褪黑素在感染性疾病治疗中的作用机制

doi:10.20199/j.issn.1672-2302.2024.05.012

摘要/Abstract

摘要：

褪黑素（melatonin, MT）是一种内源性激素，可作为安全有效的睡眠辅助剂用于调节昼夜周期。除传统功能之外，越来越多的研究表明褪黑素可以在感染性疾病的治疗中发挥重要作用。褪黑素在感染性疾病中的治疗作用机制主要涉及调控氧化应激减轻感染造成的组织损伤以及调控昼夜节律增强免疫功能两方面。此外，褪黑素还可以通过调节Th1/Th2发育及分化、NF-κB的磷酸化等方面发挥抗炎效应，并影响细胞凋亡途径等发挥一定的抗感染作用。本文概述褪黑素在感染性疾病治疗中的研究现状及上述作用机制，以期为褪黑素在临床抗感染领域的应用提供理论依据。

关键词: 褪黑素, 感染性疾病, 氧化应激, 免疫调节, 抗炎, 抑制凋亡

Abstract:

Melatonin (MT) is an endogenous hormone that acts as a safe and effective sleep aid for regulating the circadian cycle. In addition to its traditional functions, more researches suggest that MT can play an important role in the treatment of infectious diseases. The therapeutic mechanism of MT in infectious diseases mainly involves the effect of reducing tissue damage caused by infection via regulating oxidative stress and enhancing immune function induced by regulating circadian rhythm to recruit immune cells. Moreover, MT can exert an anti-inflammatory effect by regulating Th1/Th2 development and differentiation, NF-κB phosphorylation and so on, and affect the apoptosis pathway to play a certain anti-infective effect. Based on the above functions of MT, this article summarizes the research status and mechanism of MT in the treatment of infectious diseases in order to provide a theoretical basis for the application of MT against infection in clinical settings.

Key words: Melatonin, Infectious diseases, Oxidative stress, Immunomodulation, Anti-inflammatory, Apoptosis inhibition

中图分类号:

R183

高洋, 关飞, 雷家慧. 褪黑素在感染性疾病治疗中的作用机制[J]. 热带病与寄生虫学, 2024, 22(5): 315-320.

GAO Yang, GUAN Fei, LEI Jiahui. Role and mechanism of melatonin in the treatment of infectious diseases[J]. Journal of Tropical Diseases and Parasitology, 2024, 22(5): 315-320.

