Russian Journal of Biological Physics and Chemisrty Russian Journal of Biological Physics and Chemisrty АКТУАЛЬНЫЕ ВОПРОСЫ БИОЛОГИЧЕСКОЙ ФИЗИКИ И ХИМИИ 2499-9962 54404 МЕДИЦИНСКАЯ БИОФИЗИКА И БИОФИЗИЧЕСКАЯ ХИМИЯ MEDICAL BIOPHYSICS AND BIOPHYSICAL CHEMISTRY МЕДИЦИНСКАЯ БИОФИЗИКА И БИОФИЗИЧЕСКАЯ ХИМИЯ THE ROLE OF MITOCHONDRIA-TARGETED ANTIOXIDANT SkQ1 IN REGULATION OF SIGNAL SYSTEM KEAP1/Nrf2/ARE AND APOPTOSIS IN THE BRAIN UNDER OXIDATIVE STRESS РОЛЬ МИТОХОНДРИАЛЬНО-НАПРАВЛЕННОГО АНТИОКСИДАНТА SkQ1 В РЕГУЛЯЦИИ СИГНАЛЬНОЙ СИСТЕМЫ KEAP1/Nrf2/ARE И АПОПТОЗА В ГОЛОВНОМ МОЗГЕ ПРИ ОКИСЛИТЕЛЬНОМ СТРЕССЕ Внуков В. В. Vnukov V. V. Гуценко О. И. Gutsenko O. I. Милютина Н. П. Milutina N. P. natmilut@rambler.ru Ананян А. А. Ananyan A. A. Корниенко И. В. Kornienko I. V. Плотников А А Plotnikov A A Южный федеральный университет Ростов-на-Дону Россия Southern Federal University Rostov-on-Don Russian Federation Южный федеральный университет Ростов-на-Дону Россия Southern Federal University Rostov-on-Don Russian Federation Южный федеральный университет Ростов-на-Дону Россия Southern Federal University Rostov-on-Don Russian Federation Южный федеральный университет Rostov-on-Don Россия Southern Federal University Rostov-on-Don Russian Federation Южный федеральный университет Ростов-на-Дону Россия Southern Federal University Rostov-on-Don Russian Federation Южный федеральный университет, Академия биологии и биотехнологии им. Д.И. Ивановского ru Southern Federal University, Academy of Biology and Biotechnology ru 25 03 2019 25 03 2019 4 1 94 101 20 03 2019 20 03 2019 https://rusjbpc.ru/en/nauka/article/54404/view

В работе исследовано влияние митохондриально-направленного антиоксиданта SkQ1 на уровень экспрессии гена фактора транскрипции Nrf2, Nrf2-зависимых генов антиоксидантных ферментов, гена CASP3 и активность ферментов, кодируемых исследуемыми генами, в коре больших полушарий мозга крыс при окислительном стрессе, индуцированном гипербарооксигенацией (ГБО). Установлено, что в физиологических условиях введение SkQ1 в дозе 50 нмоль/кг в течение 5 дней приводит к значительному повышению уровня мРНК фактора транскрипции Nrf2 и Nrf2-индуцируемых генов антиоксидантных ферментов SOD1, SOD2, CAT, GPx4 на фоне базального уровня экспрессии гена CАSP3 в коре больших полушарий мозга крыс. При этом наблюдается активация антиоксидантных ферментов - супероксиддисмутазы (SOD), каталазы (CAT), глутатионпероксидазы (GPx), глутатион-S-трансферазы (GST) и повышение концентрации восстановленного глутатиона (GSH), активность каспазы-3 не изменяется. При ГБО-индуцированном окислительном стрессе (0,5 МПа, 90 мин) отмечено снижение уровня мРНК фактора транскрипции Nrf2, значительное повышение экспрессии гена CASP3, тогда как не выявлено достоверных различий в транскрипционной активности Nrf2-регулируемых генов антиоксидантных ферментов ( SOD1-3 , CAT , GРx4 ) в коре больших полушарий мозга крыс. В условиях гипероксии наблюдается повышение интенсивности перекисного окисления липидов (ПОЛ) на фоне ингибирования CAT и умеренной активации GST, сохранения стационарного уровня активности SOD и GРx и существенной активации каспазы-3 в больших полушариях мозга крыс. Предварительное применение SkQ1 перед сеансом ГБО приводит к повышению уровня мРНК фактора транскрипции Nrf2 и Nrf2-регулируемых генов антиоксидантных ферментов SOD1-2, CAT и GРx4 и поддержанию базального уровня экспрессии гена CASP3 в коре больших полушарий мозга при окислительном стрессе. Одновременно наблюдается увеличение активности антиоксидантных ферментов, содержания восстановленного глутатиона и поддержание близкой к норме активности каспазы-3. Предполагается, что защитный эффект SkQ1 в условиях ГБО-индуцированного окислительного стресса может реализоваться посредством прямого антиоксидантного действия, а также путем стимуляции редокс-зависимой сигнальной системы Keap1/Nrf2/ARE и активации антиапоптотических механизмов.

