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  1. Article ; Online: BRD4 is a novel therapeutic target for liver fibrosis.

    Ding, Ning / Hah, Nasun / Yu, Ruth T / Sherman, Mara H / Benner, Chris / Leblanc, Mathias / He, Mingxiao / Liddle, Christopher / Downes, Michael / Evans, Ronald M

    Proceedings of the National Academy of Sciences of the United States of America

    2015  Volume 112, Issue 51, Page(s) 15713–15718

    Abstract: ... This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications. ... Liver fibrosis is characterized by the persistent deposition of extracellular matrix components ... cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers ...

    Abstract Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.
    MeSH term(s) Animals ; Azepines/pharmacology ; Azepines/therapeutic use ; Cells, Cultured ; Hepatic Stellate Cells/drug effects ; Liver Cirrhosis, Experimental/drug therapy ; Male ; Mice ; Mice, Inbred C57BL ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/physiology ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/physiology ; Triazoles/pharmacology ; Triazoles/therapeutic use
    Chemical Substances (+)-JQ1 compound ; Azepines ; Brd4 protein, mouse ; Nuclear Proteins ; Transcription Factors ; Triazoles
    Language English
    Publishing date 2015-12-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1522163112
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
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  2. Article ; Online: MicroRNA-29a is a key regulon that regulates BRD4 and mitigates liver fibrosis in mice by inhibiting hepatic stellate cell activation.

    Huang, Ying-Hsien / Kuo, Hsing-Chun / Yang, Ya-Ling / Wang, Feng-Sheng

    International journal of medical sciences

    2019  Volume 16, Issue 2, Page(s) 212–220

    Abstract: ... of bromodomain-4 protein (BRD4) represents a novel therapeutic target in hepatic fibrosis. Therefore, the purpose ... it a promising target for the pharmacologic treatment of hepatic fibrosis. ... of this study is to investigate the miR-29a regulation of BRD4 signaling in a bile duct-ligation (BDL ...

    Abstract MicroRNA-29a is a key regulon that regulates hepatic stellate cells (HSCs) and mitigates liver fibrosis. However, the mechanism by which it does so remains largely undefined. The inhibition of bromodomain-4 protein (BRD4) represents a novel therapeutic target in hepatic fibrosis. Therefore, the purpose of this study is to investigate the miR-29a regulation of BRD4 signaling in a bile duct-ligation (BDL) animal model with regard to developing cholestatic liver fibrosis. Hepatic tissue in miR-29a transgenic mice (miR-29aTg mice) displayed weak fibrotic matrix, as shown by α-smooth muscle actin staining within affected tissues compared to wild-type mice. miR-29a overexpression reduced the BDL exaggeration of BRD4 and SNAI1 expression. Increased miR-29a signaling caused the downregulation of EZH2, MeCP2, and SNAI1, as well as the upregulation of PPAR-γ expression, in primary HSCs. We further demonstrated that the administration of JQ1, a BRD4 inhibitor, could inhibit BRD4, C-MYC, EZH2, and SNAI1 expression, while both JQ1 and a miR-29a mimic could inhibit the migration and proliferation of HSCs. In short, our research demonstrates that miR-29a negatively regulates HSC activation by inhibiting BRD4 and EZH2 function, thus making it a promising target for the pharmacologic treatment of hepatic fibrosis.
    MeSH term(s) Animals ; Cell Movement ; Cell Proliferation ; Cholestasis/complications ; Cholestasis/metabolism ; Enhancer of Zeste Homolog 2 Protein/metabolism ; Hepatic Stellate Cells/physiology ; Liver Cirrhosis/etiology ; Liver Cirrhosis/metabolism ; Male ; Methyl-CpG-Binding Protein 2/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; MicroRNAs/metabolism ; Nuclear Proteins/metabolism ; PPAR gamma/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Snail Family Transcription Factors/metabolism ; Transcription Factors/metabolism
    Chemical Substances Brd4 protein, mouse ; MIRN29 microRNA, mouse ; Mecp2 protein, mouse ; Methyl-CpG-Binding Protein 2 ; MicroRNAs ; Nuclear Proteins ; PPAR gamma ; Proto-Oncogene Proteins c-myc ; Snai1 protein, mouse ; Snail Family Transcription Factors ; Transcription Factors ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; Ezh2 protein, mouse (EC 2.1.1.43)
    Language English
    Publishing date 2019-01-01
    Publishing country Australia
    Document type Journal Article
    ZDB-ID 2151424-0
    ISSN 1449-1907 ; 1449-1907
    ISSN (online) 1449-1907
    ISSN 1449-1907
    DOI 10.7150/ijms.29930
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis.

    Zhubanchaliyev, Altynbek / Temirbekuly, Aibar / Kongrtay, Kuralay / Wanshura, Leah C / Kunz, Jeannette

    Frontiers in pharmacology

    2016  Volume 7, Page(s) 462

    Abstract: Liver fibrosis is the result of a deregulated wound healing process characterized by the excessive ... to date that can target this early, reversible, stage in liver fibrosis. Several new lines ... the potential of targeting their activity with small molecule drugs for fibrosis reversal. ...

    Abstract Liver fibrosis is the result of a deregulated wound healing process characterized by the excessive deposition of extracellular matrix. Hepatic stellate cells (HSCs), which are activated in response to liver injury, are the major source of extracellular matrix and drive the wound healing process. However, chronic liver damage leads to perpetual HSC activation, progressive formation of pathological scar tissue and ultimately, cirrhosis and organ failure. HSC activation is triggered largely in response to mechanosignaling from the microenvironment, which induces a profibrotic nuclear transcription program that promotes HSC proliferation and extracellular matrix secretion thereby setting up a positive feedback loop leading to matrix stiffening and self-sustained, pathological, HSC activation. Despite the significant progress in our understanding of liver fibrosis, the molecular mechanisms through which the extracellular matrix promotes HSC activation are not well understood and no effective therapies have been approved to date that can target this early, reversible, stage in liver fibrosis. Several new lines of investigation now provide important insight into this area of study and identify two nuclear targets whose inhibition has the potential of reversing liver fibrosis by interfering with HSC activation: Yes-associated protein (YAP), a transcriptional co-activator and effector of the mechanosensitive Hippo pathway, and bromodomain-containing protein 4 (BRD4), an epigenetic regulator of gene expression. YAP and BRD4 activity is induced in response to mechanical stimulation of HSCs and each protein independently controls waves of early gene expression necessary for HSC activation. Significantly, inhibition of either protein can revert the chronic activation of HSCs and impede pathological progression of liver fibrosis in clinically relevant model systems. In this review we will discuss the roles of these nuclear co-activators in HSC activation, their mechanism of action in the fibrotic process in the liver and other organs, and the potential of targeting their activity with small molecule drugs for fibrosis reversal.
    Language English
    Publishing date 2016-12-01
    Publishing country Switzerland
    Document type Review ; Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2016.00462
    Database MEDical Literature Analysis and Retrieval System OnLINE

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