富含蛋白质的食物、海产品和肠道微生物群可增强慢性疾病和癌症的免疫反应 - 将 PERK 作为治疗慢性炎症性疾病、神经退行性疾病和癌症的新策略。

IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Fatma Saaoud , Yifan Lu , Keman Xu , Ying Shao , Domenico Praticò , Roberto I. Vazquez-Padron , Hong Wang , Xiaofeng Yang
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引用次数: 0

摘要

内质网(ER)是一种细胞器,在生理上负责蛋白质折叠、钙平衡和脂质生物合成。氧化应激、缺血、钙平衡失调、正常和/或折叠缺陷蛋白质的生成增加等病理刺激都会导致折叠错误的蛋白质在 ER 中积累,从而引起 ER 应激。对ER压力的适应性反应是激活未折叠蛋白反应(UPR),这种反应会影响多种细胞功能,以维持ER平衡或导致细胞凋亡。三种不同的ER跨膜传感器,包括PKR样ER激酶(PERK)、激活转录因子6(ATF6)和肌醇需要酶-1(IRE1),负责启动UPR。UPR 涉及多种信号转导途径,它们通过增强ER 驻留伴侣、限制蛋白质翻译和加速未折叠蛋白质降解来减少未折叠蛋白质的积累。ER是目前公认的感知危险和决定细胞生死的关键细胞器。另一方面,UPR 在心血管疾病(CVD)、代谢性疾病、慢性肾脏疾病、神经系统疾病和癌症等多种疾病的发生和发展过程中发挥着关键作用。在这里,我们批判性地分析了ER应激主调控作用的最新知识,特别是PERK通路作为条件性危险受体、细胞器串扰调控因子和蛋白质翻译调控因子的作用。我们强调,PERK 不仅是通过感知 UPR 和 ER 应激的 ER 应激调节器,还是肠道微生物群产生的代谢物的前沿传感器和直接感应器。我们的工作还进一步强调了 PERK 作为中心枢纽的功能,它导致代谢重编程和表观遗传修饰,从而进一步增强炎症反应和促进训练有素的免疫力。此外,我们还强调了ER应激和PERK在癌症、心血管疾病、肾脏疾病和神经退行性疾病等多种疾病的发病机制中的作用。最后,我们讨论了ER应激和PERK在癌症治疗中的治疗靶点,以及在心血管疾病、代谢性疾病和神经退行性疾病中潜在的新型治疗靶点。通过开发针对 PERK 和 UPR 的小分子药物来抑制 ER 应激是一种很有前景的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Protein-rich foods, sea foods, and gut microbiota amplify immune responses in chronic diseases and cancers – Targeting PERK as a novel therapeutic strategy for chronic inflammatory diseases, neurodegenerative disorders, and cancer

The endoplasmic reticulum (ER) is a cellular organelle that is physiologically responsible for protein folding, calcium homeostasis, and lipid biosynthesis. Pathological stimuli such as oxidative stress, ischemia, disruptions in calcium homeostasis, and increased production of normal and/or folding-defective proteins all contribute to the accumulation of misfolded proteins in the ER, causing ER stress. The adaptive response to ER stress is the activation of unfolded protein response (UPR), which affect a wide variety of cellular functions to maintain ER homeostasis or lead to apoptosis. Three different ER transmembrane sensors, including PKR-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme-1 (IRE1), are responsible for initiating UPR. The UPR involves a variety of signal transduction pathways that reduce unfolded protein accumulation by boosting ER-resident chaperones, limiting protein translation, and accelerating unfolded protein degradation. ER is now acknowledged as a critical organelle in sensing dangers and determining cell life and death. On the other hand, UPR plays a critical role in the development and progression of several diseases such as cardiovascular diseases (CVD), metabolic disorders, chronic kidney diseases, neurological disorders, and cancer. Here, we critically analyze the most current knowledge of the master regulatory roles of ER stress particularly the PERK pathway as a conditional danger receptor, an organelle crosstalk regulator, and a regulator of protein translation. We highlighted that PERK is not only ER stress regulator by sensing UPR and ER stress but also a frontier sensor and direct senses for gut microbiota-generated metabolites. Our work also further highlighted the function of PERK as a central hub that leads to metabolic reprogramming and epigenetic modification which further enhanced inflammatory response and promoted trained immunity. Moreover, we highlighted the contribution of ER stress and PERK in the pathogenesis of several diseases such as cancer, CVD, kidney diseases, and neurodegenerative disorders. Finally, we discuss the therapeutic target of ER stress and PERK for cancer treatment and the potential novel therapeutic targets for CVD, metabolic disorders, and neurodegenerative disorders. Inhibition of ER stress, by the development of small molecules that target the PERK and UPR, represents a promising therapeutic strategy.

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来源期刊
CiteScore
23.00
自引率
0.70%
发文量
222
审稿时长
90 days
期刊介绍: Pharmacology & Therapeutics, in its 20th year, delivers lucid, critical, and authoritative reviews on current pharmacological topics.Articles, commissioned by the editor, follow specific author instructions.This journal maintains its scientific excellence and ranks among the top 10 most cited journals in pharmacology.
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