基于生物信息学分析、分子对接和体外实验，鉴定通过增加 HDL-C 水平治疗动脉粥样硬化的天然产物。
Identifying the natural products in the treatment of atherosclerosis by increasing HDL-C level based on bioinformatics analysis, molecular docking, and in vitro experiment.
机构信息
Shanghai Innovation Center of Traditional Chinese Medicine Health Service, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Mathematics and Physics, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
出版信息
J Transl Med. 2023 Dec 19;21(1):920. doi: 10.1186/s12967-023-04755-7.
BACKGROUND
Previous studies have demonstrated that high-density lipoprotein cholesterol (HDL-C) plays an anti-atherosclerosis role through reverse cholesterol transport. Several studies have validated the efficacy and safety of natural products in treating atherosclerosis (AS). However, the study of raising HDL-C levels through natural products to treat AS still needs to be explored.
METHODS
The gene sets associated with AS were collected and identified by differential gene analysis and database query. By constructing a protein-protein interaction (PPI) network, the core submodules in the network are screened out. At the same time, by calculating node importance (Nim) in the PPI network of AS disease and combining it with Kyoto Encyclopedia of genes and genomes (KEGG) pathways enrichment analysis, the key target proteins of AS were obtained. Molecular docking is used to screen out small natural drug molecules with potential therapeutic effects. By constructing an in vitro foam cell model, the effects of small molecules on lipid metabolism and key target expression of foam cells were investigated.
RESULTS
By differential gene analysis, 451 differential genes were obtained, and a total of 313 disease genes were obtained from 6 kind of databases, then 758 AS-related genes were obtained. The enrichment analysis of the KEGG pathway showed that the enhancement of HDL-C level against AS was related to Lipid and atherosclerosis, Cholesterol metabolism, Fluid shear stress and atherosclerosis, PPAR signaling pathway, and other pathways. Then we intersected 31 genes in the core module of the PPI network, the top 30 genes in Nims, and 32 genes in the cholesterol metabolism pathway, and finally found 3 genes. After the above analysis and literature collection, we focused on the following three related gene targets: APOA1, LIPC, and CETP. Molecular docking showed that Genistein has a good binding affinity for APOA1, CETP, and LIPC. In vitro, experiments showed that Genistein can up-regulated APOA1, LIPC, and CETP levels.
CONCLUSIONS
Based on our research, Genistein may have the effects of regulating HDL-C and anti-atherosclerosis. Its mechanism of action may be related to the regulation of LIPC, CETP, and APOA1 to improve lipid metabolism.
背景
先前的研究表明，高密度脂蛋白胆固醇（HDL-C）通过胆固醇逆转运发挥抗动脉粥样硬化作用。多项研究已经验证了天然产物治疗动脉粥样硬化（AS）的疗效和安全性。然而，通过天然产物提高 HDL-C 水平来治疗 AS 的研究仍有待探索。
方法
通过差异基因分析和数据库查询收集与 AS 相关的基因集，并进行鉴定。构建蛋白质-蛋白质相互作用（PPI）网络，筛选网络中的核心子模块。同时，通过计算 AS 疾病 PPI 网络中的节点重要性（Nim），并结合京都基因与基因组百科全书（KEGG）通路富集分析，获得 AS 的关键靶蛋白。分子对接筛选具有潜在治疗效果的小分子天然药物。通过构建体外泡沫细胞模型，研究小分子对泡沫细胞脂质代谢和关键靶基因表达的影响。
结果
通过差异基因分析，获得了 451 个差异基因，从 6 种数据库中共获得 313 个疾病基因，最终获得 758 个 AS 相关基因。KEGG 通路富集分析显示，提高 HDL-C 水平对 AS 的作用与脂质和动脉粥样硬化、胆固醇代谢、流体切应力与动脉粥样硬化、PPAR 信号通路等通路有关。然后我们对 PPI 网络核心模块中的 31 个基因、Nims 中的前 30 个基因和胆固醇代谢通路中的 32 个基因进行了交集，最终找到了 3 个基因。经过上述分析和文献收集，我们重点关注了以下三个相关基因靶点：APOA1、LIPC 和 CETP。分子对接显示染料木黄酮与 APOA1、CETP 和 LIPC 具有良好的结合亲和力。体外实验表明，染料木黄酮可以上调 APOA1、LIPC 和 CETP 的水平。
结论
基于我们的研究，染料木黄酮可能具有调节 HDL-C 和抗动脉粥样硬化的作用。其作用机制可能与调节 LIPC、CETP 和 APOA1 以改善脂质代谢有关。
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