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Targeting IL‐10, ZO‐1 gene expression and IL‐6/STAT‐3 trans‐signaling by a combination of atorvastatin and mesalazine to enhance anti‐inflammatory effects and attenuates progression of oxazolone‐induced colitis
Fundamental & Clinical Pharmacology ( IF 2.9 ) Pub Date : 2020-05-08 , DOI: 10.1111/fcp.12563
Nageh Ahmed El-Mahdy 1 , Magda El-Sayed El-Sayad 1 , Aya Hassan El-Kadem 1 , Sally El-Sayed Abu-Risha 1
Affiliation  

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffused inflammation of the colon and rectum mucosa. The pathogenesis of UC is multifactorial, and the exact underlying mechanisms remain poorly understood. This study aims to investigate the effect of mesalazine and atorvastatin combination in enhancing anti‐inflammatory effects and attenuates progression of oxazolone colitis in rats. In the present study, male albino rats (N = 60) were divided into six groups (10 rats each), the first two groups served as normal control and a control saline group. Colitis was induced by intra‐rectal administration of oxazolone in the 5th and 7th days after pre‐sensitization. Then, rats were divided into untreated group, groups treated with mesalazine or atorvastatin or their combination. Colitis was assessed by colon length, body weight, and incidence of diarrhea, rectal bleeding, and histopathology of colon tissue. Colon tissues were used for measuring interleukin 6 (IL‐6), tumor necrosis factor alpha (TNF‐α), IL‐13, signal transducer and activator of transcription‐3 (STAT‐3), myeloperoxidase activity (MPO), reduced glutathione(GSH), and tissue expression of IL‐10, tight junction protein zonula occludens (ZO‐1), and caspase‐3 genes. The combination therapy significantly attenuated progression of UC by decreasing incidence of diarrhea, rectal bleeding, weight loss, IL‐13, IL‐6, TNF‐α, STAT‐3, caspase‐3, and MPO activity and significantly increased IL‐10, ZO‐1, colon length, and GSH content, and these effects were more superior to single drugs. These findings showed that combination therapy was able to ameliorate progression of UC and enhance anti‐inflammatory effects possibly by restoring IL‐10 and ZO‐1 levels and limiting IL‐6/STAT‐3 trans‐signaling.

中文翻译:

联合阿托伐他汀和美沙拉嗪靶向 IL-10、ZO-1 基因表达和 IL-6/STAT-3 转信号以增强抗炎作用并减缓恶唑酮诱导的结肠炎的进展

溃疡性结肠炎(UC)是一种慢性炎症性疾病,其特征是结肠和直肠粘膜的弥漫性炎症。UC 的发病机制是多因素的,确切的潜在机制仍然知之甚少。本研究旨在研究美沙拉嗪和阿托伐他汀联合用药在增强大鼠的抗炎作用和减缓恶唑酮结肠炎进展方面的作用。在本研究中,雄性白化大鼠(N = 60)分为六组(每组10只),前两组作为正常对照组和生理盐水对照组。结肠炎是在预致敏后第 5 天和第 7 天通过直肠内给药恶唑酮引起的。然后,将大鼠分为未治疗组、美沙拉嗪或阿托伐他汀或其组合治疗组。结肠炎通过结肠长度、体重、腹泻发生率、直肠出血和结肠组织的组织病理学进行评估。结肠组织用于测量白介素 6(IL-6)、肿瘤坏死因子 α(TNF-α)、IL-13 信号转导和转录激活因子 3 (STAT-3)、髓过氧化物酶活性 (MPO)、还原型谷胱甘肽 (GSH) 以及 IL-10、紧密连接蛋白封闭小带 (ZO-1) 和 caspase-3 基因的组织表达. 联合治疗通过降低腹泻、直肠出血、体重减轻、IL-13、IL-6、TNF-α、STAT-3、caspase-3 和 MPO 活性的发生率显着减缓 UC 的进展,并显着增加 IL-10, ZO-1、结肠长度、GSH含量,且这些作用均优于单药。这些发现表明,联合治疗可能通过恢复 IL-10 和 ZO-1 水平并限制 IL-6/STAT-3 转信号来改善 UC 的进展并增强抗炎作用。
更新日期:2020-05-08
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