视神经蛋白突变在肌萎缩侧索硬化症中的研究进展

视神经蛋白(OPTN)目前被认为是原发性开角型青光眼(POAG),肌萎缩侧索硬化症(ALS)等神经退行性疾病的病理学标记蛋白。OPTN参与不同的细胞功能,例如调控后高尔基体膜运输、分泌、胞内病原体自噬、抗病毒先天免疫反应、有丝分裂、核因子-κB(NF-κB)通路、基因表达等。在OPTN突变的ALS临床病例中,受损的运动神经元呈现出胞质内OPTN泛素化聚集改变,蛋白质包涵体形成以及与ALS相关病理蛋白铜锌超氧化物歧化酶1(SOD1)、反式激活-反应性DNA结合蛋白-43(TDP43)、肉瘤熔合基因(FUS)的共定位。本文着重阐述OPTN突变在肌萎缩侧索硬化症中的研究进展,探讨其致病机制、病理改变以及治疗方法。     

骨形成蛋白与神经生长发育的研究进展

骨形成蛋白（ｂｏｎｅｍｏｒｐｈｏｇｅｎｅｔｉｃｐｒｏｔｅｉｎｓ,ＢＭＰｓ）是一种高效骨诱导物质,能够诱导血管周围的未分化间充质细胞向骨软骨细胞发生不可逆地分化。随着胚胎学、分子生物学、细胞生物学等学科的发展,对ＢＭＰｓ的研究也不断扩展和深化。ＢＭＰｓ家族至少包括２０个以上的成员,依据结构特点与氨基酸同源性,可将ＢＭＰｓ家族分为以下五组：（１）Ｄｐｐ、ＢＭＰ２和ＢＭＰ４;（２）６０Ａ、ＢＭＰ５、ＢＭＰ６（Ｖｇｒ１）、ＢＭＰ７（ＯＰ１）、ＢＭＰ８ａ（ＯＰ２）和ＢＭＰ８ｂ（ＯＰ３）;（３）ＢＭ…     

白介素-33的功能作用及研究进展

IL-33是白介素-1(IL-1)家族成员之一,在多种外周组织和中枢神经系统广泛表达。IL-33既可在细胞核中发挥转录作用,亦可分泌到细胞外发挥炎症因子作用。在细胞损伤或病毒感染时,IL-33作为细胞的“警报素”释放,与ST2受体结合,调节机体的自身免疫和炎症反应。同样,IL-33在中枢神经系统疾病也具有重要功能。本文围绕IL-33/ST2的结构和功能,并聚焦于IL-33最新研究进展,旨在探讨IL-33在炎症性和神经系统疾病发生发展中的作用及其可能的治疗前景。     

