枸杞多糖对泡沫细胞泡沫化与胆固醇酯流出的影响及内质网应激作用机制的研究

目的研究枸杞多糖(LBP)对单核细胞源性泡沫细胞泡沫化与胆固醇酯流出的影响及内质网应激的作用机制。方法原代培养单核细胞源性泡沫细胞后,用50、100、200μg.mL-1 LBP孵育72 h,油红O染色法检测泡沫细胞的数量;用荧光分光光度法分析细胞内总胆固醇(TC)、游离胆固醇(FC)和胆固醇酯(CE)的含量;用酶联免疫吸附法检测细胞中氧化低密度脂蛋白(ox-LDL)及内质网应激蛋白(Grp78,CHOP,Xbp-1)的含量。结果 LBP可减少泡沫细胞的形成和细胞内TC、FC、CE的含量,同时可降低细胞内ox-LDL与内质网应激蛋白的含量(P<0.05,P<0.01)。结论 LBP通过降低ox-LDL及内质网应激蛋白的含量引起泡沫细胞内胆固醇的含量下降从而发挥抗动脉粥样硬化的作用。     

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...     

内质网应激与代谢性疾病

内质网是真核细胞内合成代谢的重要场所,细胞内稳态改变可引起内质网应激.适宜的内质网应激有利于细胞内环境的恢复,过度的应激则导致代谢障碍.内质网应激介导的炎症通路及细胞凋亡通路改变与细胞的生长、分化、存活及凋亡有密切联系,在代谢性疾病发生发展过程中起重要作用.维持适当的应激状态,减少过度应激有利于代谢性疾病的恢复,内质网应激为进一步认识和治疗代谢性疾病提供了新的视野和思路.     

中药多糖防治心血管疾病作用机制的研究进展

心血管疾病是危害人们健康的最主要的疾病之一。中药多糖可改善心肌缺血再灌注损伤、心肌梗死、动脉粥样硬化、心肌肥厚等多种心血管疾病，其保护机制为通过激活或抑制核因子-κB、磷脂酰肌醇3-激酶/蛋白激酶B、内质网应激、核因子E2相关因子2等多种信号通路，进而发挥抗氧化应激、抗炎、抗内质网应激、抗细胞凋亡和调节能量代谢紊乱作用来实现对心血管疾病的保护。总结了中药多糖防治心血管疾病的作用机制，以期为预防和治疗心血管疾病提供参考。     

内质网应激介导的肾损伤及干预和保护策略

内质网应激是真核细胞对各种有害刺激的保护性应答机制,可触发以未折叠蛋白反应为核心的相关信号通路,且未折叠蛋白反应在内质网应激初期具有细胞保护作用,但在内质网应激过度(即过强或时间过长)时则会导致细胞程序性死亡。新近研究发现,内质网应激与多种肾毒物引发的肾损伤机制密切相关。本文通过简介内质网应激的相关信号通路及介导的细胞凋亡机制以及其生理病理学意义,并以若干典型肾毒物为例,着重对内质网应激在各类肾毒物引发肾损伤过程中的作用作一综述,探讨对内质网应激介导肾损伤的干预和保护策略。     

TXNIP介导的氧化应激在疾病中的作用机制

硫氧还蛋白相互作用蛋白(TXNIP)通过与硫氧还蛋白(Trx)的结合而抑制Trx的抗氧化作用,促进了活性氧簇(ROS)的产生与积聚,诱发内质网应激与线粒体应激,最终可诱导炎症或细胞凋亡。TXNIP所介导的氧化应激在糖尿病及其并发症(糖尿病肾病、糖尿病视网膜病变等)、动脉粥样硬化、缺血/再灌注损伤、癌症(肝细胞癌、膀胱癌、乳腺癌、白血病)等疾病的发生、发展过程中起着重要的调控作用。该文就TXNIP介导的氧化应激在相关疾病中的作用机制及研究进展进行综述。     

