БИОХИМИЯ, 2021, том 86, вып. 11, с. 1635–1653

УДК 577.577.12

Роль глутатионпероксидаз и пероксиредоксинов при свободнорадикальных патологиях

Обзор

© 2021 М.Г. Шарапов 1*sharapov.mars@gmail.com, С.В. Гудков 2,3,4, В.З. Ланкин 5, В.И. Новоселов 1

Институт биофизики клетки ФИЦ ПНЦБИ РАН, 142290 Пущино, Московская обл., Россия

Институт общей физики им. А.М. Прохорова РАН, 119991 Москва, Россия

Нижегородский государственный университет им. Н.И. Лобачевского, Институт биологии и биомедицины, 603022 Нижний Новгород, Россия

Всероссийский научно-исследовательский институт фитопатологии, 143050 Большие Вяземы, Россия

ФГБУ «НМИЦ кардиологии» Минздрава России, 121552 Москва, Россия

Поступила в редакцию 27.05.2021
После доработки 19.09.2021
Принята к публикации 19.09.2021

DOI: 10.31857/S0320972521110038

КЛЮЧЕВЫЕ СЛОВА: активные формы кислорода, дикарбонилы, лучевая болезнь, атеросклероз, диабет, пероксиредоксины, глутатионпероксидазы.

Аннотация

В обзоре рассмотрен патогенез заболеваний, сопряжённых с развитием окислительного стресса, таких как: атеросклероз, диабет и лучевая болезнь. Обсуждаются возможности терапевтического использования низкомолекулярных природных и синтетических антиоксидантов для коррекции свободнорадикальных патологий. Основное внимание в обзоре уделено роли двух филогенетически близких семейств гидропероксид-восстанавливающих антиоксидантных ферментов: пероксиредоксинов и глутатионпероксидаз. Обсуждается роль этих ферментов в противодействии окислительному стрессу, а также рассматривается их участие в предупреждении свободнорадикальных патологий. Представлены примеры успешного применения экзогенных рекомбинантных ферментов-антиоксидантов в качестве терапевтических агентов при лечении патологических состояний, связанных со свободнорадикальными процессами. Обсуждаются перспективы дальнейших исследований экзогенных ферментов-антиоксидантов, а также способы улучшения их терапевтических свойств.

Сноски

* Адресат для корреспонденции.

Финансирование

Работа выполнена при финансовой поддержке Российского фонда фундаментальных исследований (гранты №№ 19‑04‑00080 и 20‑34‑70037).

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит каких-либо исследований с участием людей или использованием животных в качестве объектов исследований.

Список литературы

1. Ланкин В. З., Тихазе А. К. (2016) Важная роль свободнорадикальных процессов в этиологии и патогенезе атеросклероза и сахарного диабета, Кардиология, 56, 97-105.

2. Forman, H. J., Zhang, H. (2021) Targeting oxidative stress in disease: promise and limitations of antioxidant therapy, Nat. Rev. Drug Discov., 20, 689-709, doi: 10.1038/s41573-021-00233-1.

3. Sies, H., Berndt, C., and Jones, D. P. (2017) Oxidative stress, Annu. Rev. Biochem., 86, 715-748, doi: 10.1146/annurev-biochem-061516-045037.

4. Sies, H., and Jones, D. P. (2020) Reactive oxygen species (ROS) as pleiotropic physiological signalling agents, Nat. Rev. Mol. Cell Biol., 21, 363-383, doi: 10.1038/s41580-020-0230-3.

5. Lankin, V. Z., Tikhaze, A. K., Kapel’ko, V. I., Shepel’kova, G. S., Shumaev, K. B., et al. (2007) Mechanisms of oxidative modification of low density lipoproteins under conditions of oxidative and carbonyl stress, Biochemistry (Moscow), 72, 1081-1090, doi: 10.1134/s0006297907100069.

6. Altomare, A., Baron, G., Gianazza, E., Banfi, C., Carini, M., and Aldini, G. (2021) Lipid peroxidation derived reactive carbonyl species in free and conjugated forms as an index of lipid peroxidation: limits and perspectives, Redox Biol., 42, 101899, doi: 10.1016/j.redox.2021.101899.

7. Anderson, M. M., Hazen, S. L., Hsu, F. F., Heinecke, J. W. (1997) Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to convert hydroxy-amino acids into glycolaldehyde, 2-hydroxypropanal, and acrolein: a mechanism for the generation of highly reactive α-hydroxy and α,β-unsaturated aldehydes by phagocytes at sites of inflammation, J. Clin. Invest., 99, 424-432, doi: 10.1172/JCI119176.

8. Talukdar, D., Chaudhuri, B. S., Ray, M., and Ray, S. (2009) Critical evaluation of toxic versus beneficial effects of methylglyoxal, Biochemistry (Moscow), 74, 1059-1069, doi: 10.1134/s0006297909100010.

