БИОХИМИЯ, 2021, том 86, вып. 4, с. 511–528

УДК 577.24::57.052.6

Регуляция белков циркадных ритмов и Nrf2-опосредованной антиоксидантной защиты: двойная роль киназы гликогенсинтазы 3

Обзор

© 2021 Г.А. Шиловский 1,2,3*, Т.С. Путятина 2, Г.В. Моргунова 2, А.В. Селиверстов 3, В.В. Ашапкин 1, Е.В. Сорокина 2, А.В. Марков 2, В.П. Скулачев 1

НИИ физико-химической биологии имени А.Н. Белозерского, Московский государственный университет имени М.В. Ломоносова, 119991 Москва, Россия; электронная почта: gregory_sh@list.ru, grgerontol@gmail.com

Московский государственный университет имени М.В. Ломоносова, биологический факультет, 119234 Москва, Россия

Институт проблем передачи информации РАН, 127051 Москва, Россия

Поступила в редакцию 14.07.2020
После доработки 11.01.2021
Принята к публикации 11.01.2021

DOI: 10.31857/S0320972521040059

КЛЮЧЕВЫЕ СЛОВА: GSK3, Nrf2, окислительный стресс, старение, биологические ритмы, программы старения и антистарения, антиоксиданты.

Аннотация

В обзоре рассматриваются некоторые генетические и молекулярные пути, связывающие циркадный хронометраж с метаболизмом и образующие системы положительной и отрицательной обратной связи – регуляторные петли. Путь Nrf2 (транскрипционного фактора 2 семейства NFE) считается компонентом антивозрастной программы – хранителем периода здоровой жизни и долголетия. Nrf2 обеспечивает адаптацию к стрессу путем положительной регуляции клеточной антиоксидантной защиты и других метаболических процессов, контролируя экспрессию более 200 генов-мишеней при различных видах стресса. Система киназы гликогенсинтазы 3 (GSK3) представляет собой «регулирующий клапан», контролирующий небольшие колебания уровней Nrf2, в отличие от Keap1, предотвращающего большие колебания уровня Nrf2 в отсутствии окислительного стресса и инактивирующегося при окислительном стрессе. Кроме того, GSK3 модифицирует коровые белки циркадных ритмов (Bmal1, Clock, Per, Cry, Rev-erbα). При этом модификация GSK3 приводит к инактивации и деградации белков, положительно регулирующих биоритмы (Bmal1, Clock), и наоборот, ведет к активации и ядерной транслокации негативно регулирующих биоритмы белков (Per, Rev-erbα). Исключением является Cry, опосредующий, видимо, тонкую настройку биологических часов. Функция GSK3 представляется одним из узловых пунктов перекрестной регуляции циркадных ритмов и антиоксидантной защиты. Обсуждается перекрестное взаимодействие между мощнейшей антиоксидантной защитой клетки (системой Nrf2) и системой биоритмов у млекопитающих (включая влияние сверхэкспрессии/нокаута GSK3 на биоритмы и влияние нокаута/сверхэкспрессии генов циркадных биоритмов на работу системы Nrf2). Понимание механизмов взаимодействия регуляторных каскадов, связывающих программы поддержания гомеостаза и ответа клетки на окислительный стресс, способствует выяснению молекулярных механизмов, лежащих в основе старения и долголетия.

Сноски

* Адресат для корреспонденции.

Финансирование

Исследование выполнено при  инансовой поддержке Российского фонда фундаментальных исследований (грант № 18-29-13037).

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

В данной работе не было никаких исследований, в которых были использованы в качестве объектов люди или животные.

Список литературы

1. Skulachev, V. P., Shilovsky, G. A., Putyatina, T. S., Popov, N. A., Markov, A. V, et al. (2020) Perspectives of Homo sapiens lifespan extension: focus on external or internal resources? Aging (Albany NY), 12, 5566-5584, doi: 10.18632/aging.102981.

2. Lewis, K. N., Wason, E., Edrey, Y. H., Kristan, D. M., Nevo, E., and Buffenstein, R. (2015) Regulation of Nrf2 signaling and longevity in naturally long-lived rodents, Proc. Natl. Acad. Sci. USA, 112, 3722-3727, doi: 10.1073/pnas.1417566112.