参考文献 89

[1]	Bagnaresi P, Nakabashi M, Thomas AP, et al. The role of melatonin in parasite biology[J]. Mol Biochem Parasitol, 2012, 181(1):1-6.
[2]	Acuña-Castroviejo D, Escames G, Venegas C, et al. Extrapineal melatonin: sources, regulation, and potential functions[J]. Cell Mol Life Sci, 2014, 71(16):2997-3025. doi: 10.1007/s00018-014-1579-2 pmid: 24554058
[3]	Minich DM, Henning M, Darley C, et al. Is melatonin the "next vitamin D" ?: a review of emerging science, clinical uses, safety, and dietary supplements[J]. Nutrients, 2022, 14(19):3934.
[4]	Tan DX, Manchester LC, Esteban-Zubero E, et al. Melatonin as a potent and inducible endogenous antioxidant: synthesis and metabolism[J]. Molecules, 2015, 20(10):18886-18906.
[5]	Mistraletti G, Paroni R, Umbrello M, et al. Melatonin pharmacological blood levels increase total antioxidant capacity in critically ill patients[J]. Int J Mol Sci, 2017, 18(4):759.
[6]	Carrillo-Vico A, Lardone PJ, Alvarez-Sánchez N, et al. Melatonin: buffering the immune system[J]. Int J Mol Sci, 2013, 14(4):8638-8683. doi: 10.3390/ijms14048638 pmid: 23609496
[7]	Mocayar Marón FJ, Ferder L, Reiter RJ, et al. Daily and seasonal mitochondrial protection: unraveling common possible mechanisms involving vitamin D and melatonin[J]. J Steroid Biochem Mol Biol, 2020,199:105595.
[8]	Amstrup AK, Sikjaer T, Heickendorff L, et al. Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial[J]. J Pineal Res, 2015, 59(2):221-229. doi: 10.1111/jpi.12252 pmid: 26036434
[9]	Messina G, Lissoni P, Marchiori P, et al. Enhancement of the efficacy of cancer chemotherapy by the pineal hormone melatonin and its relation with the psychospiritual status of cancer patients[J]. J Res Med Sci, 2010, 15(4):225-228. pmid: 21526086
[10]	Furio AM, Brusco LI, Cardinali DP. Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study[J]. J Pineal Res, 2007, 43(4):404-409. pmid: 17910609
[11]	Zhao W, Wang L, Zhang L. How does academia respond to the burden of infectious and parasitic disease?[J]. Health Res Policy Syst, 2022, 20(1):89.
[12]	靳莉, 徐超, 张华, 等. 褪黑素调控MEG3/miR-223/NLRP3轴对流感病毒感染小鼠模型肺损伤的影响[J]. 中国免疫学杂志, 2023, 39(12):2528-2533.
[13]	桑伊妙, 潘璐璐, 顾孝红, 等. 褪黑素在病毒性心肌炎中的保护作用[J]. 医学研究杂志, 2017, 46(7):52-56,136.
[14]	Valko M, Rhodes CJ, Moncol J, et al. Free radicals, metals and antioxidants in oxidative stress-induced cancer[J]. Chem Biol Interact, 2006, 160(1):1-40.
[15]	Galano A, Tan DX, Reiter RJ. On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK[J]. J Pineal Res, 2013, 54(3):245-257. doi: 10.1111/jpi.12010 pmid: 22998574
[16]	Reiter RJ, Mayo JC, Tan DX, et al. Melatonin as an antioxidant: under promises but over delivers[J]. J Pineal Res, 2016, 61(3):253-278. doi: 10.1111/jpi.12360 pmid: 27500468
[17]	Tan DX, Manchester LC, Reiter RJ, et al. Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation[J]. Free Radic Biol Med, 2000, 29(11):1177-1185.
[18]	Tapias V, Escames G, López LC, et al. Melatonin and its brain metabolite N¹-acetyl-5-methoxykynuramine prevent mitochondrial nitric oxide synthase induction in parkinsonian mice[J]. J Neurosci Res, 2009, 87(13):3002-3010.
[19]	Ortiz F, García JA, Acuña-Castroviejo D, et al. The beneficial effects of melatonin against heart mitochondrial impairment during sepsis: inhibition of iNOS and preservation of nNOS[J]. J Pineal Res, 2014, 56(1):71-81. doi: 10.1111/jpi.12099 pmid: 24117944
[20]	López A, García JA, Escames G, et al. Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production[J]. J Pineal Res, 2009, 46(2):188-198. doi: 10.1111/j.1600-079X.2008.00647.x pmid: 19054298
