培哚普利通过靶向炎症和氧化还原失调减轻大鼠甲氨蝶呤诱导的肠道损伤：TLR4/NF-κB 和 c-Fos/c-Jun 促炎途径以及 PPAR-γ/SIRT1 细胞保护信号的作用。
Targeting inflammation and redox aberrations by perindopril attenuates methotrexate-induced intestinal injury in rats: Role of TLR4/NF-κB and c-Fos/c-Jun pro-inflammatory pathways and PPAR-γ/SIRT1 cytoprotective signals.
机构信息
Biochemistry Laboratory, Chemistry Department, Faculty of Science, Assiut University, 71515, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
出版信息
Chem Biol Interact. 2022 Jan 5;351:109732. doi: 10.1016/j.cbi.2021.109732. Epub 2021 Oct 29.
AIMS
The use of methotrexate (MTX), a classical immunosuppressant and anti-cancer agent, is associated with multiple organ toxicities, including the intestinal injury. Components of the renin-angiotensin system are expressed in the intestinal epithelium and mucosal immune cells where they provoke pro-inflammatory and pro-oxidant action. The present study was conducted to investigate the potential ability of perindopril (PER), an angiotensin-converting enzyme inhibitor (ACEI), to attenuate MTX-induced intestinal injury with emphasis on the role of the pro-inflammatory TLR4/NF-κB and c-Fos/c-Jun pathways alongside PPAR-γ and SIRT1 cytoprotective signals.
MATERIALS AND METHODS
The intestinal injury was induced by a single-dose injection of 20 mg/kg of MTX i.p at the end of the 5th day. PER was administrated once daily in a dose of 1 mg/kg, i.p, for five days before MTX and five days later.
RESULTS
Herein, perindopril attenuated the intestinal injury as seen by lowering the histopathological aberrations and preserving the goblet cells in villi/crypts. These beneficial actions were associated with downregulating the expression of the pro-inflammatory angiotensin II, TNF-α, IL-1β, and IL-6 cytokines, alongside upregulating the anti-inflammatory angiotensin (1-7) and IL-10. At the molecular level, perindopril downregulated the TLR4/NF-κB and c-Fos/c-Jun pathways in inflamed intestine of rats. Moreover, it attenuated the pro-oxidant events by lowering intestinal MDA and boosting GSH, SOD, and GST antioxidants together with PPAR-γ and SIRT1 cytoprotective signals. The aforementioned findings were also highlighted using molecular docking and network pharmacology analysis.
CONCLUSIONS
Perindopril demonstrated notable mitigation of MTX-induced intestinal injury through suppression of TLR4/NF-κB and c-Fos/c-Jun pathways alongside the augmentation of PPAR-γ/SIRT1 cytoprotective signals.
目的
甲氨蝶呤（MTX）是一种经典的免疫抑制剂和抗癌药物，其使用与多种器官毒性有关，包括肠道损伤。肾素-血管紧张素系统的成分在肠道上皮和黏膜免疫细胞中表达，引发促炎和促氧化作用。本研究旨在探讨血管紧张素转换酶抑制剂（ACEI）培哚普利（PER）减轻 MTX 诱导的肠道损伤的潜在能力，重点研究促炎 TLR4/NF-κB 和 c-Fos/c-Jun 途径以及 PPAR-γ 和 SIRT1 细胞保护信号的作用。
材料和方法
通过在第 5 天结束时腹腔注射 20mg/kg MTX 单次注射诱导肠道损伤。PER 在 MTX 前 5 天和后 5 天每天 1mg/kg 腹腔注射一次。
结果
培哚普利通过降低组织病理学异常和保护绒毛/隐窝中的杯状细胞来减轻肠道损伤。这些有益作用与下调促炎血管紧张素 II、TNF-α、IL-1β 和 IL-6 细胞因子的表达以及上调抗炎血管紧张素（1-7）和 IL-10 有关。在分子水平上，培哚普利下调了 TLR4/NF-κB 和 c-Fos/c-Jun 途径在大鼠炎症肠道中的表达。此外，它通过降低肠道 MDA 并增强 GSH、SOD 和 GST 抗氧化剂以及 PPAR-γ 和 SIRT1 细胞保护信号来减轻促氧化事件。使用分子对接和网络药理学分析也强调了这些发现。
结论
培哚普利通过抑制 TLR4/NF-κB 和 c-Fos/c-Jun 途径以及增强 PPAR-γ/SIRT1 细胞保护信号，对 MTX 诱导的肠道损伤表现出显著的缓解作用。
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