Quercetin inhibits mesothelial-mesenchymal transition and alleviates postoperative peritoneal adhesions by blocking the TGF-β1/PI3K/AKT pathway
Quercetin inhibits mesothelial-mesenchymal transition and alleviates postoperative peritoneal adhesions by blocking the TGF-β1/PI3K/AKT pathway
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DOI：
10.1016/j.jep.2023.117242
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发表时间：
2023-10-05
影响因子：
5.4
通讯作者：
Jiang，Zhengdong
中科院分区：
文献类型：
--
作者：
Li，Gan;Ren，Yiwei;Jiang，Zhengdong
红花是菊科植物红花（Carthamus tinctorius（L.）丹红注射液由丹参和蒲公英组成，可预防术后腹膜粘连的形成。槲皮素（Quercetin，QUE）是槲皮素的一种活性成分，也被证明具有预防术后腹腔和宫腔粘连的作用。但QUE是否为促腹膜粘连的关键成分及其预防术后腹膜粘连的机制尚未见报道，本研究的目的预测QUE是否为促腹膜粘连的关键分子，探讨QUE预防术后腹膜粘连的作用及机制。采用盲肠-胎侧磨损法建立粘连模型，采用粘连评分系统评价QUE的防粘连效果。采用网络药理学方法预测QUE抗粘连作用的靶点和可能机制。通过免疫荧光、Western blot、伤口愈合实验、分子对接等方法进一步验证了槲皮素的作用机制。动物实验表明，QUE能有效改善粘连，降低间皮-间质转化相关标志物和TGF-β1的表达。此外，通过蛋白质-蛋白质相互作用和京都基因百科全书和基因组富集分析预测TGF-β1/PI 3 K/AKT通路在QUE预防粘附中起关键作用。体外实验和分子对接表明，QUE通过与TβR-II形成稳定的结合，阻断TGF-β1/PI 3 K/AKT通路，从而抑制MMT，减轻腹膜粘连。结论QUE不仅能降低术后TGF-β1，而且能阻断TGF-β1/PI 3 K/AKT通路，抑制间皮细胞MMT，减轻术后腹膜粘连。这些发现可能为开发安全有效的抗粘连药物预防术后腹膜粘连提供见解。
Ethnopharmacological relevanceCarthami flosis a dried flower of the Asteraceae plantCarthamus tinctorius(L.). Danhong injection, composed ofCarthami flosand Danshen can prevent the formation of postoperative peritoneal adhesions. Quercetin (QUE), an active compound ofCarthami flos, has also been proved to prevent postoperative abdominal and uterine cavity adhesions. However, whether QUE is the key component inCarthami flosand the mechanism in preventing postoperative peritoneal adhesions has not been studied.Aim of the studyTo predict whether QUE is the key molecule in Carthami flos and explore the effect and mechanism of QUE in preventing postoperative peritoneal adhesions.Materials and methodsDrug composition and target analysis was used to predict the key component inCarthami flos. The method of cecum-sidewall abrasion was used to establish adhesion models, and the antiadhesion effect of QUE was evaluated with the adhesion scoring system. Network pharmacology was used to predict the targets and potential mechanism of QUE in preventing adhesion. The mechanism was further verified by immunofluorescence, Western blot, wound healing experiment, and molecular docking.ResultsQuercetin was predicted to be the key to preventing postoperative peritoneal adhesions inCarthami flos. Animal experiments revealed that QUE effectively ameliorated adhesions and reduced the expression of mesothelial-mesenchymal transition (MMT) related markers and TGF-β1. Moreover, the TGF-β1/PI3K/AKT pathway was predicted via protein-protein interaction and Kyoto encyclopedia of Genes and Genomes enrichment analysis to play a crucial part in preventing adhesion by QUE. Furthermore, in vitro experiments and molecular docking demonstrated that QUE could block the TGF-β1/PI3K/AKT pathway through forming a stable combination with TβR-II, thereby inhibiting MMT and ameliorating peritoneal adhesion.ConclusionsQUE can not only reduce postoperative TGF-β1 but also block the TGF-β1/PI3K/AKT pathway to inhibit MMT of mesothelial cells, and finally alleviate postoperative peritoneal adhesions. These findings may provide insights towards development of a safe and effective anti-adhesive drug for prevention of postoperative peritoneal adhesions.