聚集体自噬在运动性骨骼肌损伤中的特征

文题释义： 蛋白质质量控制：机体通过分子伴侣系统、泛素-蛋白酶体系统和蛋白聚集体自噬重新折叠或降解未折叠和错误折叠的蛋白质,防止蛋白质聚集产生毒性,避免损害细胞的正常功能。 聚集体自噬：细胞内蛋白聚集体的特异性清除途径是选择性自噬的一种,承担了大部分降解蛋白聚集体的任务,在异常蛋白质量控制系统中起了决定性作用。 组蛋白去乙酰化酶6：是聚集体自噬过程的关键调节因子,它通过泛素连接结构域特异性地连接在泛素化的蛋白聚集物上,另一端连接微管的Dynein蛋白,并通过乙酰化α-tubulin运输蛋白聚集物到微管组织中心,形成蛋白聚集体。 背景：一次大负荷离心运动会诱导骨骼肌损伤、内质网应激、错误折叠蛋白增多,聚集体自噬作为蛋白质质量控制的途径之一,在损伤修复过程中应当发挥一定的作用。 目的：探讨一次大负荷离心运动诱导骨骼肌损伤恢复过程中聚集体自噬的激活程度,分析聚集体自噬在运动诱导骨骼肌损伤中的作用,以完善运动诱导骨骼肌损伤的蛋白降解途径。 方法：将64只成年雄性SD大鼠(购自北京维通利华实验技术有限公司)随机分为安静对照组(n=8)和运动组(n=56),运动组又按运动后时相分为0,3,6,12,24,48,72 h组,每组8只。运动组大鼠进行一次跑台下坡跑运动(-16°,16 m/min,90 min),分别在运动后的相应时刻取比目鱼肌,使用透视电子显微镜观察损伤发生程度,采用 Western Blot方法检测比目鱼肌难溶蛋白聚集体自噬相关蛋白组蛋白去乙酰化酶6和微管相关蛋白1轻链3Ⅱ/Ⅰ的蛋白表达。实验获得北京体育大学运动科学实验伦理委员会批准(2016030A)。 结果与结论：①透射电镜显示一次大负荷离心运动后,大鼠比目鱼肌出现一过性的肌节紊乱、变宽,Z线呈水波状、断裂直至消失,线粒体肿胀、分布不均、结构不清,其中运动后12 h损伤最为严重,于运动后       72 h完全恢复;②Western Blot检测显示,一次性离心运动后即刻组蛋白去乙酰化酶6显著增高,运动后    6 h达到峰值,之后逐渐降低,运动后72 h恢复到对照组水平;一次性离心运动后3 h的微管相关蛋白1轻链3Ⅱ/Ⅰ显著升高,运动后12 h达到峰值,之后显著降低,运动后72 h恢复到对照组水平;③结果表明,一次大负荷离心运动后一过性发生聚集体自噬,在清除错误折叠蛋白、维持细胞环境稳定和骨骼肌损伤恢复中发挥着重要作用。 ORCID: 0000-0002-6365-7822(高扬) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

伴侣蛋白Mortalin与神经退行性疾病的研究进展

1993年,Wadhwa等[1]在小鼠胚胎成纤维细胞(mouse embryonic fibroblasts, MEF)中首次克隆出了Mortalin(mtHSP70/HSP75/Grp75/TRAP-1/PBP74),它是热休克蛋白70(heat-shock protein 70, HSP70)家族成员之一.研究表明,Mortalin参与了多种生理功能的调控,包括细胞存活、细胞增殖、压力应激、线粒体合成、细胞内转运等,并且可能在神经系统疾病中发挥作用.在此,本文就Mortalin的基本结构、生理功能以及与神经系统疾病尤其是神经退行性疾病的相关性作一个综述.     

激素调控神经干细胞生成和分化的研究进展

体内各种激素,如性激素、代谢性激素(甲状腺激素)、应激激素(糖皮质激素)、神经激素(褪黑激素)等,通过其特异性受体作用于神经干细胞,直接或间接地促进其增殖和分化,并诱导新生的神经元向特定的脑区迁移。激素可以影响神经系统发育,并通过神经干细胞对损伤的神经组织进行修复。     

自噬的抑制和糖原合成酶激酶-3β的激活促进tau蛋白聚集体形成

神经纤维缠结(NFT)是阿尔茨海默病的特征性病理标志。据报道糖原合成酶激酶-3β(GSK-3β)在tau蛋白形成NFT中起着重要作用,而自噬障碍可能有助于tau蛋白聚集体形成。最近,韩美科学家报道了他们针对GSK-3β介导的tau蛋白磷酸化在自噬降解中的作用的研究。他们分别将T4(野生型tau蛋白)、T4C3(由caspase-3在Asp421位点对tau蛋白切割成的片段)和T4-2EC(在Ser396/Ser404位点低磷酸化的tau蛋白)转染至中国仓鼠卵巢(CHO)细胞,用激活的或被酶灭活的     

硫化氢对神经退行性疾病保护作用的研究进展

硫化氢(hydrogen sulfide,H2S)一直被认为是一种有毒气体.近年来,越来越多的研究显示H2S在哺乳动物体内可以调节及参与一定范围的生理和病理过程.H2S在中枢神经系统中扮演着重要的角色.H2S具有抗氧化应激、抗凋亡以及抗炎的作用,而这些生理学意义对研究防治包括阿尔茨海默病、帕金森氏病在内的神经退行性疾病有着重要的启示.     