3. Cuadrado, A. (2015) Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP, Free Radic. Biol. Med., 88, 147-157, doi: 10.1016/j.freeradbiomed.2015.04.029.

4. Skulachev, M. V., Severin, F. F., and Skulachev, V. P. (2015) Aging as an evolvability-increasing program which can be switched off by organism to mobilize additional resources for survival, Curr. Aging Sci., 8, 95-109, doi: 10.2174/1874609808666150422122401.

5. Galimov, E. R., Lohr, J. N., and Gems, D. (2019) When and how can death be an adaptation? Biochemistry (Moscow), 84, 1433-1437, doi: 10.1134/S0006297919120010.

6. Duan, W. S., Zhang, R. Y., Guo, Y. S., Jiang, Y. F., Huang, Y. L., et al. (2009) Nrf2 activity is lost in the spinal cord and its astrocytes of aged mice, In vitro Cell. Dev. Biol. Anim., 45, 388-397, doi: 10.1007/s11626-009-9194-5.

7. Skulachev, V. P., Holtze, S., Vyssokikh, M. Y., Bakeeva, L. E., Skulachev, M. V., et al. (2017) Neoteny, prolongation of youth: from naked mole rats to “naked apes” (humans), Physiol. Rev., 97, 699-720, doi: 10.1152/physrev.00040.2015.

8. Skulachev, V. P. (2019) Phenoptosis as a phenomenon widespread among many groups of living organisms including mammals [Commentary to the paper by E. R. Galimov, J. N. Lohr, and D. Gems (2019), Biochemistry (Moscow), 84, 1433-1437], Biochemistry (Moscow), 84, 1438-1441, doi: 10.1134/S0006297919120022.

9. Vyssokikh, M. Y., Holtze, S., Averina, O. A, Lyamzaev, K. G., Panteleeva, A. A., et al. (2020) Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program, Proc. Natl. Acad. Sci. USA, 117, 6491-6501, doi: 10.1073/pnas.1916414117.

10. Kobayashi, E. H., Suzuki, T., Funayama, R., Nagashima, T., Hayashi, M., et al. (2016) Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription, Nat. Commun., 7, 11624, doi: 10.1038/ncomms11624.

11. Aw Yeang, H. X., Hamdam, J. M., Al-Huseini, L. M., Sethu, S., Djouhri, L., et al. (2012) Loss of transcription factornuclear factor-erythroid 2 (NF-E2) p45-related factor-2 (Nrf2) leads to dysregulation of immune functions, redox homeostasis, and intracellular signaling in dendritic cells, J. Biol. Chem., 287, 10556-10564, doi: 10.1074/jbc.M111.322420.

12. He, X., Kan, H., Cai, L., and Ma, Q. (2009) Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes, J. Mol. Cell. Cardiol., 46, 47-58, doi: 10.1016/j.yjmcc.2008.10.007.

13. Xu, S. F., Ji, L. L., Wu, Q., Li, J., and Liu, J. (2018) Ontogeny and aging of Nrf2 pathway genes in livers of rats, Life Sci., 203, 99-104, doi: 10.1016/j.lfs.2018.04.018.

14. Levy, S., and Forman, H. J. (2010) C-Myc is a Nrf2-interacting protein that negatively regulates phase II genes through their electrophile responsive elements, IUBMB Life, 62, 237-246, doi: 10.1002/iub.314.

15. Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., and Dinkova-Kostova, A. T. (2015) 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., 88, 108-146, doi: 10.1016/j.freeradbiomed.2015.06.021.

16. Jain, A. K., and Jaiswal, A. K. (2007) GSK3β acts upstream of Fyn kinase in regulation of nuclear export and degradation of NF-E2 related factor 2, J. Biol. Chem., 282, 16502-16510, doi: 10.1074/jbc.M611336200.

17. Huang, H. C., Nguyen, T., and Pickett, C. B. (2000) Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2, Proc. Natl. Acad. Sci. USA, 97, 12475-12480, doi: 10.1073/pnas.220418997.

18. Tong, K. I., Kobayashi, A., Katsuoka, F., and Yamamoto, M. (2006) Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism, Biol. Chem., 387, 1311-1320, doi: 10.1515/BC.2006.164.

19. Bonaconsa, M., Malpeli, G., Montaruli, A., Carandente, F., Grassi-Zucconi, G., and Bentivoglio, M. (2014) Differential modulation of clock gene expression in the suprachiasmatic nucleus, liver and heart of aged mice, Exp. Gerontol., 5, 70-79, doi: 10.1016/j.exger.2014.03.011.

