沉默信息调节因子3在神经退行性疾病中的作用CSCD

沉默信息调节因子3(silent information regulator 3,SIRT3)是一种NAD+依赖性Ⅲ类组蛋白去乙酰化酶,在代谢活跃的组织中高表达,如肾脏、心肌、棕色脂肪、脑等。越来越多的研究表明,SIRT3通过对组蛋白以及多种非组蛋白的去乙酰化,在能量代谢、肿瘤、衰老等过程中起到了重要作用。近年研究发现,在神经退行性疾病中,SIRT3激活可以减缓或者抑制线粒体功能障碍,从而表现出了明显的神经保护作用。本文对SIRT3在神经退行性疾病中的保护作用及其可能机制作一综述。     

沉默信息调节因子3在神经退行性疾病中的作用

沉默信息调节因子3(silent information regulator 3,SIRT3)是一种NAD+依赖性Ⅲ类组蛋白去乙酰化酶,在代谢活跃的组织中高表达,如肾脏、心肌、棕色脂肪、脑等。越来越多的研究表明,SIRT3通过对组蛋白以及多种非组蛋白的去乙酰化,在能量代谢、肿瘤、衰老等过程中起到了重要作用。近年研究发现,在神经退行性疾病中,SIRT3激活可以减缓或者抑制线粒体功能障碍,从而表现出了明显的神经保护作用。本文对SIRT3在神经退行性疾病中的保护作用及其可能机制作一综述。     

靶向调控SIRT1与阿尔茨海默病治疗

沉默信息调节因子1 (silent information regulator 1, SIRT1)是哺乳动物NAD+依赖的去乙酰化酶沉默信息调节因子(sirtuin)家族的七种蛋白质之一。SIRT1具有神经保护作用,且研究揭示SIRT1在阿尔茨海默病(Alzheimer’s disease, AD)中具有潜在神经保护作用。SIRT1调节许多AD相关病理过程,包括调节淀粉样蛋白前体蛋白(amyloid-β precursor protein, APP)剪切、神经炎症、神经退行性变和线粒体功能障碍等。SIRT1在AD中受到了特别的关注,药理学或遗传学手段激活sirtuin通路在AD实验模型中显示出治疗作用。本综述阐述了SIRT1在AD中的病理作用机制最新研究进展,并对SIRT1诱导剂及其在AD中的治疗潜力进行了概述。     

沉默信息调节因子1在阿尔茨海默病中的神经保护作用

沉默信息调节因子1(silent information regulator1,SIRT1)作为NAD+依赖的脱乙酰基酶,参与基因转录、能量代谢以及细胞衰老过程的调节。近年研究显示,SIRT1具有明显的神经保护作用。但SIRT1在阿尔茨海默病(Alzheimer’s disease,AD)中如何发挥对神经元的调节及保护作用仍不甚明了。本文结合近年的研究,重点总结了SIRT1在AD中的神经保护作用及其可能的分子机制,为防治神经退行性疾病提供新思路。     

沉默信息调节因子2同源蛋白1通过Akt/PKB通路抑制人退变椎间盘髓核细胞凋亡

沉默信息调节因子2同源蛋白1(silent mating type information regulation 2 homolog 1, SIRT1/sirtuin 1)是组蛋白去乙酰化酶,参与表观遗传修饰调节,促进多种细胞的生存,但目前对椎间盘髓核细胞的作用未见研究．为了阐明临床不同来源的椎间盘髓核手术标本SIRT1的表达变化,用免疫组化、定量RT-PCR、Western blot方法对中老年腰椎间盘突出症病人及青壮年腰椎骨折病人术中髓核标本进行研究,表明老年人髓核SIRT1的mRNA及蛋白质水平均显著低于青壮年的髓核．同时,用resveratrol(SIRT1激动剂)、烟碱(SIRT1抑制剂)、SIRT1-siRNA对培养的退变髓核细胞进行处理或转染后,用流式细胞仪检测凋亡率变化,结果表明resveratrol能显著促进退变髓核细胞生存,相反,当烟碱或SIRT1-siRNA转染后则显著促进髓核细胞凋亡．为了进一步分析SIRT1抑制退变髓核细胞凋亡的分子机制,应用Western blot及抑制剂方法研究表明,当SIRT1-siRNA转染髓核细胞后能降低磷酸化Akt蛋白的表达,而白藜芦醇处理则促进磷酸化Akt蛋白的表达,当用LY294002(PI3K抑制剂)或Akt-siRNA转染后显著抑制髓核细胞的生存率．研究结果表明,SIRT1通过Akt通路能显著抑制髓核细胞凋亡,为深入揭示退变性椎间盘疾病的病理生理及生物治疗提供新的思路和靶点．     

