胰岛β细胞中调控内质网应激信号通路的新机制

《科学·信号转导》杂志发表了中国科学院上海生命科学研究院营养科学研究所刘勇研究组的最新研究成果,揭示了脚手架蛋白RACKI以分子开关的方式,在胰岛β细胞中内质网应激信号通路的动态调控中发挥关键作用。     

胰岛β细胞功能评价

β细胞功能异常是糖尿病发病中心环节之一,通过分泌模式和数量两方面来评价其功能具有重要意义。本文总结了常用的β细胞功能评价方法及其典型特点,以期通过分析它们之间的优缺点来选择最符合要求的临床评估方法。     

内质网应激在纳米材料毒性效应中的作用研究进展

活性氧生成和氧化应激是纳米材料引发细胞毒性的主要作用机制之一。内质网作为细胞内蛋白质合成、加工以及钙储存的重要场所,对细胞应激十分敏感并参与氧化应激诱导的细胞损伤。氧化应激、钙稳态失衡等可诱导内质网应激(ERS),激活未折叠蛋白反应,从而促进细胞内稳态的恢复。但持续或严重的ERS可触发细胞凋亡信号通路,导致细胞死亡。已有研究表明,ERS是纳米材料毒性效应的早期、敏感指标。这一发现为纳米材料毒作用机制研究提供了新角度。此外,纳米材料诱导ERS的水平与颗粒理化性质、作用模式、细胞类型等有关。本文对ERS在纳米材料毒性效应中的作用及其机制进行简要综述。     

细胞凋亡与内质网应激机制

内质网应激介导的细胞凋亡是一种新的凋亡途径,不同于死亡受体信号途径和线粒体途径.短期的内质网应激有保护细胞的作用,但是长期的内质网应激将激活一些凋亡信号分子如CHOP、JNK、Caspase,而诱导细胞凋亡.     

肥胖者胰岛β细胞功能和质量的研究进展

肥胖是糖尿病发生、发展的主要驱动因素。目前有研究报道肥胖者胰岛β细胞质量增加、功能增强,在肥胖的持续状态下,胰岛β细胞功能由增强、代偿高分泌,直至胰岛β细胞功能失代偿、逐渐减弱以及血糖增高、体重减轻、β细胞逐步凋亡。在这些变化中糖毒性、脂毒性、氧化应激、巨噬细胞自噬等多种机制参与其中。本文从肥胖人群胰岛β细胞功能、质量特征变化以及其涉及的相关病理生理改变及机制等几个方面进行归纳与综述。     

高尿酸对胰岛β细胞生存与功能的影响

目的 探讨高尿酸对胰岛β细胞生存及功能的影响.方法 采用免疫荧光染色方法检测正常小鼠(A组)和高尿酸小鼠(B组)胰岛形态及胰岛素水平变化.采用CCK-8方法观察尿酸浓度为0 mg/dl(C组)、5 mg/dl(D组)和15 mg/dl(E组)大鼠胰岛细胞系INS-1细胞活力.采用ELISA法检测尿酸浓度为0 mg/dl(F组)、15 mg/dl(G组)小鼠分离的胰岛胰岛素分泌量及储藏量变化.结果 与A组比较,B组小鼠胰岛面积明显缩小,胰岛素水平降低(P＜0.05).与C组比较,D组、E组INS-1细胞活力呈剂量依赖性显著降低(P＜0.05).与F组比较,G组细胞胰岛素的分泌水平和储存水平均显著降低(P＜0.05和P＜0.01).结论 尿酸对胰岛β细胞有直接损伤作用.     

内质网应激在肾脏疾病中的作用

内质网是存在于细胞质中的一种充满囊泡和管腔的连续性网膜状细胞器,是分泌型或结构型蛋白质进行合成、正确折叠组装、修饰的主要场所,负责合成大部分分泌性蛋白质,同时也是脂类合成及Ca2＋储存的重要场所。在病理情况下,如缺血缺氧、能量不足、糖代谢紊乱、氧化还原反应及Ca2＋浓度失衡时,以及蛋白质合成分泌增加或折叠、     

胰岛β细胞葡萄糖毒性分子机制的研究进展

慢性高糖可损伤胰岛β细胞,这被称为“葡萄糖毒性”。胰岛β细胞葡萄糖毒性涉及多种机制包括氧化应激、内质网应激、线粒体功能失调、炎症、糖基化终末产物形成、低氧状态与低氧诱导因子激活、胰岛β细胞分化表型丧失,等等。目前认为,氧化应激、内质网应激和胰岛β细胞分化表型的丧失在胰岛β细胞葡萄糖毒性中的作用较为明确;其中氧化应激在糖尿病胰岛β细胞葡萄糖毒性中发挥中心性作用。     

