{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:19:29Z","timestamp":1787224769489,"version":"build-2736575974"},"reference-count":65,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Archiv der Pharmazie"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Methotrexate (MTX)\u2010induced hepatotoxicity is a serious adverse effect that may limit its use. Therefore, eligible drugs to ameliorate MTX\u2010induced hepatotoxicity are required. <jats:sc>l<\/jats:sc>\u2010Carnitine (LC) is a natural molecule with beneficial metabolic effects and infliximab (INF) is an anti\u2010inflammatory monoclonal antibody against tumor necrosis factor\u2010alpha (TNF\u2010\u03b1). Recently, Notch1\/Hes\u20101 signaling was found to play a key role in the pathogenesis of liver injury. However, its role in MTX\u2010induced hepatotoxicity is unclear. This study aimed to evaluate the modulatory effects of LC or INF on MTX\u2010induced hepatotoxicity and to explore the underlying mechanism with emphasis on the Notch1\/Hes\u20101 signaling pathway. Sixty rats were randomized into six groups (<jats:italic>n<\/jats:italic>\u2009=\u200910): (1) control (saline); (2) MTX (20\u2009mg\/kg MTX, intraperitoneal [ip], once); (3) LC group (500\u2009mg\/kg ip, 5 days); (4) INF (7\u2009mg\/kg INF ip, once); (5) MTX+LC (20\u2009mg\/kg ip, once, 500\u2009mg\/kg ip, 5 days, respectively); (6) MTX+INF (20\u2009mg\/kg ip, once, 7\u2009mg\/kg INF ip, once, respectively). Oxidative stress, inflammatory markers, and Notch1\/Hes\u20101 were investigated. MTX induced the expression of Notch1 and Hes\u20101 proteins and increased the levels of TNF\u2010\u03b1, interleukin (IL)\u20106, and IL\u20101\u03b2 in the liver. Cotreatment with LC or INF showed apparent antioxidant and anti\u2010inflammatory effects. Interestingly, the downregulation of Notch1 and Hes\u20101 expression was more prominent in LC cotreatment as compared with INF. In conclusion, LC or INF attenuates MTX\u2010induced hepatotoxicity through modulation of Notch1\/Hes\u20101 signaling. The LC ameliorative effect against MTX\u2010induced hepatotoxicity is significantly better than that of INF. Therefore, LC cotreatment may present a safe and therapeutically effective therapy in alleviating MTX\u2010induced hepatotoxicity.<\/jats:p>","DOI":"10.1002\/ardp.202300312","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T19:27:02Z","timestamp":1692991622000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The beneficial effects of <scp>l<\/scp>\u2010carnitine and infliximab in methotrexate\u2010induced hepatotoxicity: Emphasis on Notch1\/Hes\u20101 signaling"],"prefix":"10.1002","volume":"356","author":[{"given":"Sara M.","family":"Radwan","sequence":"first","affiliation":[{"name":"Biochemistry Department, Faculty of Pharmacy Ain Shams University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada A.","family":"Abdel\u2010Latif","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Department, Faculty of Pharmacy Misr International University (MIU) Cairo Egypt"},{"name":"Translational and Clinical Research Unit, Faculty of Pharmacy Misr International University (MIU) Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samah S.","family":"Abbas","sequence":"additional","affiliation":[{"name":"Pharmacology and Toxicology Department, Faculty of Pharmacy Misr International University (MIU) Cairo Egypt"},{"name":"Translational and Clinical Research Unit, Faculty of Pharmacy Misr International University (MIU) Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noura F.","family":"Elmongy","sequence":"additional","affiliation":[{"name":"Physiology Department, Faculty of Medicine Al\u2010Azhar University Damietta Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7711-0473","authenticated-orcid":false,"given":"Eman F.","family":"Wasfey","sequence":"additional","affiliation":[{"name":"Biochemistry Department, Faculty of Pharmacy Ain Shams University Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"73","volume":"6","author":"David S.","year":"2010","journal-title":"US Gastroenterol. 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