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In the current study, we examined the protective effect of human placenta extract (HPE) against MTX-induced liver damage in rats, as well as its ability to regulate antioxidative and anti-inflammatory liver responses.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Male rats were orally administered MTX at a daily dose of 5\u00a0mg\/kg-body-weight in the presence or absence of HPE (10.08\u00a0mg\/kg) for 2\u00a0weeks. We measured the biological effects of MTX and HPE on the levels of liver enzymes, lipid\u00a0profile, lipid peroxidation, oxidative stress biomarkers, and cytokines [tumor necrosis factor alpha (TNF-\u03b1), interleukin-6 (IL-6), and interleukin-10 (IL-10)]. In addition, histological examination and histopathological scoring of liver tissues were performed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>MTX-treated rats showed significantly increased (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) liver enzyme levels for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, total cholesterol, and triglyceride levels. However,\u00a0HPE supplementation in MTX-treated rats significantly decreased (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) these elevated levels. HPE supplementation also significantly reduced the oxidative stress biomarker malondialdehyde (MDA), reversed the reduction in glutathione (GSH), and markedly increased the antioxidant enzyme activities of catalase (CAT) and superoxide dismutase (SOD) in the livers of MTX-treated rats. Furthermore, HPE supplementation significantly decreased the MTX-elevated levels of the pro-inflammatory cytokines TNF-\u03b1, IL-6, and IL-10. Histopathological examinations showed that MTX produced severe cellular damage and inflammatory lesions in liver tissues, while treatment with HPE improved hepatic histologic architecture.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>HPE has the ability to ameliorate methotrexate-induced liver injury in rats by mechanisms that include boosting antioxidative responses and down-regulating MDA and pro-inflammatory cytokine production.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00280-021-04349-4","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T10:03:38Z","timestamp":1631268218000},"page":"961-971","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Human placental extract ameliorates methotrexate-induced hepatotoxicity in rats via regulating antioxidative and anti-inflammatory responses"],"prefix":"10.1007","volume":"88","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1087-7127","authenticated-orcid":false,"given":"Mamdooh","family":"Ghoneum","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S. 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