内质网应激在肺动脉高压发病机制中的研究进展

肺动脉高压指肺动脉压力升高超过一定界值的一种血流动力学和病理生理状态,由于肺微血管结构重塑,导致肺血管阻力增加,压力值升高,最终引起右心室衰竭和死亡,但其发生的分子机制尚不清楚。近年来,研究表明内质网应激可能在肺动脉高压的发病机制中起关键作用。本文就内质网应激在肺动脉高压中的作用进行综述,首先回顾内质网应激后未折叠蛋白反应的机制,介绍内质网应激对不同血管细胞的影响,最后讨论减轻内质网应激对肺动脉高压的治疗作用,以期为肺动脉高压的治疗带来新的方向。     

内质网应激与2型糖尿病发病机制的关系

蛋白质的错误折叠可触发细胞内质网应激,适度的内质网应激对细胞有保护作用,而过高或持续的内质网应激则导致细胞凋亡。内质网应激通过促进胰岛细胞凋亡及参与胰岛素抵抗介导了2型糖尿病的发生、发展。     

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.     

C／EBP同源性蛋白对脑细胞的杀伤作用

脑缺血后，某些特定的生物化学事件可以导致神经元变性，出现一系列病理生理改变。由于其机制尚未阐明，现仍为重要的研究课题。脑缺血时，内质网中蛋白的修饰因葡萄糖和氧的供应不足而导致神经元细胞中内质网的应激。C／EBP同源性蛋白(CHOP或GADD153)是一种内质网相关促凋亡蛋白，发挥转录因子的作用，参与调控与生存、死亡相关的基因的表达。但在脑缺血时，CHOP在内质网应激介导的神绎元凋亡中的作用机制还不明确。     

New insights into mechanisms of statin-associated myotoxicity

Statin drugs represent a major improvement in the treatment of hypercholesterolemia that constitutes the main origin of atherosclerosis, leading to coronary heart disease. Besides the tremendous beneficial effects of statins, various forms of muscular toxicity (myalgia, cramp, exercise intolerance, fatigability) occur frequently. Many hypotheses were proposed to explain statin myotoxicity. The goal of this review is to highlight some of the most recent findings that can account for interpreting the pathophysiological mechanisms for statin-induced myotoxicity. Statin-induced myotoxicity appears multifactorial. Apart from the deleterious effect due to a reduction in cholesterol biosynthesis, statins have a direct effect on the respiratory chain of the mitochondria. It is proposed that mitochondrial impairment leads to a mitochondrial calcium leak that directly interferes with the regulation of sarcoplasmic reticulum calcium cycling without excluding a direct effect of statin on the sarcoplasmic reticulum. Both mitochondrial and calcium impairments may account for apoptosis process, oxidative stress, and muscle remodeling and degeneration that have been extensively reported to explain statin myotoxicity and functional symptoms described by treated patients.     

Analysis of endoplasmic reticulum stress in placentas of HIV-infected women treated with protease inhibitors

Combined antiretroviral therapy has proven efficacy in decreasing vertical HIV transmission. However, endoplasmic reticulum stress is a known side effect of HIV protease inhibitors. We investigated endoplasmic reticulum stress in placentas of HIV-infected and uninfected mothers by PCR-based splicing analysis of the specific endoplasmic reticulum stress marker XBP1 in post-delivery placental samples of uninfected mothers and in HIV-infected mothers taking antiretroviral therapy. No elevated XBP1 splicing could be detected in placentas of uninfected mothers and most of the mothers receiving combined anti-retroviral therapy. However, markedly elevated XBP1 splicing was found in the placentas of three individuals on combined antiviral therapy, all receiving lopinavir or atazanavir. In vitro experiments confirmed induction of endoplasmic reticulum stress by lopinavir and atazanavir in trophoblast-derived cell lines. Since endoplasmic reticulum stress occurred in selective patients only, individual differences in susceptibility of HIV-infected mothers to protease inhibitor induced endoplasmic reticulum stress can be postulated.     

