Explore the mechanism of Pachymic acid in the treatment of myocardial fibrosis based on network pharmacology and in vitro experiments
Objective:To investigate the mechanism of Pachymic acid in the treatment of myocardial fibrosis(MF)based on network pharmacology and in vitro validation.Methods:The targets of Pachymic acid,oxidative stress and MF were predicted us-ing SwissTargetPrediction,GeneCards and other databases,and the three intersection targets were selected to construct the pro-tein interaction(PPI)network in STRING database.Visualization analysis was carried out by Cytoscape 3.7.2 software,and the core targets were selected.GO and KEGG enrichment analysis were performed using Metascape database to predict the mecha-nism of Pachymic acid in the treatment of MF,which was verified by molecular docking technique and rat cardiac fibroblasts(CFs).Results:According to the prediction,there were 164 potential targets of Pachymic acid,12139 oxidative stress targets,4 441 MF targets and 84 intersection targets of the three,involving 9 core targets such as Bcl-2,PTGS2,Bcl-2L1 and MMP-2.GO analysis found that biological processes mainly act on antioxidant activity and response to hypoxia.KEGG analysis showed that the main signaling pathway of Pachymic acid in MF treatment was PI3K/Akt.The molecular docking results showed that Pachy-mic acid had good binding activity with 9 core targets such as Bcl-2,PTGS2,Bcl-2L1 and MMP-2.The results showed that Pachymic acid(5,10,20 μmol/L)could significantly inhibit the migration of CFs(P<0.01),decrease the levels of ROS and MDA(P<0.05),and increase the level of SOD(P<0.05),down-regulated mRNA levels of Collagen Ⅰ,Collagen Ⅲ,MMP-9,MMP-2 and PTGS2(P<0.05)and protein expressions of Collagen Ⅰ,Collagen Ⅲ and α-SMA(P<0.05).Pachymic acid also up-regulated mRNA levels of PI3K,Akt,Bcl-2 and Bcl-2L1(P<0.05),and protein expressions of p-PI3K and p-Akt(P<0.05).After the use of PI3K inhibitor(LY294002),the effects of Pachymic acid on ROS,SOD,MDA,Collagen Ⅰ,Colla-gen Ⅲ,α-SMA,p-PI3K and p-Akt in CFs cells were reversed(P<0.05).Conclusion:The results show that Pachymic acid can inhibit oxidative stress injury of CFs and myocardial fibrosis,which is closely related to the regulation of PI3K/Akt signaling path-way.
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