内质网应激在心室重构中作用的研究进展

内质网是真核细胞的重要细胞器,是蛋白折叠与成熟的加工厂。内质网应激是细胞针对错误折叠或未折叠蛋白质的一种适应性机制,但持续或过强的内质网应激则诱导细胞凋亡与自噬失衡,造成组织损伤。研究显示内质网应激是冠状动脉粥样硬化性心脏病、缺血性心脏病、心力衰竭及糖尿病心肌病等心血管疾病发生、发展的共同通路,可诱导心肌细胞肥大、纤维化、凋亡,致使心室重构的发生。故调控内质网应激可能成为预防心室重构进而治疗相关心血管疾病的新靶点。     

Endoplasmic reticulum stress and metallothionein

Much attention has been paid to lifestyle-related diseases including type 2 diabetes mellitus, cardiovascular disease, hypertension, and hyperlipidemia because the incidence rates of these diseases are increasing in developed countries. Elucidation of factors contributing to the development of obesity and insulin resistance is needed. Metallothionein (MT), a ubiquitous metal-binding protein, is induced not only by heavy metals but also by various kinds of stresses. Endoplasmic reticulum (ER) stress is caused by accumulation of misfolded proteins in ER. Recently, increased ER stress by obesity and impairment of insulin action by ER stress have been reported. Exposure to ER stress increased induction of MT synthesis, and an enhanced response to ER stress evaluated as expression of Bip/GRP78mRNA was observed in the liver of MT-null mice, suggesting that MT attenuates expression of ER stress. MT may prevent ER stress and thereby modulate the development of obesity and insulin resistance. A possible role of metallothionein in response reaction for ER stress is discussed.     

内质网应激与动脉粥样硬化

在动脉粥样硬化的病理机制的研究中,内质网应激的作用越来越受到关注。本文拟就内质网应激与动脉粥样硬化的关系作一综述。内质网应激通过在炎症反应、脂质代谢异常、细胞凋亡中起的潜在作用,可能参与动脉粥样硬化发生和发展的机理。同时,血浆高半胱氨酸、高血糖等独立危险因子与内质网应激过程相互作用而诱导动脉粥样硬化。     

Endoplasmic reticulum stress in murine liver and kidney exposed to microcystin-LR

To investigate the effect of microcystin-LR (MC-LR) on apoptosis based on the endoplasmic reticulum stress (ERS) pathway in mouse liver and kidney, male ICR mice were intraperitoneally injected with 20 μg kg⁻¹ body weight MC-LR for 21 days, and mRNA and protein levels of ERS special molecules in liver and kidney were analyzed using quantitative real-time PCR and western blotting. MC-LR significantly improved mRNA and protein expression of C/EBP homologous protein (CHOP) and cleaved caspase-12 in liver, whereas it inhibited expression of CHOP and caspase-12 in kidney. MC-LR also induced significant down-regulation of B-cell lymphoma/leukemia-2 (Bcl-2) mRNA expression in liver and weak up-regulation in kidney. These results indicated the involvement of the ERS pathway in MC-LR-induced apoptosis of hepatic cells but not in renal cells of mice. The weight changes and histological damage of liver and kidney were in accordance with the appearance of ERS. Our results indicate that ERS plays an important role in hepatic cell apoptosis induced by MC-LR, and is considered as a new pathway of liver toxicity. Its relative special genes might be considered as potentially new biomarkers used for risk assessment of MC-LR in the environment.     

内质网应激及其介导的凋亡在锰致神经毒性中的作用

目的探讨内质网应激(ERS)及其介导的细胞凋亡在锰引起的神经毒性中的作用。方法以人神经母细胞瘤SH-SY5Y细胞为细胞模型,通过MTT比色法检测MnCl2对细胞存活的影响,流式细胞技术(FCM)检测MnCl2对细胞凋亡的影响,Western blot检测MnCl2作用后,细胞ERS分子伴侣BiP、Sigma-1受体(Sig-1R)、CHOP及凋亡相关蛋白Caspase-4表达的变化。结果 MnCl2可呈时间、剂量依赖性地降低细胞存活率,并诱导SH-SY5Y细胞凋亡;MnCl2上调ERS分子伴侣Bip、Sig-1R、CHOP及Caspase-4的表达。结论 MnCl2可诱导SH-SY5Y细胞发生ERS,早期的ERS对细胞具有保护性效应,持续的ERS通过上调CHOP和Cappase 12的表达介导细胞凋亡,这可能是锰神经毒性机制之一。     

