Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis.
Tetrandrine Modulates Rheb-mTOR Signaling-Mediated Selective Autophagy and Protects Pulmonary Fibrosis.
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粉防己碱调节 Rheb-mTOR 信号介导的选择性自噬并保护肺纤维化
DOI：
10.3389/fphar.2021.739220
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发表时间：
2021
影响因子：
5.6
通讯作者：
Dong H
中科院分区：
文献类型：
--
作者：
Liu Y;Zhong W;Zhang J;Chen W;Lu Y;Qiao Y;Zeng Z;Huang H;Cai S;Dong H
特发性肺纤维化是一种以间质重塑为特征的进行性致死性疾病，致死率高，目前缺乏有效的药物治疗。粉防己碱已被提出具有抗纤维化作用，但其疗效和机制尚未得到系统评价。本研究旨在探讨汉防己甲素对肺纤维化的潜在治疗作用及其机制。在博莱霉素诱导的小鼠模型和TGF-β1刺激的小鼠肺成纤维细胞中评价粉防己碱的抗纤维化作用。我们进行了染色质免疫沉淀（ChIP），免疫沉淀（IP），和mRFP-GFP-MAP 1 LC 3B腺病毒构建，以研究粉防己碱诱导自噬的新机制。粉防己碱可降低TGF-β1诱导的成纤维细胞α-平滑肌肌动蛋白、纤连蛋白、波形蛋白和1型胶原的表达及增殖。汉防己甲素可恢复TGF-β1诱导的受损自噬流，并增强SQSTM 1和MAP 1 LC 3-Ⅱ的相互作用。ChIP研究显示粉防己碱通过增加NRF 2和SQSTM 1启动子的结合来诱导自噬。此外，粉防己碱通过降低Rheb的活化，抑制TGF-β1诱导的mTOR磷酸化。在体内汉防己甲素抑制博莱霉素诱导的纤维化标志物的表达和改善肺功能。粉防己碱可能通过促进Rheb-mTOR和NRF 2-SQSTM 1介导的自噬而发挥抗肺纤维化作用。汉防己甲素因此可能被用作一种新的治疗药物对IPF。
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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影响因子：
--
作者：
Lippai M;Lőw P
通讯作者：
Lőw P
影响因子：
13.3
作者：
Hu B;Zhang Y;Jia L;Wu H;Fan C;Sun Y;Ye C;Liao M;Zhou J
通讯作者：
Zhou J
影响因子：
6.6
作者：
Hariharan, Nirmala;Zhai, Peiyong;Sadoshima, Junichi
通讯作者：
Sadoshima, Junichi
粉防己碱通过强制自噬介导的分化来拮抗急性巨核细胞白血病的生长
影响因子：
7.3
作者：
Liu, Ting;Zhang, Zhenxing;Li, Wenhua
通讯作者：
Li, Wenhua
DOI：
10.1165/rcmb.2011-0121oc
发表时间：
2012-06-01
影响因子：
6.4
作者：
Baek, Hyun Ah;Kim, Do Sung;Chung, Myoung Ja
通讯作者：
Chung, Myoung Ja