20. Bunger, M. K., Wilsbacher, L. D., Moran, S. M., Clendenin, C., Radcliffe, L. A., et al. (2000) Mop3 is an essential component of the master circadian pacemaker in mammals, Cell, 103, 1009-1017, doi: 10.1016/s0092-8674(00)00205-1.

21. Wijnen, H., and Young, M. W. (2006) Interplay of circadian clocks and metabolic rhythms, Annu. Rev. Genet., 40, 409-448, doi: 10.1146/annurev.genet.40.110405.090603.

22. Okamura, H. (2003) Integration of mammalian circadian clock signals: from molecule to behavior, J. Endocrinol., 177, 3-6, doi: 10.1677/joe.0.1770003.

23. Kennaway, D. J. (2005) The role of circadian rhythmicity in reproduction, Hum. Reprod. Update, 11, 91-101, doi: 10.1093/humupd/dmh054.

24. Harada, Y., Sakai, M., Kurabayashi, N., Hirota, T., and Fukada, Y. (2005) Ser-557-phosphorylated mCRY2 is degraded upon synergistic phosphorylation by glycogen synthase kinase-3 beta, J. Biol. Chem., 280, 31714-3172110, doi: 1074/jbc.M506225200.

25. Alessandro, M. S., Golombek, D. A., and Chiesa, J. J. (2019) Protein kinases in the photic signaling of the mammalian circadian clock, Yale J. Biol. Med., 92, 241-250.

26. Morgunova, G. V., and Klebanov, A. A. (2019) Age-related AMP-activated protein kinase alterations: from cellular energetics to longevity, Cell Biochem. Funct., 37, 169-176, doi: 10.1002/cbf.3384.

27. Suter, D. M., and Schibler, U. (2009) Physiology. Feeding the clock, Science, 326, 378-379, doi: 10.1126/science.1181278.

28. Xue, M., Momiji, H., Rabbani, N., Bretschneider, T., Rand, D. A., and Thornalley, P. J. (2015) Frequency modulated translocational oscillations of Nrf2, a transcription factor functioning like a wireless sensor, Biochem. Soc. Trans., 43, 669-673, doi: 10.1042/BST20150060.

29. Lo, S. C., and Hannink, M. (2008) PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria, Exp. Cell Res., 314, 1789-1803, doi: 10.1016/j.yexcr.2008.02.014.

30. Theodore, M., Kawai, Y., Yang, J., Kleshchenko, Y., Reddy, S. P., Villalta, F., and Arinze, I. J. (2008) Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2, J. Biol. Chem., 283, 8984-8994, doi: 10.1074/jbc.M709040200.

31. Chowdhry, S., Zhang, Y., McMahon, M., Sutherland, C., Cuadrado, A., and Hayes, J. D. (2013) Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity, Oncogene, 32, 3765-3781, doi: 10.1038/onc.2012.388.

32. Rada, P., Rojo, A. I., Chowdhry, S., McMahon, M., Hayes, J. D., and Cuadrado, A. (2011) SCF/{ beta} -TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner, Mol. Cell. Biol., 31, 1121-1133, doi: 10.1128/MCB.01204-10.

33. Baird, L., Llères, D., Swift, S., and Dinkova-Kostova, A. T. (2013). Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex, Proc. Natl. Acad. Sci. USA, 110, 15259-15264, doi: 10.1073/pnas.1305687110.

34. Pekovic-Vaughan, V., Gibbs, J., Yoshitane, H., Yang, N., Pathiranage, D., et al. (2014) The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis, Genes Dev., 28, 548-560, doi: 10.1101/gad.237081.113.

35. Xu, Y.Q., Zhang, D., Jin, T., Cai, D. J., Wu, Q., et al. (2012) Diurnal variation of hepatic antioxidant gene expression in mice, PLoS One, 7, e44237, doi: 10.1371/journal.pone.0044237.

36. Early, J. O., Menon, D., Wyse, C. A., Cervantes-Silva, M. P., Zaslona, Z., et al. (2018) Circadian clock protein BMAL1 regulates IL-1β in macrophages via NRF2, Proc. Natl. Acad. Sci. USA, 115, 8460-8468, doi: 10.1073/pnas.1800431115.