[21]	Agil A, El-Hammadi M, Jiménez-Aranda A, et al. Melatonin reduces hepatic mitochondrial dysfunction in diabetic obese rats[J]. J Pineal Res, 2015, 59(1):70-79. doi: 10.1111/jpi.12241 pmid: 25904243
[22]	Deng ZY, He M, Hu HB, et al. Melatonin attenuates sepsis-induced acute kidney injury by promoting mitophagy through SIRT3-mediated TFAM deacetylation[J]. Autophagy, 2024, 20(1):151-165.
[23]	Zatta P, Tognon G, Carampin P. Melatonin prevents free radical formation due to the interaction between beta-amyloid peptides and metal ions[Al(III), Zn(II), Cu(II), Mn(II), Fe(II)][J]. J Pineal Res, 2003, 35(2):98-103.
[24]	Parmar P, Limson J, Nyokong T, et al. Melatonin protects against copper-mediated free radical damage[J]. J Pineal Res, 2002, 32(4):237-242. pmid: 11982793
[25]	Anhê GF, Caperuto LC, Pereira-Da-Silva M, et al. In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus[J]. J Neurochem, 2004, 90(3):559-566.
[26]	Szanto A, Balint BL, Nagy ZS, et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPARγ-regulated gene expression in macrophages and dendritic cells[J]. Immunity, 2010, 33(5):699-712.
[27]	Xia YY, Chen SY, Zeng SJ, et al. Melatonin in macrophage biology: Current understanding and future perspectives[J]. J Pineal Res, 2019, 66(2):e12547.
[28]	Alonso M, Collado PS, González-Gallego J. Melatonin inhibits the expression of the inducible isoform of nitric oxide synthase and nuclear factor kappa B activation in rat skeletal muscle[J]. J Pineal Res, 2006, 41(1):8-14. doi: 10.1111/j.1600-079X.2006.00323.x pmid: 16842535
[29]	Matute JD, Arias AA, Wright NA, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity[J]. Blood, 2009, 114(15):3309-3315. doi: 10.1182/blood-2009-07-231498 pmid: 19692703
[30]	Winterbourn CC, Hampton MB, Livesey JH, et al. Modeling the reactions of superoxide and myeloperoxidase in the neutrophil phagosome:implications for microbial killing[J]. J Biol Chem, 2006, 281(52):39860-39869. doi: 10.1074/jbc.M605898200 pmid: 17074761
[31]	Aycicek A, Iscan A, Erel O, et al. Oxidant and antioxidant parameters in the treatment of meningitis[J]. Pediatr Neurol, 2007, 37(2):117-120. pmid: 17675026
[32]	Gerber J, Lotz M, Ebert S, et al. Melatonin is neuroprotective in experimental Streptococcus pneumoniae meningitis[J]. J Infect Dis, 2005, 191(5):783-790.
[33]	Spreer A, Gerber J, Baake D, et al. Antiinflammatory but no neuroprotective effects of melatonin under clinical treatment conditions in rabbit models of bacterial meningitis[J]. J Neurosci Res, 2006, 84(7):1575-1579. pmid: 16998917
[34]	Sener G, Tuğtepe H, Velioğlu-Oğünç A, et al. Melatonin prevents neutrophil-mediated oxidative injury in Escherichia coli-induced pyelonephritis in rats[J]. J Pineal Res, 2006, 41(3):220-227.
[35]	Gitto E, Pellegrino S, Gitto P, et al. Oxidative stress of the newborn in the pre- and postnatal period and the clinical utility of melatonin[J]. J Pineal Res, 2009, 46(2):128-139. doi: 10.1111/j.1600-079X.2008.00649.x pmid: 19054296
[36]	Ciriolo MR, Palamara AT, Incerpi S, et al. Loss of GSH, oxidative stress, and decrease of intracellular pH as sequential steps in viral infection[J]. J Biol Chem, 1997, 272(5):2700-2708. doi: 10.1074/jbc.272.5.2700 pmid: 9006907
[37]	To EE, Vlahos R, Luong R, et al. Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy[J]. Nat Commun, 2017, 8(1):69. doi: 10.1038/s41467-017-00057-x pmid: 28701733
