in Russian).Wang B., Cao W., Biswal S., Doré S. Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia. Stroke. 2011; 42 (9): 2605–2610. DOI: 10.1161/STROKEAHA.110.607101.Wang B., Cao W., Biswal S., Doré S. Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia. Stroke. 2011; 42 (9): 2605–2610. DOI: 10.1161/STROKEAHA.110.607101.Cavicchioli F., Cesarotti I.M., Fangman M. et al. Carbon monoxide therapy using hybrid carbon monoxide-releasing/Nrf2-inducing molecules through a neuroprotective lens. Chemistry. 2021; 3 (3): 800–817. DOI: 10.3390/chemistry3030057.Cavicchioli F., Cesarotti I.M., Fangman M. et al. Carbon monoxide therapy using hybrid carbon monoxide-releasing/Nrf2-inducing molecules through a neuroprotective lens. Chemistry. 2021; 3 (3): 800–817. DOI: 10.3390/chemistry3030057.Назаров Е.И., Мами Н., Хлусов И.А., Панов С.А. Принципы изменения гормонального статуса пациентки при реабилитации медицинскими газами. Актуальные проблемы теоретической и клинической медицины. 2023; (3): 40–53. DOI: 10.5281/zenodo.8392145.Nazarov E.I., Mami N., Panov S.A. [Principles of changing the patient’s hormonal status in rehabilitation with medical gases]. Aktual'nye problemy teoreticheskoy i klinicheskoy meditsiny. 2023; (3): 40–53. DOI: 10.5281/zenodo.8392145 (in Russian).Matsumoto A., Yamafuji M., Tachibana T. et al. Oral “hydrogen water” induces neuroprotective ghrelin secretion in mice. Sci. Rep. 2013; 3: 3273. DOI: 10.1038/srep03273.Matsumoto A., Yamafuji M., Tachibana T. et al. Oral “hydrogen water” induces neuroprotective ghrelin secretion in mice. Sci. Rep. 2013; 3: 3273. DOI: 10.1038/srep03273.Ostojic S.M. Does H2 alter mitochondrial bioenergetics via GHS-R1α activation? Theranostics. 2017; 7 (5): 1330–1332. DOI: 10.7150/thno.18745.Ostojic S.M. Does H2 alter mitochondrial bioenergetics via GHS-R1α activation? Theranostics. 2017; 7 (5): 1330–1332. DOI: 10.7150/thno.18745.Логинова О.А., Орлова.Е.Г., Ширшев С.В. Физиологические эффекты грелина. Вестник Пермского университета. Серия Биология. 2018; (4): 443–453. Доступно на: https://press.psu.ru/index.php/bio/article/view/2773Loginova O.A., Orlova.E.G., Shirshev S.V. [Physiological effects of ghrelin]. Vestnik Permskogo universiteta. Seriya Biologiya. 2018; (4): 443–453. Available at: https://press.psu.ru/index.php/bio/article/view/2773 (in Russian).Васюкова О.В., Витебская А.В. Грелин: биологическое значение и перспективы применения в эндокринологии. Проблемы Эндокринологии. 2006; 52 (2): 3–7. DOI: 10.14341/probl20065223-7.Vasyukova О.V., Vitebskaya A.V. [Grelin: biological significance and prospects for use in endocrinology]. Problemy Endokrinologii. 2006; 52 (2): 3–7. DOI: 10.14341/probl20065223-7 (in Russian).Xiao W., Loscalzo J. Metabolic responses to reductive stress. Antioxid. Redox Signal. 2020; 32 (18): 1330–1347. DOI: 10.1089/ars.2019.7803.Xiao W., Loscalzo J. Metabolic responses to reductive stress. Antioxid. Redox Signal. 2020; 32 (18): 1330–1347. DOI: 10.1089/ars.2019.7803.Zhang X., Min X., Li C. et al. Involvement of reductive stress in the cardiomyopathy in transgenic mice with cardiac-specific overexpression of heat shock protein 27. Hypertension. 2010; 55 (6): 1412–1427. DOI: 10.1161/hypertensionaha.109.147066.Zhang X., Min X., Li C. et al. Involvement of reductive stress in the cardiomyopathy in transgenic mice with cardiac-specific overexpression of heat shock protein 27. Hypertension. 2010; 55 (6): 1412–1427. DOI: 10.1161/hypertensionaha.109.147066.Lu L.Y., Ou N., Lu Q.B. Antioxidant Induces DNA damage, cell death and mutagenicity in human lung and skin normal cells. Sci. Rep. 2013; 3: 3169. DOI: 10.1038/srep03169.Lu L.Y., Ou N., Lu Q.B. Antioxidant Induces DNA damage, cell death and mutagenicity in human lung and skin normal cells. Sci. Rep. 2013; 3: 3169. DOI: 10.1038/srep03169.Ducrocq C., Blanchard B., Pignatelli B., Ohshima H. Peroxynitrite: an endogenous oxidizing and nitrating agent. Cell. Mol. Life Sci. 1999; 55 (9): 1068–1077. DOI: 10.1007/s000180050357.Ducrocq C., Blanchard B., Pignatelli B., Ohshima H. Peroxynitrite: an endogenous oxidizing and nitrating agent. Cell. Mol. Life Sci. 1999; 55 (9): 1068–1077. DOI: 10.1007/s000180050357.

The authors declare that there are no conflicts of interest present.