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Network pharmacology and experimental verification to explore the molecular mechanisms of Astragaloside IV against
Yong Wang1, Qianqian Yang2, Yanchao Lu3
1Department of Medical Imaging, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China; Department of Radiology and Nuclear Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China.
Purpose:
Diabetic encephalopathy (DE) is a neurological complication caused by diabetes mellitus, and its underlying mechanism has not been fully clarified. Astragaloside IV (AS-IV) has been demonstrated to have treatment effects on multiple neurologic diseases. The objective of this research is to explore the role and underlying mechanism of AS-IV in the treatment of DE, utilizing the methods of network pharmacology and experimental validation.
Methods:
Multiple public databases were used to search for the targets of AS-IV. Gene Expression Omnibus (GEO) dataset (GSE16135) was analyzed to identify differentially expressed genes (DEGs) in DE. The Venn diagram was employed to determine the intersecting genes. These genes were considered potential therapeutic targets of AS-IV in DE and were annotated using bioinformatics techniques. Subsequently, a protein-protein interaction (PPI) network was constructed utilizing Cytoscape software to identify the core targets of action. Additionally, molecular docking was conducted to validate the binding affinity of AS-IV to the main targets. Finally, we validated the predictive outcomes of network pharmacology in a DE rat model induced by intraperitoneal injection of streptozotocin (STZ).
Results:
Through the application of network pharmacology and bioinformatics analyses, we discovered the top two hub targets (EGFR and JAK2). Subsequent molecular docking analysis showed that AS-IV was precisely located within the binding sites of both EGFR and JAK2, with binding energies of -8.18 kJ/mol and -10.94 kJ/mol, respectively. Behavioral experiments demonstrated that the treated rats showed improvements in cognitive impairment. Following AS-IV treatment, there was a significant reduction in amyloid-β (Aβ) plaques deposition and neurofibrillary tangles in the hippocampal tissue of DE rats. Furthermore, TUNEL staining and Western blot analyses demonstrated that AS-IV suppressed neuronal apoptosis and inhibited the activation of the EGFR/JAK2/STAT3 signaling pathway.
Conclusion:
These results demonstrated that the AS-IV has the potential to improve cognitive impairment in DE rats by mitigating neuronal apoptosis through the EGFR/JAK2/STAT3 signaling pathway, which provides important implications for the treatment of DE.
