Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis.
Brahma-related gene 1 acts as a profibrotic mediator and targeting it by micheliolide ameliorates peritoneal fibrosis.
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DOI：
10.1186/s12967-023-04469-w
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发表时间：
2023-09-19
影响因子：
7.4
通讯作者：
Peng, Fenfen
中科院分区：
文献类型：
--
作者：
Li, Shuting;Luo, Congwei;Chen, Sijia;Zhuang, Yiyi;Ji, Yue;Zeng, Yiqun;Zeng, Yao;He, Xiaoyang;Xiao, Jing;Wang, Huizhen;Chen, Xiaowen;Long, Haibo;Peng, Fenfen
进行性腹膜纤维化是影响接受腹膜透析（PD）的患者的全球公共卫生问题，但没有有效的治疗方法。我们以前的研究表明，一种新的化合物，micheliolide（MCL）抑制小鼠腹膜纤维化。然而，其机制仍不清楚。Brahma相关基因1（BRG 1）是器官纤维化的关键因素，但其在PD相关腹膜纤维化中的潜在功能以及MCL和BRG 1之间的关系仍不清楚。在小鼠PD模型和体外腹膜间皮细胞中检测MCL对BRG 1诱导的纤维化反应和TGF-β1-Smads通路的影响。采用免疫共沉淀法、MCL-生物素下拉法、分子对接法和细胞热位移法研究MCL对BRG 1的靶向作用机制。BRG 1在小鼠PD模型和在TGF-β1或PD液体条件下培养的腹膜间皮细胞中显著升高。体外BRG 1过表达增强了纤维化反应，并促进了TGF-β1增加的Smad 2和Smad 3磷酸化。同时，BRG 1基因的敲低可抑制TGF-β1诱导的纤维化反应，阻断TGF-β1-Smad 2/3通路。在小鼠PD模型和体外实验中，MCL均能改善BRG 1过表达诱导的腹膜纤维化，并阻断TGF-β1-Smad 2/3信号通路。MCL通过与BRG 1的天冬酰胺（N1540）结合，阻止BRG 1识别并附着于组蛋白H3赖氨酸14乙酰化位点，从而抑制纤维化反应和TGF-β1-Smad 2/3信号通路。N1540突变为丙氨酸（N1540 A）后，MCL不能与BRG 1结合，因此不能抑制BRG 1诱导的纤维化反应和TGF-β1-Smad 2/3信号通路。我们的研究表明，BRG 1可能是腹膜纤维化的关键介质，靶向BRG 1的N1540残基的MCL可能是对抗PD相关腹膜纤维化的新治疗策略。在线版本包含补充材料，可通过10.1186/s12967-023-04469-w获得。
Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown. The effects of MCL on BRG1-induced fibrotic responses and TGF-β1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed. BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-β1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-β1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-β1-induced fibrotic responses and blocked TGF-β1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-β1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-β1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-β1-Smad2/3 signaling pathway. Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis. The online version contains supplementary material available at 10.1186/s12967-023-04469-w.
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影响因子：
5.5
作者：
Eftekhari A;Arjmand A;Asheghvatan A;Švajdlenková H;Šauša O;Abiyev H;Ahmadian E;Smutok O;Khalilov R;Kavetskyy T;Cucchiarini M
通讯作者：
Cucchiarini M
影响因子：
5.6
作者：
Ruiqi L;Ming P;Qihang S;Yangyang L;Junli C;Wei L;Chao G;Xinyue L;Kang Y;Hongtao Y
通讯作者：
Hongtao Y
DOI：
10.2147/dddt.s355059
发表时间：
2022
期刊：
Drug design, development and therapy
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/j.jbc.2021.101145
发表时间：
2021-10
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Enríquez P;Krajewski K;Strahl BD;Rothbart SB;Dowen RH;Rose RB
通讯作者：
Rose RB
影响因子：
7.3
作者：
Li J;Li S;Guo J;Li Q;Long J;Ma C;Ding Y;Yan C;Li L;Wu Z;Zhu H;Li KK;Wen L;Zhang Q;Xue Q;Zhao C;Liu N;Ivanov I;Luo M;Xi R;Long H;Wang PG;Chen Y
通讯作者：
Chen Y