The administration of SkQ1 (50 nmol/kg for 5 days) significantly increased mRNA level of transcription factor Nrf2 and Nrf2-controlled genes encoding antioxidant enzymes SOD1 , SOD2 , and CAT with inconsiderable changes in mRNA level of SOD3 and GPx4 in the cerebral cortex of rat brain. This was accompanied by the activation of antioxidant enzymes (SOD, CAT, GPx, GST) and increase in reduced glutathione level. Hyperoxia-induced oxidative stress (0.5 Pa for 90 min) decreased the mRNA level of transcription factor Nrf2; the changes in transcriptional activity of Nrf2-induced genes encoding antioxidant enzymes ( SOD1-3 , CAT , GPx4 ) were insignificant in rat cerebral cortex. Hyperoxia resulted in increased lipid peroxidation intensity, inhibition of CAT, and increase in GST activity, and maintenance of stationery level of SOD and GPx activity in rat cerebral cortex. Pretreatment with SkQ1 before hyperoxic exposure lead to increase in mRNA level of transcription factor Nrf2 and Nrf2-induced genes encoding antioxidant enzymes SOD1-2 , CAT , and GPx4 ; SOD3 expression was unchanged in the cerebral cortex under oxidative stress. The activity of these antioxidant enzymes (SOD, CAT, GPx, GST) and reduced glutathione level were concurrently increased. The effect of the mitochondria-targeted antioxidant SkQ1 on the level of expression of the CASP3 gene and the caspase-3 activity in the cortex of the cerebral hemispheres was studied in normal conditions and in HBO-induced oxidative stress. It was found that under physiological conditions the applying of SkQ1 (50 nmol/kg, 5 days) does not lead to a change in the expression of the CASP3 gene and caspase-3 activity in the cells of the cerebral cortex. In HBO-induced oxidative stress (0.5 MPa, 90 min), a significant increase in the mRNA level of the CASP3 gene and caspase-3 activity in the cortex of the cerebral hemispheres was revealed. The preliminary applying of SkQ1 before the HBO session promotes maintaining the basal level of expression of the CASP3 gene and the activity of the enzyme in the cells of the cerebral cortex and also leads to the normalization of caspase-3 activity. We suggest that the protective effect of SkQ1 under hyperoxia-induced oxidative stress may be realized via direct antioxidant activity, the activation of defense system Keap1/Nrf2/ARE and stimulation of antiapoptotic mechanisms.

 окислительный стресс гипероксия митохондриально-направленный антиокcидант головной мозг экспрессия генов антиоксидантные ферменты каспаза -3 oxidative stress hyperoxia mitochondria-targeted antioxidant brain gene expression antioxidant enzymes caspase-3

Suzuki T., Yamamoto M. Molecular basis of the Keap1-Nrf2 system, Free Radic. Biol. Med., 2015, vol. 88, no. 6. DOI: 10.1016/j.freeradbiomed. Suzuki T., Yamamoto M. Molecular basis of the Keap1-Nrf2 system, Free Radic. Biol. Med., 2015, vol. 88, no. 6. DOI: 10.1016/j.freeradbiomed. Holmström K.M., Baird L., Zhang Y., Hargreaves I., Chalasani A., Land J.M., Stanyer L., Yamamoto M., Dinkova-Kostova A.T. Abramov A.Y. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biology Open, 2013, vol. 2, no. 8, DOI: 10.1242/bio.20134853. Holmström K.M., Baird L., Zhang Y., Hargreaves I., Chalasani A., Land J.M., Stanyer L., Yamamoto M., Dinkova-Kostova A.T. Abramov A.Y. