Mechanism of Wenshen Yangxue Prescription Improving Endometrial Receptivity of Aged Female Mice by Regulating PI3K/Akt/FoxO3A Signaling Pathway / 中国实验方剂学杂志

ABSTRACT

Objective:To explore the effective components， targets， and possible mechanisms of Wenshen Yangxue prescription in improving endometrial receptivity of aged female mice based on network pharmacology and experimental verification. Method:Based on Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine （BATMAN-TCM） and Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine， the components and targets of Wenshen Yangxue prescription were retrieved， and the targets of ovulatory dysfunctional infertility were collected from the Online Mendelian Inheritance in Man （OMIM） and GeneCards with "anovulatory sterility" and "anovulatory infertility" as keywords. The protein-protein interaction （PPI） network was constructed based on STRING and the core targets of Wenshen Yangxue prescription against ovulatory dysfunctional infertility were screened by Cytoscape， followed by Gene Ontology （GO） term enrichment and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment of the core targets in DAVID database. Then， the "medicinal-component-target-pathway" network was established and the core targets were verified by animal experiment. Result:A total of 253 components and 326 targets of Wenshen Yangxue prescription， 819 disease targets， and 74 common targets were screened out. The common targets were mainly involved in the biological processes such as positive regulation of nitric oxide biosynthetic process， positive regulation of cell proliferation， response to estradiol， aging， response to oxidative stress， and angiogenesis. The GO term of response to oxidative stress and five of the top 20 KEGG pathways were analyzed. According to the "medicinal-component-target-biological process/pathway" network， 41 chemical components in 20 medicinals participated in hypoxia inducible factor-1 （HIF-1） signaling pathway， tumor necrosis factor （TNF） signaling pathway， forkhead box O （FOXO） signaling pathway， Toll-like receptor （TLR） signal pathway， and phosphatidylinositol 3-kinase/protein kinase B （PI3K/Akt） signaling pathway by affecting 35 targets. The results of animal experiment showed that the prescription could increase the expression of PI3K， phosphorylated PI3K （p-PI3K）， Akt， phosphorylated Akt （p-Akt）， forkhead box O3A （FoxO3A）， and phosphorylated FoxO3A （p-FoxO3A） in uterus of aged female ICR mice. Conclusion:Wenshen Yangxue prescription interferes with oxidative stress and PI3K/Akt/FoxO3A signaling pathway by influencing Akt1， dual oxidase 2 （DUOX2）， epidermal growth factor receptor （EGFR）， heme oxygenase-1 （HMOX1）， myeloperoxidase （MPO）， and other targets， thereby improving endometrial receptivity of aged female mice.