Chen Qian, Chen TianYi, Xiao He, Wang Fangjie, Li ChaoFan, Hu Nana, Bao Lingbo, Tong Xueling, Feng Yan, Xu Yu, Li ChunXue, Zhu Jian Wu, Wang Dong, Li Meng Xia
Cancer Center of Daping Hospital Army Medical University, Chongqing 400042, China.
Cancer Center of Daping Hospital Army Medical University, Chongqing 400042, China.
Free Radic Biol Med. 2024 Nov 20;225:359-373. doi: 10.1016/j.freeradbiomed.2024.10.260. Epub 2024 Oct 9.
Ulcerative colitis (UC) can lead to the generation of large amounts of reactive oxygen species and DNA damage. DNA repair caused by base excision repair (BER) enzymes is an important mechanism for maintaining genomic integrity. However, the specific relationship between the function of BER enzymes and UC remains unclear. To address this, we conducted a study on non-cancerous colon tissue from patients with UC, focusing on the role of apurinic/apyrimidinic endonuclease 1 (APEX1) in BER to explore its significance in the progression of UC. Our research found that the expression of APEX1 in epithelium cells was significantly correlated to the severity of inflammatory bowel disease (IBD) and the infiltration and function of neutrophils in human UC and mouse models, particularly in relation to neutrophil extracellular traps (NETs) and the degranulation processes. APEX1 deficiency resulted in decreased production of the chemokines CXCL1 by the NF-κB pathway in epithelium cells, leading to reduced accumulation and activation of neutrophils associated with colitis in colon tissue, as well as decreased levels of IL-1β. Furthermore, APEX1 deficiency reduced symptoms of colitis by decreasing epithelial cell apoptosis and altering the gut microbiome. Studies related to the redox activity of APEX1 have shown that the combination of the redox inhibitor E3330 with 5-aminosalicylic acid (5-ASA) can effectively alleviate colitis, indicating that APEX1 has promising prospects for clinical treatment of IBD. APEX1 is required for interactions between neutrophil and intestinal epithelial cells. This study provided a mechanism demonstrating that APEX1 protein triggered the risk of UC by promoting neutrophil infiltration and compromising intestinal epithelial barrier function.
溃疡性结肠炎（UC）可导致大量活性氧的产生和DNA损伤。碱基切除修复（BER）酶引起的DNA修复是维持基因组完整性的重要机制。然而，BER酶的功能与UC之间的具体关系仍不清楚。为了解决这个问题，我们对UC患者的非癌性结肠组织进行了一项研究，重点关注脱嘌呤/脱嘧啶内切核酸酶1（APEX1）在BER中的作用，以探讨其在UC进展中的意义。我们的研究发现，APEX1在上皮细胞中的表达与炎症性肠病（IBD）的严重程度以及人类UC和小鼠模型中中性粒细胞的浸润和功能显著相关，特别是与中性粒细胞胞外陷阱（NETs）和脱颗粒过程有关。APEX1缺陷导致上皮细胞中NF-κB途径产生的趋化因子CXCL1减少，导致结肠组织中与结肠炎相关的中性粒细胞积累和活化减少，以及IL-1β水平降低。此外，APEX1缺陷通过减少上皮细胞凋亡和改变肠道微生物群来减轻结肠炎症状。与APEX1氧化还原活性相关的研究表明，氧化还原抑制剂E3330与5-氨基水杨酸（5-ASA）联合使用可有效缓解结肠炎，这表明APEX1在IBD的临床治疗中具有广阔前景。APEX1是中性粒细胞与肠上皮细胞相互作用所必需的。这项研究提供了一种机制，证明APEX1蛋白通过促进中性粒细胞浸润和损害肠上皮屏障功能引发UC风险。