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biology Open, 2013, vol. 2, no. 8, DOI: 10.1242/bio.20134853. Tebay L.E., Robertson H., Durant S.T., Vitale S.R., Penning T.M., Dinkova-Kostova A.T., Haye J.D. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic. Biol. Med., 2015, vol. 88, pt. B, DOI: 10.1016/j.freeradbiomed. Tebay L.E., Robertson H., Durant S.T., Vitale S.R., Penning T.M., Dinkova-Kostova A.T., Haye J.D. Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic. Biol. Med., 2015, vol. 88, pt. B, DOI: 10.1016/j.freeradbiomed. Sinha K., Das, J., Pal P.B., Sil P.C. Oxidative stress: the mitochondria_dependent and mitochondria-independent pathways of apoptosis, Arch. Toxicol., 2013, vol. 87, no. 7, DOI: 10.1007/s00204-013-1034-4 Sinha K., Das, J., Pal P.B., Sil P.C. Oxidative stress: the mitochondria_dependent and mitochondria-independent pathways of apoptosis, Arch. Toxicol., 2013, vol. 87, no. 7, DOI: 10.1007/s00204-013-1034-4 Redza-Dutordoir M., Averill_Bates D.A. Activation of apoptosis signalling pathways by reactive oxygen species, Biochim. Biophys. Acta, 2016, vol. 1863, no. 12, DOI: 10.1016/j.bbamcr. Redza-Dutordoir M., Averill_Bates D.A. Activation of apoptosis signalling pathways by reactive oxygen species, Biochim. Biophys. Acta, 2016, vol. 1863, no. 12, DOI: 10.1016/j.bbamcr. Gore A., Muralidhar M., Espey M.G., Degenhardt K., Mantell L.L. Hyperoxia sensing: from molecular mechanisms to significance in disease, J. Immunotoxicol., 2010, vol. 7, no. 4, DOI: 10.3109/1547691X.2010.492254 Gore A., Muralidhar M., Espey M.G., Degenhardt K., Mantell L.L. Hyperoxia sensing: from molecular mechanisms to significance in disease, J. Immunotoxicol., 2010, vol. 7, no. 4, DOI: 10.3109/1547691X.2010.492254 Лукаш А.И., Внуков В.В., Ананян A.A., Милютина Н.П., Кваша П.Н. Металлосодержащие соединения плазмы крови при гипербарической оксигенации. (Экспериментальные и клинические аспекты), Ростов-на-Дону: Изд-во РГУ, 1996, 107 с. [Lukash A.I., Vnukov V.V., Ananyan A.A., Milyutina N.P., Kvasha P.N. Metal-containing compounds of blood plasma during hyperbaric oxygenation. (Experimental and clinical aspects), Rostov-on-Don: RSU, 1996, 107 p. (In Russ.)] Lukash A.I., Vnukov V.V., Ananyan A.A., Milyutina N.P., Kvasha P.N. Metallosoderzhaschie soedineniya plazmy krovi pri giperbaricheskoy oksigenacii. (Eksperimental'nye i klinicheskie aspekty), Rostov-na-Donu: Izd-vo RGU, 1996, 107 s. [Lukash A.I., Vnukov V.V., Ananyan A.A., Milyutina N.P., Kvasha P.N. Metal-containing compounds of blood plasma during hyperbaric oxygenation. (Experimental and clinical aspects), Rostov-on-Don: RSU, 1996, 107 p. (In Russ.)] Chistyakov V.A., Serezhenkov V.A., Alexandrova A.A., Milyutina N.P., Prokof’ev V.N., Mashkina E.V., Gutnikova L.V., Dem’yanenko S.V. Effect of plastoquinone derivative 10-(6’-plastoquinonyl) decyltriphenylphosphonium (SkQ1) on contents of steroid hormones and NO level in rats, Biochemistry (Moscow), 2010, vol. 75, no. 11. DOI: 10.1134/S0006297911060150. Chistyakov V.A., Serezhenkov V.A., Alexandrova A.A., Milyutina N.P., Prokof’ev V.N., Mashkina E.V., Gutnikova L.V., Dem’yanenko S.V. Effect of plastoquinone derivative 10-(6’-plastoquinonyl) decyltriphenylphosphonium (SkQ1) on contents of steroid hormones and NO level in rats, Biochemistry (Moscow), 2010, vol. 75, no. 11. DOI: 10.1134/S0006297911060150. Сирота Т.