9. Król, M., Kepinska, M. (2020) Human nitric oxide synthase – its functions, polymorphisms, and inhibitors in the context of inflammation, diabetes and cardiovascular diseases, Int. J. Mol. Sci., 22, 56, doi: 10.3390/ijms22010056.

10. Augusto, O., Bonini, M. G., Amanso, A. M., Linares, E., Santos, C. C. X., and De Menezes, S. L. (2002) Nitrogen dioxide and carbonate radical anion: two emerging radicals in biology, Free Radic. Biol. Med., 32, 841-859, doi: 10.1016/s0891-5849(02)00786-4.

11. Aicardo, A., Martinez, D. M., Campolo, N., Bartesaghi, S., and Radi, R. (2016) Biochemistry of nitric oxide and peroxynitrite: sources, targets and biological implications, Biochem. Oxid. Stress, 49-77, doi: 10.1007/978-3-319-45865-6_5.

12. Gupta, D., Harish, B., Kissner, R., and Koppenol, W. H. (2009) Peroxynitrate is formed rapidly during decomposition of peroxynitrite at neutral pH, Dalt. Trans., 29, 5730-5736, doi: 10.1039/b905535e.

13. Phaniendra, A., Jestadi, D. B., and Periyasamy, L. (2015) Free radicals: properties, sources, targets, and their implication in various diseases, Ind. J. Clin. Biochem., 30, 11-26, doi: 10.1007/s12291-014-0446-0.

14. Xue, Q., Yan, Y., Zhang, R., and Xiong, H. (2018) Regulation of iNOS on immune cells and its role in diseases, Int. J. Mol. Sci., 19, 3805, doi: 10.3390/ijms19123805.

15. Radi, R. (2013) Peroxynitrite, a stealthy biological oxidant, J. Biol. Chem., 288, 26464-26472, doi: 10.1074/jbc.R113.472936.

16. Ярмоненко С. П., Вайнсон А. А. (2004) Радиобиология человека и животных, Высшая школа, Москва.

17. Mu, H., Sun, J., Li, L., Yin, J., Hu, N., et al. (2018) Ionizing radiation exposure: hazards, prevention, and biomarker screening, Environ. Sci. Pollut. Res. Int., 25, 15294-15306, doi: 10.1007/s11356-018-2097-9.

18. Gerschman, R., Gilbert, D. L., Nye, S. W., Dwyer, P., and Fenn, W. O. (1954) Oxygen poisoning and X-irradiation: a mechanism in common, Science, 119, 623-626, doi: 10.1126/science.119.3097.623.

19. Bernheim, F. (1963) Biochemical implications of pro-oxidants and antioxidants, Radiat. Res., Suppl 3, 17-32.

20. Ward, J.F. (1988) DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability, Prog. Nucleic Acid Res. Mol. Biol., 35, 95-125, doi: 10.1016/s0079-6603(08)60611-x.

21. Dong, S., Lyu, X., Yuan, S., Wang, S., Li, W., et al. (2020) Oxidative stress: a critical hint in ionizing radiation induced pyroptosis, Radiat. Med. Prot., 1, 179-185, doi: 10.1016/j.radmp.2020.10.001.

22. Sharapov, M. G., Novoselov, V. I., and Gudkov, S. V. (2019) Radioprotective role of peroxiredoxin 6, Antioxidants (Basel), 8, 15, doi: 10.3390/antiox8010015.

23. Vasin, M. V., and Ushakov, I. B. (2020) Radiomodulators as agents of biological protection against oxidative stress under the influence of ionizing radiation, Biol. Bull. Rev., 10, 251-265, doi: 10.1134/S2079086420040106.

24. Legeza, V. I., Grebenyuk, A. N., and Drachev, I. S. (2019) Radiomitigators: classification, pharmacological properties, and application prospects, Biol. Bull., 46, 1625-1632, doi: 10.1134/S1062359019120045.

25. Gudkov, S. V., Popova, N. R., and Bruskov, V. I. (2015) Radioprotective substances: history, trends and prospects, Biophysics, 60, 659-667, doi: 10.1134/S0006350915040120.

26. Sun, J., Chen, Y., Li, M., and Ge, Z. (1998) Role of antioxidant enzymes on ionizing radiation resistance, Free Radic. Biol. Med., 24, 586-593, doi: 10.1016/s0891-5849(97)00291-8.

27. Diamond, A. M., Murray, J. L., Dale, P., Tritz, R., Sandstrom, P. A., and Grdina, D. J. (1995) Effects of selenium on glutathione peroxidase activity and radioprotection in mammalian cells, Radiat. Oncol. Invest., 3, 383-386.

