Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt.
Arch Biochem Biophys. 2019 Aug 15;671:185-195. doi: 10.1016/j.abb.2019.07.014. Epub 2019 Jul 18.
Variations in Nrf-2 and NF-κB expression profiles have been reported in ulcerative colitis (UC), in which an interplay between these two critical pathways has been identified. The therapeutic potential of angiotensin receptor blockers (ARBs) for oxidative damage and inflammation has recently received considerable attention. Dextran sodium sulfate (DSS)-induced colitis in rats closely resembles human UC and is associated with oxidative damage and the production of pro-inflammatory mediators. Therefore, we aimed to investigate the effect of orally administered telmisartan (TEL) (1.75, 3.5 and 7 mg/kg) in a rat model of DSS-induced colitis. Our study revealed that TEL, particularly at 7 mg/kg, alleviated tissue injury and inflammatory signs upon histological analysis and enhanced survival and recovery during DSS-induced colitis. The levels of colonic IL-1β, IL-6, TNF-α and serum C-reactive protein (CRP) were downregulated, while the level of colonic IL-10 was upregulated. TEL repressed DSS-induced neutrophil infiltration and improved the colonic antioxidant defence machinery. TEL inhibited apoptotic signalling as indicated by lower caspase 3 expression, increased CD36 gene expression and exhibited PPARγ agonistic activity. In addition, TEL downregulated gene expression and inhibited phosphorylation of the NF-κB p65 subunit. On the other hand, TEL upregulated the gene expression of Nrf-2 and HO-1. We concluded that TEL, besides its PPARγ agonistic activity, acted as a modulator of Nrf-2/NF-κB interactions and exhibited anti-apoptotic activity after tissue damage and that PPARγ and CD36 might play a critical role in the pathogenesis of murine colitis. Therefore, our findings suggest that further investigations on human IBDs are warranted.
在溃疡性结肠炎（UC）中已经报道了 Nrf-2 和 NF-κB 表达谱的变化，其中已经确定了这两个关键途径之间的相互作用。血管紧张素受体阻滞剂（ARBs）在氧化损伤和炎症方面的治疗潜力最近受到了相当多的关注。葡聚糖硫酸钠（DSS）诱导的大鼠结肠炎类似于人类 UC，与氧化损伤和促炎介质的产生有关。因此，我们旨在研究替米沙坦（TEL）（1.75、3.5 和 7mg/kg）在 DSS 诱导的大鼠结肠炎模型中的作用。我们的研究表明，TEL，特别是在 7mg/kg 时，通过组织学分析减轻了组织损伤和炎症迹象，并在 DSS 诱导的结肠炎中提高了存活率和恢复能力。结肠 IL-1β、IL-6、TNF-α 和血清 C-反应蛋白（CRP）水平下调，而结肠 IL-10 水平上调。TEL 抑制了 DSS 诱导的中性粒细胞浸润，并改善了结肠抗氧化防御机制。TEL 抑制了凋亡信号，表现为 caspase 3 表达降低、CD36 基因表达增加并表现出 PPARγ 激动活性。此外，TEL 下调了 NF-κB p65 亚基的基因表达和磷酸化。另一方面，TEL 上调了 Nrf-2 和 HO-1 的基因表达。我们得出结论，除了其 PPARγ 激动活性外，TEL 还作为 Nrf-2/NF-κB 相互作用的调节剂，在组织损伤后表现出抗凋亡活性，并且 PPARγ 和 CD36 可能在小鼠结肠炎的发病机制中发挥关键作用。因此，我们的研究结果表明，有必要对人类 IBD 进行进一步研究。
