Pharmacological Modulation of BET Family in Sepsis.
Pharmacological Modulation of BET Family in Sepsis.
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DOI：
10.3389/fphar.2021.642294
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发表时间：
2021
影响因子：
5.6
通讯作者：
Tang D
中科院分区：
文献类型：
--
作者：
Wang N;Wu R;Comish PB;Kang R;Tang D
脓毒症和脓毒性休克的第三次国际共识定义（脓毒症3.0）建议将脓毒症定义为由宿主对感染的不受控制的反应引起的危及生命的器官功能障碍。布罗莫结构域和末端外（BET）蛋白家族（例如BRD 2、BRD 3和BRD 4）是基因转录的表观遗传调节剂，最近被认为是炎症和免疫应答（包括细胞因子和趋化因子产生）的重要脓毒症调节剂。从机制上讲，两个N-末端保守的串联布罗莫结构域（即第一布罗莫结构域[BD 1]和第二布罗莫结构域[BD 2]）有利于BET与乙酰化组蛋白或转录因子结合，从而在CycT 1和CDK 9（也称为P-TEFb）被募集到基因启动子以磷酸化RNA pol II后启动基因转录机制。值得注意的是，BD 1和BD 2在功能上并不冗余，因为它们在先天免疫细胞中具有不同的靶基因。针对不同BD的小分子BET抑制剂（BET is），例如I-BET、JQ 1、I-BET 151、阿帕贝隆、RVX-297和dBET 1在实验性脓毒症模型中显示出有希望的治疗效果。本文综述了BETs的作用及其在脓毒症中的应用，讨论了BETis存在的不足，并介绍了该领域未来可能的研究方向。
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) recommended defining sepsis as a life-threatening organ dysfunction caused by the host's uncontrolled response to infection. The bromodomain and extra-terminal (BET) protein family (such as BRD2, BRD3, and BRD4), an epigenetic regulator of gene transcription, has recently been recognized as a significant septic regulator of inflammation and immune response, including cytokine and chemokine production. Mechanistically, the two N-terminal conserved tandem bromodomains (namely the first bromodomain [BD1] and the second bromodomain [BD2]) favor the binding of BETs to acetylated histones or transcription factors, thereby initiating gene transcription machinery after CycT1 and CDK9 (also known as P-TEFb) are recruited to gene promoters to phosphorylate RNA pol II. Notably, BD1 and BD2 are not functionally redundant because they have different target genes in innate immune cells. Small-molecule BET inhibitors (BETis) for different BDs, such as I-BET, JQ1, I-BET151, apabetalone, RVX-297, and dBET1 have shown promising therapeutic effects in experimental sepsis models. This mini-review summarizes the emerging roles of BETs and the applications of BETis in sepsis, discusses the existing shortcomings of BETis, and introduces possible future research directions in this area.
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DOI：
10.1126/science.aaz8455
发表时间：
2020-04-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gilan O;Rioja I;Knezevic K;Bell MJ;Yeung MM;Harker NR;Lam EYN;Chung CW;Bamborough P;Petretich M;Urh M;Atkinson SJ;Bassil AK;Roberts EJ;Vassiliadis D;Burr ML;Preston AGS;Wellaway C;Werner T;Gray JR;Michon AM;Gobbetti T;Kumar V;Soden PE;Haynes A;Vappiani J;Tough DF;Taylor S;Dawson SJ;Bantscheff M;Lindon M;Drewes G;Demont EH;Daniels DL;Grandi P;Prinjha RK;Dawson MA
通讯作者：
Dawson MA
影响因子：
10.6
作者：
Kang, Rui;Chen, Ruochan;Zhang, Qiuhong;Hou, Wen;Wu, Sha;Cao, Lizhi;Huang, Jin;Yu, Yan;Fan, Xue-gong;Yan, Zhengwen;Sun, Xiaofang;Wang, Haichao;Wang, Qingde;Tsung, Allan;Billiar, Timothy R.;Zeh, Herbert J., III;Lotze, Michael T.;Tang, Daolin
通讯作者：
Tang, Daolin
影响因子：
64.8
作者：
Moriniere, Jeanne;Rousseaux, Sophie;Petosa, Carlo
通讯作者：
Petosa, Carlo
BET 抑制剂 JQ1 阻止炎症和骨质破坏
影响因子：
7.6
作者：
Meng, S.;Zhang, L.;Chen, J.
通讯作者：
Chen, J.
DOI：
10.1073/pnas.1700109114
发表时间：
2017-05-16
影响因子：
11.1
作者：
Bao, Yan;Wu, Xuewei;Chen, Lin-Feng
通讯作者：
Chen, Lin-Feng