28. Verma, P., Kunwar, A., Arai, K., Iwaoka, M., and Priyadarsini, K. I. (2018) Mechanism of radioprotection by dihydroxy-1-selenolane (DHS): effect of fatty acid conjugation and role of glutathione peroxidase (GPx), Biochimie, 144, 122-133, doi: 10.1016/j.biochi.2017.10.021.

29. Mansur, D. B., Kataoka, Y., Grdina, D. J., Diamond, A. M. (2001) Radiosensitivity of mammalian cell lines engineered to overexpress cytosolic glutathione peroxidase, Radiat. Res., 155, 536-542, doi: 10.1667/0033-7587(2001)155[0536:romcle]2.0.co;2.

30. Stevens, G. N., Joiner, M. C., Joiner, B., Johns, H., and Stratford, M. R. (1989) Role of glutathione peroxidase in the radiation response of mouse kidney, Int. J. Radiat. Oncol. Biol. Phys., 16, 1213-1217, doi: 10.1016/0360-3016(89)90286-1.

31. Toppo, S., Flohé, L., Ursini, F., Vanin, S., and Maiorino, M. (2009) Catalytic mechanisms and specificities of glutathione peroxidases: variations of a basic scheme, Biochim. Biophys. Acta Gen. Subj., 1790, 1486-1500, doi: 10.1016/j.bbagen.2009.04.007.

32. Jiao, Y., Wang, Y., Guo, S., and Wang, G. (2017) Glutathione peroxidases as oncotargets, Oncotarget, 8, 80093-80102, doi: 10.18632/oncotarget.20278.

33. Lee, H. C., Kim, D. W., Jung, K. Y., Park, I. C., Park, M. J., et al. (2004) Increased expression of antioxidant enzymes in radioresistant variant from U251 human glioblastoma cell line, Int. J. Mol. Med., 13, 883-887.

34. Zhang, S., Wang, W., Gu, Q., Xue, J., Cao, H., et al. (2014) Protein and miRNA profiling of radiation-induced skin injury in rats: the protective role of peroxiredoxin-6 against ionizing radiation, Free Radic. Biol. Med., 69, 96-107, doi: 10.1016/j.freeradbiomed.2014.01.019.

35. Lee, K., Park, J. S., Kim, Y. J., Soo Lee, Y., Sook Hwang, T., et al. (2002) Differential expression of Prx I and II in mouse testis and their up-regulation by radiation, Biochem. Biophys. Res. Commun., 296, 337-342, doi: 10.1016/s0006-291x(02)00801-x.

36. Miura, Y., Kano, M., Yamada, M., Nishine, T., Urano, S., et al. (2007) Proteomic study on X-irradiation-responsive proteins and ageing: search for responsible proteins for radiation adaptive response, J. Biochem., 142, 145-155, doi: 10.1093/jb/mvm118.

37. An, J. H., and Seong, J. S. (2006) Proteomics analysis of apoptosis-regulating proteins in tissues with different radiosensitivity, J. Radiat. Res., 47, 147-155, doi: 10.1269/jrr.47.147.

38. Cerda, M.B., Lloyd, R., Batalla, M., Giannoni, F., Casal, M., and Policastro, L. (2017) Silencing peroxiredoxin-2 sensitizes human colorectal cancer cells to ionizing radiation and oxaliplatin, Cancer Lett., 388, 312-319, doi: 10.1016/j.canlet.2016.12.009.

39. Diaz, A.J.G., Tamae, D., Yen, Y., Li, J., and Wang, T. (2013) Enhanced radiation response in radioresistant MCF-7 cells by targeting peroxiredoxin II, Breast Cancer Targets Ther., 5, 87-101, doi: 10.2147/BCTT.S51378.

40. Sharapov, M. G., and Novoselov, V. I. (2019) Catalytic and signaling role of peroxiredoxins in carcinogenesis, Biochemistry (Moscow), 84, 79-100, doi: 10.1134/S0006297919020019.

41. Chen, M.-F., Keng, P. C., Shau, H., Wu, C.-T., Hu, Y.-C., et al. (2006) Inhibition of lung tumor growth and augmentation of radiosensitivity by decreasing peroxiredoxin I expression, Int. J. Radiat. Oncol. Biol. Phys., 64, 581-591, doi: 10.1016/j.ijrobp.2005.10.012.

42. Li, G., Xie, B., Li, X., Chen, Y., Xu, Y., et al. (2015) Downregulation of peroxiredoxin-1 by β-elemene enhances the radiosensitivity of lung adenocarcinoma xenografts, Oncol. Rep., 33, 1427-1433, doi: 10.3892/or.2015.3732.

43. Kwee, J. K. (2014) A paradoxical chemoresistance and tumor suppressive role of antioxidant in solid cancer cells: a strange case of Dr. Jekyll and Mr. Hyde, Biomed Res. Int., 2014, 209845, doi: 10.1155/2014/209845.

