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.

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
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.

己酮可可碱单用或联合美沙拉胺通过鞘氨醇激酶1/磷酸鞘氨醇1和隐球菌1途径对结肠炎的结肠保护作用:新的分子途径。
溃疡性结肠炎(UC)的发病机制涉及多种信号通路,包括鞘氨醇激酶1 (SPHK)/鞘氨醇-1-磷酸(S1P)、amp活化蛋白激酶(AMPK)/哺乳动物雷帕霉素靶点(mTOR)/NLR家族pyrin结构域3 (NLRP3)、封闭带-1 (ZO-1)和转录信号转导和激活因子3 (STAT3)。我们旨在研究己酮茶碱(PTX)对UC大鼠模型的保护色和抗溃疡作用。结肠炎是由2 mL 3% (v/v)乙酸(AA)在结肠内引起的。35只大鼠随机分为5组(每组7只):正常对照组、结肠炎组、美沙拉明组、PTX组、PTX联合美沙拉明组。通过疾病活动性指数、结肠重量和长度测量、组织学检查和caspase-3的免疫组织化学检测来评估疾病活动性。分析结肠组织匀浆中白细胞介素-6 (IL-6)、S1P、SPHK、mTOR、血红素加氧酶-1 (HO-1)、核因子红细胞2相关因子2 (Nrf2)、AMPK和STAT3的水平。同时检测ZO-1和NLRP3的基因表达。结肠内AA对结肠组织造成明显的功能、生化和炎症损伤。用PTX、美沙拉明或它们的联合治疗可显著减轻这些影响。具体而言,所有治疗均降低了IL-6、S1P、SPHK、mTOR、STAT3、NLRP3和caspase-3的水平,同时增加了ZO-1、HO-1、Nrf2和AMPK的水平。联合治疗组几乎完全恢复了正常的结肠结构,其特征是隐窝形态完整,固有层纤维化最小。PTX减轻结肠炎的炎症、细胞凋亡和氧化应激,支持其作为UC管理辅助治疗的潜力。
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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
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
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