ABSTRACT
Atherosclerosis is a cardiovascular disease, accounting for the most common mortality cause worldwide. Notoginsenoside R1 (NGR1) is a characteristic saponin of Radix notoginseng that exhibits anti-inflammatory and antioxidant effects while modulating lipid metabolism. Evidence suggests that NGR1 exerts cardioprotective, neuroprotective, and anti-atherosclerosis effects. However, underlying NGR1 mechanisms alleviating atherosclerosis (AS) have not been examined. This study used a network pharmacology approach to construct the drug-target-disease correlation and protein-protein interaction (PPI) network of NGR1 and AS. Moreover, functional annotation and pathway enrichment analyses deciphered the critical biological processes and signaling pathways potentially regulated by NGR1. The protective effect of NGR1 against AS and the underlying mechanism(s) was assessed in an atherogenic apolipoprotein E-deficient (ApoE-/-) mice in vivo and an oxidized low-density lipoprotein (ox-LDL)-induced macrophage model in vitro. The network pharmacology and molecular docking analyses revealed that NGR1 protects against AS by targeting the NLRP3/caspase-1/IL-1ß pathway. NGR1 reduced foam cell formation in ox-LDL-induced macrophages and decreased atherosclerotic lesion formation, serum lipid metabolism, and inflammatory cytokines in AS mice in vivo. Therefore, NGR1 downregulates the NLRP3 inflammasome complex gene expression of NLRP3, caspase-1, ASC, IL-1ß, and IL-18, in vivo and in vitro.
Subject(s)
Atherosclerosis , Ginsenosides , Inflammasomes , Macrophages , NLR Family, Pyrin Domain-Containing 3 Protein , Network Pharmacology , Animals , Ginsenosides/pharmacology , Ginsenosides/chemistry , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Mice , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Inflammasomes/metabolism , Inflammasomes/drug effects , Macrophages/drug effects , Macrophages/metabolism , Male , Molecular Docking Simulation , Lipoproteins, LDL , Mice, Inbred C57BL , Disease Models, Animal , Apolipoproteins E/genetics , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Buyang Huanwu Decoction (BHD) is used to regulate blood circulation and clear collaterals and is widely used in coronary heart disease. However, the active compounds and the mechanism of BHD used to treat restenosis are less understood. OBJECTIVE: The study aimed to explore the potential mechanism of Buyang Huanwu decoction BHD for the treatment of restenosis using network pharmacology and molecular docking experiments. METHODS: The bioactive components of BHD and their corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Encyclopaedia of Traditional Chinese Medicine (ETCM) databases as well as literature. Restenosisassociated therapeutic genes were identified from the OMIM, Drugbank, GEO, and Dis- GeNET databases. Genes related to the vascular smooth muscle cell (VSMC) phenotype were obtained from the gene ontology (GO) database and literature. The core target genes for the drug-disease-VSMC phenotype were identified using the Venn tool and Cytoscape software. Moreover, the "drug-component-target-pathway" network was constructed and analyzed, and pathway enrichment analysis was performed. The connection between the main active components and core targets was analyzed using the AutoDock tool, and PyMOL was used to visualize the results. RESULTS: The "compound-target-disease" network included 80 active ingredients and 599 overlapping targets. Among the bioactive components, quercetin, ligustrazine, ligustilide, hydroxysafflor yellow A, and dihydrocapsaicin had high degree values, and the core targets included TP53, MYC, APP, UBC, JUN, EP300, TGFB1, UBB, SP1, MAPK1, SMAD2, CTNNB1, FOXO3, PIN1, EGR1, TCF4, FOS, SMAD3, and CREBBP. A total of 365 items were obtained from the GO functional enrichment analysis (p < 0.05), whereas the enrichment analysis of the KEGG pathway identified 30 signaling pathways (p < 0.05), which involved the TGF-ß signaling pathway, Wnt signaling pathway, TRAF6-mediated induction of NF-κB and MAPK pathway, TLR7/8 cascade, and others. The molecular docking results revealed quercetin, luteolin, and ligustilide to have good affinity with the core targets MYC and TP53. CONCLUSION: The active ingredients in BHD might act on TP53, MYC, APP, UBC, JUN, and other targets through its active components (such as quercetin, ligustrazine, ligustilide, hydroxysafflor yellow A, and dihydrocapsaicin). This action of BHD may be transmitted via the involvement of multiple signaling pathways, including the TGF-ß signaling pathway, Wnt signaling pathway, TRAF6-mediated induction of NF-κB and MAPK pathway, and TLR7/8 cascade, to treat restenosis by inhibiting the phenotype switching and proliferation of VSMC.
Subject(s)
NF-kappa B , Network Pharmacology , Molecular Docking Simulation , Muscle, Smooth, Vascular , Quercetin/pharmacology , TNF Receptor-Associated Factor 6 , Toll-Like Receptor 7 , Cell Proliferation , Transforming Growth Factor betaABSTRACT
Review the research and development status that Chinese medicine are compatible with Tripterygium wilfordii for attenuation and synergy for recent year. From modern medicine view and Chinese medicine dialectical perspective explain the mechanisms and methods of compatibility applied to attenuation and synergy of T. wilfordii. Provide a reference for reasonable application of other toxic Chinese medicine. Prefer the suggestion that Chinese medicinal formulae can be developed into Chinese medicine compound preparation.