44. Song, I.-S., Kim, H.-K., Jeong, S.-H., Lee, S.-R., Kim, N., et al. (2011) Mitochondrial peroxiredoxin III is a potential target for cancer therapy, Int. J. Mol. Sci., 12, 7163-7185, doi: 10.3390/ijms12107163.

45. Chen, W. C., McBride, W. H., Iwamoto, K. S., Barber, C. L., Wang, C. C., et al. (2002) Induction of radioprotective peroxiredoxin-I by ionizing irradiation, J. Neurosci. Res., 70, 794-798, doi: 10.1002/jnr.10435.

46. Zhang, B., Wang, Y., and Su, Y. (2009) Peroxiredoxins, a novel target in cancer radiotherapy, Cancer Lett., 286, 154-160, doi: 10.1016/j.canlet.2009.04.043.

47. Jia, W., Chen, P., and Cheng, Y. (2019) PRDX4 and its roles in various cancers, Technol. Cancer Res. Treat., 18, 1533033819864313, doi: 10.1177/1533033819864313.

48. Ho, J. N., Lee, S. B., Lee, S. S., Yoon, S. H., Kang, G. Y., et al. (2010) Phospholipase A2 activity of peroxiredoxin 6 promotes invasion and metastasis of lung cancer cells, Mol. Cancer Ther., 9, 825-832, doi: 10.1158/1535-7163.MCT-09-0904.

49. Sharapov, M. G., Glushkova, O. V., Parfenyuk, S. B., Gudkov, S. V., Lunin, S. M., and Novoselova, E. G. (2021) The role of TLR4/NF-κB signaling in the radioprotective effects of exogenous Prdx6, Arch. Biochem. Biophys., 702, 108830, doi: 10.1016/j.abb.2021.108830.

50. Lankin, V. Z., and Tikhaze, A. K. (2016) Role of oxidative stress in the genesis of atherosclerosis and diabetes mellitus: a personal look back on 50 years of research, Curr. Aging Sci., 10, 18-25, doi: 10.2174/1874609809666160926142640.

51. Lankin, V. Z., Tikhaze, A. K. (2003) Free Radicals, Nitric Oxide, and Inflammation: Molecular, Biochemical, and Clinical Aspects, IOS Press, NATO Science Series, Amsterdam.

52. Mushenkova, N. V., Bezsonov, E. E., Orekhova, V. A., Popkova, T. V., Starodubova, A. V., and Orekhov, A. N. (2021) Recognition of oxidized lipids by macrophages and its role in atherosclerosis development, Biomedicines, 9, 915, doi: 10.3390/biomedicines9080915.

53. Tribble, D. L., Barcellos-Hoff, M. H., Chu, B. M., and Gong, E. L. (1999) Ionizing radiation accelerates aortic lesion formation in fat-fed mice via SOD-inhibitable processes, Arterioscler. Thromb. Vasc. Biol., 19, 1387-1392, doi: 10.1161/01.atv.19.6.1387.

54. Lankin, V. Z., Tikhaze, A. K., and Kumskova, E. M. (2012) Macrophages actively accumulate malonyldialdehyde-modified but not enzymatically oxidized low density lipoprotein, Mol. Cell. Biochem., 365, 93-98, doi: 10.1007/s11010-012-1247-5.

55. Chistiakov, D. A., Orekhov, A. N., and Bobryshev, Y. V. (2016) LOX-1-mediated effects on vascular cells in atherosclerosis, Cell. Physiol. Biochem., 38, 1851-1859, doi: 10.1159/000443123.

56. Shumaev, K. B., Ruuge, E. K., Dmitrovsky, A. A., Bykhovskyб V. Ya., and Kukharchuk, V. V. (1997) Effect of lipid peroxidation products and antioxidants on the formation of probucol radical in low density lipoproteins, Biochemistry (Moscow), 62, 657-660.

57. Lankin, V. Z., Tikhaze, A. K., and Osis, Y. G. (2002) Modeling the cascade of enzymatic reactions in liposomes including successive free radical peroxidation, reduction, and hydrolysis of phospholipid polyenoic acyls for studying the effect of these processes on the structural-dynamic parameters of the membranes, Biochemistry (Moscow), 67, 566-574, doi: 10.1023/a:1015502429453.

58. Lankin, V. Z., Tikhaze, A. K., Kukharchuk, V. V., Konovalova, G. G., Pisarenko, O. I., et al. (2003) Antioxidants decreases the intensification of low density lipoprotein in vivo peroxidation during therapy with statins, Mol. Cell. Biochem., 249, 129-140.

