{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:37:17Z","timestamp":1791383837526,"version":"4.3.3"},"reference-count":77,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Acetaminophen (APAP) is a popular and safe pain reliever. Due to its widespread availability, it is commonly implicated in intentional or unintentional overdoses, which result in severe liver impairment. Pristimerin (Prist) is a natural triterpenoid that has potent antioxidant and anti-inflammatory properties. Our goal was to explore the protective effects of Prist against APAP-induced acute liver damage. Method: Mice were divided into six groups: control, Prist control, N-acetylcysteine (NAC) + APAP, APAP, and two Prist + APAP groups. Prist (0.4 and 0.8 mg\/kg) was given for five days and APAP on day 5. Liver and blood samples were taken 24 h after APAP administration and submitted for different biochemical and molecular assessments. Results: Prist counteracted APAP-induced acute liver damage, as it decreased general liver dysfunction biomarkers, and attenuated APAP-induced histopathological lesions. Prist decreased oxidative stress and enforced hepatic antioxidants. Notably, Prist significantly reduced the genetic and protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-II), p-phosphatidylinositol-3-kinase (p-PI3K), p-protein kinase B (p-AKT), and the inflammatory cytokines: nuclear factor kappa B (NF-\u03baB), tumor necrosis factor-\u03b1 (TNF-\u03b1), and interleukins-(IL-6 and IL-1\u03b2) in hepatic tissues. Additionally, the m-RNA and protein levels of the apoptotic Bcl2-associated X protein (BAX) and caspase-3 were lowered and the anti-apoptotic B-cell leukemia\/lymphoma 2 (BCL-2) was increased upon Prist administration. Conclusion: Prist ameliorated APAP-induced liver injury in mice via its potent anti-inflammatory\/antioxidative and anti-apoptotic activities. These effects were mediated through modulation of NF-\u03baB\/iNOS\/COX-II\/cytokines, PI3K\/AKT, and BAX\/BCL-2\/caspase-3 signaling pathways.<\/jats:p>","DOI":"10.3390\/pharmaceutics17081003","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T06:37:47Z","timestamp":1754030267000},"page":"1003","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pristimerin Dampens Acetaminophen-Induced Hepatotoxicity; The Role of NF-\u03baB\/iNOS\/COX-II\/Cytokines, PI3K\/AKT, and BAX\/BCL-2\/Caspase-3 Signaling Pathways"],"prefix":"10.3390","volume":"17","author":[{"given":"Mohammed A.","family":"Altowijri","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"},{"name":"Eradah Complex and Mental Health, Ministry of Health, Qassim 12571, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2283-5327","authenticated-orcid":false,"given":"Marwa E.","family":"Abdelmageed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0211-1030","authenticated-orcid":false,"given":"Randa","family":"El-Gamal","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"},{"name":"Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"},{"name":"Department of Medical Biochemistry, Horus University\u2014Egypt (HUE), New Damietta 44921, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0941-9696","authenticated-orcid":false,"given":"Tahani","family":"Saeedi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Pharmacy, Taibah University, Medina 42353, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7545-6235","authenticated-orcid":false,"given":"Dina S.","family":"El-Agamy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"ref_1","first-page":"FE01","article-title":"Ten challenges associated with management of paracetamol overdose: An update on current practice and relevant evidence from epidemiological and clinical studies","volume":"15","author":"Fathelrahman","year":"2021","journal-title":"J. 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