Novel formononetin-7-sal ester ameliorates pulmonary fibrosis via MEF2c signaling pathway
Novel formononetin-7-sal ester ameliorates pulmonary fibrosis via MEF2c signaling pathway
复制标题
新型芒柄花素-7-sal酯通过MEF2c信号通路改善肺纤维化
DOI：
10.1016/j.taap.2018.07.005
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发表时间：
2018
影响因子：
3.8
通讯作者：
Li Minge
中科院分区：
文献类型：
--
作者：
Zhao Xueying;Qu Guiwu;Song Chenguang;Li Rongrong;Liu Weili;Lv Changjun;Song Xiaodong;Zhang Jinjin;Li Minge
肺纤维化是一种进行性疾病，预后差，治疗选择有限。因此，应在临床前研究中开发新的治疗药物。本研究设计并合成了一个新化合物芒柄花素-7-水杨酸酯（FS）。同时观察其对转化生长因子β 1（TGF-β1）刺激的肺上皮细胞和成纤维细胞的抗肺纤维化作用以及对博莱霉素（BLM）诱导的肺纤维化作用。FS强烈阻断TGF-β1激活的细胞增殖和迁移，从而降低肺纤维化标志物的表达，如波形蛋白、α-平滑肌肌动蛋白（α-SMA）、Snail和胶原I和III，并增加上皮细胞标志物E-cadherin的表达。FS可改善BLM诱导的小鼠肺纤维化，降低组织病理学纤维化评分和胶原沉积。与BLM灌注组相比，FS处理组肺组织中羟脯氨酸、波形蛋白、α-SMA和Snail的表达较低，而E-cadherin的表达较高。利用肺纤维化相关信号通路的分子芯片，我们检测了FS对肺纤维化相关信号通路的调节作用，发现FS对肌细胞增强因子2c（MEF 2c）信号通路有显著的抑制作用。设计了功能获得和丧失研究、拯救实验和启动子活性测试以进一步在体内和体外证实该结果。总的来说，我们的研究结果表明，FS通过MEF 2c信号通路预防肺纤维化。
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.