Colo-Protective 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.
Fatemah A Alherz, Mahmoud S Abdallah, Esraa M Mosalam, Mostafa M Bahaa, Thanaa A Elmasry, Mohamad A El-Gammal, Walaa A Negm, AyaIbrahim Elberri, Nora Elshorbagi, Hend E Abo Mansour, Amir O Hamouda, Muhammed M Salahuddin, Mohamed Yasser, Mamdouh Eldesoqui, Sarah Alrubia, Amsha S Alsegiani, Eman El-Khateeb, Mohamed Kh ElMahdy, Eman Wahsh
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引用次数: 0
Abstract
Multiple signaling pathways have been implicated in the pathogenesis of ulcerative colitis (UC), including Sphingosine Kinase 1 (SPHK)/Sphingosine-1-Phosphate (S1P), AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/NLR family pyrin domain-containing 3 (NLRP3), zonula occludens-1 (ZO-1), and signal transducer and activator of transcription 3 (STAT3). We aimed to investigate the Colo protective and anti-ulcerative effects of pentoxifylline (PTX) in a rat model of UC. Colitis was induced by intracolonic administration of 2 mL of 3% (v/v) acetic acid (AA). Thirty-five rats were randomly assigned to five groups (n = 7 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-3. Colonic tissue homogenates were analyzed for interleukin-6 (IL-6), S1P, SPHK, mTOR, heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), AMPK, and STAT3 levels. Gene expression of ZO-1 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-6, S1P, SPHK, mTOR, STAT3, NLRP3, and caspase-3, while increasing levels of ZO-1, HO-1, Nrf2, and AMPK. The combination treatment group exhibited near-complete 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.
期刊介绍:
PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS