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BRD4 inhibitor JQ1 inhibits and reverses mechanical injury-induced corneal scarring
Corneal scarring is characterized by the improper deposition of extracellular matrix components and myofibroblast differentiation from keratocytes. The bromodomain-containing protein 4 (BRD4) inhibitor JQ1 has been shown to attenuate pathological fibrosis. The present study aimed to explore the pote...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060126/ https://www.ncbi.nlm.nih.gov/pubmed/30062054 http://dx.doi.org/10.1038/s41420-018-0066-1 |
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author | Qu, Mingli Zhang, Xiaoping Hu, Xiaoli Dong, Muchen Pan, Xiaojing Bian, Jiang Zhou, Qingjun |
author_facet | Qu, Mingli Zhang, Xiaoping Hu, Xiaoli Dong, Muchen Pan, Xiaojing Bian, Jiang Zhou, Qingjun |
author_sort | Qu, Mingli |
collection | PubMed |
description | Corneal scarring is characterized by the improper deposition of extracellular matrix components and myofibroblast differentiation from keratocytes. The bromodomain-containing protein 4 (BRD4) inhibitor JQ1 has been shown to attenuate pathological fibrosis. The present study aimed to explore the potential therapeutic effect of JQ1 on mechanical injury-induced mouse corneal scarring and TGFβ-induced human corneal myofibroblast differentiation and the related mechanism. The corneal scarring and myofibroblast differentiation were evaluated with clinical observation and fibrosis-related gene expression analysis. In mice, subconjunctivally injected JQ1 suppressed the initial development and reversed the established progression of corneal scarring, while having no impairment on the epithelial regenerative capacity. BRD4 inhibition with either JQ1 or small-interfering RNA inhibited the differentiation and promoted the dedifferentiation of human corneal myofibroblasts. Moreover, JQ1 attenuated the accumulation of intracellular reactive oxygen species induced by TGFβ treatment, induced Nrf2 nuclear translocation and activated the expression of Nrf2-ARE downstream antioxidant genes. In conclusion, this study implicates that JQ1 suppresses and reverses corneal scarring through the regulation of BRD4 inhibition and Nrf2-dependant antioxidant induction. |
format | Online Article Text |
id | pubmed-6060126 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-60601262018-07-30 BRD4 inhibitor JQ1 inhibits and reverses mechanical injury-induced corneal scarring Qu, Mingli Zhang, Xiaoping Hu, Xiaoli Dong, Muchen Pan, Xiaojing Bian, Jiang Zhou, Qingjun Cell Death Discov Article Corneal scarring is characterized by the improper deposition of extracellular matrix components and myofibroblast differentiation from keratocytes. The bromodomain-containing protein 4 (BRD4) inhibitor JQ1 has been shown to attenuate pathological fibrosis. The present study aimed to explore the potential therapeutic effect of JQ1 on mechanical injury-induced mouse corneal scarring and TGFβ-induced human corneal myofibroblast differentiation and the related mechanism. The corneal scarring and myofibroblast differentiation were evaluated with clinical observation and fibrosis-related gene expression analysis. In mice, subconjunctivally injected JQ1 suppressed the initial development and reversed the established progression of corneal scarring, while having no impairment on the epithelial regenerative capacity. BRD4 inhibition with either JQ1 or small-interfering RNA inhibited the differentiation and promoted the dedifferentiation of human corneal myofibroblasts. Moreover, JQ1 attenuated the accumulation of intracellular reactive oxygen species induced by TGFβ treatment, induced Nrf2 nuclear translocation and activated the expression of Nrf2-ARE downstream antioxidant genes. In conclusion, this study implicates that JQ1 suppresses and reverses corneal scarring through the regulation of BRD4 inhibition and Nrf2-dependant antioxidant induction. Nature Publishing Group UK 2018-06-28 /pmc/articles/PMC6060126/ /pubmed/30062054 http://dx.doi.org/10.1038/s41420-018-0066-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Qu, Mingli Zhang, Xiaoping Hu, Xiaoli Dong, Muchen Pan, Xiaojing Bian, Jiang Zhou, Qingjun BRD4 inhibitor JQ1 inhibits and reverses mechanical injury-induced corneal scarring |
title | BRD4 inhibitor JQ1 inhibits and reverses mechanical injury-induced corneal scarring |
title_full | BRD4 inhibitor JQ1 inhibits and reverses mechanical injury-induced corneal scarring |
title_fullStr | BRD4 inhibitor JQ1 inhibits and reverses mechanical injury-induced corneal scarring |
title_full_unstemmed | BRD4 inhibitor JQ1 inhibits and reverses mechanical injury-induced corneal scarring |
title_short | BRD4 inhibitor JQ1 inhibits and reverses mechanical injury-induced corneal scarring |
title_sort | brd4 inhibitor jq1 inhibits and reverses mechanical injury-induced corneal scarring |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060126/ https://www.ncbi.nlm.nih.gov/pubmed/30062054 http://dx.doi.org/10.1038/s41420-018-0066-1 |
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