{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:43:58Z","timestamp":1789087438329,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution \u2018Petrovsky National Research Centre of Surgery\u2019","award":["122030200535-1"],"award-info":[{"award-number":["122030200535-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Circadian rhythm disruption induced by exposure to light\u2014excessive in duration and intensity (dark deprivation)\u2014and the impact of hepatotoxins are both significant risk factors for liver pathology. The purpose of this research was to evaluate the potentially synergistic effects of continuous lighting and carbon tetrachloride (CCl4) toxicity on the structural and functional organization and daily (circadian) rhythmicity of the liver in rats, as well as to look at the corrective capability of exogenous melatonin under such influences. The experiment was conducted on 200 outbred 6-month-old Wistar rat males, which were distributed into five groups, including a control (normal light\/dark cycle), dark deprivation (constant light), CCl4 intoxication, and combined exposure to CCl4 and dark deprivation with or without melatonin administration (0.3 mg\/kg). Histological, immunohistochemical (Ki-67, Per2, and Bmal1), biochemical, and ELISA methods were used. Circadian rhythms were analyzed using cosinor. It was shown that dark deprivation and CCl4 intoxication act synergistically, potentiating liver damage. The most severe necrosis (54.17 \u00b1 9.13%), steatosis (57.85 \u00b1 12.14%), and suppression of regenerative potential (decreased proportion of binucleated hepatocytes to 2.17 \u00b1 0.21%) were observed in the group with combined exposure. This correlated with a substantial decline in melatonin content in blood plasma (7.85 \u00b1 2.1 pg\/mL) and a profound disruption in circadian rhythms. Administration of exogenous melatonin exerted pronounced hepatoprotective and chronotropic effects: it significantly reduced pathological changes (necrosis reduced to 16.35 \u00b1 6.17%), stimulated regeneration (binucleated hepatocytes increased to 13.57 \u00b1 0.81%), and restored the circadian rhythms of the studied parameters to levels close to those of the control. The key pathogenetic link in the potentiation of CCl4 hepatotoxicity under dark deprivation is light-induced deficiency of endogenous melatonin. Exogenous melatonin demonstrated high efficacy in correcting both structural and functional damage and liver desynchronosis, confirming its therapeutic potential under conditions of combined exposure to chronodisruptors and toxins.<\/jats:p>","DOI":"10.3390\/cimb47121046","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T13:32:37Z","timestamp":1765805557000},"page":"1046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Corrective Role of Melatonin in Synergism of Dark Deprivation and CCl4 Intoxication in the Pathogenesis of Liver Damage a in Rats"],"prefix":"10.3390","volume":"47","author":[{"given":"Sevil A.","family":"Grabeklis","sequence":"first","affiliation":[{"name":"Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 117418 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liudmila M.","family":"Mikhaleva","sequence":"additional","affiliation":[{"name":"Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 117418 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander M.","family":"Dygai","sequence":"additional","affiliation":[{"name":"Research Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rositsa A.","family":"Vandysheva","sequence":"additional","affiliation":[{"name":"Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 117418 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna I.","family":"Anurkina","sequence":"additional","affiliation":[{"name":"Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 117418 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Kozlova","sequence":"additional","affiliation":[{"name":"Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 117418 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3006-6281","authenticated-orcid":false,"given":"David A.","family":"Areshidze","sequence":"additional","affiliation":[{"name":"Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 117418 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.bbadis.2018.08.037","article-title":"Animal models of drug-induced liver injury","volume":"1865","author":"McGill","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"154020","DOI":"10.1016\/j.tox.2024.154020","article-title":"Preclinical liver toxicity models: Advantages, limitations and recommendations","volume":"511","author":"Ezhilarasan","year":"2025","journal-title":"Toxicology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"C1158","DOI":"10.1152\/ajpcell.00551.2022","article-title":"Circadian regulation of liver metabolism: Experimental approaches in human, rodent, and cellular models","volume":"325","author":"Daniels","year":"2023","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13054-018-2041-x","article-title":"Clinical chronobiology: A timely consideration in critical care medicine","volume":"22","author":"McKenna","year":"2018","journal-title":"Crit. Care"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Walker, W.H., Bumgarner, J.R., and Walton, J.C. (2020). Light Pollution and Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249360"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1146\/annurev.pharmtox.47.120505.105208","article-title":"Circadian rhythms: Mechanisms and therapeutic implications","volume":"47","author":"Levi","year":"2007","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e14239","DOI":"10.1111\/apha.14239","article-title":"Getting in the zone: Metabolite transport across liver zones","volume":"240","author":"Paulusma","year":"2024","journal-title":"Acta Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/S0092-8674(00)81199-X","article-title":"A serum shock induces circadian gene expression in mammalian tissue culture cells","volume":"93","author":"Balsalobre","year":"1998","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/liv.15501","article-title":"Circadian rhythms and the liver","volume":"43","author":"Costa","year":"2023","journal-title":"Liver Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1038\/s41591-018-0271-8","article-title":"The emerging link between cancer, metabolism, and circadian rhythms","volume":"24","author":"Masri","year":"2018","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1017\/S0029665118000198","article-title":"Dark matters: Effects of light at night on metabolism","volume":"Volume 77","author":"Nelson","year":"2018","journal-title":"Proceedings of the Nutrition Society"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Talib, W.H., Alsayed, A.R., Abuawad, A., Daoud, S., and Mahmod, A.I. (2021). Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities. Molecules, 26.","DOI":"10.3390\/molecules26092506"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1615\/CritRevOncog.2021039881","article-title":"Circadian Rhythm and Melatonin in Liver Carcinogenesis: Updates on Current Findings","volume":"26","author":"Han","year":"2021","journal-title":"Crit. Rev. Oncog."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"83686","DOI":"10.1007\/s11356-022-21655-3","article-title":"Influence of constant lightning on liver health: An experimental study","volume":"29","author":"Areshidze","year":"2022","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13030-019-0163-2","article-title":"Weight loss in conservative treatment of obesity in women is associated with physical activity and circadian phenotype: A longitudinal observational study","volume":"13","author":"Schneider","year":"2019","journal-title":"Biopsychosoc. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4199","DOI":"10.1002\/ptr.8367","article-title":"Insights Into Effects of Natural Bioactive Components on Inflammatory Diseases in Respiratory Tract","volume":"39","author":"Luo","year":"2025","journal-title":"Phytother. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e12639","DOI":"10.1111\/jpi.12639","article-title":"Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies","volume":"68","author":"Sato","year":"2020","journal-title":"J. Pineal Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2740","DOI":"10.1002\/jcp.30735","article-title":"Beneficial effects of melatonin on liver fibrosis: A systematic review of current biological evidence","volume":"237","author":"Mauriz","year":"2022","journal-title":"J. Cell. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4828","DOI":"10.2174\/1381612819666131119102155","article-title":"Protective role of melatonin in liver damage","volume":"20","author":"Chojnacki","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.phrs.2016.01.018","article-title":"Melatonin\u2019s role in preventing toxin-related and sepsis-mediated hepatic damage: A review","volume":"105","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Grabeklis, S.A., Kozlova, M.A., and Mikhaleva, L.M. (2024). Effect of Constant Illumination on the Morphofunctional State and Rhythmostasis of Rat Livers at Experimental Toxic Injury. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252212476"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1007\/s00210-020-01810-8","article-title":"\u03b2-Sitosterol attenuates carbon tetrachloride-induced oxidative stress and chronic liver injury in rats","volume":"393","author":"Devaraj","year":"2020","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_23","first-page":"70","article-title":"Effect of light regimens and melatonin on homeostasis, life span and spontaneous tumorigenesis in male rats","volume":"54","author":"Vinogradova","year":"2008","journal-title":"Vopr. Onkol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1016\/j.lfs.2005.04.013","article-title":"Melatonin ameliorates carbon tetrachloride-induced hepatic fibrogenesis in rats via inhibition of oxidative stress","volume":"77","author":"Wang","year":"2005","journal-title":"Life Sci."},{"key":"ref_25","first-page":"78","article-title":"In vivo hepatic oxidative stress because of carbon tetrachloride toxicity: Protection by melatonin and pinoline","volume":"49","author":"Aranda","year":"2010","journal-title":"J. Pineal Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s10565-006-0019-y","article-title":"Comparison of the effects of melatonin and pentoxifylline on carbon tetrachloride-induced liver toxicity in mice","volume":"22","author":"Noyan","year":"2006","journal-title":"Cell Biol. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.molmed.2019.02.006","article-title":"Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation","volume":"25","author":"Lazzeri","year":"2019","journal-title":"Trends Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/BF01923944","article-title":"Calmodulin mediates melatonin cytoskeletal effects","volume":"49","year":"1993","journal-title":"Experientia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0024-3205(93)90670-X","article-title":"Binding of 3H-melatonin to calmodulin","volume":"53","year":"1993","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kozlova, M.A., Kirillov, Y.A., Makartseva, L.A., Chernov, I., and Areshidze, D.A. (2021). Morphofunctional State and Circadian Rhythms of the Liver under the Influence of Chronic Alcohol Intoxication and Constant Lighting. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313007"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1007\/s11596-022-2530-7","article-title":"Melatonin Alleviates Liver Fibrosis by Inhibiting Autophagy","volume":"42","author":"Jie","year":"2022","journal-title":"Curr. Med. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4015","DOI":"10.1002\/jcp.26209","article-title":"Melatonin application in targeting oxidative-induced liver injuries: A review","volume":"233","author":"Mortezaee","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Hardeland, R. (2019). Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051223"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1111\/jpi.12404","article-title":"Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice","volume":"62","author":"Das","year":"2017","journal-title":"J. Pineal Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e21803","DOI":"10.1096\/fj.202002556RRR","article-title":"Melatonin induces Nrf2-HO-1 reprogramming and corrections in hepatic core clock oscillations in Non-alcoholic fatty liver disease","volume":"35","author":"Joshi","year":"2021","journal-title":"FASEB J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Owino, S., Contreras-Alcantara, S., Baba, K., and Tosini, G. (2016). Melatonin Signaling Controls the Daily Rhythm in Blood Glucose Levels Independent of Peripheral Clocks. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0148214"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/12\/1046\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T14:15:58Z","timestamp":1765808158000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/47\/12\/1046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cimb47121046"],"URL":"https:\/\/doi.org\/10.3390\/cimb47121046","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]}}}