| Summary: | Yingying Pan,1,* Xianrong Feng,2,* Wei Song,1,* Xin Zhou,1 Zhen Zhou,3 Gaoyang Chen,1 Tao Shen,1 Xiaobo Zhang1 1School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 3Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia*These authors contributed equally to this workCorrespondence: Xiaobo Zhang; Tao Shen, School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China, Email zhangxiaobo@stu.cdutcm.edu.cn; shentaotcm@aliyun.comBackground: Atherosclerosis (AS) is an immunoinflammatory disease associated with dyslipidemia. Zhuyu Pill (ZYP) is a classic Chinese herbal compound that has been shown to exhibit anti-inflammatory and lipid-lowering effects on AS in our previous studies. However, the underlying mechanisms by which ZYP ameliorates atherosclerosis have not yet been fully investigated. In this study, network pharmacology and in vivo experiments were conducted to explore the underlying pharmacological mechanisms of ZYP on ameliorating AS.Methods: The active ingredients of ZYP were acquired from our previous study. The putative targets of ZYP relevant to AS were obtained from TCMSP, SwissTargetPrediction, STITCH, DisGeNET, and GeneCards databases. Protein-protein interactions (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted using the Cytoscape software. Furthermore, in vivo experiments were carried out for target validation in apolipoprotein E (ApoE) -/- mice.Results: Animal experiments revealed that ZYP ameliorated AS mainly through lowering blood lipids, alleviating vascular inflammation, and decreasing the levels of vascular cell adhesion molecule-1 (VCAM1), intercellular adhesion molecule-1 (ICAM1), monocyte chemotactic protein-1 (MCP-1), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α). Additionally, the results of Real-Time quantitative PCR revealed that ZYP inhibited the gene expressions of mitogen-activated protein kinase (MAPK) p38, extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor kappa-B (NF-κB) p65. The Immunohistochemistry and Western blot assays showed the inhibitory effect of ZYP on the proteins level of p38, p-p38, p65, and p-p65.Conclusion: This study has provided valuable evidence on the pharmacological mechanisms of action of ZYP in ameliorating AS that will be useful for forming the rationale of future research studying the cardio-protection and anti-inflammation effects of ZYP.Keywords: atherosclerosis, Zhuyu Pill, network pharmacology, MAPK, NF-κB
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