Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis

Idiopathic pulmonary fibrosis is a progressive fatal disease characterized by interstitial remodeling, with high lethality and a lack of effective medical therapies. Tetrandrine has been proposed to present anti-fibrotic effects, but the efficacy and mechanisms have not been systematically evaluated...

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Autores principales:	Yuanyuan Liu, Wenshan Zhong, Jinming Zhang, Weimou Chen, Ye lu, Yujie Qiao, Zhaojin Zeng, Haohua Huang, Shaoxi Cai, Hangming Dong
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	lung fibrosis tetrandrine autophagy mTOR COL-I Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/bca73e8f2be449509de5b840f1899701
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spelling	oai:doaj.org-article:bca73e8f2be449509de5b840f18997012021-11-22T06:59:21ZTetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis1663-981210.3389/fphar.2021.739220https://doaj.org/article/bca73e8f2be449509de5b840f18997012021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.739220/fullhttps://doaj.org/toc/1663-9812Idiopathic pulmonary fibrosis is a progressive fatal disease characterized by interstitial remodeling, with high lethality and a lack of effective medical therapies. Tetrandrine has been proposed to present anti-fibrotic effects, but the efficacy and mechanisms have not been systematically evaluated. We sought to study the potential therapeutic effects and mechanisms of tetrandrine against lung fibrosis. The anti-fibrotic effects of tetrandrine were evaluated in bleomycin-induced mouse models and TGF-β1-stimulated murine lung fibroblasts. We performed Chromatin Immunoprecipitation (ChIP), Immunoprecipitation (IP), and mRFP-GFP-MAP1LC3B adenovirus construct to investigate the novel mechanisms of tetrandrine-induced autophagy. Tetrandrine decreased TGF-β1-induced expression of α-smooth muscle actin, fibronectin, vimentin, and type 1 collagen and proliferation in fibroblasts. Tetrandrine restored TGF-β1-induced impaired autophagy flux, accompanied by enhanced interaction of SQSTM1 and MAP1LC3-Ⅱ. ChIP studies revealed that tetrandrine induced autophagy via increasing binding of NRF2 and SQSTM1 promoter. Furthermore, tetrandrine inhibited TGF-β1-induced phosphorylation of mTOR by reducing activation of Rheb. In vivo tetrandrine suppressed the bleomycin-induced expression of fibrotic markers and improved pulmonary function. Our data suggest that protective effect of tetrandrine against lung fibrosis might be through promoting Rheb-mTOR and NRF2-SQSTM1 mediated autophagy. Tetrandrine may thus be potentially employed as a novel therapeutic medicine against IPF.Yuanyuan LiuWenshan ZhongJinming ZhangWeimou ChenYe luYujie QiaoZhaojin ZengHaohua HuangShaoxi CaiHangming DongFrontiers Media S.A.articlelung fibrosistetrandrineautophagymTORCOL-ITherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	lung fibrosis tetrandrine autophagy mTOR COL-I Therapeutics. Pharmacology RM1-950
spellingShingle	lung fibrosis tetrandrine autophagy mTOR COL-I Therapeutics. Pharmacology RM1-950 Yuanyuan Liu Wenshan Zhong Jinming Zhang Weimou Chen Ye lu Yujie Qiao Zhaojin Zeng Haohua Huang Shaoxi Cai Hangming Dong Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis
description	Idiopathic pulmonary fibrosis is a progressive fatal disease characterized by interstitial remodeling, with high lethality and a lack of effective medical therapies. Tetrandrine has been proposed to present anti-fibrotic effects, but the efficacy and mechanisms have not been systematically evaluated. We sought to study the potential therapeutic effects and mechanisms of tetrandrine against lung fibrosis. The anti-fibrotic effects of tetrandrine were evaluated in bleomycin-induced mouse models and TGF-β1-stimulated murine lung fibroblasts. We performed Chromatin Immunoprecipitation (ChIP), Immunoprecipitation (IP), and mRFP-GFP-MAP1LC3B adenovirus construct to investigate the novel mechanisms of tetrandrine-induced autophagy. Tetrandrine decreased TGF-β1-induced expression of α-smooth muscle actin, fibronectin, vimentin, and type 1 collagen and proliferation in fibroblasts. Tetrandrine restored TGF-β1-induced impaired autophagy flux, accompanied by enhanced interaction of SQSTM1 and MAP1LC3-Ⅱ. ChIP studies revealed that tetrandrine induced autophagy via increasing binding of NRF2 and SQSTM1 promoter. Furthermore, tetrandrine inhibited TGF-β1-induced phosphorylation of mTOR by reducing activation of Rheb. In vivo tetrandrine suppressed the bleomycin-induced expression of fibrotic markers and improved pulmonary function. Our data suggest that protective effect of tetrandrine against lung fibrosis might be through promoting Rheb-mTOR and NRF2-SQSTM1 mediated autophagy. Tetrandrine may thus be potentially employed as a novel therapeutic medicine against IPF.
format	article
author	Yuanyuan Liu Wenshan Zhong Jinming Zhang Weimou Chen Ye lu Yujie Qiao Zhaojin Zeng Haohua Huang Shaoxi Cai Hangming Dong
author_facet	Yuanyuan Liu Wenshan Zhong Jinming Zhang Weimou Chen Ye lu Yujie Qiao Zhaojin Zeng Haohua Huang Shaoxi Cai Hangming Dong
author_sort	Yuanyuan Liu
title	Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis
title_short	Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis
title_full	Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis
title_fullStr	Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis
title_full_unstemmed	Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis
title_sort	tetrandrine modulates rheb-mtor signaling-mediated selective autophagy and protects pulmonary fibrosis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/bca73e8f2be449509de5b840f1899701
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_version_	1718418124757270528

Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis

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