В. Новый подход в исследовании процесса аутоокисления адреналина и использования его для измерения активности супероксиддисмутазы. Вопр. мед. химии, 1999, т. 45, c. 14-15. [Sirota T.V. New approach to investigation of autooxidation of adrenaline and its use for change of superoxide dismutase. Vopr. Med. Khim., 1999, vol. 45, pp. 14-15. (In Russ.)] Sirota T.V. Novyy podhod v issledovanii processa autookisleniya adrenalina i ispol'zovaniya ego dlya izmereniya aktivnosti superoksiddismutazy. Vopr. med. himii, 1999, t. 45, c. 14-15. [Sirota T.V. New approach to investigation of autooxidation of adrenaline and its use for change of superoxide dismutase. Vopr. Med. Khim., 1999, vol. 45, pp. 14-15. (In Russ.)] Королюк М.А., Иванова Л.И., Майорова И.Г., Токарев В.Е. Метод определения активности каталазы. Лаб. дело, 1988, № 1, с. 16-19. [Korolyuk M.A., Ivanova L.I., Maiorova I.G., Tokarev V.E. A method for determination of сatalase activity, Lab. Delo, 1988, no. 1, pp. 16-19. (In Russ.)] Korolyuk M.A., Ivanova L.I., Mayorova I.G., Tokarev V.E. Metod opredeleniya aktivnosti katalazy. Lab. delo, 1988, № 1, s. 16-19. [Korolyuk M.A., Ivanova L.I., Maiorova I.G., Tokarev V.E. A method for determination of satalase activity, Lab. Delo, 1988, no. 1, pp. 16-19. (In Russ.)] Арутюнян А.В., Дубинина Е.Е., Зыбина Н.Н. Методы оценки свободнорадикального окисления и антиоксидантной системы организма. Методические рекомендации. СПб: ИКФ «Фолиант», 2000, 104 с. [Arutyunyan A.V., Dubinina E.E., Zybina N.N. Metodi otsenki svobodnoradikalnogo okislenia i antioksidantnoi sistemi organizma. Metodicheskie recomendatsii (Methods for assessing free radical oxidation and the body's antioxidant system. Guidelines), SPb: IKF "Foliant", 2000, 104 p. (In Russ.)] Arutyunyan A.V., Dubinina E.E., Zybina N.N. Metody ocenki svobodnoradikal'nogo okisleniya i antioksidantnoy sistemy organizma. Metodicheskie rekomendacii. SPb: IKF «Foliant», 2000, 104 s. [Arutyunyan A.V., Dubinina E.E., Zybina N.N. Metodi otsenki svobodnoradikalnogo okislenia i antioksidantnoi sistemi organizma. Metodicheskie recomendatsii (Methods for assessing free radical oxidation and the body's antioxidant system. Guidelines), SPb: IKF "Foliant", 2000, 104 p. (In Russ.)] Стальная И.Д. Метод определения диеновой конъюгации ненасыщенных высших жирных кислот. Современные методы в биохимии (под ред. В.Н. Ореховича), М.: Медицина, 1977, с. 63-64. [Stalnaya I.D. Method for determination of diene conjugation of unsaturated higher fatty acids. Modern methods in biochemistry (V.N. Orechovich, ed.), M.: Medcine, 1977, pp.63-64. (In Russ.)] Stal'naya I.D. Metod opredeleniya dienovoy kon'yugacii nenasyschennyh vysshih zhirnyh kislot. Sovremennye metody v biohimii (pod red. V.N. Orehovicha), M.: Medicina, 1977, s. 63-64. [Stalnaya I.D. Method for determination of diene conjugation of unsaturated higher fatty acids. Modern methods in biochemistry (V.N. Orechovich, ed.), M.: Medcine, 1977, pp.63-64. (In Russ.)] Стальная И.Д., Гаришвили Т.Г. Метод определения малонового диальдегида с помощью тиобарбитуровой кислоты. Современные методы в биохимии (под ред. В.