Department of Clinical Nursing, Affiliated Hospital to Binzhou Medical University, Binzhou 256602, China; Department of Cellular and Genetic Medicine, School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
Department of Cellular and Genetic Medicine, School of Pharmaceutical Sciences, Binzhou Medical University, Yantai 264003, China.
Toxicol Appl Pharmacol. 2018 Oct 1;356:15-24. doi: 10.1016/j.taap.2018.07.005. Epub 2018 Jul 7.
Pulmonary fibrosis is a progressive disorder with poor prognosis and limited treatment options. Therefore, novel therapeutic drugs should be developed in preclinical studies. In this study, we designed and synthesized a novel compound named formononetin-7-sal ester (FS). We also investigated its anti-pulmonary fibrosis ability on transforming growth factor beta 1 (TGF-β1)-stimulated pulmonary epithelial cells and fibroblasts in vitro and on bleomycin (BLM)-induced pulmonary fibrosis in vivo. FS strongly blocked cell proliferation and migration, which were activated by TGF-β1, thereby reducing the expression of lung fibrosis markers, such as vimentin, alpha-smooth muscle actin (α-SMA), Snail, and collagen I and III, and increasing the expression of the epithelial cell marker E-cadherin. FS ameliorated BLM-induced pulmonary fibrosis in mice and decreased histopathologic fibrosis scores and collagen deposition. A low expression of hydroxyproline, vimentin, α-SMA, and Snail and a high expression of E-cadherin were found in FS-treated lungs compared with BLM-instilled lungs. Using the Cignal Finder 45-Pathway Reporter Array, we tested the regulation of FS in pulmonary fibrosis-associated signaling pathways and observed that FS significantly inhibited the myocyte enhancer factor-2c (MEF2c) signaling pathway. Gain- and loss-of-function studies, rescue experiments and promoter activity testing were designed to further confirm this result in vivo and in vitro. Collectively, our results demonstrated that FS prevents pulmonary fibrosis via the MEF2c signaling pathway.
肺纤维化是一种进行性疾病，预后不良，治疗选择有限。因此，应该在临床前研究中开发新的治疗药物。在这项研究中，我们设计并合成了一种名为芒柄花素-7-水杨酯（FS）的新型化合物。我们还研究了它在转化生长因子β1（TGF-β1）刺激的肺上皮细胞和纤维母细胞中的抗肺纤维化能力，以及在博来霉素（BLM）诱导的肺纤维化中的体内作用。FS 强烈抑制 TGF-β1激活的细胞增殖和迁移，从而降低肺纤维化标志物，如波形蛋白、α-平滑肌肌动蛋白（α-SMA）、Snail 和胶原 I 和 III 的表达，增加上皮细胞标志物 E-钙粘蛋白的表达。FS 改善了 BLM 诱导的小鼠肺纤维化，降低了组织病理学纤维化评分和胶原沉积。与 BLM 处理的肺相比，FS 处理的肺中羟脯氨酸、波形蛋白、α-SMA 和 Snail 的低表达和 E-钙粘蛋白的高表达。通过 Cignal Finder 45-Pathway Reporter Array，我们测试了 FS 对肺纤维化相关信号通路的调节作用，观察到 FS 显著抑制肌细胞增强因子 2c（MEF2c）信号通路。设计了增益和失活功能研究、挽救实验和启动子活性测试，以进一步在体内和体外证实这一结果。总之，我们的结果表明，FS 通过 MEF2c 信号通路预防肺纤维化。
