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Naringin (Nar) is a flavonoid derived from Citrus paradise, and has been shown to possess several pharmacological activities, including free-radical scavenging and antioxidant properties. In the present study, we first tested the possible protective effects of multiple doses of Nar against MTX-induced acute hepatotoxicity in rats, and then we investigated the growth inhibition and apoptotic effects of MTX and\/or Nar against the HepG2 hepatocarcinoma cell line. Our in vivo results showed that Nar significantly reduced MTX-induced increases in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin levels. Nar also reduced MTX-induced oxidative stress by significantly reducing liver malondialdehyde (MDA) and nitric oxide (NO) content and increasing superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH). In addition, Nar significantly counteracted MTX-induced increases in hepatic interleukin-6 and tumor necrosis factor-\u03b1 (TNF-\u03b1). Further, Nar greatly protected hepatocyte ultrastructure against MTX-induced injury. In contrast, in vitro MTX and\/or Nar treatment of HepG2 cells for 48\u2009h exhibited a cytotoxic effect and induced apoptosis in a dose-dependent manner mediated by a significant increase in the Bax\/Bcl-2 protein expression ratio. Noticeably, Nar potentiated the MTX effect on the Bax\/Bcl-2 ratio. In conclusion, Nar decreased MTX-induced functional and ultrastructural liver damage in a tumor-free animal model. Also, our data introduce MTX and Nar as promising antiproliferative agents with a distinctive mode of action, inducing apoptosis in HepG2 tumor cells through activation of Bax and down-regulation of Bcl-2 protein expression.<\/jats:p>","DOI":"10.1042\/bsr20193686","type":"journal-article","created":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T07:21:52Z","timestamp":1590564112000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Naringin alleviates methotrexate-induced liver injury in male albino rats and enhances its antitumor efficacy in HepG2 cells"],"prefix":"10.1042","volume":"40","author":[{"given":"Hany","family":"Elsawy","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Science, King Faisal University, Al-Ahsa, Saudi Arabia"},{"name":"Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulmohsen\u00a0I.","family":"Algefare","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Faisal University, Hofuf 31982, Al-Ahsa, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal","family":"Alfwuaires","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Faisal University, Hofuf 31982, Al-Ahsa, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Khalil","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, Beirut Arab University, Beirut, Lebanon"},{"name":"Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar\u00a0M.","family":"Elmenshawy","sequence":"additional","affiliation":[{"name":"Department of Zoology, Faculty of Science, Al-Azhar University, Cairo, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azza","family":"Sedky","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Faisal University, Hofuf 31982, Al-Ahsa, Saudi Arabia"},{"name":"Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0270-703X","authenticated-orcid":false,"given":"Ashraf\u00a0M.","family":"Abdel-Moneim","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Science, King Faisal University, Hofuf 31982, Al-Ahsa, Saudi Arabia"},{"name":"Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2020,6,10]]},"reference":[{"key":"2021111620150586600_B1","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.urology.2006.10.041","article-title":"Chemotherapy for bladder cancer: treatment guidelines for neoadjuvant chemotherapy, bladder preservation, adjuvant chemotherapy, and metastatic cancer","volume":"69","author":"Sternberg","year":"2007","journal-title":"Urology"},{"key":"2021111620150586600_B2","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s11899-013-0159-0","article-title":"The Treatment of Adolescents and Young Adults with Acute Lymphoblastic Leukemia","volume":"8","author":"Lukenbill","year":"2013","journal-title":"Curr. 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