脑铁代谢相关蛋白研究进展

铁作为人体重要的微量元素,广泛分布于脑组织,并起重要的生理作用.研究显示脑铁代谢的区域性失衡与许多中枢神经系统退行性疾病有关.     

The proteasome inhibitor, PS-341, causes cytokeratin aggresome formation

Mallory body (MB) experimental induction takes 10 weeks of drug ingestion. Therefore, it is difficult to study the dynamics and mechanisms involved in vivo. Consequently, an in vitro study was done using primary tissue culture of hepatocytes from drug-primed mice livers in which MBs had already formed. The hypothesis to be tested was that MBs are cytokeratin aggresomes, which form when hepatocytes have a defective ubiquitin-proteasome pathway by which turnover of cytokeratin proteins is prevented. To test this hypothesis, primary tissue cultures of the hepatocytes from normal and MB-forming livers were incubated with the proteasome inhibitor PS-341 and then the cytokeratin filaments and the filament connecting proteins, that is, β-actin, and ZO1, were visualized by immunofluorescence microscopy. PS-341 caused detachment of the cytokeratins from the cell surface plasma membrane. The cytokeratin filaments retracted toward the nucleus and cytokeratin aggresomes formed. In human livers, MBs showed colocalization of cytokeratin-8 (CK-8) with ubiquitin but not with β-actin or ZO1. Mouse hepatoma cell lines were studied using PS-341 to induce cytokeratin aggresome formation. In these cell lines, the cytokeratin filaments first retracted toward the nucleus then formed cytokeratin-ubiquitin aggresomes polarized at one side of the nucleus. At the same time, the cells became dissociated from each other, however. The results simulated MB formation. MBs differ from cytokeratin aggresomes both morphologically and in ultrastructure.     

组蛋白去乙酰化酶6在宫颈癌组织中的表达及其临床意义

目的:探讨组蛋白去乙酰化酶6(HDAC6)在宫颈癌组织中的表达及其临床价值。方法:采用免疫组织化学染色法检测63例宫颈癌组织、38例宫颈上皮内瘤变(CIN)组织和63例正常宫颈上皮组织中HDAC6蛋白的表达,并分析其与宫颈癌患者临床病理参数之间的关系。采用Westernblotting随机检测4例宫颈癌组织及自身相对应正常宫颈上皮组织中HDAC6蛋白的表达。结果:宫颈癌组织中HDAC6蛋白表达的阳性率显著高于CIN组织和正常宫颈上皮组织(P<0.05)。HDAC6蛋白表达与宫颈癌患者年龄和组织学分化无关(P>0.05),但与临床分期、浸润深度和淋巴结转移密切相关(P<0.01或P<0.05)。进一步的Westernblotting结果表明宫颈癌组织中HDAC6蛋白的表达均显著高于正常宫颈上皮组织(P<0.05)。结论:HDAC6有望成为评价宫颈癌恶性程度和预后的指标。     

ATP-sensitive potassium channels: A double-edged sword in neurodegenerative diseases