翻译后修饰调节SIRT1生物学功能

SIRT1(silent mating type information regulation 2 homolog)是哺乳动物中与酵母菌沉默信息调节因子2(silent information regulator 2,Sir2)同源性最高的同系物。它通过去乙酰化作用调节基因转录、染色体稳定性及靶蛋白活性,参与调节DNA损伤修复、糖脂代谢、抑制炎症及氧化应激等病理生理过程。SIRT1作为重要的蛋白去乙酰化酶,深入了解其翻译后化学修饰及生物学功能具有重要意义。     

SIRT3在心血管疾病中的作用

沉默信息调节因子2相关酶类3(silent mating type information regulation2 homolog-3,SIRT3)是一种依赖于烟酰胺腺嘌呤二核苷酸(nicotinamide-adenine dinucleotide,NAD)的III类去乙酰化酶。SIRT3主要定位于线粒体,广泛分布于肾脏、脑、心脏及肝脏等富含线粒体的组织器官中,其可对组蛋白和非组蛋白去乙酰化在调控细胞代谢、细胞周期、细胞凋亡及细胞寿命方面起着重要的作用。SIRT3通过去乙酰化相关靶蛋白调节其生物活性,在抵抗氧化应激反应,改善血管内皮细胞功能等多种心血管疾病中,都起到了保护性作用。该文旨在对SIRT3在常见的心血管疾病中的作用的研究进展进行综述。     

白藜芦醇对高糖刺激下人肾小管上皮细胞发生EMT的作用

该文研究了白藜芦醇及其下游信号分子沉默信息调节因子1(silent information regulator 1,SIRT1)对高糖培养条件下人肾小管上皮细胞(HK-2)转化的作用和机制。体外常规培养HK-2细胞,采用Western blot检测平滑肌肌动蛋白(α-SMA)、E-钙黏着蛋白(E-cadherin)及信号蛋白SIRT1、过氧化物酶体增殖物激活受体γ协同刺激因子-1α(peroxisome proliferator-activated receptor gamma coactivator-1α,PGC-1α)的蛋白表达,采用细胞免疫荧光对SIRT1的表达进行检测。与高糖刺激0 h组相比,高糖刺激12,24,48 h均导致HK-2细胞SIRT1蛋白明显减少,且随时间呈下降趋势;低糖培养细胞0,12,24,48 h的SIRT1蛋白表达没有明显差异。白藜芦醇明显提高高糖培养条件下HK-2细胞的SIRT1表达,而SIRT1特异性抑制剂EX527能够减弱白藜芦醇的作用。进一步的研究表明,白藜芦醇能够明显增加HK-2细胞中E-钙黏着蛋白的表达,抑制高糖导致的α-SMA表达升高,而EX527对高糖诱导的HK-2细胞转分化没有显著影响。此外,研究发现,白藜芦醇能够明显增加高糖刺激下HK-2细胞PGC-1α蛋白表达。该研究结果提示,白藜芦醇可能通过SIRT1和PGC-1α信号通路抑制了高糖诱导的HK-2细胞转化过程。     

运动提高沉默信息调节因子2相关酶1改善阿尔兹海默症

阿尔兹海默症(Alzheimer's disease, AD)是一种神经退行性疾病,β-淀粉样蛋白(β-amyloid, Aβ)沉积和Tau蛋白过度磷酸化是其主要病理特征。沉默信息调节因子2相关酶1 (silent mating-type information regulation 2 homolog 1, SIRT1)具有去乙酰化作用,能够使多种类型组蛋白及非组蛋白脱乙酰化,在AD发病过程中占据重要地位。近年研究发现,运动能够激活SIRT1减缓AD进程,其机制可能是:抑制β-分泌酶活性、提高α-分泌酶活性,减少Aβ生成;减少过度磷酸化Tau蛋白集聚;与过氧化体增殖物激活型受体γ辅激活因子-1α(peroxisome proliferator-activated receptor γ coactivator-1α,PGC-1α)相互作用以促进线粒体生物发生;上调同源性磷酸酶张力蛋白诱导激酶1(phosphatase and tensin homolog induced putative kinase1,PINK1)/Parkin信号通路改善线粒体自噬;去乙酰化核转录因子-κB(nuclear factor kappa B, NF-κB)以抑制神经炎症;提高海马中脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)、神经胶质源性营养因子(glial cellline-derived neurotrophic factor,GDNF)等营养因子的蛋白质水平,以及抑制ApoE4基因进而增强神经元突触可塑性。本文总结了运动通过调控SIRT1改善AD的作用和机制,为预防及治疗AD提供新的思路。     

