Polygonum cuspidatum (PC) has been reported to exert a potent antihyperlipidemic effect. However, its mechanisms of action and active ingredients remain elusive and require further research. In this study, we first conducted in vivo experiments to validate that Polygonum cuspidatum extract (PCE) could ameliorate the blood lipid level in hyperlipidemia model rats. Then, ultrahigh performance liquid chromatography coupled with Q-Exactive MS/MS (UPLC-QE-MS/MS) was applied to verify its 12 main active ingredients. The pharmacophore matching model was employed to predict the target point of the active ingredient, and 27 overlapping genes were identified via database and literature mining. String online database and Cytoscape software were utilized to construct a Protein-Protein Interaction (PPI) network, followed by function annotation analysis and pathway enrichment analysis. The results showed that the PI3K/AKT signaling pathway and its downstream FOXO3/ERα factors were significantly enriched. Furthermore, in vitro experiments were performed to determine the lipid content and oxidative stress (OS) indicators in OA-induced HepG2 cells, and immunofluorescence and western blotting analysis were carried out to analyze the effects of PCE on related proteins. Our experimental results show that the mechanism of antihyperlipidemic action of PCE is related to the activation of the PI3K/AKT signaling pathway and its downstream FOXO3/ERα factors, and polydatin and resveratrol are the main active ingredients in PCE that exert antihyperlipidemic effects.

中文翻译：

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虎杖提取物通过调节 PI3K/AKT/FOXO3 信号通路发挥抗高血脂作用

据报道，虎杖（PC）发挥有效的抗高血脂作用。然而，其作用机制和活性成分仍然难以捉摸，需要进一步研究。在这项研究中，我们首先进行了体内实验来验证虎杖提取物（PCE）可改善高脂血症模型大鼠的血脂水平。然后，应用超高效液相色谱与 Q-Exactive MS/MS (UPLC-QE-MS/MS) 联用对其 12 种主要活性成分进行验证。采用药效团匹配模型预测活性成分的靶点，通过数据库和文献挖掘鉴定出27个重叠基因。利用String在线数据库和Cytoscape软件构建蛋白质-蛋白质相互作用（PPI）网络，然后进行功能注释分析和通路富集分析。结果表明，PI3K/AKT信号通路及其下游FOXO3/ERα因子显着富集。此外，体外通过实验测定OA诱导的HepG2细胞的脂质含量和氧化应激（OS）指标，并通过免疫荧光和蛋白质印迹分析分析PCE对相关蛋白的影响。我们的实验结果表明，PCE的降血脂作用机制与激活PI3K/AKT信号通路及其下游的FOXO3/ERα因子有关，虎杖苷和白藜芦醇是PCE中发挥降血脂作用的主要活性成分。