目的 探究首明山胶囊对高脂血症大鼠的调血脂作用及相关机制。方法 将60只6周龄SPF级雄性SD大鼠随机分为对照组、模型组、阿托伐他汀（阳性药，0.9 mg·kg_-1）组以及首明山胶囊高、中、低剂量（1.36、0.68、0.34 g·kg_-1，以胶囊制剂质量计）。除对照组外，其余各组以高脂饲料喂养28 d造模，同时每天ig给予相应药物。末次给药后，采用酶法检测大鼠血清中血脂水平及氧化应激指标，采用实时荧光定量PCR（qRT-PCR）技术检测大鼠肝脏组织炎症因子水平，采用苏木精-伊红（HE）染色法观察肝脏组织病理情况，采用油红O染色法观察肝脏脂肪变性情况。采用超高效液相色谱串联飞行时间质谱联用技术（UPLC-Q/TOF-MS）检测首明山胶囊的入血成分。应用PubChem、Swiss Target Prediction等数据库预测首明山胶囊入血成分的潜在作用靶点，应用DrugBank、OMIM等数据库筛选高脂血症效应靶点，构建二者交集靶点的蛋白质-蛋白质相互作用（PPI）网络并筛选核心靶点，对核心靶点进行京都基因与基因组百科全书（KEGG）通路分析和基因本体（GO）功能分析。采用Western blotting法检测大鼠肝脏组织磷脂酰肌醇3-激酶（PI3K）-丝氨酸/苏氨酸激酶（Akt）信号通路相关蛋白的表达水平。结果 与模型组相比，首明山胶囊组血清中总胆固醇（TC）、三酰甘油（TG）、低密度脂蛋白胆固醇（LDL-C）含量显著降低（P＜0.05、0.01、0.001），超氧化物歧化酶（SOD）水平显著升高（P＜0.05、0.01），丙二醛（MDA）水平显著降低（P＜0.01）；肝脏脂肪性变化及脂质异常累积减少，肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β） mRNA相对表达量显著降低（P＜0.01、0.001），p-PI3K/PI3K、p-Akt/Akt蛋白表达量显著升高（P＜0.05、0.01）。网络药理学筛选出首明山胶囊入血成分166个，获得与高脂血症相关的交集靶点299个，其中IL-6、肿瘤坏死因子（TNF）、AKT1、IL1B、过氧化物酶体增殖物激活受体γ（PPARG）为关键靶点，异鼠李素、异丹叶大黄素、柚皮苷二氢查尔酮为主要活性成分。结论 首明山胶囊通过改善血脂水平防治高脂血症，其机制可能与减轻氧化损伤，抑制炎症反应，上调PI3K-Akt通路相关。

Objective To explore the lipid-regulating effect of Shoumingshan Capsule on hyperlipidemic rats and its related mechanisms. Methods Sixty 6-week-old SPF male SD rats were randomly divided into the control group, model group, atorvastatin (positive drug, 0.9 mg·kg^-1) group, and high-, medium-, and low-dose Shoumingshan Capsule groups (1.36, 0.68, and 0.34 g·kg^-1, respectively, based on the mass of the capsule preparation). Except for the control group, the other groups were fed a high-fat diet for 28 days to establish the model, and were simultaneously administered the corresponding drugs by intragastric administration. After the last administration, the levels of blood lipids and oxidative stress indicators in the rat serum were detected by enzymatic methods. The levels of inflammatory factors in the liver tissue were detected by real-time fluorescence quantitative PCR (qRT-PCR) technology. The pathological conditions of the liver tissue were observed by hematoxylin-eosin (HE) staining, and the fatty degeneration of the liver was observed by oil red O staining. The components of Shoumingshan Capsule entering the blood were detected by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS). The potential target sites of the components of Shoumingshan Capsule entering the blood were predicted by databases such as PubChem and Swiss Target Prediction, and the effect targets of hyperlipidemia were screened by databases such as DrugBank and OMIM. The protein-protein interaction (PPI) network of the intersection targets was constructed and the core targets were screened. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional analysis were performed on the core targets. The expression levels of proteins related to the phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinase (Akt) signaling pathway in the liver tissue of rats were detected by Western blotting. Results Compared with the model group, the levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in the serum of the Shoumingshan Capsule groups were significantly decreased (P < 0.05, 0.01, 0.001), the level of superoxide dismutase (SOD) was significantly increased (P < 0.05, 0.01), and the level of malondialdehyde (MDA) was significantly decreased (P < 0.01). The fatty changes and abnormal lipid accumulation in the liver were reduced, and the relative mRNA expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were significantly decreased (P < 0.01, 0.001). The protein expression levels of p-PI3K/PI3K and p-Akt/Akt were significantly increased (P < 0.05, 0.01). Network pharmacology screened out 166 components of Shoumingshan Capsule entering the blood, and 299 intersection targets related to hyperlipidemia were obtained. Among them, IL-6, tumor necrosis factor (TNF), AKT1, IL1B, and peroxisome proliferator-activated receptor γ (PPARG) were the key targets, and isorhamnetin, isorhamnetin-3-O-glucoside, and naringin dihydrochalcone were the main active components. Conclusion Shoumingshan Capsule can prevent and treat hyperlipidemia by improving blood lipid levels. Its mechanism may be related to reducing oxidative damage, inhibiting inflammatory responses, and upregulating the PI3K-Akt pathway.

R285

天津市科学技术局科技创新基地项目（24ZYJDSY00280）