Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, PR China.
The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, PR China; Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy, Hefei 230001, Anhui, PR China.
Bioorg Chem. 2022 Feb;119:105519. doi: 10.1016/j.bioorg.2021.105519. Epub 2021 Nov 26.
Traditional Chinese medicine has a long history of treating complex diseases, especially for the conditioning of systemic diseases. It has been reported that Baixianfeng (BXF) decoction used to treat rheumatoid arthritis (RA) may be due to its systemic regulatory effect, but the specific mechanism still remains to be elucidated. The research philosophy and methods of systemic pharmacology were used to explore the mechanism of BXF decoction in treating RA in this study. TCMSP database was used to search the ingredients of BXF decoction and screen the ADME parameters. The parameter index was set as OB ≥ 30%, DL ≥ 0.18, HL ≥ 4 h. The targets of the screened compounds were searched and predicted by TCMSP and Target-Prediction platforms. The disease targets of RA were obtained through the DisGeNET, OMIM, and PharmGkb databases. A series of network construction and analysis relied on Cytoscape 3.2.1 software, and the DAVID database was used for pathway enrichment. The adjuvant arthritis rat model was used for the verification of animal experiments to verify the predicted pathway results in terms of pathological phenotype, inflammatory factors, and pathway protein expression. The results showed that the related targets of 81 active ingredients in the drug crossed 56 targets of RA, and these common targets were enriched in 83 significant pathways, among which the TNF signaling pathway had research significance. Animal experiments have proved that BXF decoction was effective in treating adjuvant arthritis rats. The drug relieved the pathological phenotype of rats in dose-dependent. It reduced the serum content of TNF-α and IL-1β, and reduced the gene expression of TNF-α and IL-6 in spleen tissue. In the cartilage tissue protein of rats, it inhibited the degradation of collagen Ⅱ protein. Further, BXF decoction reduced the activation of p-PI3K, p-Akt, and p-P65 protein, and decreased the overexpression of apoptotic proteins such as cleaved-caspase8 and cleaved-caspase3 in cartilage tissue. Meanwhile, it inhibited the protein expression of MMP9, TNF-α, IL-6, and IL-1β. In conclusion, this study successfully practiced the combination of systemic pharmacology and experimental verification, and clarified that BXF decoction inhibited the progression of adjuvant arthritis rats through the TNF-PI3K-Akt-NF-κB signal axis. It provides new evidence for the study of the mechanism of BXF decoction in treating RA.
中药治疗复杂疾病有着悠久的历史，特别是对系统性疾病的调理。有报道称，白芍风（BXF）汤治疗类风湿关节炎（RA）可能是由于其系统调节作用，但具体机制仍有待阐明。本研究采用系统药理学的研究理念和方法，探讨 BXF 汤治疗 RA 的作用机制。利用 TCMSP 数据库检索 BXF 汤的成分，筛选 ADME 参数。将参数指标设定为 OB≥30%、DL≥0.18、HL≥4 h。通过 TCMSP 和 Target-Prediction 平台搜索筛选化合物的靶标，通过 DisGeNET、OMIM 和 PharmGkb 数据库获取 RA 的疾病靶标。一系列网络构建和分析依赖于 Cytoscape 3.2.1 软件，DAVID 数据库用于通路富集。采用佐剂性关节炎大鼠模型进行动物实验验证，验证预测通路在病理表型、炎症因子和通路蛋白表达方面的结果。结果表明，药物中 81 种活性成分的相关靶标与 RA 的 56 个靶标交叉，这些共同靶标富集在 83 个显著通路中，其中 TNF 信号通路具有研究意义。动物实验证明，BXF 汤对佐剂性关节炎大鼠有效。药物在剂量依赖性下缓解大鼠的病理表型。它降低了血清 TNF-α和 IL-1β含量，降低了脾组织中 TNF-α和 IL-6 的基因表达。在大鼠软骨组织蛋白中，它抑制胶原 Ⅱ 蛋白的降解。此外，BXF 汤降低了软骨组织中 p-PI3K、p-Akt 和 p-P65 蛋白的激活，并减少了 cleaved-caspase8 和 cleaved-caspase3 等凋亡蛋白的过度表达。同时，它抑制了 MMP9、TNF-α、IL-6 和 IL-1β的蛋白表达。综上所述，本研究成功实践了系统药理学与实验验证的结合，阐明了 BXF 汤通过 TNF-PI3K-Akt-NF-κB 信号轴抑制佐剂性关节炎大鼠的进展，为研究 BXF 汤治疗 RA 的机制提供了新的证据。
