Liu Xue, Shao Yumeng, Zhang Xinyue, Ji Xiang, Xie Min, Liu Huaman
First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China; Department of Respiration, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
Acta Histochem. 2021 Jul;123(5):151746. doi: 10.1016/j.acthis.2021.151746. Epub 2021 Jun 30.
The precise etiology and pathogenesis of idiopathic pulmonary fibrosis are not completely understood, and no satisfactory treatment exists. This work aimed to examine the effects of calycosin (CA, an isoflavone compound) on pulmonary fibrosis (PF) and explore the underlying mechanism. In this study, we established a mice model of PF induced by 5 mg/mL bleomycin (BLM), and mice were orally administrated with 7 mg/kg or 14 mg/kg CA once a day for three weeks. In vitro, after pretreated with 80 μM CA, MLE-12 cells were stimulated with 10 ng/mL transforming growth factor-β1 (TGF-β1) for inducing epithelial-mesenchymal transition (EMT). The results showed that CA treatment ameliorated the severity of fibrosis and the lung tissue damage, as well as suppressed the secretion of inflammation factors in a dose-dependent manner of the PF mice model induced by BLM. Subsequently, CA inhibited the BLM-induced PF progression by repressing EMT, evidenced by the reverse of the downregulation of E-cadherin and the upregulation of vimentin, α-SMA, and fibronectin. Moreover, the elevated phosphorylation of AKT and GSK3β induced by BLM (or TGF-β1) was decreased by CA treatment, leading to the rescue of the high expression of β-catenin. CA prevented the translocation of β-catenin from the cytoplasm to the nucleus. The repressed effects of CA on the TGF-β1-induced EMT and the AKT/GSK3β/β-catenin axis, as well as the translocation of β-catenin were all reversed by a AKT activator SC79. Taken together, CA ameliorated PF by the EMT inhibition upon suppressing the AKT/GSK3β/β-catenin signaling pathway.
特发性肺纤维化的确切病因和发病机制尚未完全明确，且尚无令人满意的治疗方法。本研究旨在探讨毛蕊异黄酮（CA，一种异黄酮化合物）对肺纤维化（PF）的影响，并探索其潜在机制。在本研究中，我们建立了由5mg/mL博来霉素（BLM）诱导的PF小鼠模型，小鼠每天口服7mg/kg或14mg/kg CA，持续三周。在体外，用80μM CA预处理后，用10ng/mL转化生长因子-β1（TGF-β1）刺激MLE-12细胞以诱导上皮-间质转化（EMT）。结果表明，CA治疗改善了纤维化的严重程度和肺组织损伤，并以剂量依赖的方式抑制了BLM诱导的PF小鼠模型中炎症因子的分泌。随后，CA通过抑制EMT抑制了BLM诱导的PF进展，这通过E-钙黏蛋白下调和波形蛋白、α-平滑肌肌动蛋白和纤连蛋白上调的逆转得以证明。此外，CA治疗降低了BLM（或TGF-β1）诱导的AKT和GSK3β磷酸化升高，导致β-连环蛋白高表达的恢复。CA阻止了β-连环蛋白从细胞质向细胞核的转位。AKT激活剂SC79逆转了CA对TGF-β1诱导的EMT和AKT/GSK3β/β-连环蛋白轴的抑制作用，以及β-连环蛋白的转位。综上所述，CA通过抑制AKT/GSK3β/β-连环蛋白信号通路抑制EMT来改善PF。