37. Wible, R. S, Ramanathan, C., Sutter, C. H., Olesen, K. M., Kensler, T. W., et al. (2018) NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus, Elife, 7, e31656, doi: 10.7554/eLife.31656.

38. Spiers, J. G., Breda, C., Robinson, S., Giorgini, F., and Steinert, J. R. (2019) Drosophila Nrf2/Keap1 mediated redox signaling supports synaptic function and longevity and impacts on circadian activity, Front. Mol. Neurosci., 12, 86, doi: 10.3389/fnmol.2019.00086.

39. Hansen, J. M., Watson, W. H., and Jones, D. P. (2004) Compartmentation of Nrf2 redox control: regulation of cytoplasmic activation by glutathione and DNA binding by thioredoxin-1, Toxicol. Sci., 82, 308-317, doi: 10.1093/toxsci/kfh231.

40. Embi, N., Rylatt, D. B., and Cohen, P. (1980) Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase, Eur. J. Biochem., 107, 519-527, doi: 10.1111/j.1432-1033.1980.tb06059.x.

41. Doble, B. W., and Woodgett, J. R. (2003) GSK-3: tricks of the trade for a multi-tasking kinase, J. Cell. Sci., 116, 1175-1186, doi: 10.1242/jcs.00384.

42. Mukai, F., Ishiguro, K., Sano, Y., and Fujita, S. C. (2002) Alternative splicing isoform of tau protein kinase I/glycogen synthase kinase 3beta, J. Neurochem., 81, 1073-1083, doi: 10.1046/j.1471-4159.2002.00918.x.

43. Souder, D. C., and Anderson, R. M. (2019) An expanding GSK3 network: Implications for aging research, GeroScience, 41, 369-382, doi: 10.1007/s11357-019-00085-z.

44. Yang, K., Chen, Z., Gao, J., Shi, W., Li, L., et al. (2017) The key roles of GSK-3beta in regulating mitochondrial activity, Cell. Physiol. Biochem., 44, 1445-1459, doi: 10.1159/000485580.

45. Jaworski, T., Banach-Kasper, E., and Gralec, K. (2019) GSK-3β at the intersection of neuronal plasticity and neurodegeneration, Neural Plast., 2019, 4209475, doi: 10.1155/2019/4209475.

46. Alt, J. R. (2000) Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation, Genes Dev., 14, 3102-3114, doi: 10.1101/gad.854900.

47. Morfini, G., Szebenyi, G., Elluru, R., Ratner, N., and Brady, S. T. (2002) Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility, EMBO J., 21, 281-293, doi: 10.1093/emboj/21.3.281.

48. Iitaka, C., Miyazaki, K., Akaike, T., and Ishida, N. (2005) A role for glycogen synthase kinase-3β in the mammalian circadian clock, J. Biol. Chem., 280, 29397-29402, doi: 10.1074/jbc.M503526200.

49. Krishnankutty, A., Kimura, T., Saito, T., Aoyagi, K., Asada, A., et al. (2017) In vivo regulation of glycogen synthase kinase 3β activity in neurons and brains, Sci. Rep., 7, 8602, doi: 10.1038/s41598-017-09239-5.

50. Kaidanovich-Beilin, O., and Woodgett, J. R. (2011) GSK3: functional insights from cell biology and animal models, Front. Mol. Neurosci., 4, 40, doi: 10.3389/fnmol.2011.00040.

51. Lesort, M., Jope, R. S., and Johnson, G. V. (1999) Insulin transiently increases tau phosphorylation: involvement of glycogen synthase kinase-3beta and Fyn tyrosine kinase, J. Neurochem., 72, 576-584, doi: 10.1046/j.1471-4159.1999.0720576.x.

52. Beaulieu, J. M., Sotnikova, T. D., Marion, S., Lefkowitz, R. J., et al. (2011) An Akt/β-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior, Cell, 122, 261-273, doi: 10.1016/j.cell.2005.05.012.

53. Thornton, T. M., Pedraza-Alva, G., Deng, B., and Wood, C. D., Aronshtam, A., et al. (2008) Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation, Science, 320, 667-670, doi: 10.1126/science.1156037.

