Rivas Alexis, Vidal René Luis, Hetz Claudio
University of Chile, Biomedical Neuroscience Institute, Faculty of Medicine , Santiago , Chile.
Expert Opin Ther Targets. 2015;19(9):1203-18. doi: 10.1517/14728222.2015.1053869. Epub 2015 Jul 13.
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) generates a stress condition that engages the unfolded protein response (UPR). The UPR is an adaptive reaction that aims to reestablish ER proteostasis by recovering the folding capacity of the cell. However, chronic ER stress results in apoptosis.
This review focuses on discussing the emerging role of the UPR as a driver of several human pathologies including diabetes, neurodegenerative diseases and cancer. The involvement of specific UPR signaling components on different diseases is highlighted based on preclinical models and pharmacological and genetic manipulation of the pathway.
Therapeutic strategies directed to regulate the activity of different UPR signaling arms may reduce stress levels with a therapeutic gain. Recent drug discovery efforts have identified small molecules that target specific UPR components, providing protection on various disease models. However, important side effects are predicted in the chronic administration due to the fundamental role of the UPR in highly secretory organs such as liver and pancreas. To overcome these problems, we propose the use of combinatorial treatments of selected drugs with natural compounds that are known to modulate the ER proteostasis network.
内质网（ER）中错误折叠蛋白的积累会产生一种应激状态，引发未折叠蛋白反应（UPR）。UPR是一种适应性反应，旨在通过恢复细胞的折叠能力来重建内质网蛋白质稳态。然而，慢性内质网应激会导致细胞凋亡。
本综述重点讨论UPR作为包括糖尿病、神经退行性疾病和癌症在内的几种人类疾病驱动因素的新作用。基于临床前模型以及该通路的药理学和基因操作，强调了特定UPR信号成分在不同疾病中的作用。
针对调节不同UPR信号臂活性的治疗策略可能会降低应激水平并带来治疗益处。最近的药物发现工作已经确定了靶向特定UPR成分的小分子，在各种疾病模型中提供保护。然而，由于UPR在肝脏和胰腺等高分泌器官中的基本作用，预计长期给药会产生重要的副作用。为克服这些问题，我们建议将选定药物与已知可调节内质网蛋白质稳态网络的天然化合物联合使用。