Н. Ореховича), M.: Медицина, 1977, с. 66-68. [Stalnaya I.D., Garishvily T.G. Method for the determination of malonic dialdehyde using thiobarbituric acid. Modern methods in biochemistry (V.N. Orechovich, ed.), M.: Medcine, 1977, pp. 66-68. (In Russ.)] Stal'naya I.D., Garishvili T.G. Metod opredeleniya malonovogo dial'degida s pomosch'yu tiobarbiturovoy kisloty. Sovremennye metody v biohimii (pod red. V.N. Orehovicha), M.: Medicina, 1977, s. 66-68. [Stalnaya I.D., Garishvily T.G. Method for the determination of malonic dialdehyde using thiobarbituric acid. Modern methods in biochemistry (V.N. Orechovich, ed.), M.: Medcine, 1977, pp. 66-68. (In Russ.)] Bidlack, W.R., Tappel, A.T. Fluorescent products of phospholipids during lipid peroxidation. Lipids, 1973, vol. 8, no. 4. DOI: 10.1007/BF02544636. Bidlack, W.R., Tappel, A.T. Fluorescent products of phospholipids during lipid peroxidation. Lipids, 1973, vol. 8, no. 4. DOI: 10.1007/BF02544636. Bligh, E., Dyer, W. Rapid method of lipids extraction and purification. Can. J. Biochem. Physiol., 1959, vol. 37, no. 8. DOI: 10.1139/o59-099. Bligh, E., Dyer, W. Rapid method of lipids extraction and purification. Can. J. Biochem. Physiol., 1959, vol. 37, no. 8. DOI: 10.1139/o59-099. Vnukov V.V., Gutsenko O.I., Milyutina N.P., Ananyan A.A., Danilenko A.O., Panina S.B., Kornienko I.V. Influence of SkQ1 on Expression of Nrf2 Transcription Factor Gene, ARE-Controlled Genes of Antioxidant Enzymes and Their Activity in Rat Blood Leukocytes. Biochemistry (Moscow), 2015, vol. 80, no. 5. DOI: 10.1134/S0006297915050107. Vnukov V.V., Gutsenko O.I., Milyutina N.P., Ananyan A.A., Danilenko A.O., Panina S.B., Kornienko I.V. Influence of SkQ1 on Expression of Nrf2 Transcription Factor Gene, ARE-Controlled Genes of Antioxidant Enzymes and Their Activity in Rat Blood Leukocytes. Biochemistry (Moscow), 2015, vol. 80, no. 5. DOI: 10.1134/S0006297915050107. Vnukov V.V., Gutsenko O.I., Milyutina N.P., Kornienko I.V., Ananyan A.A., Danilenko A.O., Panina S.B., Plotnikov A.A., Makarenko M.S. Influence of SkQ1 on Expression of Nrf2 Gene, ARE-Controlled Genes of Antioxidant Enzymes and Their Activity in Rat Blood Leukocytes under Oxidative Stress. Biochemistry (Moscow), 2015, vol. 80. no.12, DOI: 10.1134/S0006297915120081. Vnukov V.V., Gutsenko O.I., Milyutina N.P., Kornienko I.V., Ananyan A.A., Danilenko A.O., Panina S.B., Plotnikov A.A., Makarenko M.S. Influence of SkQ1 on Expression of Nrf2 Gene, ARE-Controlled Genes of Antioxidant Enzymes and Their Activity in Rat Blood Leukocytes under Oxidative Stress. Biochemistry (Moscow), 2015, vol. 80. no.12, DOI: 10.1134/S0006297915120081. Forman H.J., Davies K.J.A., Ursini F. How do nutritional antioxidants really work: Nucleophilic tone and parahormesis versus free radical scavenging in vivo. Free Radic. Biol. Med., 2014, vol. 66, SI. DOI: 10.1016/j.freeradbiomed.2013.05.045. Forman H.J., Davies K.J.A., Ursini F. How do nutritional antioxidants really work: Nucleophilic tone and parahormesis versus free radical scavenging in vivo. Free Radic. Biol. Med., 2014, vol. 66, SI. DOI: 10.1016/j.freeradbiomed.2013.05.045. Antonenko Y.N., Avetisyan A.V., Bakeeva L.E., Chernyak B.V., Chertkov V.A., Domnina L.V., Ivanova O.Y., Izyumov D.S., Khailova L.S., Klishin S.S., Korshunova G.A., Lyamzaev K.G., Muntyan M.S., Nepryakhina O.K., Pashkovskaya A.A., Pletjushkina O.Y., Pustovidko A.V., Roginsky V.A., Rokitskaya T.I., Ruuge E.K., Saprunova V.B., Severina I.I., Simonyan R.A., Skulachev I.V., Skulachev M.V., Sumbatyan N.V., Sviryaeva I.V., Tashlitsky V.N., Vassiliev J.M., Vyssokikh M.Y., Yaguzhinsky L.S., Zamyatnin A.A., Jr., Skulachev V.P. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies. Biochemistry (Moscow), 2008, vol. 73, no. 12, DOI: 10.1134/S0006297908120018. Antonenko Y.N., Avetisyan A.V., Bakeeva L.E., Chernyak B.V., Chertkov V.A., Domnina L.V., Ivanova O.Y., Izyumov D.S., Khailova L.S., Klishin S.S., Korshunova G.A., Lyamzaev K.G., Muntyan M.S., Nepryakhina O.K., Pashkovskaya A.A., Pletjushkina O.Y., Pustovidko A.V., Roginsky V.A., Rokitskaya T.I., Ruuge E.K., Saprunova V.B., Severina I.I., Simonyan R.A., Skulachev I.V., Skulachev M.V., Sumbatyan N.V., Sviryaeva I.V., Tashlitsky V.N., Vassiliev J.M., Vyssokikh M.Y., Yaguzhinsky L.S., Zamyatnin A.A., Jr., Skulachev V.P. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies. Biochemistry (Moscow), 2008, vol. 73, no. 12, DOI: 10.1134/S0006297908120018. Kwak M.K., Itoh K., Yamamoto M., Kensler T.W. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol.Cell Biol., 2002, vol. 22, no. 9, DOI: 10.1128/mcb.22.9.2883-2892.2002. Kwak M.K., Itoh K., Yamamoto M., Kensler T.W. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol.Cell Biol., 2002, vol. 22, no. 9, DOI: 10.1128/mcb.22.9.2883-2892.2002. Harder В., Jiang Т., Wu Т., Tao S., Rojo de la Vega M., Tian W., Chapman E., Zhang D.D. Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention. Biochem. Soc. Trans., 2015, vol. 43, no. 4, DOI: 10.1042/BST20150020. Harder V., Jiang T., Wu T., Tao S., Rojo de la Vega M., Tian W., Chapman E., Zhang D.D. Molecular mechanisms of Nrf2 regulation and how these influence chemical modulation for disease intervention. Biochem. Soc. Trans., 2015, vol. 43, no. 4, DOI: 10.1042/BST20150020. Bryan H.K., Olayanju A., Goldring C.E., Park B.K. The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem.Pharmacol., 2013, vol. 85, no. 4, DOI: 10.1042/BST20150020. Bryan H.K., Olayanju A., Goldring C.E., Park B.K. The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem.Pharmacol., 2013, vol. 85, no. 4, DOI: 10.1042/BST20150020. Sandberg M., Patil J., D’Angelo B., Weber S.G., Mallard C. NRF2-regulation in brain health and disease: Implication of cerebral inflammation, Neuropharmacology, 2014, vol. 79, SI, DOI: 10.1016/j.neuropharm.2013.11.004 Sandberg M., Patil J., D’Angelo B., Weber S.G., Mallard C. NRF2-regulation in brain health and disease: Implication of cerebral inflammation, Neuropharmacology, 2014, vol. 79, SI, DOI: 10.1016/j.neuropharm.2013.11.004 Сho H.-Y., Jedlicka A.E., Reddy S.P., Zhang L.Y., Kensler T.W., Kleeberger S.R. Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Am. J. Respir. Cell Mol. Biol., 2002, vol. 26, no. 1, DOI: 10.1165/ajrcmb.26.1.4536. Sho H.-Y., Jedlicka A.E., Reddy S.P., Zhang L.Y., Kensler T.W., Kleeberger S.R. Linkage analysis of susceptibility to hyperoxia. Nrf2 is a candidate gene. Am. J. Respir. Cell Mol. Biol., 2002, vol. 26, no. 1, DOI: 10.1165/ajrcmb.26.1.4536. Reddy S.P. The antioxidant response element and oxidative stress modifiers in airway diseases. Curr. Mol. Med., 2008, vol. 8, no. 5. Reddy S.P. The antioxidant response element and oxidative stress modifiers in airway diseases. Curr. Mol. Med., 2008, vol. 8, no. 5. Saric A., Sobocanec S., Safranko Z.M., Hadzija M.P., Bagaric R., Farkas V., Svarc A., Marotti T., Balog T. Diminished resistance to hyperoxia in brains of reproductively senescent female CBA/H mice. Med. Sci. Monit. Basic Res., 2015, vol. 21, no. 9. DOI: 10.12659/MSMBR.895356. Saric A., Sobocanec S., Safranko Z.M., Hadzija M.P., Bagaric R., Farkas V., Svarc A., Marotti T., Balog T. Diminished resistance to hyperoxia in brains of reproductively senescent female CBA/H