Endothelial damage and stem cell repair in atherosclerosis

Atherosclerosis is a slowly progressing and multifactorial disease, in which endothelial dysfunction and damage play an initial role. Many risk factors for atherosclerosis can lead to endothelial damage of the vessel, especially in the areas where blood flow is disturbed. In the presence of hyperlipidemia, disturbed blood flow results in increased endothelial turnover in the arterial wall. It was demonstrated that disturbed blood flow activates endoplasmic reticulum stress initiating a signal pathway leading to endothelial apoptosis. Following endothelial death, the neighboring mature endothelial cells actively proliferate and migrate to heal the wound. However, stem cell repairing may be needed if endothelial damage is severe. As rapid development of stem cell research, it is expected that stem/progenitor cells may serve as a new source for vascular repair. In this review, we aim at examining key elements of endothelial turnover in atherosclerosis, i.e. damage and repair. We will also discuss the mechanisms of the process repaired by mature endothelial as well as stem cells, and highlight recent reciprocal stem cell application, which may provide a new hope to the treatment of severe atherosclerotic complications.     

内质网应激对小鼠卵巢卵泡发育的影响

摘要：目的 探索小鼠卵巢内质网应激对卵泡发育的影响。方法 对照组小鼠4只,实验组小鼠6只,应用经典 内质网应激诱导物衣霉素经腹腔注射诱导小鼠卵巢内质网应激激活,实时荧光定量逆转录聚合酶链反应（RT qPCR）检测未折叠蛋白质应答（UPR）标志分子HSPA5、CHOP、ATF4 mRNA表达情况,明确小鼠卵巢内质网应激激活 状态,苏木精伊红染色（HE染色）检测小鼠卵巢卵泡发育状态,明确内质网应激对小鼠卵巢卵泡发育的影响。结果 衣霉素的处理明显上调了小鼠卵巢内质网应激标志分子的表达,与对照组相比,衣霉素处理组小鼠卵巢卵泡发育明 显受限。结论 内质网应激的激活明显抑制了小鼠卵巢卵泡的发育     

Naltrexone changes the expression of lipid metabolism‐related proteins in the endoplasmic reticulum stress induced hepatic steatosis in mice

Endoplasmic reticulum (ER) stress is closely associated with several chronic diseases such as obesity, atherosclerosis, type 2 diabetes, and hepatic steatosis. Steatosis in hepatocytes may also lead to disorders such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), fibrosis, and possibly cirrhosis. Opioid peptides are involved in triglyceride and cholesterol dysregulation. Naltrexone also attenuates ER stress induced hepatic steatosis in mice. In this study, we evaluated the effects of naltrexone on the expression of lipid metabolism‐related nuclear factors and enzymes in the ER stress induced hepatic steatosis. C57/BL6 mice received saline, DMSO and naltrexone as control groups. In a fourth group, ER stress was induced by tunicamycin (TM) injection and in the last group, naltrexone was given before TM administration. Histopathological evaluations, real‐time RT‐PCR and western blot were performed. We found that GRP78, IRE1α, PERK and ATF6 gene expression and steatosis significantly reduced in naltrexone treated animals. Naltrexone alleviated the gene and protein expression of SREBP1c. Expression of ACAT1, apolipoprotein B (ApoB) and PPARα also increased after naltrexone treatment. In conclusion, this study, for the first time, shows that naltrexone has a considerable role in attenuation of ER stress‐induced liver injury.     

Cytoprotection following endoplasmic reticulum stress protein induction in continuous cell lines