59. Lankin, V. Z., Tikhaze, A. K., Konovalova, G. G., Odinokova, O. A., Doroshchuk, N. A., and Chazova, I. E. (2018) Oxidative and carbonyl stress as a factors of the modification of proteins and DNA destruction in diabetes, Ter. Arkh., 90, 46-50, doi: 10.26442/terarkh201890104-50.

60. Sena, C. M., Pereira, A. M., and Seiça, R. (2013) Endo-thelial dysfunction – a major mediator of diabetic vascular disease, Biochim. Biophys. Acta Mol. Basis Dis., 1832, 2216-2231, doi: 10.1016/j.bbadis.2013.08.006.

61. Lankin, V. Z., Shumaev, K. B., Tikhaze, A. K., and Kurganov, B. I. (2017) Influence of dicarbonyls on kinetic characteristics of glutathione peroxidase, Dokl. Biochem. Biophys., 475, 287-290, doi: 10.1134/S1607672917040123.

62. Sharapov, M. G., Goncharov, R. G., Gordeeva, A. E., Novoselov, V. I., Antonova, O. A., et al. (2016) Enzymatic antioxidant system of endotheliocytes, Dokl. Biochem. Biophys., 471, 410-412, doi: 10.1134/S1607672916060090.

63. Kisucka, J., Chauhan, A. K., Patten, I. S., Yesilaltay, A., Neumann, C., et al. (2008) Peroxiredoxin1 prevents excessive endothelial activation and early atherosclerosis, Circ. Res., 103, 598-605, doi: 10.1161/CIRCRESAHA.108.174870.

64. Ihida-Stansbury, K., Ames, J., Chokshi, M., Aiad, N., Sanyal, S., et al. (2015) Role played by Prx1-dependent extracellular matrix properties in vascular smooth muscle development in embryonic lungs, Pulm. Circ., 5, 382-397, doi: 10.1086/681272.

65. Park, J.-G., Yoo, J.-Y., Jeong, S.-J., Choi, J.-H., Lee, M.-R., et al. (2011) Peroxiredoxin 2 deficiency exacerbates atherosclerosis in apolipoprotein E-deficient mice, Circ. Res., 109, 739-749, doi: 10.1161/CIRCRESAHA.111.245530.

66. Jeong, S. J., Park, J. G., and Oh, G. T. (2021) Peroxiredoxins as potential targets for cardiovascular disease, Antioxidants (Basel), 10, 1244, doi: 10.3390/antiox10081244.

67. Wang, X., Phelan, S. A., Forsman-Semb, K., Taylor, E. F., Petros, C., et al. (2003) Mice with targeted mutation of peroxiredoxin 6 develop normally but are susceptible to oxidative stress, J. Biol. Chem., 278, 25179-25190, doi: 10.1074/jbc.M302706200.

68. Wang, X., Phelan, S. A., Petros, C., Taylor, E. F., Ledinski, G., et al. (2004) Peroxiredoxin 6 deficiency and atherosclerosis susceptibility in mice: significance of genetic background for assessing atherosclerosis, Atherosclerosis, 177, 61-70, doi: 10.1016/j.atherosclerosis.2004.06.007.

69. Burillo, E., Jorge, I., Martínez-López, D., Camafeita, E., Blanco-Colio, L. M., et al. (2016) Quantitative HDL proteomics identifies peroxiredoxin-6 as a biomarker of human abdominal aortic aneurysmm, Sci. Rep., 6, 38477, doi: 10.1038/srep38477.

70. Lankin, V. Z., Sharapov, M. G., Goncharov, R. G., Tikhaze, A. K., and Novoselov, V. I. (2019) Natural dicarbonyls inhibit peroxidase activity of peroxiredoxins, Dokl. Biochem. Biophys., 485, 132-134, doi: 10.1134/S1607672919020157.

71. Maruhashi, T., and Higashi, Y. (2021) Pathophysiological Association between diabetes mellitus and endothelial dysfunction, Antioxidants (Basel), 10, 1306, doi: 10.3390/antiox10081306.

72. Vladimirov, Y. A., and Proskurnina, E. V. (2009) Free radicals and cell chemiluminescence. Biochemistry (Moscow), 74, 1545-1566, doi: 10.1134/s0006297909130082.

73. Lankin, V. Z., Antonovsky, V. L., and Tikhaze, A. K. (2004) Regulation of free radical lipoperoxidation and organic peroxides metabolism during normal station and pathologies, in Peroxides at the Beginning of the Third Millennium, Nova Sci. Publ., p. 85-111.

74. Lankin, V., Konovalova, G., Tikhaze, A., Shumaev, K., Kumskova, E., and Viigimaa, M. (2014) The initiation of free radical peroxidation of low-density lipoproteins by glucose and its metabolite methylglyoxal: a common molecular mechanism of vascular wall injure in atherosclerosis and diabetes, Mol. Cell. Biochem., 395, 241252, doi: 10.1007/s11010-014-2131-2.