54. Zmijewski, J. W., and Jope, R. S. (2004) Nuclear accumulation of glycogen synthase kinase-3 during replicative senescence of human fibroblasts, Aging Cell, 3, 309-317, doi: 10.1111/j.1474-9728.2004.00117.x.

55. Iwahana, E., Hamada, T., Uchida, A., and Shibata, S. (2007) Differential effect of lithium on the circadian oscillator in young and old hamsters, Biochem. Biophys. Res. Commun., 354, 752-756, doi: 10.1016/j.bbrc.2007.01.042.

56. Hoshi, M., Takashima, A., Noguchi, K., Murayama, M., Sato, M., et al. (1996) Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain, Proc. Natl. Acad. Sci. USA, 93, 2719-2723, doi: 10.1073/pnas.93.7.2719.

57. Salcedo-Tello, P., Ortiz-Matamoros, A., and Arias, C. (2011) GSK3 function in the brain during development, neuronal plasticity, and neurodegeneration, Int. J. Alzheimers Dis., 11, 1-12, doi: 10.4061/2011/189728.

58. Martin, M., Rehani, K., Jope, R. S., and Michalek, S. M. (2005) Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3, Nat. Imunnol., 6, 777-784, doi: 10.1038/ni1221.

59. Sutherland, C. (2011) What are the bona fide GSK3 substrates? Int. J. Alzheimers Dis., 2011, 505-607, doi: 10.4061/2011/505607.

60. Robertson, H., Hayes, J. D., and Sutherland, C. A. (2018) A partnership with the proteasome; the destructive nature of GSK3, Biochem. Pharmacol., 147, 77-92, doi: 10.1016/j.bcp.2017.10.016.

61. Jin, J., Cardozo, T., Lovering, R. C., Elledge, S. J., Pagano, M., and Harper, J. W. (2004) Systematic analysis and nomenclature of mammalian F-box proteins, Genes Dev., 18, 2573-2580, doi: 10.1101/gad.1255304.

62. Siepka, S. M., Yoo, S. H., Park, J., Song, W., Kumar, V., et al. (2007) Circadian mutant overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression, Cell, 129, 1011-1023, doi: 10.1016/j.cell.2007.04.030.

63. Godinho, S. I., Maywood, E. S., Shaw, L., Tucci, V., Barnard, A. R., et al. (2007) The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period, Science, 316, 897-900, doi: 10.1126/science.1141138.

64. Shirogane, T., Jin, J., Ang, X. L., and Harper, J. W. (2005) SCFβ-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein, J. Biol. Chem., 280, 26863-26872, doi: 10.1074/jbc.M502862200.

65. Najumuddin, Fakhar, M., Gul, M., and Rashid, S. (2018) Interactive structural analysis of βTrCP1 and PER2 phosphoswitch binding through dynamics simulation assay, Arch. Biochem. Biophys., 651, 34-42, doi: 10.1016/j.abb.2018.05.020.

66. Cole, A., Frame, S., and Cohen, P. (2004) Further evidence that the tyrosine phosphorylation of glycogen synthase kinase-3 (GSK3) in mammalian cells is an autophosphorylation event, Biochem. J., 377, 249-255, doi: 10.1042/BJ20031259.

67. Beurel, E., Grieco, S. F., and Jope, R. S. (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases, Pharmacol. Ther., 148, 114-131, doi: 10.1016/j.pharmthera.2014.11.016.

68. Tsuchiya, Y., Taniguchi, H., Ito, Y., Morita, T., Karim, M. R., and Ohtake, N. (2013) The casein kinase 2-NRF1 axis controls the clearance of ubiquitinated proteins by regulating proteasome gene expression, Mol. Cell. Biol., 33, 3461-3472, doi: 10.1128/MCB.01271-12.

69. Zee, P. C., Attarian, H., and Videnovic, A. (2013) Circa-dian rhythm abnormalities, Continuum (Minneap. Minn), 19, 132-147, doi: 10.1212/01.CON.0000427209.21177.aa.

70. Patel, S. A., Velingkaar, N. S., and Kondratov, R. V. (2014) Transcriptional control of antioxidant defense by the circadian clock, Antioxid. Redox Signal., 20, 2997-3006, doi: 10.1089/ars.2013.5671.

71. Golombek, D. A., and Rosenstein, R. E. (2010) Physiology of circadian entrainment, Physiol. Rev., 90, 1063-1102, doi: 10.1152/physrev.00009.2009.

