Study on the mechanism of Xiongshi Shiwei Wendan decoction promoting RCT and treat AS based on network pharmacology, molecular docking and in vitro experiment

doi:10.12092/j.issn.1009-2501.2025.08.003

Abstract

Abstract: AIM: Xiongshi Shiwei Wendan decoction (SWD) comes from Xiong Jibai, a master of traditional Chinese medicine, and has been widely used in the treatment of AS. ABCA1 is an important pathway for macrophages to export cholesterol and plays a protective role in the occurrence and development of AS. The purpose of this study was to study the effects of SWD on ABCA1 expression and cholesterol efflux through network pharmacology, molecular docking and in vitro experiments, and explore the pathway mechanism of promoting reverse cholesterol transport (RCT). METHODS: The active components of SWD drugs were screened by TCMSP and HERB databases, RCT targets were predicted, the component-target network map was constructed, the PPI network was constructed and the GO and KEGG pathways were enriched and analyzed by STRING database, and the key active components of SWD were selected for molecular docking with ABCA1 protein and miR-33 by AutoDockVina. In vitro, RAW264.7 was used to establish foam cell model, oil red O staining, NBD-cholesterol staining and lentivirus overexpression cell miRNA-33 were used to study the effect of SWD on lipid accumulation and cholesterol outflow rate of RAW264.7 cells. Western blotting was used to detect the expression of ABCA1. RESULTS: According to network pharmacology, 336 active components of SWD, 267 targets of RCT and 46 targets of intersection of RCT and SWD were obtained, which involved multiple signal pathways such as lipid and atherosclerosis. Molecular docking showed that the main active components had stable conformation with ABCA1 and miR-33. In vitro experiment, it was found that the lipid content was significantly decreased (P<0.01), the cholesterol outflow rate was significantly increased (P<0.01) and the expression of ABCA1 protein was up-regulated in SWD group (P<0.01), but the expression of ABCA1 in miR-33 overexpression group was significantly decreased (P<0.01). CONCLUSION: SWD has the characteristics of multi-components and multi-targets, which can promote RCT and treat AS through miRNA-33-ABCA1 pathway.

Key words: Xiongshi Shiwei Wendan decoction, atherosclerosis, reverse cholesterol transport, ABCA1, miR-33

CLC Number:

R965.2

MA Xingyu^{1, 2}, XIE Xuejiao², LI Chunqiao¹, ZHANG Zheng¹. Study on the mechanism of Xiongshi Shiwei Wendan decoction promoting RCT and treat AS based on network pharmacology, molecular docking and in vitro experiment[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2025, 30(8): 1026-1036.

