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Junping Zhu,1– 3 Ziyan Wang,4,5 Chengxin Liu,4,5 Min Shi,1,5 Zhihua Guo,1,4,5 Ya Li,2 Rong Yu,1,3 Jiaming Wei1,5 1School of Chinese Medical Sciences, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 2School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 3Hunan Key Laboratory of TCM Prescription and Syndromes Translational Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 4First Hospital and First Clinical College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha, 410208, People’s Republic of China; 5Hunan Key Laboratory of Colleges and Universities of Intelligent Traditional Chinese Medicine Diagnosis and Preventive Treatment of Chronic Diseases of Hunan Universities of Chinese Medicine, Changsha, 410208, People’s Republic of ChinaCorrespondence: Jiaming Wei; Rong Yu, School of Chinese Medical Sciences, Hunan University of Chinese Medicine, 300 Xueshi Road, Science & Technology Industrial Park, Yuelu District, Changsha, Hunan, 410208, People’s Republic of China, Email 004916@hnucm.edu.cn; 002165@hnucm.edu.cnBackground: Xin-Tong-Tai Granule (XTTG), a Chinese medicine (CM) formula, has demonstrated significant therapeutic effects on atherosclerosis (AS) in both clinical and experimental settings. Nonetheless, the mechanisms underlying XTTG’s efficacy remain largely unexplored. This study aimed to elucidate the mechanisms through which XTTG acts against AS, employing network pharmacology, molecular docking, and experimental validation techniques.Methods: Initially, target identification for the main chemical components of XTTG was conducted using database, followed by determining the intersection targets between these compounds and disease. Protein-protein interaction (PPI) network analysis, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were subsequently utilized to investigate the potential pathways through which XTTG exerts its effects on AS. Molecular docking was done to confirm the binding efficacy of XTTG’s active components. Additionally, the effects of XTTG were evaluated in vitro using oxidized low-density lipoprotein (ox-LDL) induced human aortic vascular smooth muscle cells (HAVSMCs) and in vivo in apolipoprotein E gene knockout (ApoE−/−) mice fed a high-fat diet (HFD).Results: 229 therapeutic targets were screened for PPI network and enrichment analysis. Notably, the nuclear factor kappa-B (NF-κB) signaling pathway, along with processes related to inflammation and autophagy, were significantly enriched, highlighting their importance. In vitro studies showed that XTTG repressed cell proliferation and lipid droplet aggregation in ox-LDL-induced HAVSMCs. It also decreased the ratio of phosphorylated NF-κB p65/ NF-κB p65, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels, and elevated microtubule-associated protein light chain 3 (LC3) and decreased p62 protein expression. In vivo, XTTG ameliorated blood lipid profiles and aortic pathology in HFD-fed ApoE−/− mice, reduced NF-κB p65 expression and serum levels of TNF-α and IL-6, increased the ratio of LC3II/LC3I while decreasing p62 protein expression.Conclusion: XTTG mitigates AS primarily through anti-inflammatory and autophagy-modulating mechanisms, particularly via inhibition of NF-κB p65 expression. These findings underscore the potential of CM in treating AS and support its further clinical exploration. Keywords: Xin-Tong-Tai granule, atherosclerosis, network pharmacology, molecular docking, experimental verification |
