The mechanism of Epimedium in the treatment of coronary atherosclerotic heart disease based on network pharmacology, molecular docking, and in vitro studies.

OBJECTIVE: There are many challenges related to the treatment of coronary atherosclerotic heart disease (CAD). Studies have confirmed that Epimedium extract inhibits myocardial injury induced by myocardial ischaemia, but the mechanism of action remains unclear. This study aimed at analysed the effective components and mechanisms of Epimedium in treating CAD based on network pharmacology and molecular docking studies and to verify the mechanism in vitro. MATERIALS AND METHODS: The TCMSP and UniProt databases were used to filter for the active components and drug targets of Epimedium. The GeneCards database was used to screen disease targets associated with CAD. The intersection of the drug targets of Epimedium and the disease targets of coronary heart disease was studied to identify the targets of Epimedium in the treatment of CAD. Cytoscape software was used to establish and analyse an activity-target network. The STRING database was used to analyse a protein-protein interaction (PPI) network, and proteins in the PPI network were visualized in the R language. Bioconductor software was used for GO function and KEGG pathway enrichment analyses, and visualization analysis was performed in the R language. PyMOL software was used to verify the molecular docking between selected active components of Epimedium and the targets of CAD, and the potential key effective components of Epimedium in the treatment of coronary heart disease were identified. The involvement of the PI3K/Akt pathway was validated by Western blot analysis. RESULTS: (1) Twenty-three active compounds, including Epimedium glycoside, quercetin, luteolin, and olive resin, were screened out. There were 68 common targets of Epimedium and CAD, including IL-6, ESR1, RELA, FOS, NCOA1, CCND1, EGFR, MAPK8, VEGFA, and CASP8. The potential signaling pathways involved in the treatment of CAD by Epimedium included the human cytomegalovirus infection pathway, the PI3K-Akt signaling pathway, the TNF signaling pathway, and the HIF-1 signaling pathway. (2) Luteolin, quercetin, sitosterol, and anhydroicaritin showed strong binding to targets of CAD based on molecular docking studies. (3) Epimedium extract increased the expression of PI3K, Akt and P-Akt but decreased the expression of IL-6  in vitro. CONCLUSIONS: (1) Icariin, quercetin and luteolin may act on target proteins, including IL-6, ESR1, EGFR, MAPK8, VEGFA and CASP8, to participate in the regulation of the human cytomegalovirus infection pathway, the PI3K-Akt signaling pathway, the TNF signaling pathway and other signaling pathways in order to effectively treat CAD. (2) In vitro studies confirmed that Epimedium extract can treat CAD by upregulating PI3K, Akt and P-Akt protein expression and downregulating IL-6 protein expression in SD rat cardiomyocytes.

Associations of cardiorespiratory fitness and parental history of diabetes with risk of type 2 diabetes.

AIMS: We examined the independent and joint associations of cardiorespiratory fitness (CRF) and parental diabetes history on type 2 diabetes risk. METHODS: A cohort of 11,627 individuals aged 20-79 years was free of baseline diabetes, cardiovascular disease, and cancer. We measured CRF using a maximal treadmill exercise test, and parental diabetes by a medical history questionnaire. RESULTS: During an average 5.5 year follow-up, 572 cases of type 2 diabetes occurred. Compared with the least fit 20%, the multivariate hazard ratio (HR) (95% CI) was 0.59 (0.43-0.83) for the middle fit 40%, and 0.53 (0.38-0.75) for the high fit 40%. Those with parental diabetes had a 1.40-fold higher risk for developing type 2 diabetes. In combined analyses using fit, no parental diabetes as the referent, unfit with no parental diabetes was 1.79 (95% CI 1.25-2.57) times more likely to develop type 2 diabetes, while the risk with parental diabetes was 1.41 (95% CI 1.12-1.78) and 2.37 (95% CI 1.25-4.49) times higher in the fit and unfit, respectively. CONCLUSIONS: While high CRF did not fully attenuate the risk of diabetes associated with parental diabetes, being fit reduces diabetes risk regardless of parental history.