75. Lankin, V. Z., Shadyro, O. I., Shumaev, K. B., Shumaev, K. B., Tikhaze, A. K., and Sladkova, A. A. (2019) Non-enzymatic methylglyoxal formation from glucose metabolites and generation of superoxide anion radical during methylglyoxal-dependent cross-links reaction, J. Antioxid. Act., 1, 33-45, doi: 10.14302/issn.2471-2140.jaa-19-2997.

76. Lankin, V. Z., Konovalova, G. G., Tikhaze, A. K., Shumaev, K. B., Belova Kumskova, E. M., et al. (2016) Aldehyde inhibition of antioxidant enzymes in the blood of diabetic patients, J. Diabetes, 8, 398-404, doi: 10.1111/1753-0407.12309.

77. Oberley, L. W. (1988) Free radicals and diabetes, Free Radic. Biol. Med., 5, 113-124, doi: 10.1016/0891-5849(88)90036-6.

78. Huang, J. Q., Zhou, J. C., Wu, Y. Y., Ren, F. Z., and Lei, X. G. (2018) Role of glutathione peroxidase 1 in glucose and lipid metabolism-related diseases, Free Radic. Biol. Med., 127, 108-115, doi: 10.1016/j.freeradbiomed.2018.05.077.

79. Matsushima, S., Kinugawa, S., Ide, T., Matsusaka, H., Inoue, N., et al. (2006) Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart, Am. J. Physiol. Hear. Circ. Physiol., 291, 2237-2245, doi: 10.1152/ajpheart.00427.2006.

80. Koulajian, K., Ivovic, A., Ye, K., Desai, T., Shah, A., et al. (2013) Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo, Am. J. Physiol. Endocrinol. Metab., 305, 254-262, doi: 10.1152/ajpendo.00481.2012.

81. Stancill, J. S., Happ, J. T., Broniowska, K. A., Hogg, N., and Corbett, J. A. (2020) Peroxiredoxin 1 plays a primary role in protecting pancreatic β-cells from hydrogen peroxide and peroxynitrite, Am. J. Physiol. Regul. Integr. Comp. Physiol., 318, R1004-R1013, doi: 10.1152/ajpregu.00011.2020.

82. Ding, Y., Yamada, S., Wang, K. Y., Shimajiri, S., Guo, X., et al. (2010) Overexpression of peroxiredoxin 4 protects against high-dose streptozotocin-induced diabetes by suppressing oxidative stress and cytokines in transgenic mice, Antioxidants Redox Signal., 13, 1477-1490, doi: 10.1089/ars.2010.3137.

83. Pacifici, F., Arriga, R., Sorice, G. P., Capuani, B., Scioli, M. G., et al. (2014) Peroxiredoxin 6, a novel player in the pathogenesis of diabetes, Diabetes, 63, 3210-3220, doi: 10.2337/db14-0144.

84. Меньщикова Е. Б., Ланкин В. З., Зенков Н. К., Бондарь И. А., Круговых Н. Ф., Труфакин В. А. (2006) Окислительный стресс. Прооксиданты и антиоксиданты, Слово, Москва, с. 556.

85. Vasin, M. V., and Ushakov, I. B. (2019) Potential ways to increase body resistance to damaging action of ionizing radiation with radiomitigators, Biol. Bull. Rev., 9, 503-519, doi: 10.1134/S2079086419060082.

86. Sharapov, M. G., Gudkov, S. V., and Lankin, V. Z. (2021) Hydroperoxide-reducing enzymes in the regulation of free-radical processes, Biochemistry (Moscow), 86, 1256-1274, doi: 10.1134/S0006297921100084.

87. McCord, J. M., and Fridovich, I. (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein), J. Biol. Chem., 244, 6049-6055, doi: 10.1016/S0021-9258(18)63504-5.

88. Borrelli, A., Schiattarella, A., Mancini, R., Morrica, B., Cerciello, V., et al. (2009) A recombinant MnSOD is radioprotective for normal cells and radiosensitizing for tumor cells, Free Radic. Biol. Med., 46, 110-116, doi: 10.1016/j.freeradbiomed.2008.10.030.

89. Cataldi, S., Borrelli, A., Ceccarini, M. R., Nakashidze, I., Codini, M., et al. (2019) Neutral sphingomyelinase modulation in the protective/preventive role of rMnSOD from radiation-induced damage in the brain, Int. J. Mol. Sci., 20, 5431, doi: 10.3390/ijms20215431.

90. Pisani, A., Sabbatini, M., Riccio, E., Rossano, R., Andreucci, M., et al. (2014) Effect of a recombinant manganese superoxide dismutase on prevention of contrast-induced acute kidney injury, Clin. Exp. Nephrol., 18, 424-431, doi: 10.1007/s10157-013-0828-2.