Prior induction of an endoplasmic reticulum stress response has been associated with an increased tolerance to cellular toxins in in vitro systems, primarily involving renal and neuronal cells. Reactive intermediates are involved in toxicity in many tissues, therefore, we wished to determine if cytoprotection after induction of an endoplasmic reticulum stress response was a general phenomenon in other cell types. A stress response was induced by tunicamycin in a human hepatocyte cell line (HepG2), a rat hepatocyte cell line (H4IIE), a porcine kidney cell line (LLC-PK1), and a human lymphocyte cell line (K562). Induction of the endoplasmic reticulum stress proteins GRP78, GRP94, calreticulin and protein disulfide isomerase was assessed by immunoblotting. Cytotoxicity was assessed 24 hr after a 3 hr exposure to iodoacetamide, tert-butylhydrogenperoxide, menadione, or sulfamethoxazole hydroxylamine, or after a 2 hr exposure to N-acetyl-p-benzoquinoneimine, the reactive metabolite of acetaminophen. Induction of endoplasmic reticulum stress proteins in LLC-PK1 cells resulted in a 2-6 times increase in the concentration of all the cytotoxins required to cause a 50% decrease in cell viability at 24 hr. In contrast, tunicamycin pretreatment only resulted in a 1.7-times increase for iodo-acetamide in HepG2 cells and a 2.2-times increase for N-acetyl-p-benzoquinoneimine in the H4IIE cells, but had no effect on the other toxins tested. Induction of endoplasmic reticulum stress proteins in K562 cells did not alter susceptibility to any toxins tested. Our results indicate that protection afforded by the induction of an endoplasmic reticulum stress response is dependent on the cell type and may be toxin specific. These results suggest that either the molecular pathways of cell death for individual toxins are different between cell types and toxins, or that the function of endoplasmic reticulum stress proteins are dependent on the cell type.     

T 淋巴细胞在OSAS 促动脉粥样硬化中作用的研究进展

摘要： 阻塞性睡眠呼吸暂停综合征 （OSAS） 是促进动脉粥样硬化的独立危险因素, OSAS 可诱导系统炎症、 氧化应激及血管内皮细胞的功能障碍等, 进而导致动脉粥样硬化的发生与进展。氧化应激和系统炎症能够激活 T 淋巴细胞, 增加淋巴细胞对血管内皮细胞的毒性, 加速炎症/免疫反应, 参与动脉粥样硬化的进展。免疫系统的激活是炎症/ 免疫反应导致动脉粥样硬化的早期步骤, 本文以 T 淋巴细胞为例, 综述 OSAS 促进动脉粥样硬化发生发展的淋巴细胞基础与机制。     

β受体阻滞剂对乳鼠心肌细胞内质网应激致凋亡途径的影响

目的通过体外培养乳鼠心肌细胞,探讨β受体阻滞剂对乳鼠心肌细胞凋亡率及内质网应激作用的影响。方法培养乳鼠心肌细胞,确定β受体阻滞剂的饱和浓度,原代培养乳鼠心肌细胞72h后给予β受体阻滞剂溶液和衣霉素溶液干预,实验分4组:空白对照组、50μg/ml美托洛尔组、10μg/ml衣霉素组、10μg/ml衣霉素+50μg/ml美托洛尔组。确定美托洛尔的饱和浓度;反转录-聚合酶链反应(RT-PCR)检测各组内质网应激指标GRP78、内质网应激致凋亡指标Caspase12,流式细胞术检测实验各组乳鼠心肌细胞凋亡率,确定美托洛尔对内质网应激致凋亡途径的影响作用。结果①美托洛尔的浓度为50μg/ml时,对内质网应激的影响已达最大。②与空白对照组比较,50μg/ml美托洛尔组心肌细胞内质网应激致凋亡指标Caspase12表达及心肌细胞凋亡率差异无统计学意义(P>0.05)。10μg/ml衣霉素组、50μg/ml美托洛尔+10μg/ml衣霉素组心肌细胞内质网应激致凋亡指标Caspase12及心肌细胞凋亡率较空白对照组均明显增加(均P<0.05),且在衣霉素组时心肌细胞中内质网应激致凋亡指标Caspase12及心肌细胞凋亡率均最高,而50μg/ml美托洛尔+10μg/ml衣霉素组与10μg/ml衣霉素组比较,心肌细胞内质网应激致凋亡指标Casepase12及心肌细胞凋亡率降低,差异有统计学意义(均P<0.05)。结论美托洛尔浓度在50μg/ml时为内质网应激保护的饱和浓度,β受体阻滞剂可以减轻内质网应激所致的凋亡途径。