{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T17:53:57Z","timestamp":1785779637843,"version":"3.56.0"},"reference-count":31,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Methotrexate (MTX)\u2010induced pulmonary toxicity severely limits its clinical use and effective preventive strategies are lacking. This study evaluated the protective effects of agomelatine (AGO), a melatonergic antidepressant, against MTX\u2010induced lung injury, focusing on its dual\u2010pathway action targeting both immune cell infiltration and apoptotic signaling. Thirty\u2010two female Wistar rats were assigned to: Control, AGO (20\u2009mg\/kg\/day, p.o., 7\u2009days), MTX (single i.p. dose, 20\u2009mg\/kg), and MTX\u2009+\u2009AGO groups. Lung tissues were examined by histopathology, immunohistochemistry (CD45\n                    <jats:sup>+<\/jats:sup>\n                    , CD68\n                    <jats:sup>+<\/jats:sup>\n                    ), and RT\u2010qPCR (BAX, BCL2). MTX administration caused marked pulmonary damage (histopathological score: 2.75\u2009\u00b1\u20090.25,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), significant infiltration of CD45\n                    <jats:sup>+<\/jats:sup>\n                    leukocytes and CD68\n                    <jats:sup>+<\/jats:sup>\n                    macrophages and an elevated BAX\/BCL2 ratio (3.5\u2009\u00b1\u20090.4 vs. 1.0\u2009\u00b1\u20090.2 in Control,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). AGO cotreatment significantly ameliorated these alterations via its dual activity, lowering the histopathological score (1.25\u2009\u00b1\u20090.25,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01), reducing CD45\n                    <jats:sup>+<\/jats:sup>\n                    \/CD68 immunopositivity, and restoring the BAX\/BCL2 ratio toward cell survival (1.4\u2009\u00b1\u20090.3,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01 vs. MTX). These findings provide integrated immunohistochemical and molecular evidence supporting the concurrent modulation of immune cell infiltration and apoptotic signaling by AGO in MTX\u2010induced lung injury. Given its established clinical use and favorable safety profile, AGO may represent a potential adjunctive candidate to reduce the risk of MTX\u2010related pulmonary complications, through concurrent targeting of immune and apoptotic pathways.\n                  <\/jats:p>","DOI":"10.1002\/jat.70097","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T23:39:01Z","timestamp":1770853141000},"page":"3034-3042","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Agomelatine Alleviates Methotrexate\u2010Induced Lung Injury by Concurrently Inhibiting CD45\/CD68\u2010Positive Immune Cell Infiltration and Modulating the BAX\/BCL2 Apoptosis Pathway"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2766-2349","authenticated-orcid":false,"given":"Zafer","family":"Usta","sequence":"first","affiliation":[{"name":"Department of Genetics, Faculty of Veterinary Medicine Burdur Mehmet Akif Ersoy University  Burdur Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7442-7232","authenticated-orcid":false,"given":"\u015eakir","family":"Pekg\u00f6z","sequence":"additional","affiliation":[{"name":"Department of Medical Services and Techniques, Isparta Vocational School of Health Services S\u00fcleyman Demirel University  Isparta Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9207-6931","authenticated-orcid":false,"given":"Melda","family":"\u015eahin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine Burdur Mehmet Akif Ersoy University  Burdur Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4117-0455","authenticated-orcid":false,"given":"Ya\u011fmur","family":"Kara","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Reanimation, Division of Critical Care Medicine Isparta City Hospital  Isparta Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1835-1082","authenticated-orcid":false,"given":"\u00d6zlem","family":"\u00d6zmen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Veterinary Medicine Burdur Mehmet Akif Ersoy University  Burdur 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