91. Жариков А. А., Терехов О. В., Пасов В. В. (2013) Лечение больных с поздними лучевыми повреждениями органов малого таза с применением препарата рексод, Онкология, 5, 26-30.

92. Guo Dong Mao, Thomas, P. D., Lopaschuk, G. D., and Poznansky, M. J. (1993) Superoxide dismutase (SOD)-catalase conjugates. Role of hydrogen peroxide and the Fenton reaction in SOD toxicity, J. Biol. Chem., 268, 416-420.

93. Maksimenko, A. V. (2016) Widening and elaboration of consecutive research into therapeutic antioxidant enzyme derivatives, Oxid. Med. Cell. Longev., 2016, 3075695, doi: 10.1155/2016/3075695.

94. Isarankura-Na-Ayudhya, C., Yainoy, S., Tantimongcolwat, T., Bülow, L., and Prachayasittikul, V. (2010) Engineering of a novel chimera of superoxide dismutase and Vitreoscilla Hemoglobin for rapid detoxification of reactive oxygen species, J. Biosci. Bioeng., 110, 633-637, doi: 10.1016/j.jbiosc.2010.07.001.

95. Guan, T., Song, J., Wang, Y., Guo, L., Yuan, L., et al. (2017) Expression and characterization of recombinant bifunctional enzymes with glutathione peroxidase and superoxide dismutase activities, Free Radic. Biol. Med., 110, 188-195, doi: 10.1016/j.freeradbiomed.2017.06.005.

96. Sharapov, M. G., Novoselov, V. I., and Ravin, V. K. (2016) Construction of a fusion enzyme exhibiting superoxide dismutase and peroxidase activity, Biochemistry (Moscow), 81, 420-427, doi: 10.1134/S0006297916040131.

97. Sharapov, M. G., Gudkov, S. V., Gordeeva, A. E., Karp, O. E., Ivanov, V. E., et al. (2016) Peroxiredoxin 6 is a natural radioprotector, Dokl. Biochem. Biophys., 467, 110-112, doi: 10.1134/S1607672916020095.

98. Sharapov, M. G., Novoselov, V. I., Fesenko, E. E., Bruskov, V. I., and Gudkov, S. V. (2017) The role of peroxiredoxin 6 in neutralization of X-ray mediated oxidative stress: effects on gene expression, preservation of radiosensitive tissues and postradiation survival of animals, Free Radic. Res., 51, 148-166, doi: 10.1080/10715762.2017.1289377.

99. Sharapov, M. G., Novoselov, V. I., Samygina, V. R., Konarev, P. V., Molochkov, A. V., et al. (2020) A chimeric recombinant protein with peroxidase and superoxide dismutase activities: physico-chemical characterization and applicability to neutralize oxidative stress caused by ionizing radiation, Biochem. Eng. J., 159, 107603, doi: 10.1016/j.bej.2020.107603.

100. Sharapov, M. G., and Gudkov, S. V. (2021) Peroxiredoxin 1 – Multifunctional antioxidant enzyme, protects from oxidative damages and increases the survival rate of mice exposed to total body irradiation, Arch. Biochem. Biophys., 697, 108671, doi: 10.1016/j.abb.2020.108671.

101. Sharapov, M. G., Novoselov, V. I., Penkov, N. V., Fesenko, E. E., Vedunova, M. V., et al. (2019) Protective and adaptogenic role of peroxiredoxin 2 (Prx2) in neutralization of oxidative stress induced by ionizing radiation, Free Radic. Biol. Med., 134, 76-86, doi: 10.1016/j.freeradbiomed.2018.12.032.

102. Hellweg, C. E., Spitta, L. F., Henschenmacher, B., Diegeler, S., and Baumstark-Khan, C. (2016) Transcription factors in the cellular response to charged particle exposure, Front. Oncol., 6, 61, doi: 10.3389/fonc.2016.00061.

103. Ji, Z., He, L., Regev, A., and Struhl, K. (2019) Inflammatory regulatory network mediated by the joint action of NF-kB, STAT3, and AP-1 factors is involved in many human cancers, Proc. Natl. Acad. Sci. USA, 116, 9453-9462, doi: 10.1073/pnas.1821068116.

104. Novoselova, E. G., Glushkova, O. V., Lunin, S. M., Khrenov, M. O., Parfenyuk, S. B., et al. (2020) Peroxiredoxin 6 attenuates alloxan-induced type 1 diabetes mellitus in mice and cytokine-induced cytotoxicity in RIN-m5F Beta cells, J. Diabetes Res., 2020, 7523892, doi: 10.1155/2020/7523892.

