1、 中草药 中草药 2023 年年 3 月月 第第 54 卷卷 第第 5 期期 Chinese Traditional and Herbal Drugs 2023 March Vol.54 No.5 1487 基于网络药理学和分子对接探究地骨皮调血脂的作用机制 赵少磊1,2，原 震2，朱艳茹1,2，丁浩强2，郑鑫杰2，张静泽1,2，刘岱琳1,2*1.天津中医药大学，天津 301617 2.天津现代创新中药科技有限公司，天津 300384 摘 要：目的 基于网络药理学与分子对接技术探讨地骨皮调血脂的作用机制。方法 使用 TCMSP 数据库并查阅相关文献确定地骨皮活性成分；采用 SwissTarge
2、tPrediction、GeneCard 和 OMIM 数据库预测地骨皮活性成分靶点和高脂血症相关靶点，应用 Venny 2.1 取两者交集；运用 Cytoscape 3.8.2 软件绘制成分-靶点-疾病网络；应用 String 数据库构建交集靶点的蛋白质-蛋白质相互作用（protein-protein interaction，PPI）网络；将交集靶点输入 Metascape 数据库进行基因本体（gene ontology，GO）功能及京都基因与基因组百科全书（Kyoto encyclopedia of genes and genomes，KEGG）通路富集分析，利用 Cytoscape 3.
3、8.2 软件绘制地骨皮活性成分-靶点-通路网络，预测其调血脂作用机制；采用分子对接和细胞实验进一步探究地骨皮的调血脂作用机制。结果 共筛选出地骨皮潜在活性成分 14 个以及 153 个交集靶点；GO 功能和 KEGG 通路分析发现主要涉及过氧化物酶体增殖物激活受体（peroxisome proliferator activated receptor，PPAR）信号通路、AMP 激活的蛋白激酶（AMP-activated protein kinase，AMPK）信号通路、脂质和动脉粥样硬化、胰岛素抵抗、脂肪消化吸收以及胆汁分泌等。分子对接结果显示，地骨皮中金合欢素、蒙花苷、-谷甾醇以及大黄素等活
4、性成分与关键靶蛋白之间具有良好的结合作用。细胞实验结果显示，蒙花苷、-谷甾醇以及大黄素均能够抑制油酸诱导的人肝癌 HepG2 细胞脂质蓄积（P0.05、0.01）。Western blotting 实验结果显示，蒙花苷和大黄素均能上调人结肠腺癌 Caco-2 细胞中腺苷三磷酸结合盒转运蛋白 A1（ATP binding cassette transport protein A1，ABCA1）蛋白表达（P0.05、0.01）。结论 地骨皮中的蒙花苷、大黄素、-谷甾醇等活性成分可能是通过作用于 PPAR、PPAR 等靶点干预 PPAR 和 AMPK 等信号通路，影响下游蛋白 ABCA1 的表达，抑
5、制细胞中的脂质蓄积从而发挥调血脂作用。关键词：地骨皮；调血脂；网络药理学；分子对接；蒙花苷；大黄素；-谷甾醇；金合欢素；氧化物酶体增殖物激活受体 中图分类号：R285.5 文献标志码：A 文章编号：0253-2670(2023)05-1487-11 DOI:10.7501/j.issn.0253-2670.2023.05.015 Mechanism of hypolipidemic effect of Lycii Cortex based on network pharmacology and molecular docking ZHAO Shao-lei1,2,YUAN Zhen2,ZHU
6、Yan-ru1,DING Hao-qiang2,ZHENG Xin-jie2,ZHANG Jing-ze1,2,LIU Dai-lin1,2 1.Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China 2.Modern TCM Innovation Center,Tianjin 300384,China Abstract:Objective To explore the mechanism of hypolipidemic effect of Digupi(Lycii Cortex)based on net
7、work pharmacology and molecular docking technology.Methods The active ingredients were determined by Using TCMSP database and browsing literatures.SwissTargetPrediction,GeneCard and OMIM databases were used to predict the active component targets of Lycii Cortex and hyperlipidemia-related targets,an
8、d Venny 2.1 was used to obtain intersection targets.Cytoscape 3.8.2 software was used to map the component-intersection targets-disease network.Protein-protein interaction(PPI)network with intersecting targets was constructed by String database.The intersection targets were input into Metascape data
