Hepatic BRD4 Is Upregulated in Liver Fibrosis of Various Etiologies and Positively Correlated to Fibrotic Severity

Wu, Cichun; Cheng, Da; Peng, Yanghui; Liu, Ying; Fu, Chunyan; Wang, Ying; Fu, Ling; Peng, Shifang; Ni, Xin

doi:10.3389/fmed.2021.683506

Cited by 7 publications

(3 citation statements)

References 54 publications

(59 reference statements)

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“…In addition, the RNA-Sequencing (RNA-Seq) data was standardized and screened for DEGs using the R language. The specifics of RNA-seq operation were discussed in our previous study ( Wu C. et al, 2021 ). The clinical characteristics of the patients are shown in Supplementary Table S2 .…”

Section: Methodsmentioning

confidence: 99%

TRAF2 as a key candidate gene in clinical hepatitis B-associated liver fibrosis

Zhang

Wang

et al. 2023

Front. Mol. Biosci.

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Objectives: Approximately 240 million individuals are infected with chronic hepatitis B virus (HBV) worldwide. HBV infection can develop into liver fibrosis. The mechanism of HBV-related liver fibrosis has not been fully understood, and there are few effective treatment options. The goal of this study was to use transcriptomics in conjunction with experimental validation to identify new targets to treat HBV-related liver fibrosis.Methods: To identify differentially expressed genes (DEGs), five liver tissues were collected from both healthy individuals and patients with chronic hepatitis B. NovoMagic and Java GSEA were used to screen DEGs and key genes, respectively. Immunocell infiltration analysis of RNA-seq data was, and the results were confirmed by Western blotting (WB), real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemistry.Results: We evaluated 1,105 genes with differential expression, and 462 and 643 genes showed down- and upregulation, respectively. The essential genes, such as tumor necrosis factor (TNF) receptor-associated factor-2 (TRAF2), were screened out of DEGs. TRAF2 expression was abnormally high in hepatic fibrosis in patients with hepatitis B compared with healthy controls. The degree of hepatic fibrosis and serum levels of glutamate transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were positively linked with TRAF2 expression. TRAF2 may be crucial in controlling T lymphocyte-mediated liver fibrosis.Conclusion: Our findings imply that TRAF2 is essential for HBV-induced liver fibrosis progression, and it may potentially be a promising target for the treatment of hepatic fibrosis in hepatitis B.

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Section: Methodsmentioning

confidence: 99%

TRAF2 as a key candidate gene in clinical hepatitis B-associated liver fibrosis

Zhang

Wang

et al. 2023

Front. Mol. Biosci.

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“…Several chemokines and receptors belong to the panel of genes whose expression levels in the liver of HCV-associated early-stage cirrhosis patients are significantly associated with the risk of progression [32]. As such, the upregulated expression of CXCL6, as a possible consequence of that of the bromodomain-containing protein 4, was proposed to participate in the development and progression of HBV-induced liver fibrosis [33]. Moreover, the upregulation of the CXCL10/CXCR3 chemokine/chemokine receptor pair has been correlated with the progression toward liver disease [34].…”

Section: From Chronic Inflammation To Oncogenic Transformation: Focus...mentioning

confidence: 99%

The Chemokine System in Oncogenic Pathways Driven by Viruses: Perspectives for Cancer Immunotherapy

Schlecht-Louf

Deback

Bachelerie

2022

Cancers

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Chemokines interact with glycosaminoglycans of the extracellular matrix and activate heptahelical cellular receptors that mainly consist of G Protein-Coupled Receptors and a few atypical receptors also with decoy activity. They are well-described targets of oncogenic pathways and key players in cancer development, invasiveness, and metastasis acting both at the level of cancer cells and cells of the tumor microenvironment. Hence, they can regulate cancer cell proliferation and survival and promote immune or endothelial cell migration into the tumor microenvironment. Additionally, oncogenic viruses display the potential of jeopardizing the chemokine system by encoding mimics of chemokines and receptors as well as several products such as oncogenic proteins or microRNAs that deregulate their human host transcriptome. Conversely, the chemokine system participates in the host responses that control the virus life cycle, knowing that most oncoviruses establish asymptomatic latent infections. Therefore, the deregulated expression and function of chemokines and receptors as a consequence of acquired or inherited mutations could bias oncovirus infection toward pro-oncogenic pathways. We here review these different processes and discuss the anticancer therapeutic potential of targeting chemokine availability or receptor activation, from signaling to decoy-associated functions, in combination with immunotherapies.

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“…Bromodomain and extra-terminal domain (BET) proteins play an important role in epigenetic regulation and are linked to several diseases, including acute liver injury, − acute myeloid leukemia, triple negative breast cancer, − inflammation, fibrosis, HIV, myeloid neoplasms, and cardiovascular disease. , Therefore, BET proteins are interesting targets for disease treatment.…”

Section: Introductionmentioning

confidence: 99%

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations

Shi,

Zheng,

Zhou

et al. 2023

ACS Omega

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Bromodomain and extra-terminal domain (BET) proteins play an important role in epigenetic regulation and are linked to several diseases; therefore, they are interesting targets. BET has two bromodomains: bromodomain 1 (BD1) and BD2. Selective targeting of BD1 or BD2 may produce different activities and greater effects than pan-BD inhibitors. However, the selective mechanism of the specific core must be studied at the atomic level. This study determined the effectiveness of pyrrolopyridone analogues to selectively inhibit BD2 using a pan-BD inhibitor (ABBV-075) and a selective-BD2 inhibitor (ABBV-744). Molecular dynamics simulations and calculations of binding free energies were used to systematically study the selectivity of BD2 inhibition by the pyrrolopyridone analogues. Overall, the pyrrolopyridone analogue inhibitors targeting BD2 interacted mainly with the following amino acid pairs between bromodomain-containing protein 4 (BRD4)-BD1 and BRD4-BD2 complexes: I146/V439, N140/N433, D144/H437, P82/P375, V87/V380, D88/D381, and Y139/Y432. The pyrrolopyridone analogues targeting BRD4-BD2 were divided into five regions based on selectivity mechanism. These results suggest that the R3 and R5 regions of pyrrolopyridone analogues can be modified to improve the selectivity between BRD4-BD1 and BRD4-BD2. The selectivity of BD2 inhibition by pyrrolopyridone analogues can be used to design novel BD2 inhibitors based on a pyrrolopyridone core.

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Hepatic BRD4 Is Upregulated in Liver Fibrosis of Various Etiologies and Positively Correlated to Fibrotic Severity

Cited by 7 publications

References 54 publications

TRAF2 as a key candidate gene in clinical hepatitis B-associated liver fibrosis

TRAF2 as a key candidate gene in clinical hepatitis B-associated liver fibrosis

The Chemokine System in Oncogenic Pathways Driven by Viruses: Perspectives for Cancer Immunotherapy

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations

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