72. Oosthuizen, M. K., Bennett, N. C., and Cooper, H. M. (2005) Fos expression in the suprachiasmatic nucleus in response to light stimulation in a solitary and social species of African mole-rat (family Bathyergidae), Neuroscience, 133, 555-560, doi: 10.1016/j.neuroscience.2005.01.017.

73. Slominski, R. M., Reiter, R. J., Schlabritz-Loutsevitch, N., Ostrom, R. S., and Slominski, A. T. (2012) Melatonin membrane receptors in peripheral tissues: distribution and functions, Mol. Cell. Endocrinol., 351, 152-166, doi: 10.1016/j.mce.2012.01.004.

74. Fang, J., Yan, Y., Teng, X., Wen, X., Li, N., et al. (2018) Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating Nrf2 and inhibiting ER stress, Aging (Albany NY), 10, 2954-2972, doi: 10.18632/aging.101602.

75. Slominski, A. T., Zmijewski, M. A., and Jetten, A. M. (2016) RORα is not a receptor for melatonin (response to DOI: 10.1002/bies.201600018), Bioessays, 38, 1193-1194, doi: 10.1002/bies.201600204.

76. Fang, N., Hu, C., Sun, W., Xu, Y., Gu, Y., et al. (2020) Identification of a novel melatonin-binding nuclear receptor: vitamin D receptor, J. Pineal. Res., 68, e12618, doi: 10.1111/jpi.12618.

77. Iwahana, E., Akiyama, M., Miyakawa, K., Uchida, A., Kasahara, J., et al. (2004) Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase-3 protein expression in the mouse suprachiasmatic nuclei, Eur. Neurosci., 19, 2281-2287, doi: 10.1111/j.0953-816X.2004.03322.x.

78. Besing, R. C., Paul, J. R., Hablitz, L. M., Rogers, C. O., Johnson, R. L., et al. (2015) Circadian rhythmicity of active GSK3 isoforms modulates molecular clock gene rhythms in the suprachiasmatic nucleus, Biol. Rhythms, 30, 155-160, doi: 10.1177/0748730415573167.

79. Paul, J. R., McKeown, A. S., Davis, J. A., Totsch, S. K., Mintz, E. M., et al. (2017) Glycogen synthase kinase 3 regulates photic signaling in the suprachiasmatic nucleus, Eur. J. Neurosci., 45, 1102-1110, doi: 10.1111/ejn.13549.

80. Červená, K., Pačesová, D., Spišská, V., and Bendová, Z. (2015) Delayed effect of the light pulse on phosphorylated ERK1/2 and GSK3β Kinases in the ventrolateral suprachiasmatic nucleus of rat, Mol. Neurosci., 56, 371-376, doi: 10.1007/s12031-015-0563-0.

81. Besing, R. C., Rogers, C. O., Paul, J. R., Hablitz, L. M., Johnson, R. L., et al. (2017) GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity, Hippocampus, 27, 890-898, doi: 10.1002/hipo.22739.

82. Top, D., Harms, E., Syed, S., Adams, E. L., and Saez, L. (2016) GSK-3 and CK2 kinases converge on timeless to regulate the master clock, Cell Rep., 16, 357-367, doi: 10.1016/j.celrep.2016.06.005.

83. Kaladchibachi, S. A., Doble, B., Anthopoulos, N., Woodgett, J. R., and Manoukian, A. S. (2007) Glycogen synthase kinase 3, circadian rhythms, and bipolar disorder: a molecular link in the therapeutic action of lithium, J. Circadian Rhythms, 5, 3, doi: 10.1186/1740-3391-5-3.

84. Leloup, J. C., and Goldbeter, A. (2011) Modelling the dual role of Per phosphorylation and its effect on the period and phase of the mammalian circadian clock, IET Syst. Biol., 5, 44, doi: 10.1049/iet-syb.2009.0068.

85. Kurabayashi, N., Hirota, T., Sakai, M., Sanada, K., and Fukada, Y. (2010) DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping, Mol. Cell. Biol., 30, 1757-1768, doi: 10.1128/MCB.01047-09.

86. Sahar, S., Zocchi, L., Kinoshita, C., Borrelli, E., and Sassone-Corsi, P. (2010) Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation, PLoS One, 5, e8561, doi: 10.1371/journal.pone.0008561.