[38]	Kirkby NS, Zaiss AK, Wright WR, et al. Differential COX-2 induction by viral and bacterial PAMPs: consequences for cytokine and interferon responses and implications for anti-viral COX-2 directed therapies[J]. Biochem Biophys Res Commun, 2013, 438(2):249-256.
[39]	Guo CH, Chen PC, Lin KP, et al. Trace metal imbalance associated with oxidative stress and inflammatory status in anti-hepatitis C virus antibody positive subjects[J]. Environ Toxicol Pharmacol, 2012, 33(2):288-296.
[40]	Capone F, Guerriero E, Sorice A, et al. Characterization of metalloproteinases, oxidative status and inflammation levels in the different stages of fibrosis in HCV patients[J]. Clin Biochem, 2012, 45(7/8):525-529.
[41]	Soto ME, Pérez-Torres I, Manzano-Pech L, et al. Redox homeostasis alteration is restored through melatonin treatment in COVID-19 patients: a preliminary study[J]. Int J Mol Sci, 2024, 25(8):4543.
[42]	Huang SH, Cao XJ, Liu W, et al. Inhibitory effect of melatonin on lung oxidative stress induced by respiratory syncytial virus infection in mice[J]. J Pineal Res, 2010, 48(2):109-116.
[43]	Valero N, Mosquera J, Alcocer S, et al. Melatonin, minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental Venezuelan equine encephalitis[J]. Brain Res, 2015,1622:368-376.
[44]	Guha M, Maity P, Choubey V, et al. Melatonin inhibits free radical-mediated mitochondrial-dependent hepatocyte apoptosis and liver damage induced during malarial infection[J]. J Pineal Res, 2007, 43(4):372-381. doi: 10.1111/j.1600-079X.2007.00488.x pmid: 17910606
[45]	Brazão V, Colato RP, Santello FH, et al. Interleukin-17, oxidative stress, and inflammation: role of melatonin during Trypanosoma cruzi infection[J]. J Pineal Res, 2015, 59(4):488-496. doi: 10.1111/jpi.12280 pmid: 26432539
[46]	El-Sokkary GH, Omar HM, Hassanein AF, et al. Melatonin reduces oxidative damage and increases survival of mice infected with Schistosoma mansoni[J]. Free Radic Biol Med, 2002, 32(4):319-332.
[47]	Buijs RM, Markman M, Nunes-Cardoso B, et al. Projections of the suprachiasmatic nucleus to stress-related areas in the rat hypothalamus: a light and electron microscopic study[J]. J Comp Neurol, 1993, 335(1):42-54. pmid: 7691904
[48]	van der Beek EM, Horvath TL, Wiegant VM, et al. Evidence for a direct neuronal pathway from the suprachiasmatic nucleus to the gonadotropin-releasing hormone system: combined tracing and light and electron microscopic immunocytochemical studies[J]. J Comp Neurol, 1997, 384(4):569-579. pmid: 9259490
[49]	Buijs RM, Wortel J, van Heerikhuize JJ, et al. Anatomical and functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway[J]. Eur J Neurosci, 1999, 1(5):1535-1544.
[50]	Weaver DR, Reppert SM. The Mel1a melatonin receptor gene is expressed in human suprachiasmatic nuclei[J]. Neuroreport, 1996, 8(1):109-112. pmid: 9051762
[51]	Redman J, Armstrong S, Ng KT. Free-running activity rhythms in the rat: entrainment by melatonin[J]. Science, 1983, 219(4588):1089-1091. pmid: 6823571
[52]	崔素颖, 秦宇, 张永鹤. 睡眠调控与睡眠调节药物研究进展[J]. 中国药理学与毒理学杂志, 2022, 36(11):801-811.
[53]	Huang N, Chelliah Y, Shan YL, et al. Crystal structure of the heterodimeric CLOCK: BMAL1 transcriptional activator complex[J]. Science, 2012, 337(6091):189-194. doi: 10.1126/science.1222804 pmid: 22653727
[54]	Kornmann B, Schaad O, Bujard H, et al. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock[J]. PLoS Biol, 2007, 5(2):e34.
[55]	Dinet V, Ansari N, Torres-Farfan C, et al. Clock gene expression in the retina of melatonin-proficient (C3H) and melatonin-deficient (C57BL) mice[J]. J Pineal Res, 2007, 42(1):83-91. pmid: 17198542
