基于新型计算药理学模型筛选黄芪桂枝五物汤治疗类风湿关节炎的关键响应成分群及作用机制验证。
Screening of the key response component groups and mechanism verification of Huangqi-Guizhi-Wuwu-Decoction in treating rheumatoid arthritis based on a novel computational pharmacological model.
机构信息
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China.
出版信息
BMC Complement Med Ther. 2024 Jan 2;24(1):4. doi: 10.1186/s12906-023-04315-y.
BACKGROUND
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the destruction of synovial tissue and articular cartilage. Huangqi-Guizhi-Wuwu-Decoction (HGWD), a formula of Traditional Chinese Medicine (TCM), has shown promising clinical efficacy in the treatment of RA. However, the synergistic effects of key response components group (KRCG) in the treatment of RA have not been well studied.
METHODS
The components and potential targets of HGWD were extracted from published databases. A novel node influence calculation model that considers both the node control force and node bridging force was designed to construct the core response space (CRS) and obtain key effector proteins. An increasing coverage coefficient (ICC) model was employed to select the KRCG. The effectiveness and potential mechanism of action of KRCG were confirmed using CCK-8, qPCR, and western blotting.
RESULTS
A total of 796 key effector proteins were identified in CRS. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses confirmed their effectiveness and reliability. In addition, 59 components were defined as KRCG, which contributed to 85.05% of the target coverage of effective proteins. Of these, 677 targets were considered key reaction proteins, and their enriched KEGG pathways accounted for 84.89% of the pathogenic genes and 87.94% of the target genes. Finally, four components (moupinamide, 6-Paradol, hydrocinnamic acid, and protocatechuic acid) were shown to inhibit the inflammatory response in RA by synergistically targeting the cAMP, PI3K-Akt, and HIF-1α pathways.
CONCLUSIONS
We have introduced a novel model that aims to optimize and analyze the mechanisms behind herbal formulas. The model revealed the KRCG of HGWD for the treatment of RA and proposed that KRCG inhibits the inflammatory response by synergistically targeting cAMP, PI3K-Akt, and HIF-1α pathways. Overall, the novel model is plausible and reliable, offering a valuable reference for the secondary development of herbal formulas.
背景
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征是滑膜组织和关节软骨的破坏。黄芪桂枝五物汤（HGWD）是一种中药配方，已显示出在治疗 RA 方面有良好的临床疗效。然而，其关键反应成分群（KRCG）在治疗 RA 中的协同作用尚未得到很好的研究。
方法
从已发表的数据库中提取 HGWD 的成分和潜在靶点。设计了一种新的节点影响计算模型，该模型同时考虑了节点控制力和节点桥接力，用于构建核心反应空间（CRS）并获得关键效应蛋白。采用增加覆盖率系数（ICC）模型选择 KRCG。使用 CCK-8、qPCR 和 Western blot 验证 KRCG 的有效性和潜在作用机制。
结果
CRS 中共鉴定出 796 种关键效应蛋白。京都基因与基因组百科全书（KEGG）和基因本体论（GO）分析证实了它们的有效性和可靠性。此外，定义了 59 种成分作为 KRCG，占有效蛋白靶点覆盖率的 85.05%。其中，有 677 个靶点被认为是关键反应蛋白，其富集的 KEGG 途径占致病基因的 84.89%，占靶基因的 87.94%。最后，发现四种成分（马兜铃内酰胺、6-Paradol、肉桂酸和原儿茶酸）通过协同靶向 cAMP、PI3K-Akt 和 HIF-1α 通路抑制 RA 的炎症反应。
结论
我们引入了一种新的模型，旨在优化和分析草药配方的作用机制。该模型揭示了 HGWD 治疗 RA 的 KRCG，并提出 KRCG 通过协同靶向 cAMP、PI3K-Akt 和 HIF-1α 通路抑制炎症反应。总体而言，该新型模型是合理可靠的，为草药配方的二次开发提供了有价值的参考。
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