Potential Therapeutic Drug Targets and Pathways Prediction for Premature Ovarian Insufficiency —Based on Network Pharmacologic Method

Abstract

Ethnopharmacological relevance: The incidence of premature ovarian insufficiency (POI) is gradually increasing, the proportion is rising especially in female infertility patients. The risk of death of POI patients with cardiovascular disease also increases significantly. The cause of POI is complex and unclear, and clinical treatment is still in the exploratory stage, are two major constraints of treating POI. Traditional Chinese medicine (TCM) is widely used in the treatment of POI, and it is a good way to combine the development of modern new drugs with the help of TCM to predict the therapeutic targets.Aim of the studyIn this study, four herbs commonly used in clinical treatment of POI, namely Radix Paeoniae, Polygonatum sibiricum, Rehmannia glutinosa and Eucommia ulmoides were selected to predict their mechanism in the treatment of POI, using network pharmacology methods. Then verify the predicted targets by animal test. Aim to find more effective POI potential core treatment targets and main pathways.

Materials and methods: We screened the active ingredients of drugs from the Traditional Chinese Medicine System Pharmacology Analysis Platform (TCMSP), Performed target prediction of active ingredients from databases such as SwissTargetPrediction and compare and analyze the POI-related targets retrieved from them to obtain potential targets for drug treatment of POI. Used STRING to construct a protein interaction network, Cytoscape 3.7.2 software to construct an active ingredient-target-pathway network, and DAVID database to conduct the Kyoto Encyclopedia of Genes and Genomes (KEGG) on the intersection targets and gene ontology (GO) enrichment analysis.

Results: The result is: there were 25 key targets for the treatment of POI with Radix Paeoniae Alba, 31 for the treatment of POI by Eucommia ulmoides, 28 for the treatment of POI by Polygonatum sibiricum, and 8 key targets for the treatment of Rehmannia glutinosa. The intersection targets of four herbs were defined as the core targets, which are CYP19A1, EGF, ESR1, ESR2, MDM2, AR, PCYP17A1, PPARG. Four Chinese herbs treat POI mainly through HIF-1 signaling pathway, PI3K-Akt signaling pathway, FoxO signaling pathway, Estrogen signaling pathway etc. A mouse model of POI was constructed based on the results of network pharmacology to verify the predicted targets. The results showed that the protein expression of the core target changed, and the estrogen level was increased by reducing the expression of PPARG.

Conclusions: This study predicts the mechanism of multiple herbs in the treatment of POI, screens out more potential therapeutic drug targets and main pathways of POI treatment and provides new ideas for the subsequent development of POI therapeutic drugs.

Note:

Funding Information: This study was supported by the National Science Fund for Distinguished Young Scholars [32025029], the Non-profit Central Research Institute Fund of National Research Institute for Family Planning (2021GJZ08), the Shanghai Engineering Research Center of food microbiology program [19DZ2281100] and the National Key R&D Program of China (No.2016YF1000901).

Declaration of Interests: This study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics Approval Statement: The animal test was following the standards of the Animal Ethics Committee of the Institute of Science and Technology of the National Health Commission. The ethics approval number is NRIFH21-2101-9.

Keywords: Traditional Chinese herbs, Network pharmacology, Premature Ovarian Insufficiency, therapeutic drug targets, pathway, animal test