Mitochondrial dysfunction in diabetes mellitus

This review discusses the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of the most common form of diabetes, type II diabetes mellitus. Mitochondrial mutations have been linked to the development of diabetes mellitus as part of several rare syndromes, accounting for approximately 1.5% of all cases of the disease (“classic” mitochondrial diabetes). The characteristics of classic mitochondrial diabetes are intermediate between those of type I and type II diabetes, more closely resembling the latter. By studying the biochemical, cellular, and physiologic consequences of mitochondrial DNA mutations that cause classic mitochondrial diabetes, we may also gain important insights into the pathogenesis of type II diabetes mellitus. Individuals with classic mitochondrial diabetes exhibit a variety of defects in mitochondrial electron transfer enzyme activities. Complex I and Complex IV activities in skeletal muscle are almost universally decreased in mitochondrial diabetics compared with control individuals. The major physiologic abnormality in classic mitochondrial diabetes is delayed and insufficient insulin secretion in response to a glucose load. Insulin resistance is less commonly observed in these patients. The link between mitochondrial function and insulin secretion is supported by cellular studies in which introduction of inhibitors of oxidative phosphorylation or depletion of mitochondrial DNA markedly impairs glucose mediated insulin secretion from pancreatic β‐cells. Evidence for mitochondrial dysfunction in the common form of type II diabetes includes excessive free radical levels in the plasma of diabetics, increased reactive oxygen species, and decreased ATP synthase activity in cybrids constructed from mitochondria of diabetic patients, and maternal inheritance of the disease. By using the occurrence of diabetes in rare mitochondrial syndromes as an example, evidence supporting a relationship between mitochondrial dysfunction and the common form of type II diabetes is discussed. Mitochondrial function may represent a novel area for the development of therapeutic and diagnostic strategies for type II diabetes mellitus. Drug Dev. Res. 46:67–79, 1999. © 1999 Wiley‐Liss, Inc.     

Endoplasmic reticulum stress inhibition enhances liver tolerance to ischemia/reperfusion

In many physiopathological conditions, the cell controls its proper dysfunction via activation of the unfolded protein response to restore efficient protein synthesis and folding in the endoplasmic reticulum. However, whether the aim of unfolded protein response is to promote the cell survival, it can also lead to induction of cell death and then affect the cell fate. Recently, endoplasmic reticulum stress appeared to be critical for acute as well as chronic diseases including neurodegeneration, cardiac disease, cancer, obesity, type 2 diabetes, and ischemia/reperfusion injury. Therefore, inhibition of the endoplasmic reticulum stress could constitute a promising therapeutic strategy to limit cellular damage in pathologies such as hepatic ischemia/reperfusion.     

内质网应激与肝脏损伤的治疗

内质网应激是一种细胞自我保护性机制的信号反应通路系统,参与许多疾病的生理病理过程.内质网应激参与多种肝脏损伤的发生与发展,包括免疫性肝损伤、病毒性肝损伤、中毒性肝损伤、脂肪性肝损伤等.以内质网应激为切入点,深入探讨内质网应激的分子机制、作用功能,以及内质网应激与各种肝损伤之间的关系.结合临床药物的作用机制,内质网应激可...     

Endoplasmic reticulum stress as a novel therapeutic target in heart diseases

The endoplasmic reticulum (ER) is a multifunctional organelle responsible for the synthesis and folding of proteins as well as calcium storage and signaling. Perturbations of ER function cause ER stress leading to the unfolded protein response (UPR), which includes inhibition of protein synthesis, protein refolding and clearance of misfolded proteins. The UPR aims at restoring cellular homeostasis, however, prolonged ER stress can trigger apoptosis. ER stress-induced apoptosis has been implicated in the pathogenesis of various diseases such as brain ischemia/reperfusion, neurodegeneration, diabetes and, most recently, myocardial infarction and heart failure. Initial events leading to UPR and apoptosis in the heart include protein oxidation and disturbed calcium handling upon ischemia/reperfusion, and forced protein synthesis during cardiac hypertrophy. While XBP-1 and ATF6-mediated induction of ER chaperones seems to protect the heart from ischemia/reperfusion injury, the PERK/ATF4/CHOP branch of the UPR might transmit proapoptotic signals. The precise mechanism of ER stress-induced cardiomyocyte apoptosis remains elusive, however, recent data suggest that the mitochondrial apoptotic machinery is recruited through the upregulation of Puma, a proapoptotic member of the Bcl-2 family. Importantly, suppression of Puma activity prevented both ER stress and ischemia/reperfusion-induced cardiomyocyte loss, highlighting the ER stress pathways as potential therapeutic targets in cardiovascular diseases.