Ma Ruimin, Huang Xiaoxi, Sun Di, Wang Jingwei, Xue Changjiang, Ye Qiao
Department of Occupational Medicine and Toxicology, Clinical Center for Interstitial Lung Diseases, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Workers' Stadium South Road, Chao-Yang District, Beijing, China.
Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Inflammation. 2024 Aug;47(4):1109-1126. doi: 10.1007/s10753-023-01964-6. Epub 2024 Jan 24.
Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid derived from Stephania tetrandra S. Moor, known for its potential use in attenuating the progression of silicosis. However, the precise effects and underlying mechanisms of TET remain controversial. In this study, we aimed to elucidate the pharmacological mechanism of TET using a network pharmacology approach, while also evaluating its effect on silica-induced lung fibrosis in mice and TGF-β1-stimulated pulmonary fibroblasts in vitro. We employed network pharmacology to unravel the biological mechanisms through which TET may exert its therapeutic effects on pulmonary fibrosis and silicosis. In a silica-induced mouse model of lung fibrosis, TET was administered orally either during the early or late stage of fibrotic progression. Additionally, we examined the effects of TET on fibroblasts stimulated by TGF-β1 in vitro. Through the analysis, we identified a total of 101 targets of TET, 7,851 genes associated with pulmonary fibrosis, and 80 overlapping genes. These genes were primarily associated with key pathways such as epidermal growth factor receptor tyrosine kinase inhibitor resistance, the vascular endothelial growth factor signaling pathway, and the phosphatidylinositol 3 kinase (PI3K)-protein kinase B (PKB or AKT) signaling pathway. Furthermore, molecular docking analysis revealed the binding of TET to AKT1, the catalytic subunit of phosphatidylinositol-3 kinase, and KDR. In vivo experiments demonstrated that TET significantly alleviated silica-induced pulmonary fibrosis and reduced the expression of fibrotic markers. Moreover, TET exhibited inhibitory effects on the migration, proliferation, and differentiation of TGF-β1-induced lung fibroblasts in vitro. Notably, TET mitigated silica-induced pulmonary fibrosis by suppressing the PI3K/AKT pathway. In conclusion, our findings suggest that TET possesses the ability to suppress silica-induced pulmonary fibrosis by targeting the PI3K/AKT signaling pathway. These results provide valuable insights into the therapeutic potential of TET in the treatment of pulmonary fibrosis and silicosis.
粉防己碱（TET）是一种从防己科植物粉防己中提取的双苄基异喹啉生物碱，因其在延缓矽肺进展方面的潜在用途而闻名。然而，TET的确切作用和潜在机制仍存在争议。在本研究中，我们旨在使用网络药理学方法阐明TET的药理机制，同时评估其对小鼠二氧化硅诱导的肺纤维化和体外转化生长因子-β1（TGF-β1）刺激的肺成纤维细胞的影响。我们采用网络药理学来揭示TET可能对肺纤维化和矽肺发挥治疗作用的生物学机制。在二氧化硅诱导的小鼠肺纤维化模型中，在纤维化进展的早期或晚期口服给予TET。此外，我们在体外研究了TET对TGF-β1刺激的成纤维细胞的影响。通过分析，我们共鉴定出TET的101个靶点、7851个与肺纤维化相关的基因以及80个重叠基因。这些基因主要与关键信号通路相关，如表皮生长因子受体酪氨酸激酶抑制剂耐药、血管内皮生长因子信号通路和磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（PKB或AKT）信号通路。此外，分子对接分析显示TET与磷脂酰肌醇-3激酶的催化亚基AKT1和激酶插入域受体（KDR）结合。体内实验表明，TET显著减轻二氧化硅诱导的肺纤维化，并降低纤维化标志物的表达。此外，TET在体外对TGF-β1诱导的肺成纤维细胞的迁移、增殖和分化具有抑制作用。值得注意的是，TET通过抑制PI3K/AKT信号通路减轻二氧化硅诱导的肺纤维化。总之，我们的研究结果表明，TET具有通过靶向PI3K/AKT信号通路抑制二氧化硅诱导的肺纤维化的能力。这些结果为TET在治疗肺纤维化和矽肺方面的治疗潜力提供了有价值的见解。
