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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: Liu, Yuanyuan, Zhong, Wenshan, Zhang, Jinming, Chen, Weimou, lu, Ye, Qiao, Yujie, Zeng, Zhaojin, Huang, Haohua, Cai, Shaoxi, Dong, Hangming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645995/
https://www.ncbi.nlm.nih.gov/pubmed/34880752
http://dx.doi.org/10.3389/fphar.2021.739220
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author Liu, Yuanyuan
Zhong, Wenshan
Zhang, Jinming
Chen, Weimou
lu, Ye
Qiao, Yujie
Zeng, Zhaojin
Huang, Haohua
Cai, Shaoxi
Dong, Hangming
author_facet Liu, Yuanyuan
Zhong, Wenshan
Zhang, Jinming
Chen, Weimou
lu, Ye
Qiao, Yujie
Zeng, Zhaojin
Huang, Haohua
Cai, Shaoxi
Dong, Hangming
author_sort Liu, Yuanyuan
collection PubMed
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.
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spelling pubmed-86459952021-12-07 Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis Liu, Yuanyuan Zhong, Wenshan Zhang, Jinming Chen, Weimou lu, Ye Qiao, Yujie Zeng, Zhaojin Huang, Haohua Cai, Shaoxi Dong, Hangming Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2021-11-22 /pmc/articles/PMC8645995/ /pubmed/34880752 http://dx.doi.org/10.3389/fphar.2021.739220 Text en Copyright © 2021 Liu, Zhong, Zhang, Chen, lu, Qiao, Zeng, Huang, Cai and Dong. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Liu, Yuanyuan
Zhong, Wenshan
Zhang, Jinming
Chen, Weimou
lu, Ye
Qiao, Yujie
Zeng, Zhaojin
Huang, Haohua
Cai, Shaoxi
Dong, Hangming
Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis
title 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_short 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
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645995/
https://www.ncbi.nlm.nih.gov/pubmed/34880752
http://dx.doi.org/10.3389/fphar.2021.739220
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