[56]	Fu SQ, Kuwahara M, Uchida Y, et al. Circadian production of melatonin in cartilage modifies rhythmic gene expression[J]. J Endocrinol,2019:JOE-J19-0022. R2.
[57]	Dimitrov S, Benedict C, Heutling D, et al. Cortisol and epinephrine control opposing circadian rhythms in T cell subsets[J]. Blood, 2009, 113(21):5134-5143. doi: 10.1182/blood-2008-11-190769 pmid: 19293427
[58]	Petrovsky N, McNair P, Harrison LC. Diurnal rhythms of pro-inflammatory cytokines: regulation by plasma cortisol and therapeutic implications[J]. Cytokine, 1998, 10(4):307-312. doi: 10.1006/cyto.1997.0289 pmid: 9617577
[59]	Esquifino AI, Selgas L, Arce A, et al. Twenty-four-hour rhythms in immune responses in rat submaxillary lymph nodes and spleen: effect of cyclosporine[J]. Brain Behav Immun, 1996, 10(2):92-102. pmid: 8811933
[60]	Engeset A, Sokolowski J, Olszewski WL. Variation in output of leukocytes and erythrocytes in human peripheral lymph during rest and activity[J]. Lymphology, 1977, 10(4):198-203. pmid: 609275
[61]	Scheiermann C, Kunisaki Y, Frenette PS. Circadian control of the immune system[J]. Nat Rev Immunol, 2013,13:190-198.
[62]	Nguyen KD, Fentress SJ, Qiu YF, et al. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes[J]. Science, 2013, 341(6153):1483-1488. doi: 10.1126/science.1240636 pmid: 23970558
[63]	Maury E, Navez B, Brichard SM. Circadian clock dysfunction in human omental fat links obesity to metabolic inflammation[J]. Nat Commun, 2021,12:2388.
[64]	Early JO, Menon D, Wyse CA, et al. Circadian clock protein BMAL1 regulates IL-1β in macrophages via NRF2[J]. Proc Natl Acad Sci USA, 2018, 115(36):E8460-E8468.
[65]	Gagnidze K, Hajdarovic KH, Moskalenko M, et al. Nuclear receptor REV-ERBα mediates circadian sensitivity to mortality in murine vesicular stomatitis virus-induced encephalitis[J]. Proc Natl Acad Sci USA, 2016, 113(20):5730-5735. doi: 10.1073/pnas.1520489113 pmid: 27143721
[66]	Bonilla E, Valero-Fuenmayor N, Pons H, et al. Melatonin protects mice infected with Venezuelan equine encephalomyelitis virus[J]. Cell Mol Life Sci, 1997, 53(5):430-434. doi: 10.1007/s000180050051 pmid: 9176561
[67]	Zarezadeh M, Khorshidi M, Emami M, et al. Melatonin supplementation and pro-inflammatory mediators: a systematic review and meta-analysis of clinical trials[J]. Eur J Nutr, 2020, 59(5):1803-1813. doi: 10.1007/s00394-019-02123-0 pmid: 31679041
[68]	Shaji AV, Kulkarni SK, Agrewala JN. Regulation of secretion of IL-4 and IgG1 isotype by melatonin-stimulated ovalbumin-specific T cells[J]. Clin Exp Immunol, 2001, 111(1):181-185.
[69]	Liu ZJ, Gan L, Xu YT, et al. Melatonin alleviates inflammasome-induced pyroptosis through inhibiting NF-κB/GSDMD signal in mice adipose tissue[J]. J Pineal Res, 2017, 63(1):e12414.
[70]	Zhang Y, Li XR, Grailer JJ, et al. Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome[J]. J Pineal Res, 2016, 60(4):405-414. doi: 10.1111/jpi.12322 pmid: 26888116
[71]	Bishayi B, Adhikary R, Nandi A, et al. Beneficial effects of exogenous melatonin in acute Staphylococcus aureus and Escherichia coli infection-induced inflammation and associated behavioral response in mice after exposure to short photoperiod[J]. Inflammation, 2016, 39(6):2072-2093.
[72]	Wu UI, Mai FD, Sheu JN, et al. Melatonin inhibits microglial activation, reduces pro-inflammatory cytokine levels, and rescues hippocampal neurons of adult rats with acute Klebsiella pneumoniae meningitis[J]. J Pineal Res, 2011, 50(2):159-170.
