FASEB JOURNAL
·
2025
·Vol. 39
·期 14
·e70867
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IF 4.2
Xiaolin Dou,Zhongcheng Zhu,Qizhen Chen,Yebin Lu
Acute lung injury (ALI) is closely associated with high mortality in severe acute pancreatitis (SAP). Nr4a3 is a nuclear receptor with proinflammatory effects. The role of Nr4a3 in SAP-associated ALI is unclear. Caerulein (CRE)-induced AP mice represented significant pancreatic and lung pathological injury, with high Nr4a3 expression in lung tissues. Nr4a3 expression in lung tissues of AP mice inhibited CD31 expression, suggesting lung microvascular injury. In vitro and in vivo experiments were performed to investigate the effect of Nr4a3 inhibition in mitigating SAP-associated ALI. Nr4a3 downregulation reduced permeability, increased trans-endothelial electrical resistance (TEER) and VE-cadherin expression in TNF-α-induced human pulmonary microvascular endothelial cells (hPMVECs), suggesting recovered endothelial barrier function. Nr4a3 knockdown attenuated lung injury in AP mice, as reflected by restored lung edema and endothelial barrier function. Reduced inflammatory cell counts and mediators indicated that Nr4a3 knockdown mitigated lung inflammation in AP mice. The up-regulation of Nr4a3 in TNF-α-induced hPMVECs was further elevated after Sirt1 (a deacetylase) inhibition. Mechanistically, Sirt1 deficiency increased the enrichment of CREB at the Nr4a3 promoter through acetylating H3K27, thereby promoting Nr4a3 expression. Rescue experiments in vivo demonstrated that Nr4a3 knockdown attenuated lung injury aggravated by Sirt1 inhibition. These results suggested that Sirt1 might prevent CREB enrichment by inhibiting histone acetylation in the Nr4a3 promoter, thereby suppressing Nr4a3 expression and ultimately attenuating ALI. Graphical Mechanism diagram of Nr4a3 inhibition alleviating SAP-associated ALI. The high expression of Nr4a3 promotes inflammatory responses, increases the permeability of endothelial cells, and thus exacerbates SAP-induced ALI. Sirt1 regulates histone deacetylation in the promoter of Nr4a3, thereby affecting CREB recruitment and influencing Nr4a3 transcription. Sirt1-mediated transcriptional inhibition of Nr4a3 alleviates SAP-associated ALI. A few materials used in this figure were from Bioicons ( https://bioicons.com/ ) and these materials were all free.
研究领域:
分子生物学
·
免疫学
·
病理学
·
细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Zhongcheng Zhu,Xiaolin Dou,Qizhen Chen,Yebin Lu
Acute pancreatitis (AP) has a high mortality, involving oxidative stress and mitochondrial damage. Nuclear receptor subfamily 4 group A member 3 (Nr4a3) and BTG anti-proliferation factor 2 (Btg2) have a close connection with mitochondrial damage. Here, we found that Nr4a3 expression was upregulated in pancreatic tissues of AP mice induced by cerulein. To elucidate Nr4a3's role, we injected adeno-associated virus 9 (AAV9) carrying Nr4a3-targeting short hairpin RNA into the pancreatic duct. This intervention reduced pancreatic edema, inflammatory infiltration, and acinar cell necrosis by suppressing pancreatic enzyme activation. Moreover, Nr4a3 knockdown improved mitochondrial function in pancreatic acinar cells, evidenced by increased mitochondrial membrane potential, enhanced ATP production, and decreased superoxide levels. It also inhibited cell apoptosis by suppressing the activation of the caspase pathway. In vitro, Nr4a3 knockdown in CCK-treated pancreatic acinar cells decreased oxidative stress, mitigated mitochondrial damage, and suppressed apoptosis, while Nr4a3 overexpression exacerbated cell injury. Further investigation identified Btg2 as a downstream target of Nr4a3. Btg2 expression was elevated in pancreatic acinar cells of AP mice, and siRNA-mediated Btg2 knockdown alleviated CCK-induced cell injury. Mechanistically, Nr4a3 promoted Btg2 transcription, thereby promoting mitochondrial damage in pancreatic acinar cells and leading to cell apoptosis. Btg2 overexpression reversed the protective effects of Nr4a3 knockdown. Overall, our findings demonstrate that downregulation of Nr4a3 exerts anti-AP effects by regulating Btg2, providing potential therapeutic targets for AP.
研究领域:
分子生物学
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细胞生物学
·
生物化学
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医学研究
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遗传学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Zheng Wang,Mingyu Zhao,Yue Su,Qiangsen Zhao,Zhenhua Ma,Qiaoxian Yue,Zhiwei Zhu,Lihuan Zhang,Zhuocheng Hou,Huifeng Li
Excessive abdominal fat deposition negatively impacts poultry meat production and carcass yield. Identification of novel adipogenesis regulators may help improve production performance declines caused by excessive fat deposition. NUMB Endocytic Adaptor Protein ( NUMB ) typically functions as a cell fate determinant and plays a significant role in cell development and various diseases. Here, we found that NUMB is abundantly expressed in chicken abdominal fat depots and is induced in cultured adipocytes following adipogenic treatment. The gain- and loss-of-function experiments demonstrated that NUMB promotes the proliferation and G1/S transition of chicken adipocytes, enhances adipocyte differentiation, and increases the expression of PPARγ1 transcript. Through mRNA-seq analysis and molecular experiments, we further confirmed that NUMB inhibits the transcriptional activation of the NOTCH1 pathway and the expression of the downstream transcription factor HES1 by inducing NOTCH1 degradation. Nevertheless, the inhibition of the NOTCH1 / HES1 axis alone cannot fully explain NUMB 's role in adipogenesis, as NUMB also regulates the expression of multiple adipogenic transcription factors such as E2F1 , EGR2 , and NR4A3 . Our data suggest that NUMB is a potent activator of adipogenesis and enhances our understanding of its regulatory mechanisms in chicken abdominal fat deposition.
研究领域:
动物科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
iScience
·
2026
·
IF 4.5
Bo Pang,Siyuan Chen,Yikai Bai,Yan Zhang,Zhida Wang
Diabetic peripheral neuropathy (DPN) is a prevalent complication characterized by Schwann cell dysfunction. The role of the nuclear receptor subfamily 4 group member 3 (NR4A3) in DPN remains unclear. We found that NR4A3 expression is upregulated in the sciatic nerves of streptozotocin (STZ)-induced DPN mice. Overexpression of NR4A3 via AAV9-Mpz-NR4A3 lumbar intrathecal injection improved motor and sensory nerve function and mitigated sciatic nerve pathology. NR4A3 overexpression also reduced oxidative stress and enhanced mitochondrial function. In the high glucose (HG)-induced Schwann cell injury model, NR4A3 overexpression inhibited apoptosis, mitochondrial dysfunction, and dedifferentiation. Integrated ChIP-seq and mRNA-seq profiling identified glutaminase 2 (GLS2) as a direct transcriptional target of NR4A3. NR4A3 bound to the GLS2 promoter and promotes its transcriptional activation, and suppression of GLS2 abrogated the functional protection conferred by NR4A3 in Schwann cells. Together, NR4A3 represents a promising therapeutic target for DPN.
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产品关联
DOI
PubMed
高影响因子
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