87. Spengler, M. L., Kuropatwinski, K. K., Schumer, M., and Antoch, M. P. (2009) A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation, Cell Cycle, 8, 4138-4146, doi: 10.4161/cc.8.24.10273.

88. Yin, L., Wang, J., Klein, P. S., and Lazar, M. A. (2006) Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock, Science, 311, 1002-1005, doi: 10.1126/science.1121613.

89. Martinek, S., Inonog, S., Manoukian, A. S., and Young, M. W. (2001) A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock, Cell, 105, 769-779, doi: 10.1016/s0092-8674(01)00383-x.

90. Li, J., Lu, W. Q., Beesley, S., Loudon, A. S., and Meng, Q. J. (2012) Lithium impacts on the amplitude and period of the molecular circadian clockwork, PLoS One, 7, e33292, doi: 10.1371/journal.pone.0033292.

91. Sawai, Y., Okamoto, T., Muranaka, Y., Nakamura, R., Matsumura, R., et al. (2019) In vivo evaluation of the effect of lithium on peripheral circadian clocks by real-time monitoring of clock gene expression in near-freely moving mice, Sci. Rep., 9, 10909, doi: 10.1038/s41598-019-47053-3.

92. Jope, R. S. (2003) Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol. Sci., 24, 441-443, doi: 10.1016/S0165-6147(03)00206-2.

93. Freland, L., and Beaulieu J. M. (2012) Inhibition of GSK3 by lithium, from single molecules to signaling networks, Front. Mol. Neurosci., 5, 14, doi: 10.3389/fnmol.2012.00014.

94. Siebel, A. M., Vianna, M. R., and Bonan, C. D. (2014) Pharmacological and toxicological effects oflithium in zebrafish, ACS Chem. Neurosci., 5, 468-476, doi: 10.1021/cn500046h.79.

95. Plotnikov, E. Y., Silachev, D. N., Zorova, L. D., Pevzner, I. B., Jankauskas, S. S., et al. (2014) Lithium salts – simple but magic, Biochemistry (Moscow), 79, 740-749, doi: 10.1134/S0006297914080021.

96. Padiath, Q. S, Paranjpe, D., Jain, S., and Sharma, V. K. (2004) Glycogen synthase kinase 3beta as a likely target for the action of lithium on circadian clocks, Chronobiol. Int., 21, 43-55, doi: 10.1081/cbi-120027981.

97. Wei, H., Landgraf, D., Wang, G., and McCarthy, M. J. (2018) Inositol polyphosphates contribute to cellular circadian rhythms: Implications for understanding lithium’s molecular mechanism, Cell. Signal., 44, 82-91, doi: 10.1016/j.cellsig.2018.01.001.

98. Paul, J. R., DeWoskin, D., McMeekin, L. J., Cowell, R. M., Forger, D. B., and Gamble, K. L. (2016) Regulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability, Nat. Commun., 7, 13470, doi: 10.1038/ncomms13470.

99. Kozikowski, A. P., Gunosewoyo, H., Guo, S., Gaisina, I. N., Walter, R. L., et al. (2011) Identification of a glycogen synthase kinase-3β inhibitor that attenuates hyperactivity in CLOCK mutant mice, ChemMedChem, 6, 1593-1602, doi: 10.1002/cmdc.201100188.

100. Paul, J. R., Johnson, R. L., Jope, R. S., and Gamble, K. L. (2012) Disruption of circadian rhythmicity and suprachiasmatic action potential frequency in a mouse model with constitutive activation of glycogen synthase kinase 3, Neuroscience, 226, 1-9, doi: 10.1016/j.neuroscience.2012.08.047.

101. Lavoie, J., Hébert, M., and Beaulieu, J. M. (2013) Glycogen synthase kinase-3β haploinsufficiency lengthens the circadian locomotor activity period in mice, Behav. Brain Res., 253, 262-265, doi: 10.1016/j.bbr.2013.08.001.

102. Kon, N., Sugiyama, Y., Yoshitane, H., Kameshita, I., and Fukada, Y. (2015) Cell-based inhibitor screening identifies multiple protein kinases important for circadian clock oscillations, Commun. Integr. Biol., 8, e982405, doi: 10.4161/19420889.2014.982405.

