GENES AND IMMUNITY
·
2025
·
IF 4.5
Lin Shizhao,Liang Feihong,Chen Changgan,Lin Jiajing,Wu Yuwei,Hou Zelin,Huang Heguang,Fang Haizong,Pan Yu
Severe acute pancreatitis (SAP) poses significant challenges due to its complex pathophysiology, which includes inflammatory-immune responses that cause considerable damage to both the pancreas and other tissues. In this study, we explored the role of Annexin A1 (Anxa1), a glucocorticoid-regulated protein recognized for its anti-inflammatory properties, in regulating inflammation during acute pancreatitis. Using flow cytometry, single-cell RNA sequencing, and gene expression analysis, we examined how Anxa1 expression is regulated in myeloid cells throughout acute pancreatitis, employing various animal models to evaluate the consequences of modulating Anxa1 on injuries induced by SAP. Our findings revealed dynamic regulation of Anxa1 expression in myeloid cells, with mice lacking Anxa1 exhibiting worsened pancreatic injury and heightened systemic inflammation, resulting in significant damage to extra-pancreatic organs such as the lungs, liver, and kidneys. In contrast, treatment with Ac2-26, a synthetic peptide derived from Anxa1, effectively mitigated both pancreatic and extra-pancreatic inflammation and tissue damage. Overall, this study highlights the critical role of Anxa1 in modulating inflammatory responses during acute pancreatitis. Targeting Anxa1 presents a promising therapeutic strategy to mitigate pancreatic injury and prevent systemic complications associated with severe acute pancreatitis.
研究领域:
医学
·
免疫学
·
病理学
✓ 已验证
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2024
·Vol. 9
·期 1
·1-17
·
IF 40.8
Fang Lu,Liu Changjie,Jiang Zong-zhe,Wang Mengxiao,Geng Kang,Xu Yangkai,Zhu Yujie,Fu Yiwen,Xue Jing,Shan Wenxin,Zhang Qi,Chen Jie,Chen Jiahong,Zhao Mingming,Guo Yuxuan,Siu K. W. Michael,Chen Y. Eugene,Xu Yong,Liu Donghui,Zheng Lemin
Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.
研究领域:
分子生物学
·
内分泌学
·
代谢
·
肥胖研究
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Chuiming Jia,Dejuan Kong,Yiwei Guo,Lianqiao Li,Lina Quan
Bortezomib (BTZ) is one of the most frequently used drugs in treatment of multiple myeloma (MM), but drug-resistance often occurs and limits its clinical efficacy. Annexin A1 (ANXA1) is upregulated in MM, and its knockdown enhances chemosensitivity in MM. However, whether ANXA1 inhibition can increase antitumor activity of BTZ in MM cells remains unknown. In the present study, Cell Counting Kit-8 (CCK-8) and colony formation assays showed that ANXA1 silencing combined with BTZ treatment led to a more significant inhibition of MM cell proliferation than each treatment alone. Cell apoptosis was dramatically promoted in MM cells following silencing of ANXA1 and BTZ administration versus that in ANXA1-silenced alone or BTZ-treated alone cells, as evidenced by decreased expression of phosphorylated signal transducers and activators of transcription 3 and BCL2, and increased expression of BAX. Moreover, we demonstrated that the levels of IL-6 and IL-23 were markedly downregulated in ANXA1-silenced and BTZ-treated MM cells. Furthermore, the combination of ANXA1 knockdown and BTZ treatment distinctly suppressed tumor growth in vivo compared with BTZ treatment alone. Taken together, our results show that downregulation of ANXA1 enhances antitumor activity of BTZ in MM in vitro and in vivo , indicating that ANXA1 may be a promising target for enhancing the chemosensitivity of MM to BTZ.
研究领域:
肿瘤学
·
血液学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
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