Verjan Garcia Noel, Hong Kyung U, Matoba Nobuyuki
UofL Health-Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Biomedicines. 2023 Jul 23;11(7):2066. doi: 10.3390/biomedicines11072066.
The endoplasmic reticulum (ER) is a multifunctional organelle playing a vital role in maintaining cell homeostasis, and disruptions to its functions can have detrimental effects on cells. Dysregulated ER stress and the unfolded protein response (UPR) have been linked to various human diseases. For example, ER stress and the activation of the UPR signaling pathways in intestinal epithelial cells can either exacerbate or alleviate the severity of inflammatory bowel disease (IBD), contingent on the degree and conditions of activation. Our recent studies have shown that EPICERTIN, a recombinant variant of the cholera toxin B subunit containing an ER retention motif, can induce a protective UPR in colon epithelial cells, subsequently promoting epithelial restitution and mucosal healing in IBD models. These findings support the idea that compounds modulating UPR may be promising pharmaceutical candidates for the treatment of the disease. In this review, we summarize our current understanding of the ER stress and UPR in IBD, focusing on their roles in maintaining cell homeostasis, dysregulation, and disease pathogenesis. Additionally, we discuss therapeutic strategies that promote the cytoprotection of colon epithelial cells and reduce inflammation via pharmacological manipulation of the UPR.
内质网（ER）是一种多功能细胞器，在维持细胞内稳态方面发挥着至关重要的作用，其功能紊乱会对细胞产生有害影响。内质网应激失调和未折叠蛋白反应（UPR）与多种人类疾病有关。例如，肠道上皮细胞中的内质网应激和UPR信号通路的激活，根据激活的程度和条件，既可以加重也可以减轻炎症性肠病（IBD）的严重程度。我们最近的研究表明，EPICERTIN是一种含有内质网保留基序的霍乱毒素B亚基的重组变体，可在结肠上皮细胞中诱导保护性UPR，随后在IBD模型中促进上皮修复和黏膜愈合。这些发现支持了这样一种观点，即调节UPR的化合物可能是治疗该疾病的有前景的药物候选物。在这篇综述中，我们总结了目前对内质网应激和UPR在IBD中的理解，重点关注它们在维持细胞内稳态、失调和疾病发病机制中的作用。此外，我们还讨论了通过对UPR进行药理学操作来促进结肠上皮细胞的细胞保护和减轻炎症的治疗策略。
