[Integrating network pharmacology and transcriptomics to reveal mechanism of loganin in ameliorating isoprenaline-induced myocardial injury].

摘要

This study employed an integrated strategy combining network pharmacology, transcriptome sequencing, molecular docking, and in vivo and in vitro experimental validation to systematically investigate the protective effect of loganin against isoprenaline(ISO)-induced myocardial injury and its underlying mechanisms. In the mouse model of ISO-induced myocardial injury, administration of loganin significantly improved cardiac function parameters including left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS) and attenuated histopathological myocardial injury. In vitro, loganin treatment enhanced the viability of ISO-exposed AC16 cardiomyocytes, reduced oxidative stress markers, suppressed apoptotic processes, and restored mitochondrial membrane potential. Transcriptome profiling revealed significant enrichment of differentially expressed genes in apoptosis, mitogen-activated protein kinase(MAPK), and Forkhead box O(FoxO) signaling pathways. Further integration with network pharmacology approaches, comprehensive screening of potential targets from GeneCards, SwissTargetPrediction, and Comparative Toxicogenomics Database(CTD), followed by protein-protein interaction network construction and topological analysis, identified nuclear factor erythroid 2-related factor 2(NRF2) as the pivotal therapeutic target. Molecular docking studies confirmed favorable binding affinity between loganin and NRF2 protein with a binding energy of-7.6 kcal·mol~(-1). Mechanistically, Western blot analysis demonstrated that loganin promoted NRF2 nuclear translocation, upregulated downstream antioxidant proteins heme oxygenase-1(HO-1) and NAD(P)H: quinone oxidoreductase 1(NQO1), and concurrently inhibited phosphorylation of c-Jun N-terminal kinase(JNK) and p38 MAPK. Notably, the cardioprotective effects of loganin were substantially abolished by co-treatment with the NRF2-specific inhibitor ML385. Collectively, these findings indicate that loganin confers protection against ISO-induced myocardial injury by suppressing oxidative stress and JNK/p38 MAPK-mediated apoptosis through activation of the NRF2 signaling pathway.