Mechanism exploration of 6-Gingerol in the treatment of atherosclerosis based on network pharmacology, molecular docking and experimental validation

Abstract

BackgroundThe 6-Gingerol has significant anti-inflammatory, anti-oxidative and hypolipidemic activities and is widely used for treating cardiac-cerebral vascular diseases. However, the multi-target mechanism of 6-Gingerol in the treatment of atherosclerosis remains to be elucidated. MethodsFirstly, the therapeutic actions of 6-Gingerol anti-atherosclerosis were researched based on an atherosclerotic ApoE-deficient mice model induced by high-fat feed. Then, network pharmacology and molecular docking were employed to reveal the anti-atherogenic mechanism of 6-Gingerol. Finally, the target for these predictions was validated by target protein expression assay in vitro and in vivo experiments and further correlation analysis. ResultsFirstly, 6-Gingerol possessed obvious anti-atherogenic activity, which was manifested by a significant reduction in the plaque area, decrease in the atherosclerosis index and vulnerability index. Secondly, based on network pharmacology, 14 predicted intersection target genes between the targets of 6-Gingerol and atherogenic-related targets were identified. The key core targets of 6-Gingerol anti-atherosclerosis were found to be TP53, RELA, BAX, BCL2, and CASP3. Lipid and atherosclerosis pathways might play a critical role in 6-Gingerol anti-atherosclerosis. Molecular docking results also further revealed that the 6-Gingerol bound well and stable to key core targets from network pharmacological predictions. Then, the experimental results in vivo and in vitro verified that the up-regulation of TP53, RELA, BAX, CASP3, and down-regulation of BCL2 from atherosclerotic ApoE-deficient mice model can be improved by 6-Gingerol intervention. Meanwhile, the correlation analysis further confirmed that 6-Gingerol anti-atherosclerosis was closely related to these targets. ConclusionThe 6-Gingerol can markedly improve atherosclerosis by modulating key multi-targets TP53, RELA, BAX, CASP3, and BCL2 in lipid and atherosclerosis pathways. These novel findings shed light on the anti-atherosclerosis mechanism of 6-Gingerol from the perspective of multiple targets and pathways.