Novel pharmacological inhibition of JMJD3 improves necrotizing enterocolitis by attenuating the inflammatory response and ameliorating intestinal injury

Ma, Shu‐Rong; Xu, Lingqi; Chen, Lulu; Sun, Xu; Hu, Fangjie; Gong, Yuanyuan; Yang, Randong; Li, Jing; Wang, Qian; Huang, Shungen; Zhou, Huiting; Wang, Jian

doi:10.1016/j.bcp.2022.115165

Cited by 9 publications

(5 citation statements)

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“…It has been reported that GSK‐J4 worked as a specific inhibitor of KDM6B in the treatment of inflammatory diseases 32,33 . In the current study, the repeat intrathecal (i.t.)…”

Section: Resultsmentioning

confidence: 78%

“…It has been reported that GSK‐J4 worked as a specific inhibitor of KDM6B in the treatment of inflammatory diseases. 32 , 33 In the current study, the repeat intrathecal (i.t.) injections of GSK‐J4 at doses of 5, 25, and 50 μg were performed to examine the role of KDM6B in the CFA‐induced inflammatory pain.…”

Section: Resultsmentioning

confidence: 96%

“…It has been reported that GSK-J4 worked as a specific inhibitor of KDM6B in the treatment of inflammatory diseases. 32,33 In the current study, the repeat intrathecal (i.t.) injections of GSK-J4 at doses study, we detected a significant increased expression of TNFα, which peaked at 6 h and lasted to day 3 in the DRG (Figure 3E).…”

Section: Intrathecal Injection Of Gsk-j4 Alleviated Mechanical Allody...mentioning

confidence: 98%

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Upregulation of lysine‐specific demethylase 6B aggravates inflammatory pain through H3K27me3 demethylation‐dependent production of TNF‐α in the dorsal root ganglia and spinal dorsal horn in rats

Qiao

Bai

et al. 2023

CNS Neurosci Ther

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AimsLysine‐specific demethylase 6B (KDM6B) serves as a key mediator of gene transcription. It regulates expression of proinflammatory cytokines and chemokines in variety of diseases. Herein, the role and the underlying mechanisms of KDM6B in inflammatory pain were studied.MethodsThe inflammatory pain was conducted by intraplantar injection of complete Freund's adjuvant (CFA) in rats. Immunofluorescence, Western blotting, qRT‐PCR, and chromatin immunoprecipitation (ChIP)‐PCR were performed to investigate the underlying mechanisms.ResultsCFA injection led to upregulation of KDM6B and decrease in the level of H3K27me3 in the dorsal root ganglia (DRG) and spinal dorsal horn. The mechanical allodynia and thermal hyperalgesia following CFA were alleviated by the treatment of intrathecal injection of GSK‐J4, and by microinjection of AAV‐EGFP‐KDM6B shRNA in the sciatic nerve or in lumbar 5 dorsal horn. The increased production of tumor necrosis factor‐α (TNF‐α) following CFA in the DRGs and dorsal horn was inhibited by these treatments. ChIP‐PCR showed that CFA‐induced increased binding of nuclear factor κB with TNF‐α promoter was repressed by the treatment of microinjection of AAV‐EGFP‐KDM6B shRNA.ConclusionsThese results suggest that upregulated KDM6B via facilitating TNF‐α expression in the DRG and spinal dorsal horn aggravates inflammatory pain.

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“…It has been reported that GSK‐J4 worked as a specific inhibitor of KDM6B in the treatment of inflammatory diseases 32,33 . In the current study, the repeat intrathecal (i.t.)…”

Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 96%

Section: Intrathecal Injection Of Gsk-j4 Alleviated Mechanical Allody...mentioning

confidence: 98%

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Upregulation of lysine‐specific demethylase 6B aggravates inflammatory pain through H3K27me3 demethylation‐dependent production of TNF‐α in the dorsal root ganglia and spinal dorsal horn in rats