mice. Med. Sci. Monit. Basic Res., 2015, vol. 21, no. 9. DOI: 10.12659/MSMBR.895356. Parrish A.B., Freel C.D., Kornbluth S. Cellular mechanisms controlling caspase activation and function. Cold Spring Harb. Perspect. Biol., 2013, vol. 5, no. 6. DOI: 10.1101/cshperspect.a008672. Parrish A.B., Freel C.D., Kornbluth S. Cellular mechanisms controlling caspase activation and function. Cold Spring Harb. Perspect. Biol., 2013, vol. 5, no. 6. DOI: 10.1101/cshperspect.a008672. Liu W., Wang G., Yakovlev F.G. Identification and functional analysis of the rat caspase-3 gene promoter. J. Biol. Chem., 2002, vol. 277, no. 10, DOI: 10.1074/jbc.M110768200. Liu W., Wang G., Yakovlev F.G. Identification and functional analysis of the rat caspase-3 gene promoter. J. Biol. Chem., 2002, vol. 277, no. 10, DOI: 10.1074/jbc.M110768200. Song B., Xie B., Wang C., Li M. Caspase-3 is a target gene of c-Jun: ATF2 heterodimers during apoptosis induced by activity deprivation in cerebellar granule neurons. Neurosci. Lett., 2011, vol. 505, no. 2. DOI: 10.1016/j.neulet.2011.09.060. Song B., Xie B., Wang C., Li M. Caspase-3 is a target gene of c-Jun: ATF2 heterodimers during apoptosis induced by activity deprivation in cerebellar granule neurons. Neurosci. Lett., 2011, vol. 505, no. 2. DOI: 10.1016/j.neulet.2011.09.060. Terraneo L., Samaja M. Comparative response of brain to chronic hypoxia and hyperoxia. Int. J. Mol. Sci., 2017, vol. 18, no. 9. DOI: 10.3390/ijms18091914. Terraneo L., Samaja M. Comparative response of brain to chronic hypoxia and hyperoxia. Int. J. Mol. Sci., 2017, vol. 18, no. 9. DOI: 10.3390/ijms18091914. Niture S.K., Jaiswal A.K. Nrf2 protein upregulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J. Biol. Chem., 2012, vol. 287, no. 13. DOI: 10.1074/jbc.M111.312694. Niture S.K., Jaiswal A.K. Nrf2 protein upregulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J. Biol. Chem., 2012, vol. 287, no. 13. DOI: 10.1074/jbc.M111.312694. Zhang L., Wang K., Lei Y., Li Q., Nice E.C., Huang C. Redox signaling: Potential arbitrator of autophagy and apoptosis in therapeutic response. Free Radic. Biol. Med., 2015, vol. 89, no. 12. DOI: 10.1016/j.freeradbiomed. Zhang L., Wang K., Lei Y., Li Q., Nice E.C., Huang C. Redox signaling: Potential arbitrator of autophagy and apoptosis in therapeutic response. Free Radic. Biol. Med., 2015, vol. 89, no. 12. DOI: 10.1016/j.freeradbiomed. Liang H., Ran Q., Jang Y.C., Holstein D., Lechleiter J., McDonald-Marsh T., Musatov A., Song W., Van Remmen H., Richardson A. Glutathione peroxidase 4 differentially regulates the release of apoptogenic proteins from mitochondria. Free Radic. Biol. Med., 2009, vol. 47, no. 3. DOI: 10.1016/j.freeradbiomed. Liang H., Ran Q., Jang Y.C., Holstein D., Lechleiter J., McDonald-Marsh T., Musatov A., Song W., Van Remmen H., Richardson A. Glutathione peroxidase 4 differentially regulates the release of apoptogenic proteins from mitochondria. Free Radic. Biol. Med., 2009, vol. 47, no. 3. DOI: 10.1016/j.freeradbiomed. Yoo S.-E., Chen L., Na R., Liu Y., Rios C., Van Remmen H., Richardson A., Ran Q. Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic. Biol. Med., 2012, vol. 52, no. 9, DOI: 10.1016/j.freeradbiomed. Yoo S.-E., Chen L., Na R., Liu Y., Rios C., Van Remmen H., Richardson A., Ran Q. Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic. Biol. Med., 2012, vol. 52, no. 9, DOI: 10.1016/j.freeradbiomed.