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We aimed to investigate the Colo protective and anti\u2010ulcerative effects of pentoxifylline (PTX) in a rat model of UC. Colitis was induced by intracolonic administration of 2\u2009mL of 3% (v\/v) acetic acid (AA). Thirty\u2010five rats were randomly assigned to five groups (<jats:italic>n<\/jats:italic>\u2009=\u20097 each): normal control, colitis, mesalamine, PTX, and a combination of PTX plus mesalamine. Disease activity was assessed using the disease activity index, colon weight and length measurements, histological examination, and immunohistochemical detection of caspase\u20103. Colonic tissue homogenates were analyzed for interleukin\u20106 (IL\u20106), S1P, SPHK, mTOR, heme oxygenase\u20101 (HO\u20101), nuclear factor erythroid 2\u2013related factor 2 (Nrf2), AMPK, and STAT3 levels. Gene expression of ZO\u20101 and NLRP3 was also evaluated. Intracolonic AA induced marked functional, biochemical, and inflammatory damage to colonic tissue. Treatment with PTX, mesalamine, or their combination significantly attenuated these effects. Specifically, all treatments reduced levels of IL\u20106, S1P, SPHK, mTOR, STAT3, NLRP3, and caspase\u20103, while increasing levels of ZO\u20101, HO\u20101, Nrf2, and AMPK. The combination treatment group exhibited near\u2010complete restoration of normal colonic architecture, characterized by intact crypt morphology and minimal fibrosis in the lamina propria. PTX attenuated inflammation, apoptosis, and oxidative stress in colitis, supporting its potential as an adjuvant therapy in UC management.<\/jats:p>","DOI":"10.1002\/prp2.70115","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T13:31:21Z","timestamp":1747661481000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Colo\u2010Protective Effects of Pentoxifylline Alone or in Combination With Mesalamine in Colitis Through Sphingosine Kinase 1\/Sphingosine 1 Phosphate, and Zonula Occuldin 1 Pathways: New Molecular Approach"],"prefix":"10.1002","volume":"13","author":[{"given":"Fatemah A.","family":"Alherz","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy Princess Nourah Bint Abdulrahman University  Riyadh Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmoud 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Faculty of Pharmacy Horus University  New Damietta Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammed M.","family":"Salahuddin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Biochemistry, Faculty of Pharmacy Horus University  New Damietta Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Yasser","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Faculty of Pharmacy Port Said University  Port Said Egypt"},{"name":"Department of Pharmaceutics, Faculty of Pharmacy East Port Said National University  Port Said Egypt"},{"name":"Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy Horus University  New Damietta Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mamdouh","family":"Eldesoqui","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, College of Medicine AlMaarefa University  Riyadh 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