Celastrol as a candidate drug for silicosis: From bioinformatics and network pharmacology to experimental validation
Celastrol as a candidate drug for silicosis: From bioinformatics and network pharmacology to experimental validation
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DOI：
10.1016/j.intimp.2023.111068
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发表时间：
2023-11-08
影响因子：
5.6
通讯作者：
Wu, Jing
中科院分区：
文献类型：
--
作者：
Liang, Chao;Bai, Ying;Wu, Jing
矽肺是一种高度致命的职业性呼吸系统疾病，其特征是不可逆的肺纤维化，由于其发病机制尚不清楚，治疗仍然具有挑战性。本研究结合生物信息学、网络药理学和实验验证来探索矽肺的潜在机制和治疗药物。首先，通过GO和KEGG分析鉴定肺纤维化中的差异表达基因（DEG）和通路富集。接下来，将差异基因提交至cMap数据库进行药物预测，雷公藤红素脱颖而出，成为最有前途的候选药物。然后，网络药理学分析确定了雷公藤红素的药理靶点，并证明雷公藤红素可以调节JAK-STAT、MAPK和Toll样受体信号通路。最后验证了雷公藤红素对矽肺的治疗作用及机制。在体内，雷公藤红素可显着改善硅肺小鼠中 CS 诱导的炎症和纤维化，包括炎性细胞浸润、胶原纤维和细胞外基质沉积、成纤维细胞活化和相关因子表达。此外，它还显着改善了矽肺小鼠的肺呼吸功能。在体外，雷公藤红醇抑制 CS 诱导的细胞因子表达、巨噬细胞凋亡以及 Stat3 和 Erk1/2 信号的激活。总体而言，我们的研究确定并验证了雷公藤红素是一种新型且有前途的硅肺候选药物。
Silicosis, a highly lethal occupational respiratory disease characterized by irreversible pulmonary fibrosis, remains challenging to treat due to its unclear pathogenesis. In this study, bioinformatics, network pharmacology, and experimental validation were combined to explore potential mechanisms and therapeutic drugs for silicosis. First, the differentially expressed genes(DEGs)and pathway enrichment in pulmonary fibrosis were identified by GO and KEGG analysis. Next, the differential genes were submitted to cMap database for drug prediction and celastrol stood out as the most promising candidate drug. Then, network pharmacology analysis identified pharmacological targets of celastrol and demonstrated that celastrol could regulate JAK-STAT, MAPK, and Toll-like receptor signaling pathways. Finally, we verified the therapeutic role and mechanism of celastrol on silicosis. In vivo, celastrol significantly ameliorated CS-induced inflammation and fibrosis in silicosis mice, including in-flammatory cell infiltration, collagen fiber and extracellular matrix deposition, fibroblast activation and related factor expression. Moreover, it dramatically improved lung respiratory function of silicosis mice. In vitro, celastrol suppressed CS-induced cytokine expression, apoptosis of macrophages and activation of Stat3 and Erk1/ 2 signals. Overall, our research identified and verified celastrol as a novel and promising candidate drug for silicosis.