Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India.
Department of Surgical, Oncological and Gastroenterological Sciences, University of Padua, 35128, Padua, Italy.
Dig Dis Sci. 2022 Dec;67(12):5392-5406. doi: 10.1007/s10620-022-07467-y. Epub 2022 Mar 22.
Previous investigations have increased the knowledge about the pathological processes of inflammatory bowel diseases. Besides the complex organization of immune reactions, the mucosal epithelial lining has been recognized as a crucial regulator in the commencement and persistence of intestinal inflammation. As the intestinal epithelium is exposed to various environmental factors, the intestinal epithelial cells are confronted with diverse cellular stress conditions. In eukaryotic cells, an imbalance in the endoplasmic reticulum (ER) might cause aggregation of unfolded or misfolded proteins in the lumen of ER, a condition known as endoplasmic reticulum stress. This cellular mechanism stimulates the unfolded protein response (UPR), which elevates the potential of the endoplasmic reticulum protein folding, improves protein production and its maturation, and also stimulates ER-associated protein degradation. Current analyses reported that in the epithelium, the ER stress might cause the pathogenesis of inflammatory bowel disease that affects the synthesis of protein, inducing the apoptosis of the epithelial cell and stimulating the proinflammatory reactions in the gut. There have been significant efforts to develop small molecules or molecular chaperones that will be potent in ameliorating ER stress. The restoration of UPR balance in the endoplasmic reticulum via pharmacological intervention might be a novel therapeutic approach for the treatment of inflammatory bowel diseases (IBDs). This review provides novel insights into the role of chemical chaperone UPR modulators to modify ER stress levels. We further discuss the future directions/challenges in the development of therapeutic strategies for IBDs by targeting the ER stress. Figure depicting the role of endoplasmic reticulum stress-mediated inflammatory bowel disease and the therapeutic role of endoplasmic reticulum stress inhibitors in alleviating the diseased condition.
先前的研究增进了人们对炎症性肠病病理过程的认识。除了复杂的免疫反应组织外，黏膜上皮衬里也被认为是启动和持续肠道炎症的关键调节剂。由于肠上皮细胞暴露于各种环境因素，因此肠上皮细胞会面临各种细胞应激情况。在真核细胞中，内质网（ER）的失衡可能导致未折叠或错误折叠的蛋白质在内质网腔中聚集，这种情况称为内质网应激。这种细胞机制刺激未折叠蛋白反应（UPR），从而提高内质网蛋白折叠的潜力，改善蛋白质的产生及其成熟度，并刺激 ER 相关蛋白降解。目前的分析报告指出，在上皮细胞中，ER 应激可能导致影响蛋白质合成的炎症性肠病的发病机制，诱导上皮细胞凋亡并刺激肠道中的促炎反应。已经做出了重大努力来开发小分子或分子伴侣，这些小分子或分子伴侣将在改善 ER 应激方面具有强大的作用。通过药理学干预恢复内质网中 UPR 的平衡可能是治疗炎症性肠病（IBD）的一种新的治疗方法。本综述提供了化学伴侣 UPR 调节剂在调节 ER 应激水平方面的作用的新见解。我们进一步讨论了通过靶向 ER 应激开发治疗 IBD 的治疗策略的未来方向/挑战。该图描绘了内质网应激介导的炎症性肠病的作用以及内质网应激抑制剂在缓解疾病状况方面的治疗作用。