SIRT1在宫颈癌细胞耐药中的作用及其机制研究

摘要目的：探讨沉默交配型信息调节因子2同源蛋白1（silentmatingtypeinformationregulation2homologyl,SIRTl）在宫颈癌化疗耐药中的作用及其机制。方法：体外培养人宫颈癌Hela细胞系和宫颈癌Hela／MMC耐药细胞亚系,westernblotting检测MMC对Hela和Hela／MMC细胞内SIRTl蛋白表达的影响;MTT法检测MMC及Nicotinamide对Hela和Hela／MMC细胞增殖的影响;AnnexinV-PI试验检测Hela／MMC细胞凋亡的亡的情况;RT—PCR方法检测耐药相关蛋白P—gP的mRNA表达情况。结果：正常情况下,Hela／MMC细胞中SIRTl的表达显著高于Hela细胞（P〈0．05）,MMC处理的Hela／MMC细胞中SIRTl的表达显著高于未经MMC处理（P〈0．05）。Nicotinamide对Hela和Hela／MMC细胞具有相似的生长抑制作用,Nicotinamide可使MMC诱导的Hela／MMC细胞凋亡增加,同时降低细胞内P-gP的mRNA表达（P〈0．05）。结论：SIRTl表达下调能显著减轻Hela／MMC细胞对MMC的耐药性,其作用可能与P—gp有关。     

AMPK/SIRT1/PPARγ/PGC1α轴及其相关因子在骨关节炎脂质代谢中的作用

骨关节炎（osteoarthritis,OA）是一种退行性关节疾病,以软骨变性、骨硬化和慢性滑膜炎症为主要临床特征。在骨关节炎病理改变中,脂质代谢异常与软骨、骨的退行性改变密切相关。AMP活化的蛋白激酶（adenosine monophosphate?activated protein kinase,AMPK）活化后,可通过调节脂肪酸合成的关键酶,如肉碱脂酰转移酶（carnitine palmitoyltransferase 1,CPT?1）、链酰基辅酶A脱氢酶（medium chain acyl?CoA dehydrogenase,MCAD）和软骨细胞自噬功能,进而调节软骨细胞脂质代谢,以延缓OA的发展。过氧化物酶体增殖物激活受体γ（peroxisomal proliferator?activated receptor γ,PPARγ）和过氧化物酶体增殖物激活受体γ共激活因子1α（peroxisomal proliferator?activated receptor γ coactivator 1α,PGC?1α）也具有相似的生理功能。AMPK与沉默信息调节因子1（silencing information regulator 1,SIRT1）的激活及相互作用能介导PPARγ、PGC?1α的信号转导及生理功能。综述了AMPK/SIRT1/PPARγ/PGC1α轴在OA发病机制中的作用的最新进展,以期为OA的治疗及预防研究提供参考。     

SIRT2 interferes with autophagy-mediated degradation of protein aggregates in neuronal cells under proteasome inhibition

Abnormal protein aggregates have been suggested as a common pathogenesis of many neurodegenerative diseases. Two well-known protein degradation pathways are responsible for protein homeostasis by balancing protein biosynthesis and degradative processes: the ubiquitin–proteasome system (UPS) and autophagy-lysosomal system. UPS serves as the primary route for degradation of short-lived proteins, but large-size protein aggregates cannot be degraded by UPS. Autophagy is a unique cellular process that facilitates degradation of bulky protein aggregates by lysosome. Recent studies have demonstrated that autophagy plays a crucial role in the pathogenesis of neurodegenerative diseases characterized by abnormal protein accumulation, suggesting that regulation of autophagy may be a valuable therapeutic strategy for the treatment of various neurodegenerative diseases. Sirtuin-2 (SIRT2) is a class III histone deacetylase that is expressed abundantly in aging brain tissue. Here, we report that SIRT2 increases protein accumulation in murine cholinergic SN56 cells and human neuroblastoma SH-SY5Y cells under proteasome inhibition. Overexpression of SIRT2 inhibits lysosome-mediated autophagic turnover by interfering with aggresome formation and also makes cells more vulnerable to accumulated protein-mediated cytotoxicity by MG132 and amyloid beta. Moreover, MG132-induced accumulation of ubiquitinated proteins and p62 as well as cytotoxicity are attenuated in siRNA-mediated SIRT2-silencing cells. Taken together, these results suggest that regulation of SIRT2 could be a good therapeutic target for a range of neurodegenerative diseases by regulating autophagic flux.     

