{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T16:37:15Z","timestamp":1792255035211,"version":"4.4.0"},"reference-count":76,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,15]],"date-time":"2022-10-15T00:00:00Z","timestamp":1665792000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["RSP2022R235"],"award-info":[{"award-number":["RSP2022R235"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite its effectiveness in treating inflammatory diseases and various malignancies, methotrexate (MTX) is well known to cause hepatotoxicity, which involves increased oxidative stress and inflammation, limiting its clinical use. Herein, we looked into the effect of punicalagin (PU), a polyphenolic molecule having a variety of health-promoting attributes, on MTX-induced hepatotoxicity in mice. PU (25 and 50 mg\/kg\/day) was given orally to the mice for 10 days, while a single dose of MTX (20 mg\/kg) was injected intraperitoneally (i.p.) at day 7. The MTX-induced liver damage was demonstrated by remarkably higher transaminases (ALT and AST), ALP, and LDH, as well as significant histological alterations in hepatic tissues. MTX-injected mice also demonstrated increases in hepatic oxidative stress markers, including malondialdehyde (MDA) and nitric oxide (NO), with a concordant drop in glutathione (GSH) content and superoxide dismutase (SOD) and catalase (CAT) activities. PU significantly attenuated the MTX-induced serum transaminases, ALP and LDH elevations, and hepatic oxidative stress measures and boosted antioxidant defenses in the liver. Moreover, the liver of MTX-treated mice showed increases in NF-\u03baB p65 expression, pro-inflammatory cytokine (IL-6 and TNF-\u03b1) levels, and pro-apoptotic protein (caspase-3 and Bax) expression, whereas Bcl-2 and Nrf2 expressions were reduced, which were all attenuated by PU treatment. Collectively, PU inhibits oxidative damage, inflammation, and apoptosis and upregulates Nrf2 in the liver of MTX-induced mice. Thus, these findings suggest that PU may have great therapeutic potential for the prevention of MTX-induced hepatotoxicity, pending further exploration in upcoming studies.<\/jats:p>","DOI":"10.3390\/ijms232012334","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T02:29:46Z","timestamp":1665973786000},"page":"12334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Punicalagin Protects against the Development of Methotrexate-Induced Hepatotoxicity in Mice via Activating Nrf2 Signaling and Decreasing Oxidative Stress, Inflammation, and Cell Death"],"prefix":"10.3390","volume":"23","author":[{"given":"Alayn\u2019 Al-marddyah A.","family":"Al-khawalde","sequence":"first","affiliation":[{"name":"Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma\u2019an 71111, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4018-6925","authenticated-orcid":false,"given":"Mohammad H.","family":"Abukhalil","sequence":"additional","affiliation":[{"name":"Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma\u2019an 71111, Jordan"},{"name":"Department of Biology, College of Science, Al-Hussein Bin Talal University, Ma\u2019an 71111, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthana M.","family":"Jghef","sequence":"additional","affiliation":[{"name":"Department of Radiology, College of Medical Technology, Al-Kitab University, Kirkuk 36001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal A.","family":"Alfwuaires","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6758-7537","authenticated-orcid":false,"given":"Fatima S.","family":"Alaryani","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleem H.","family":"Aladaileh","sequence":"additional","affiliation":[{"name":"Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma\u2019an 71111, Jordan"},{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 31991, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulmohsen I.","family":"Algefare","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5558-1680","authenticated-orcid":false,"given":"Shaik","family":"Karimulla","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 31991, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2382-5892","authenticated-orcid":false,"given":"Fawaz","family":"Alasmari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5482-3625","authenticated-orcid":false,"given":"Hammad Khalifeh","family":"Aldal\u2019in","sequence":"additional","affiliation":[{"name":"Department of Medical Support, Al-Karak University College, Al-Balqa Applied University, Al-Karak 19117, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6786-2156","authenticated-orcid":false,"given":"Abdulkareem A.","family":"Alanezi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, University of Hafr Al-Batin, Hafr Al-Batin 31991, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3406-9634","authenticated-orcid":false,"given":"Osama Y.","family":"Althunibat","sequence":"additional","affiliation":[{"name":"Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma\u2019an 71111, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"s104","DOI":"10.7861\/clinmedicine.16-6-s104","article-title":"Drug-induced liver injury","volume":"16","author":"Katarey","year":"2016","journal-title":"Clin. 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