103. Hirota, T., Lewis, W. G., Liu, A. C., Lee, J. W., Schultz, P. G., and Kay, S. A. (2008) A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3beta, Proc. Natl. Acad. Sci. USA, 105, 20746-2075, doi: 10.1073/pnas.0811410106.

104. Serchov, T., Jilg, T., Radtke, I., Stehle, J. H., and Heumann, R. (2016) Ras activity oscillates in the mouse suprachiasmatic nucleus and modulates circadian clock dynamics, Mol. Neurobiol., 53, 1843-1855, doi: 10.1007/s12035-015-9135-0.

105. Ahnaou, A., and Drinkenburg, W. H. (2011) Disruption of glycogen synthase kinase-3-beta activity leads to abnormalities in physiological measures in mice, Behav. Brain Res., 221, 246-252, doi: 10.1016/j.bbr.2011.03.004.

106. Samson, D. R., and Nunn, C. L. (2015) Sleep intensity and the evolution of human cognition, Evol. Anthropol., 24, 225-237, doi: 10.1002/evan.21464.

107. Frolkis, V. V. (1982) Aging and Life-Prolonging Processes, Springer Verlag, Wien, New York.

108. Williams, G. C. (1957) Pleiotropy, natural selection and the evolution of senescence, Evolution, 11, 398-411, doi: 10.1111/j.1558-5646.1957.tb02911.x.

109. Asher, G., Gatfield, D., Stratmann, M., Reinke, H., Dibner, C., et al. (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation, Cell, 134, 317-328, doi: 10.1016/j.cell.2008.06.050.

110. Nakahata, Y., Kaluzova, M., Grimaldi, B., Sahar, S., Hirayama, J., et al. (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control, Cell, 134, 329-340, doi: 10.1016/j.cell.2008.07.002.

111. Tamaru, T., Hattori, M., Ninomiya, Y., Kawamura, G., Varès, G., et al. (2013) ROS stress resets circadian clocks to coordinate pro-survival signals, PLoS One, 8, e82006, doi: 10.1371/journal.pone.0082006.

112. Rey, G., Valekunja, U. K., Feeney, K. A., Wulund, L., Milev, N. B., et al. (2016) The pentose phosphate pathway regulates the circadian clock, Cell Metab., 24, 462-473, doi: 10.1016/j.cmet.2016.07.024.

113. Young, M. W., and Kay, S. A. (2001) Time zones: a comparative genetics of circadian clocks, Nat. Rev. Genet., 2, 702-715, doi: 10.1038/35088576.

114. Chaban, A. K., and Voronezhskaya, E. E. (2008) Involvement of transient larval neurons in osmoregulation and neurogenesis in the freshwater snails, Lymnaea stagnalis and Helisoma trivolvis, Acta Biol. Hung., 59 (Suppl.), 123-126, doi: 10.1556/ABiol.59.2008.Suppl.20.

115. Dilman, V. M. (1986) Ontogenetic model of ageing and disease formation and mechanisms of natural selection, J. Theor. Biol., 118, 73-81, doi: 10.1016/S0022-5193(86)80009-1.

116. Zinovkin, R. A., and Grebenchikov, O. A. (2020) Transcription factor Nrf2 as a potential therapeutic target for prevention of cytokine storm in COVID-19 patients, Biochemistry (Moscow), 85, 833-837, doi: 10.1134/s00062920070111.

117. Cuadrado, A., Pajares, M., Benito, C., Jiménez-Villegas, J., Escoll, M., et al. (2020) Can activation of NRF2 be a strategy against COVID-19? Trends Pharmacol. Sci., 41, 598-610, doi: 10.1016/j.tips.2020.07.003.

118. Egea, J., Buendia, I., Parada, E., Navarro, E., Cuadrado, P., et al. (2015) Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a “drug-prodrug” mechanism of action, Br. J. Pharmacol., 172, 1807-1821, doi: 10.1111/bph.13025.

119. Cecon, E., Oishi, A., and Jockers, R. (2018) Melatonin receptors: molecular pharmacology and signalling in the context of system bias, Br. J. Pharmacol., 175, 3263-3280, doi: 10.1111/bph.13950.

120. Gameiro, I., Michalska, P., Tenti, G., Cores, Á., Buendia, I., et al. (2017) Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease, Sci. Rep., 7, 45701, doi: 10.1038/srep45701.