Effects and mechanism of Kedaling tablets for atherosclerosis treatment based on network pharmacology, molecular...

Kedaling tablets (KDL) are a Chinese patented medicine derived from Corydalis yanhusuo (Y.H. Chou & Chun C.Hsu) W.T. Wang ex Z.Y. Su & C.Y. Wu (Papaveraceae). They are prescribed for the prevention of atherosclerosis (AS).

We sought to evaluate the effects of KDL treating AS, based on which we screen out the active components of KDL tablets, analyse the serum parameters of rats fed with KDL, and explore the possible mechanisms of action of KDL tablets in the treatment of AS.

ApoE knockout (ApoE^-/-) mice fed a high-fat diet were used to establish an AS model. After KDL and atorvastatin tablets (ATV) treatment for 4 weeks, Movat and haematoxylin-eosin (HE) staining were used to evaluate aortic plaques. Further, we measured total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) in serum. Through ELISA, we measured the levels of proinflammatory factors in serum. The components of KDL were comprehensively analysed using UPLC-Q/TOF-MS. Mechanisms of action were investigated via protein-protein interaction network analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and molecular docking. The expression of predicted targets in serum and aorta were then verified by ELISA.

Animal experiments confirmed that KDL could decrease the plaque area and the proportion of foam cells and collagenous fibres within the plaques of ApoE^-/- mice. In addition, KDL regulated the levels of TC, TG, HDL-C, LDL-C and proinflammatory factors (interleukin [IL]-1β, IL-17) associated with AS. UPLC-Q/TOF-MS analysis revealed 50 and 21 major components in the KDL tablets and serum of rats fed with KDL, respectively. A total of 255 potential core therapeutic targets were obtained, and the top eight key targets were screened out according to network pharmacology analysis. GO analysis revealed 883 biological processes, 136 cellular components and 202 molecular functions. KEGG analysis indicated that 177 signalling pathways, including lipid and AS, TNF, IL-17, TGF-β and other signalling pathways might be associated with AS. Molecular docking results showed that the main active components canadine, stylopine, tetrahydropalmatine and dehydrocorydaline had higher affinities for TNFA, TGFB1, and TGFB2. Furthermore, the favourable effects of KDL were mediated through the regulation of serum TGF-β and TNF-α levels in the serum and aorta of experimental animals.

KDL attenuated AS in ApoE^-/- mice, which was associated with a suppression of inflammatory signalling through the TNF and TGF-β pathways.