Sirtuin 1 overexpression mice show a reference memory deficit, but not neuroprotection

Sirtuin 1 (SIRT1) is the closest mammalian homologue of yeast silent information regulator 2 (Sir2) and has a role in lifespan modulation. Reportedly, SIRT1 is also linked to neurodegenerative diseases. However, there are limited studies that report the relation between SIRT1 and neurodegenerative diseases using in vivo transgenic (Tg) methods. In the present study, we generated neuron-specific enolase (NSE) SIRT1 Tg mice that overexpress human SIRT1 in neurons. We examined possible neuroprotective effects of SIRT1 overexpression and compared their higher brain functions with those of wild-type (WT) mice. Overexpression of SIRT1 did not have any neuroprotective effects against the neuronal damage induced by ischemia or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, SIRT1 Tg mice exhibited a reference memory deficit. These findings suggest that an excessive expression of SIRT1 might induce the memory deficit in mice, but not neuroprotective effects.     

Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models

The NAD⁺-dependent protein deacetylase sirtuin 1 (SIRT1), a member of the sirtuin family, may have a neuroprotective effect in multiple neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Many studies have suggested that overexpression-induced or resveratrol-treated activation of SIRT1 could significantly ameliorate several neurodegenerative diseases in mouse models. However, the type of SIRT1, protein expression levels and underlying mechanisms remain unclear, especially in PD. In this study, the results demonstrated that SIRT1 knockout markedly worsened the movement function in MPTP-lesioned animal model of PD. SIRT1 expression was found to be markedly decreased not only in environmental factor PD models, neurotoxin MPP⁺-treated primary culture neurons and MPTP-induced mice but also in genetic factor PD models, overexpressed α-synuclein-A30PA53T SH-SY5Y stable cell line and hm²α-SYN-39 transgenic mouse strain. Importantly, the degradation of SIRT1 during MPP⁺ treatment was mediated by the ubiquitin-proteasome pathway. Furthermore, the results indicated that cyclin-dependent kinase 5 (Cdk5) was also involved in the decrease of SIRT1 expression, which could be efficiently blocked by the inhibition of Cdk5. In conclusion, our findings revealed that the Cdk5-dependent ubiquitin-proteasome pathway mediated degradation of SIRT1 plays a vital role in the progression of PD.     

Neurodegeneration-associated TDP-43 interacts with fragile X mental retardation protein (FMRP)/Staufen (STAU1) and regulates SIRT1 expression in neuronal cells

Despite the identification of the 43 kDa transactive response DNA-binding protein (TDP-43) as a major pathological signatory protein in a wide range of neurodegenerative diseases, the mechanistic role of TDP-43 in neurodegenerative disorders is still poorly understood. Here, we report that TDP-43 is physically associated with fragile X mental retardation protein (FMRP) and Staufen (STAU1) to form a functional complex. Differential microarray analysis revealed that the expression of a collection of functionally important genes including Sirtuin (SIRT1) is regulated by this complex. RNA-immunoprecipitation (RIP) and RNA pull-down assays demonstrated that TDP-43/FMRP/STAU1 specifically binds to the 3'-UTR of SIRT1 mRNA, and that knockdown the expression of any one of these three proteins resulted in the reduction of SIRT1 mRNA and protein. SIRT1 is implicated in double-stranded DNA break repair and is required for cell survival. Indeed, depletion of TDP-43/FMRP/STAU1 sensitizes cells to apoptosis and DNA damages. Collectively, our results revealed a molecular mechanism for the cellular function of TDP-43 and might shed new light on the understanding of the mechanistic role of TDP-43 in neurodegenerative diseases.     

Sirtuin1:抗炎治疗新靶点

Sirtuin 1(SIRT1)是组蛋白去乙酰化酶的代表性成员,除可调节代谢、衰老、凋亡外,SIRT1还可通过催化组蛋白及核因子κB(NF-κB)、激活蛋白1(AP-1)等的去乙酰化,从而改变染色质构象、降低转录因子活性、下调炎症基因转录。临床研究已揭示SIRT1在某些炎症性疾病中含量明显降低,而动物实验证实白藜芦醇、SRT1720等SIRT1激活剂可有效减轻炎症损伤。因而,SIRT1有望成为抗炎治疗的新靶点。