Qiao

Bai

et al. 2023

CNS Neurosci Ther

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“…JMJD3 depletion negated downstream NF-κB proinflammatory signaling and subsequently reduced the LPS-stimulated upregulation of TNF-α, IL-1β, and IL-6 [ 44 ]. Furthermore, JMJD3 inhibition improved necrotizing enterocolitis (NEC) by attenuating the inflammatory response and ameliorating intestinal injury via the NF-κB and JAK2/STAT3 pathways in NEC mice [ 59 ]. Remarkably, targeting JMJD3 not only holds therapeutic potential for the treatment of inflammatory diseases but also represents a potential target for the treatment of IBD.…”

Section: Discussionmentioning

confidence: 99%

YAP represses intestinal inflammation through epigenetic silencing of JMJD3

Zhu,

Lu,

et al. 2024

Clin Epigenet

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Background Epigenetics plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Some studies have reported that YAP is involved in inflammatory response and can regulate target genes through epigenetic modifications. JMJD3, a histone H3K27me3 demethylase, is associated with some inflammatory diseases. In this study, we investigated the role of YAP in the development of IBD and the underlying epigenetic mechanisms. Results YAP expression was significantly increased in both in vitro and in vivo colitis models as well as in patients with IBD. Epithelial-specific knockout of YAP aggravates disease progression in dextran sodium sulfate (DSS)-induced murine colitis. In the TNF-α-activated cellular inflammation model, YAP knockdown significantly increased JMJD3 expression. Coimmunoprecipitation experiments showed that YAP and EZH2 bind to each other, and chromatin immunoprecipitation-PCR (ChIP-PCR) assay indicated that silencing of YAP or EZH2 decreases H3K27me3 enrichment on the promoter of JMJD3. Finally, administration of the JMJD3 pharmacological inhibitor GSK-J4 alleviated the progression of DSS-induced murine colitis. Conclusion Our findings elucidate an epigenetic mechanism by which YAP inhibits the inflammatory response in colitis through epigenetic silencing of JMJD3 by recruiting EZH2.

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“…A large amount of evidence suggests that histone demethylation played an important role in intestinal inflammatory responses and the transformation to colorectal cancer (CRC) [ 184 ]. Ma et al [ 185 ] showed in necrotizing colitis mice that KDM6B was activated by STAT3 and participated in JAK2/STAT3 pathway to enhance the transcription of inflammatory genes. Besides, KDM6B might interact with NF-κB to activate the transcription of TNF-a/Il1b/Il6 and ultimately aggravated intestinal inflammatory damage.…”

Section: Kdms and Inflammatory Diseasesmentioning

confidence: 99%

Histone demethylases in the regulation of immunity and inflammation

Yin

Zhao

et al. 2023

Cell Death Discov.

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Pathogens or danger signals trigger the immune response. Moderate immune response activation removes pathogens and avoids excessive inflammation and tissue damage. Histone demethylases (KDMs) regulate gene expression and play essential roles in numerous physiological processes by removing methyl groups from lysine residues on target proteins. Abnormal expression of KDMs is closely associated with the pathogenesis of various inflammatory diseases such as liver fibrosis, lung injury, and autoimmune diseases. Despite becoming exciting targets for diagnosing and treating these diseases, the role of these enzymes in the regulation of immune and inflammatory response is still unclear. Here, we review the underlying mechanisms through which KDMs regulate immune-related pathways and inflammatory responses. In addition, we also discuss the future applications of KDMs inhibitors in immune and inflammatory diseases.

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Novel pharmacological inhibition of JMJD3 improves necrotizing enterocolitis by attenuating the inflammatory response and ameliorating intestinal injury

Cited by 9 publications

References 50 publications

Upregulation of lysine‐specific demethylase 6B aggravates inflammatory pain through H3K27me3 demethylation‐dependent production of TNF‐α in the dorsal root ganglia and spinal dorsal horn in rats

Upregulation of lysine‐specific demethylase 6B aggravates inflammatory pain through H3K27me3 demethylation‐dependent production of TNF‐α in the dorsal root ganglia and spinal dorsal horn in rats

YAP represses intestinal inflammation through epigenetic silencing of JMJD3

Histone demethylases in the regulation of immunity and inflammation

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