Structural Modification and Optimisation of Hyperoside Oriented to Inhibit TGF-β-Induced EMT Activity in Alveolar Epithelial Cells.

Pulmonary fibrosis (PF) is a disease characterised by diffuse nonspecific alveolar inflammation with interstitial fibrosis, which clinically manifests as dyspnoea and a significant decline in lung function. Many studies have shown that the epithelial-mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of pulmonary fibrosis. Based on our previous findings, hypericin (Hyp) can effectively inhibit the process of the EMT to attenuate lung fibrosis. Therefore, a series of hyperoside derivatives were synthesised via modifying the structure of hyperoside, and subsequently evaluated for A549 cytotoxicity. Among these, the pre-screening of eight derivatives inhibits the EMT. In this study, we evaluated the efficacy of Z6, the most promising hyperoside derivative, in reversing TGF-β1-induced EMTs and inhibiting the EMT-associated migration of A549 cells. After the treatment of A549 cells with Z6 for 48 h, RT-qPCR and Western blot results showed that Z6 inhibited TGF-β1-induced EMTs in epithelial cells by supressing morphological changes in A549 cells, up-regulating E-cadherin ( < 0.01, < 0.001), and down-regulating Vimentin ( < 0.01, < 0.001). This treatment significantly reduced the mobility of transforming growth factor β1 (TGF-β1)-stimulated cells ( < 0.001) as assessed by wound closure, while increasing the adhesion rate of A549 cells ( < 0.001). In conclusion, our results suggest that hyperoside derivatives, especially compound Z6, are promising as potential lead compounds for treating pulmonary fibrosis, and therefore deserve further investigation.