[73]	Lowes DA, Webster NR, Murphy MP, et al. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis[J]. Br J Anaesth, 2013, 110(3):472-480. doi: 10.1093/bja/aes577 pmid: 23381720
[74]	Shang Y, Xu SP, Wu Y, et al. Melatonin reduces acute lung injury in endotoxemic rats[J]. Chin Med J, 2009, 122(12):1388-1393.
[75]	Kitidee K, Samutpong A, Pakpian N, et al. Antiviral effect of melatonin on Japanese encephalitis virus infection involves inhibition of neuronal apoptosis and neuroinflammation in SH-SY5Y cells[J]. Sci Rep, 2023, 13(1):6063. doi: 10.1038/s41598-023-33254-4 pmid: 37055489
[76]	Alizadeh Z, Keyhanian N, Ghaderkhani S, et al. A pilot study on controlling coronavirus disease 2019 (COVID-19) inflammation using melatonin supplement[J]. Iran J Allergy Asthma Immunol, 2021, 20(4):494-499. pmid: 34418903
[77]	Huang SH, Cao XJ, Wei W. Melatonin decreases TLR3-mediated inflammatory factor expression via inhibition of NF-kappa B activation in respiratory syncytial virus-infected RAW264. 7 macrophages[J]. J Pineal Res, 2008, 45(1):93-100.
[78]	Yin M, Marrone L, Peace CG, et al. NLRP3,the inflammasome and COVID-19 infection[J]. QJM, 2023, 116(7):502-507.
[79]	Peng ZY, Zhang WX, Qiao JF, et al. Melatonin attenuates airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1β in rats with COPD[J]. Int Immunopharmacol, 2018,62:23-28.
[80]	Cardinali DP, Brown GM, Pandi-Perumal SR. Can melatonin be a potential “silver bullet” in treating COVID-19 patients?[J]. Diseases, 2020, 8(4):E44.
[81]	Lan SH, Lee HZ, Chao CM, et al. Efficacy of melatonin in the treatment of patients with COVID-19:a systematic review and meta-analysis of randomized controlled trials[J]. J Med Virol, 2022, 94(5):2102-2107.
[82]	Eskes R, Desagher S, Antonsson B, et al. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane[J]. Mol Cell Biol, 2000, 20(3):929-935. doi: 10.1128/MCB.20.3.929-935.2000 pmid: 10629050
[83]	Tuñón MJ, San Miguel B, Crespo I, et al. Melatonin attenuates apoptotic liver damage in fulminant hepatic failure induced by the rabbit hemorrhagic disease virus[J]. J Pineal Res, 2011, 50(1):38-45. doi: 10.1111/j.1600-079X.2010.00807.x pmid: 20964705
[84]	García-Lastra R, San-Miguel B, Crespo I, et al. Signaling pathways involved in liver injury and regeneration in rabbit hemorrhagic disease, an animal model of virally-induced fulminant hepatic failure[J]. Vet Res, 2010, 41(1):2. doi: 10.1051/vetres/2009050 pmid: 19726019
[85]	Wang XM, Liu T, Lv X, et al. A potential nontraditional approach to combat tmexCD1-toprJ1-Mediated tigecycline resistance: melatonin as a synergistic adjuvant of tigecycline[J]. Antimicrob Agents Chemother, 2023, 67(7):e0004723.
[86]	Seabra ML, Bignotto M, Pinto LR Jr, et al. Randomized,double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment[J]. J Pineal Res, 2000, 29(4):193-200. doi: 10.1034/j.1600-0633.2002.290401.x pmid: 11068941
[87]	Masadeh MM, Alzoubi KH, Al-Azzam SI, et al. Ciprofloxacin-induced antibacterial activity is atteneuated by pretreatment with antioxidant agents[J]. Pathogens, 2016, 5(1):28.
[88]	Santello FH, Frare EO, Caetano LC, et al. Melatonin enhances pro-inflammatory cytokine levels and protects against Chagas disease[J]. J Pineal Res, 2008, 45(1):79-85. doi: 10.1111/j.1600-079X.2008.00558.x pmid: 18284549
[89]	Di WC, Jin ZX, Lei WR, et al. Protection of melatonin treatment and combination with traditional antibiotics against septic myocardial injury[J]. Cell Mol Biol Lett, 2023, 28(1):35. doi: 10.1186/s11658-022-00415-8 pmid: 37101253