105. Novoselova, E. G., Glushkova, O. V., Parfenuyk, S. B., Khrenov, M. O., Lunin, S. M., et al. (2019) Protective effect of peroxiredoxin 6 against toxic effects of glucose and cytokines in pancreatic RIN-m5F β-cells, Biochemistry (Moscow), 84, 637-643, doi: 10.1134/S0006297919060063.

106. Karaduleva, E. V., Mubarakshina, E. K., Sharapov, M. G., Volkova, A. E., Pimenov, O. Y., et al. (2016) Cardioprotective effect of modified peroxiredoxins in retrograde perfusion of isolated rat heart under conditions of oxidative stress, Bull. Exp. Biol. Med., 160, 639-642, doi: 10.1007/s10517-016-3237-1.

107. Grudinin, N. V., Bogdanov, V. K., Sharapov, M. G., Bunenkov, N. S., Mozheiko, N. P., et al. (2020) Use of peroxiredoxin for preconditioning of heterotopic heart transplantation in a rat, Vestn. Transplantologii i Iskusstv. Organov, 22, 132-136, doi: 10.15825/1995-1191-2020-2-158-164.

108. Sharapov, M. G., Gordeeva, A. E., Goncharov, R. G., Tikhonova, I. V., Ravin, V. K., et al. (2017) The effect of exogenous peroxiredoxin 6 on the state of mesenteric vessels and the small intestine in ischemia–reperfusion injury, Biophysics, 62, 998-1008, doi: 10.1134/S0006350917060239.

109. Gordeeva, A. E., Temnov, A. A., Charnagalov, A. A., Sharapov, M. G., Fesenko, E. E., and Novoselov, V. I. (2015) Protective effect of peroxiredoxin 6 in ischemia/ reperfusion-induced damage of small intestine, Dig. Dis. Sci., 60, 3610-3619, doi: 10.1007/s10620-015-3809-3.

110. Goncharov, R. G., Rogov, K. A., Temnov, A. A., Novoselov, V. I., and Sharapov, M. G. (2019) Protective role of exogenous recombinant peroxiredoxin 6 under ischemia-reperfusion injury of kidney, Cell Tissue Res., 378, 319-332, doi: 10.1007/s00441-019-03073-z.

111. Sharapov, M. G., Goncharov, R. G., Filkov, G. I., Trofimenko, A. V., Boyarintsev, V. V., and Novoselov, V. I. (2020) Comparative study of protective action of exogenous 2-cys peroxiredoxins (Prx1 and Prx2) under renal ischemia-reperfusion injury, Antioxidants (Basel), 9, 680, doi: 10.3390/antiox9080680.

112. Li, Z., Wang, F., Roy, S., Sen, C. K., and Guan, J. (2009) Injectable, highly flexible, and thermosensitive hydrogels capable of delivering superoxide dismutase, Biomacromolecules, 10, 3306-3316, doi: 10.1021/bm900900e.

113. Guryev, E. L., Volodina, N. O., Shilyagina, N. Y., Gudkov, S. V., Balalaeva, I. V., et al. (2018) Radioactive (90Y) upconversion nanoparticles conjugated with recombinant targeted toxin for synergistic nanotheranostics of cancer, Proc. Natl. Acad. Sci. USA, 115, 9690-9695, doi: 10.1073/pnas.1809258115.

114. Gil, D., Rodriguez, J., Ward, B., Vertegel, A., Ivanov, V., and Reukov, V. (2017) Antioxidant activity of SOD and catalase conjugated with nanocrystalline ceria, Bioengineering (Basel), 4, 18, doi: 10.3390/bioengineering4010018.

115. Simone, E. A., Dziubla, T. D., Arguiri, E., Vardon, V., Shuvaev, V. V., et al. (2009) Loading PEG-catalase into filamentous and spherical polymer nanocarriers, Pharm. Res., 26, 250-260, doi: 10.1007/s11095-008-9744-7.

116. Lacramioara, L., Diaconu, A., Butnaru, M., and Verestiuc, L. (2016) Biocompatible SPIONs with superoxid dismutase/catalase immobilized for cardiovascular applications, IFMBE Proc., 55, 323-326, doi: 10.1007/978-981-287-736-9_78.

117. Novoselov, V. I., Ravin, V. K., Sharapov, M. G., Sofin, A. D., Kukushkin, N. I., and Fesenko, E. E. (2011) Modified peroxiredoxins as prototypes of drugs with powerful antioxidant action, Biophysics, 56, 836-842, doi: 10.1134/S0006350911050137.

118. Chhunchha, B., Kubo, E., Kompella, U. B., and Singh, D. P. (2021) Engineered sumoylation-deficient prdx6 mutant protein-loaded nanoparticles provide increased cellular defense and prevent lens opacity, Antioxidants (Basel), 10, 1245, doi: 10.3390/antiox10081245.