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Pharmacological Modulation of BET Family in Sepsis
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 BR...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990776/ https://www.ncbi.nlm.nih.gov/pubmed/33776776 http://dx.doi.org/10.3389/fphar.2021.642294 |
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author | Wang, Nian Wu, Runliu Comish, Paul B. Kang, Rui Tang, Daolin |
author_facet | Wang, Nian Wu, Runliu Comish, Paul B. Kang, Rui Tang, Daolin |
author_sort | Wang, Nian |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7990776 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79907762021-03-26 Pharmacological Modulation of BET Family in Sepsis Wang, Nian Wu, Runliu Comish, Paul B. Kang, Rui Tang, Daolin Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2021-03-11 /pmc/articles/PMC7990776/ /pubmed/33776776 http://dx.doi.org/10.3389/fphar.2021.642294 Text en Copyright © 2021 Wang, Wu, Comish, Kang and Tang. http://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 Wang, Nian Wu, Runliu Comish, Paul B. Kang, Rui Tang, Daolin Pharmacological Modulation of BET Family in Sepsis |
title | Pharmacological Modulation of BET Family in Sepsis |
title_full | Pharmacological Modulation of BET Family in Sepsis |
title_fullStr | Pharmacological Modulation of BET Family in Sepsis |
title_full_unstemmed | Pharmacological Modulation of BET Family in Sepsis |
title_short | Pharmacological Modulation of BET Family in Sepsis |
title_sort | pharmacological modulation of bet family in sepsis |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990776/ https://www.ncbi.nlm.nih.gov/pubmed/33776776 http://dx.doi.org/10.3389/fphar.2021.642294 |
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