9、bases for gene ontology(GO)function and Kyoto encyclopedia of geneses and genomes(KEGG)pathway enrichment analysis to predict its possible hypolipidemic mechanism,the diagram of components-intersection target-pathway of Lycii Cortex were showing by Cytoscape 3.8.2 software.Molecular docking 收稿日期：202
10、2-10-10 基金项目：国家自然科学基金资助项目（81673693）；中药抗炎机制与智能制造研究创新能力建设项目（20201178）作者简介：赵少磊（1997），男，硕士研究生，主要从事中药作用物质基础研究。*通信作者：刘岱琳（1973），女，教授，主要从事中药作用物质基础研究。Tel:13821660597 E-mail: 1488 中草药 中草药 2023 年年 3 月月 第第 54 卷卷 第第 5 期期 Chinese Traditional and Herbal Drugs 2023 March Vol.54 No.5 and cell experiments were used t
11、o further explore the hypolipidemic mechanism of Lycii Cortex.Results A total of 14 potential active components and 153 intersecting targets were obtained from Lycii Cortex.GO function and KEGG pathway analysis showed that the key targets involved AMP-activated protein kinase(AMPK)signaling pathway,
12、peroxisome proliferator activated receptor(PPAR)signaling pathway,lipid and atherosclerosis,insulin resistance,fat digestion and absorption,bile secretion,etc.The molecular docking results showed that the active components of acacetin,linarin,-sitosterol and emodin displayed strong binding abilities
13、 with key targets respectively.In addition,results of cell experiments in vitro showed that linarin,-sitosterol and emodin could inhibit lipid accumulation in oleic acid-induced HepG2 cells(P 0.05,0.01).Western blotting experiments results showed that linarin and emodin could increase ATP binding ca
14、ssette transport protein A1(ABCA1)protein expression in Caco-2 cells(P 0.05,0.01).Conclusion The active components in Lycii Cortex such as linarin,emodin and-sitosterol may act on PPAR,PPAR and other targets,inhibit the lipid accumulation,increase the expression of ABCA1 through PPAR signaling pathw
15、ay,AMPK signaling pathway and other related pathways,thereby exerting a hypolipidemic effect.Key words:Lycii Cortex;hypolipidemic;network pharmacology;molecular docking;linarin;emodin;-sitosterol;acacetin;peroxisome proliferator activated receptor 近年来，脂质代谢异常已经成为仅次于高血压、吸烟的第 3 大心血管疾病独立危险因素1，高脂血症与心血管事件
16、的发生密切相关。低密度脂蛋白胆固醇升高是心血管疾病尤其是冠状动脉粥样硬化性心血管疾病的重要危险因素，因此，调节血脂对于防治心血管疾病、降低心血管事件的发生具有重要意义。中药以其疗效确切、不良反应小以及多途径、多靶点的作用特点在调节血脂异常、防治高脂血症方面具有良好的前景。地骨皮为茄科植物枸杞 Lycium chinense Mill.或宁夏枸杞 L.barbarum L.的干燥根皮。本草纲目中曾记载“春采枸杞叶，名天精草；夏采花，名长生花；秋采子，名枸杞子；冬采根，名地骨皮”。果实枸杞为药食同源的常用中药材，始载于神农本草经，具有可滋补肝肾、益精明目的功效，用于治疗虚劳精亏、腰膝酸痛、眩晕耳鸣、阳痿遗精、内热消渴、血虚萎黄、目昏不明等症2。枸杞的根皮名为地骨皮，可凉血除蒸、清肺降火，用于治疗阴虚潮热、骨蒸盗汗、肺热咳嗽、咯血、衄血、内热消渴等症3。现代药理学研究发现，地骨皮具有降血压、调血脂、降血糖、抗骨质疏松、抗炎等多种作用4。研究发现，地骨皮中的蒽醌类成分能够降低高脂血症大鼠总胆固醇、三酰甘油和低密度脂蛋白胆固醇水平，增加胆汁酸的外排，从而发挥调血脂作用5-6。地骨皮含有环肽类、黄