目的 基于网络药理学、分子对接和实验验证探讨半夏泻心汤（BXD）抗动脉粥样硬化（AS）的作用机制。方法 通过网络药理学筛选BXD治疗AS的活性成分、潜在靶点及信号通路，展开分子对接验证。体内实验构建AS大鼠模型，分别ig给予低、中、高剂量（4.1、8.2、16.4 g·kg^-1） BXD干预12周。苏木精-伊红（HE）染色观察大鼠胸主动脉和肝脏组织病理变化；油红O染色观察大鼠肝脏组织病理变化；透射电镜观察大鼠胸主动脉组织病理变化； ELISA法检测大鼠血清总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、肿瘤坏死因子（TNF-α）和白细胞介素1β（IL-1β）水平； Western blotting检测大鼠主动脉白蛋白（ALB）、核因子κB p65亚基（NF-κB p65）、蛋白激酶B1（AKT1）、肿瘤蛋白P53（TP53）、TNF-α和白细胞介素-6（IL-6）蛋白表达水平；实时荧光定量PCR（qRT-PCR）法检测大鼠主动脉TNF-α、IL-1β、IL-6和NF-κB p65 mRNA表达。结果 网络药理学筛选出BXD活性成分184个及AS疾病共同靶点174个，核心靶点包括AKT1、ALB、TNF、IL-6、TP53、IL-1β等，富集得到脂质代谢、低氧诱导因子（HIF-1）、NF-κB等通路。实验证实，与模型组相比，高剂量半夏泻心汤组主动脉和肝脏HE染色、肝脏油红O染色和主动脉透射电镜下病理损伤均减轻；血清TC、TG、LDL-C、TNF-α和IL-1β水平显著下调（P＜0.01），HDL-C水平显著升高（P＜0.05）；主动脉NF-κB p65、TNF-α、IL-6蛋白及TNF-α、IL-1β、IL-6和NF-κB p65 mRNA表达水平显著下调（P＜0.05、0.01），AKT1、ALB、TP53蛋白表达水平显著上调（P＜0.01）。结论 BXD可以通过抑制TNF-α/NF-κB/IL-6通路减轻炎症反应，调节脂质代谢，从而改善AS。

Objective This study aims to investigate the mechanism of Banxia Xiexin Decoction (BXD) in resisting atherosclerosis disease (AS) based on network pharmacology, molecular docking and experimental verification. Methods The active ingredients, potential targets and signaling pathways of BXD in treating AS were predicted by network pharmacology and carried out molecular docking verification. The AS rat model was constructed through animal experiments and given low, medium and high doses (4.1, 8.2, and 16.4 g·kg^-1) of BXD for a total of 12 weeks. HE staining was employed to observe the pathological changes in the thoracic aorta and liver tissues of the rats. The pathological changes of liver tissue in rats were observed by oil red O staining. The pathological changes of thoracic aortic tissue in rats were observed by transmission electron microscopy. ELISA was utilized to measure the levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDLC), tumor necrosis factor (TNF-α) and interleukin-1β (IL^-1β) in the serum of the rats. Western blotting was used to detect the protein expression levels of ALB, NF-κB p65, AKT1, TP53, TNF-α, and IL-6 in the aorta of the rats. The mRNA expressions of TNF-α, IL- 1β, IL-6, and NF-κB p65 in the aorta of the rats were detected by qRT-PCR. Results Network pharmacology analysis revealed 184 active components of BXD and 174 common targets of AS disease, with core targets including AKT1, ALB, TNF, IL-6, TP53, IL^-1β, etc. Enrichment analysis revealed pathways such as lipid metabolism, hypoxia-inducible factor (HIF-1), and NF-κB. Experiments confirmed that compared with the model group, in the high-dose BXD group, the HE staining of the aorta and liver, the oil red O staining of the liver, and the pathological damage of the aorta under transmission electron microscopy were all alleviated. ELISA detection revealed significant down-regulation of TC, TG, LDL-C, TNF-α, and IL^-1β levels (P<0.01), and a significant increase in HDL-C levels (P<0.05); Western blotting detection showed significant down-regulation of NF-κB p65, TNF-α, IL-6 protein and TNF- α, IL^-1β, IL-6 and NF-κB p65 mRNA expression levels, and significant up-regulation of AKT1, ALB, TP53 protein expression levels (P<0.01). Conclusion BXD may alleviate inflammation and regulate lipid metabolism by inhibiting the TNF-α/NF-κB/IL-6 pathway, thereby improving AS.

R965

国家自然科学基金资助项目（81202638）