References

[1] Moore KJ, Tabas I.Macrophages in the pathogenesis of atherosclerosis[J]. Cell, 2011, 145(3): 341-355.
[2] Galindo CL, Khan S, Zhang X, et al.Lipid-laden foam cells in the pathology of atherosclerosis: shedding light on new therapeutic targets[J]. Expert Opin Ther Targets, 2023, 27(12): 1231-1245.
[3] Zhao S, Li J, Wang L, et al.Pomegranate peel polyphenols inhibit lipid accumulation and enhance cholesterol efflux in raw264.7 macrophages[J]. Food Funct, 2016, 7(7): 3201-3210.
[4] Xu X, Song Z, Mao B, et al.Apolipoprotein A1-related proteins and reverse cholesterol transport in antiatherosclerosis therapy: Recent progress and future perspectives[J]. Cardiovasc Ther, 2022, 2022: 4610834.
[5] Bommer GT, Macdougald OA.Regulation of lipid homeostasis by the bifunctional SREBF2-miR33a locus[J]. Cell Metab, 2011, 13(3): 241-247.
[6] Zhang X, Price NL, Fernández-Hernando C.Non-coding RNAs in lipid metabolism[J]. Vascul Pharmacol, 2019, 114: 93-102.
[7] Song W, Wang W, Wang Y, et al.Characterization of fluorescent NBD-cholesterol efflux in THP-1-derived macrophages[J]. Mol Med Rep, 2015, 12(4): 5989-5996.
[8] 武青庭. 小陷胸汤对ApoE-/-小鼠脂质代谢及相关转运蛋白表达的影响 [D]. 长沙: 湖南中医药大学, 2019: 33.
[9] 何林, 彭伟, 张学建, 等. UPLC-QE-Orbitrap-MS/MS结合网络药理学和实验验证探讨西洋参治疗动脉粥样硬化的作用机制[J]. 天然产物研究与开发, 2022, 34(8): 1400-1414.
[10] 孙亚男, 黄小波, 粱伟, 等. 陈皮、半夏对动脉粥样硬化小鼠PI3K-Akt通路、SOD、MDA、SA-β-gal水平的影响[J]. 首都医科大学学报, 2018, 39(6): 805-809.
[11] 姜亚玲, 李文渊, 冯爽, 等. 木犀草素的结构修饰及其生物活性研究进展[J]. 中草药, 2023, 54(20): 6889-6902.
[12] 冯爽, 姜亚玲, 刘金海, 等. 木犀草素衍生物研究进展[J]. 化学通报, 2024, 87(3): 300-309.
[13] Bhatia G, Singh J, Nehru B.Neuroprotective effects of hydro-alcoholic extract of Eclipta alba against 1-methyl-4-phenylpyridinium-induced in vitro and in vivo models of Parkinson's disease[J]. Environ Sci Pollut Res Int, 2021, 28(8): 9390-9406.
[14] 黄威, 饶艳玲. 山奈酚通过线粒体依赖的途径减轻高糖诱导的足细胞损伤[J]. 中国老年学杂志, 2024, 44(10): 2516-2520.
[15] 周芹, 宋艳, 李金河, 等. 柚皮素通过诱导血红素加氧酶-1的表达抑制氧化应激和血管钙化[J]. 中山大学学报(医学科学版), 2021, 42(4): 528-534.
[16] 何慧, 董豆豆, 丁萌, 等. 柚皮素通过调控平滑肌细胞TIMP-3表达促进动脉粥样硬化斑块稳定 [J]. 中国动脉硬化杂志, 2024, 32(7): 567-572+582.
[17] Liu Y, Tang X, Yuan H, et al.Naringin inhibits macrophage foam cell formation by regulating lipid homeostasis and metabolic phenotype[J]. Nutrients, 2024, 16(9): 1321.
[18] 徐由财, 丁文俊, 陈思, 等. Nrf2在黄芩素抑制氧化应激诱导心肌细胞凋亡中的作用[J]. 中成药, 2022, 44(5): 1434-1440.
[19] 王亮, 刘安宁, 李红玲, 等. 黄芩素调节PPARγ/LXRα/ABCA1信号通路干预NAFLD大鼠肝功能和胰岛素抵抗研究[J]. 现代医学, 2023, 51(1): 17-23.
[20] 罗纲, 向露, 姚平, 等. 槲皮素调控巨噬细胞胆固醇稳态改善载脂蛋白E敲除小鼠动脉粥样硬化[J]. 中国药理学通报, 2022, 38(9): 1395-1400.
[21] Jiang YH, Jiang LY, Wang YC, et al.Quercetin attenuates atherosclerosis via modulating oxidized LDL-induced endothelial cellular senescence[J]. Front Pharmacol, 2020, 11: 512.
[22] 齐晶, 秦毅, 李兴培, 等. 丹参酮治疗冠心病对Nrf2/ARE信号通路和氧化应激的影响[J]. 现代生物医学进展, 2024, 24(11): 2015-2019.
[23] 胡海燕, 李跃艳, 李春霞, 等. 丹参酮ⅡA上调ABCA1表达促进泡沫细胞胆固醇流出[J]. 国际病理科学与临床杂志, 2012, 32(6): 488-495.
[24] Ortega R, Liu B, Persaud SJ.Effects of miR-33 deficiency on metabolic and cardiovascular diseases: implications for therapeutic intervention[J]. Int J Mol Sci, 2023, 24(13): 10777.
[25] Ren K, Jiang T, Zhou HF, et al.Apigenin retards atherogenesis by promoting ABCA1-mediated cholesterol efflux and suppressing inflammation[J]. Cell Physiol Biochem, 2018, 47(5): 2170-2184.
[26] Zhu F, Chang G, Tang X, et al.Doxorubicin inhibits cholesterol efflux through the miR-33/ABCA1 pathway[J]. Biochem Biophys Res Commun, 2023, 644: 149-154.
[27] Ouimet M, Ediriweera H, Afonso MS, et al.microRNA-33 regulates macrophage autophagy in atherosclerosis[J]. Arterioscler Thromb Vasc Biol, 2017, 37(6): 1058-1067.
[28] Zhao L, Huang J, Zhu Y, et al.miR-33-5p knockdown attenuates abdominal aortic aneurysm progression via promoting target adenosine triphosphate-binding cassette transporter A1 expression and activating the PI3K/Akt signaling pathway[J]. Perfusion, 2020, 35(1): 57-65.
[29] Näär AM. miR-33: a metabolic conundrum[J]. Trends Endocrinol Metab, 2018, 29(10): 667-668.
[30] Guerau-De-Arellano M, Piedra-Quintero ZL, Tsichlis PN. Akt isoforms in the immune system[J]. Front Immunol, 2022, 13: 990874.
[31] Zhao L, Wang X, Yang Y.Association between interleukin-6 and the risk of cardiac events measured by coronary computed tomography angiography[J]. Int J Cardiovasc Imaging, 2017, 33(8): 1237-1244.
[32] He L, Zhang CL, Chen Q, et al.Endothelial shear stress signal transduction and atherogenesis: From mechanisms to therapeutics[J]. Pharmacol Ther, 2022, 235: 108152.
[33] 袁点, 李为真, 王蓉, 等. 血清核因子-κB、肿瘤坏死因子-α、单核细胞趋化因子-1与老年冠状动脉粥样硬化性心脏病合并衰弱综合征的关系及预测模型构建[J]. 中国医刊, 2024, 59(8): 856-860.
[34] Dell'accio F, Sherwood J. PPARγ/mTOR signalling: striking the right balance in cartilage homeostasis[J]. Ann Rheum Dis, 2015, 74(3): 477-479.
[35] Adeshara KA, Bangar N, Diwan AG, et al.Plasma glycation adducts and various RAGE isoforms are intricately associated with oxidative stress and inflammatory markers in type 2 diabetes patients with vascular complications[J]. Diabetes Metab Syndr, 2022, 16(3): 102441.
[36] Prasad K, Khan AS, Bhanumathy KK.Does AGE-rage stress play a role in the development of coronary artery disease in obesity?[J]. Int J Angiol, 2022, 31(1): 1-9.