Department of Gastrointestinal Surgery and Central Laboratory, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, China.
Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Cell Death Dis. 2022 Sep 10;13(9):782. doi: 10.1038/s41419-022-05226-5.
This study aimed to at explore exploring the biological functions of dysregulated circRNA in Crohn's disease (CD) pathogenesis, with the overarching goal of and providing potential novel therapeutic targets. CircRNA microarray and quantitative real time-polymerase chain reaction (qRT-PCR) analyses were performed to investigate and verify the candidate dysregulated circRNA. The Next, clinical, in vivo, and in vitro studies were performed to investigate explore the biological function and mechanisms of the candidate circRNA in CD. The therapeutic effect of poly (lactic-co-glycolic acid)-microspheres (PLGA MSs)-carried oe-circGMCL1 in experimental colitis models of IL-10 knock-out mice was assessed. CircGMCL1 was identified as the candidate circRNA by microarray and qRT-PCR analyses. Results showed that circGMCL1 expression was negatively correlated with CD-associated inflammatory indices, suggesting that it is a CD-associated circRNA. Microarray and bioinformatics analyses identified miR-124-3p and Annexin 7 (ANXA7) as its downstream mechanisms. The in vitro studies revealed that circGMCL1 mediates its effects on autophagy and NLRP3 inflammasome-mediated pyroptosis in epithelial cells through the ceRNA network. Moreover, the in vivo studies identified the therapeutic effect of PLGA MSs-carried oe-circGMCL1 in experimental colitis models. This study suggests that circGMCL1 protects intestinal barrier function against Crohn's colitis through alleviating NLRP3 inflammasome-mediated epithelial pyroptosis by promoting autophagy through regulating ANXA7 via sponging miR-124-3p. Therefore, circGMCL1 can serve as a potential biological therapeutic target for Crohn's colitis.
本研究旨在探索失调 circRNA 在克罗恩病（CD）发病机制中的生物学功能，以期为 CD 提供潜在的新型治疗靶点。通过 circRNA 微阵列和定量实时聚合酶链反应（qRT-PCR）分析来研究和验证候选失调 circRNA。然后，进行临床、体内和体外研究，以探讨候选 circRNA 在 CD 中的生物学功能和机制。评估载 poly(lactic-co-glycolic acid)-微球（PLGA MS）的 oe-circGMCL1 在 IL-10 敲除小鼠实验性结肠炎模型中的治疗效果。通过微阵列和 qRT-PCR 分析鉴定 circGMCL1 为候选 circRNA。结果表明，circGMCL1 的表达与 CD 相关的炎症指数呈负相关，表明其为与 CD 相关的 circRNA。微阵列和生物信息学分析确定 miR-124-3p 和膜联蛋白 7（ANXA7）为其下游机制。体外研究表明，circGMCL1 通过 ceRNA 网络在肠上皮细胞中介导自噬和 NLRP3 炎性小体介导的焦亡。此外，体内研究确定了 PLGA MS 载 oe-circGMCL1 在实验性结肠炎模型中的治疗效果。本研究表明，circGMCL1 通过调节 ANXA7 来促进自噬，从而通过海绵吸附 miR-124-3p 来减轻 NLRP3 炎性小体介导的上皮细胞焦亡，从而保护肠道屏障功能免受克罗恩病的影响。因此，circGMCL1 可以作为治疗克罗恩病的潜在生物治疗靶点。
