Diosmetin prevents TGF-β1-induced epithelial-mesenchymal transition via ROS/MAPK signaling pathways

Aims: Epithelial-mesenchymal transition (EMT) plays a critical role in airway repair and remodeling in many respiratory diseases such as asthma and pulmonary fibrosis. The flavone aglycone, diosmetin, possesses antiremodeling activity in a murine model of chronic asthma, but little is known about its effects on EMT. Herein, we investigated whether diosmetin inhibits transforming growth factor-beta 1 (TGF-beta 1)-induced EMT with underlying mechanisms in human bronchial epithelial (HBE) cells. Main methods: HBE cellswere incubated with TGF-beta 1 (10 ng/ml), either alone or in combination with diosmetin for indicated times. We measured reactive oxygen species (ROS) levels using FAC Scan and immunofluorescent assays. We assessed protein expression of NADPH oxidase 4 (NOX4), superoxide dismutase (SOD), catalase, Akt, Erk, p38, and phosphorylation levels of Akt, Erk and p38 by Western blot analysis. Key findings: TGF-beta 1 promoted EMT and ROS generation in HBE cells. Diosmetin significantly suppressed TGF-beta 1-induced increases in cell migration and altered N-cadherin, E-cadherin, and a-smooth muscle actin expression. In addition, diosmetin prevented TGF-beta 1-induced intracellular ROS generation, down-regulated NOX4, and upregulated SOD and catalase expression. Furthermore, diosmetin remarkably inhibited TGF-beta 1-induced phosphorylation of phosphoinositide 3-kinase (PI3K)/Akt and mitogen activated protein kinase (MAPK) pathways in HBE cells. Significance: Our results demonstrate for the first time that diosmetin alleviates TGF-beta 1-induced EMT by inhibiting ROS generation and inactivating PI3K/Akt and MAPK pathways. Our findings revealed a new role for diosmetin in reducing airway remodeling and fibrogenesis. (C) 2016 Elsevier Inc. All rights reserved.