Integrating Network Pharmacology, Molecular Docking and Experimental Validation to Explore the Pharmacological Mechanisms of Quercetin Against Diabetic Wound

Abstract

The chronic non-healing diabetic wound (DW) has remained a challenge to both the society and individuals. Previous studies suggested dietary moderate consumption of quercetin (QCT) are beneficial in preventing diabetic complications, including non-healing DW. However, there were few studies that have investigated QCT-related underlying molecular mechanisms against DW. In the present study, we for the first-time combined network pharmacology with molecular docking and experimental validation to investigate QCT-related therapeutic targets and mechanisms for treating DW. Finally, 191 QCT-related targets and 1750 DW-related pathogenetic targets were obtained from online databases. After removing duplicates, a total of 90 potential therapeutic targets of quercetin for treating DW were ultimately identified. Furthermore, 7 targets with higher degree including IL-6, EGFR, SRC, TNF, AKT1, JUN and MMP9 were predicted as central therapeutic targets of QCT for treating DW. Functional enrichment analysis demonstrated that QCT exerted strong levels of multitargeting regulatory activity. In addition, the KEGG enrichment analysis indicated that several signaling pathways including AGE-RAGE signaling pathway in diabetic complications, IL-17, PI3k-AKT, TNF, HIF-1, VEGF were predicted as key regulators of QCT for treating DW. Molecular docking results suggested that QCT had strong binding activity with the predicted targets. In addition, verification experiments suggested that QCT could significantly attenuated the expression of inflammatory cytokines and the regulation of PI3K-AKT signaling pathway was probably a vital mechanism involved in the pharmacological mechanism of QCT for treating DW. Taken together, combined network pharmacological with experimental validation, we for the first time systematically investigated associated-therapeutic targets and potential pathways of QCT for DW treatment. Our study might provide theoretical basis for DW treatment.