Abstract
Methods: Relevant potential targets for EC were obtained based on Traditional Chinese Medicine System Pharmacology Database (TCMSP), a bioinformatics analysis tool for molecular mechanism of Traditional Chinese Medicine (BATMAN-TCM) and STITCH databases. The Online Mendelian Inheritance in Man (OMIM) and GeneCards databases were utilized to screen the known POI-related targets, while Cytoscape software was used for network construction and visualization. Then, the Gene Ontology (GO) and pathway enrichment analysis were carried out by the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. Furthermore, KGN cells were performed to validate the predicted results in oxidative stress (OS) model, and antioxidant effect was examined.Results: A total of 70 potential common targets for EC in the treatment of POI were obtained through network pharmacology. Metabolic process, response to stimulus and antioxidant activity occupied a leading position of Gene Ontology (GO) enrichment. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that PI3K/protein kinase B (AKT), TNF, estrogen, VEGF and MAPK signaling pathways were significantly enriched. In addition, cell experiments showed that EC exhibited antioxidant effects in an H2O2-mediated OS model in ovarian granulosa cells by regulating the expression of PI3K/AKT/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and multiple downstream antioxidant enzymes.Conclusion: EC could regulate multiple signaling pathways and several biological processes (BPs). EC had the ability to down-regulate elevated OS level through the PI3K/AKT/Nrf2 signaling pathway and represented a potential novel treatment for POI.
Highlights
Premature ovarian insufficiency (POI) is a clinical syndrome defined as decrease, or even loss of ovarian function in women before the age of 40 years
A total of 7417 targets of POI were obtained from Online Mendelian Inheritance in Man (OMIM) and GeneCards databases after deletion of overlaps
Common targets were imported into STRING and the results were imported into Cytoscape to display a visual protein–protein interaction (PPI) network
Summary
Premature ovarian insufficiency (POI) is a clinical syndrome defined as decrease, or even loss of ovarian function in women before the age of 40 years. It is characterized by menstrual disorders (amenorrhea or oligomenorrhea), hot flashes, night sweats and other perimenopausal symptoms, accompanied by elevated levels of gonadotropins and decreased estrogen concentrations [1]. (-)-Epicatechin (EC) is one of the most abundant naturally occurring polyphenol compounds found in the human diet and is commonly found in plants as a secondary metabolite [10] It is the primary form of flavan-3-alcohol, which commonly exists in cocoa, tea, apple and catechus [11]. No studies have been performed about the effect of EC on the improvement of reproductive function and protection of the ovary, as current research has mainly focused its effects on other diseases
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