ATP-sensitive potassium channels (K_ATP channels), a group of vital channels that link the electrical activity of the cell membrane with cell metabolism, were discovered on the ventricular myocytes of guinea pigs by Noma using the patch-clamp technique in 1983. Subsequently, K_ATP channels have been found to be expressed in pancreatic β cells, cardiomyocytes, skeletal muscle cells, and nerve cells in the substantia nigra (SN), hippocampus, cortex, and basal ganglia. K_ATP channel openers (KCOs) diazoxide, nicorandil, minoxidil, and the K_ATP channel inhibitor glibenclamide have been shown to have anti-hypertensive, anti-myocardial ischemia, and insulin-releasing regulatory effects. Increasing evidence has suggested that K_ATP channels also play roles in Alzheimer's disease (AD), Parkinson's disease (PD), vascular dementia (VD), Huntington's disease (HD) and other neurodegenerative diseases. KCOs and K_ATP channel inhibitors protect neurons from injury by regulating neuronal excitability and neurotransmitter release, inhibiting abnormal protein aggregation and Ca²⁺ overload, reducing reactive oxygen species (ROS) production and microglia activation. However, K_ATP channels have dual effects in some cases. In this review, we focus on the roles of K_ATP channels and their related openers and inhibitors in neurodegenerative diseases. This will enable us to precisely take advantage of the K_ATP channels and provide new ideas for the treatment of neurodegenerative diseases.     

组蛋白化学修饰改变对c-Myb结合的影响及其在职业性苯中毒患者造血损伤中的作用

 目的:研究职业性苯中毒造血损伤患者中与拓扑异构酶Ⅱα启动子调控因子c-Myb结合的组蛋白化学修饰改变, 证实组蛋白乙酰化修饰水平改变在职业性苯中毒造血损伤中发挥一定的作用。方法:25例职业性苯中毒再生障碍性贫血患者为病例组,25例正常人为对照组,提取骨髓单个核细胞,用染色质免疫沉淀(ChIP)探讨与c-Myb结合的组蛋白乙酰化和甲基化水平的改变,RT-PCR法检测c-Myb的mRNA表达水平,组蛋白去乙酰化酶(HDAC)试剂盒检测HDAC活性的变化。结果:与正常对照组相比,职业性苯中毒再生障碍性贫血患者c-Myb与乙酰化组蛋白H4、H3结合的水平下降(P<0.01), 而与甲基化组蛋白H3K4和H3K9结合的水平无明显改变,差异无统计学显著性。与正常对照组相比,职业性苯中毒再生障碍性贫血患者c-Myb的mRNA表达水平降低,HDAC活性明显升高,差异均有统计学显著性(P<0.05)。结论:拓扑异构酶Ⅱα启动子调控因子c-Myb可能通过组蛋白乙酰化修饰的改变在职业性苯中毒造血损伤中发挥作用。     

Histone deacetylase 3 is required for centromeric H3K4 deacetylation and sister chromatid cohesion

We describe here the role of histone deacetylase 3 (HDAC3) in sister chromatid cohesion and the deacetylation of histone H3 Lys 4 (H3K4) at the centromere. HDAC3 knockdown induced spindle assembly checkpoint activation and sister chromatid dissociation. The depletion of Polo-like kinase 1 (Plk1) or Aurora B restored cohesion in HDAC3-depleted cells. HDAC3 was also required for Shugoshin localization at centromeres. Finally, we show that HDAC3 depletion results in the acetylation of centromeric H3K4, correlated with a loss of dimethylation at the same position. These findings provide a functional link between sister chromatid cohesion and the mitotic "histone code".     

胰岛素抵抗在神经退行性疾病中的作用*

Insulin resistance is a condition in which the cells fail to respond to the normal actions of insulin, acting as decreased glucose utilization, abnormal glucose tolerance and compensatory increased insulin concentration in the serum. Altered insulin-related indicator has been detected in neurodegenerative diseases. Recent studies indicate that insulin resistance is involved in the occurrence and development of neurodegenerative diseases, including Alzheimers disease, Parkinsons disease, Huntingtons disease, etc. This review summarizes the relationship between insulin resistance and neurodegenerative diseases.     

The aggresome pathway as a target for therapy in hematologic malignancies

Misfolded or unfolded proteins are often refolded with the help of chaperones or degraded by the 26S proteasome. An alternative fate of these proteins is the aggresome pathway. The microtubule-organizing center (MTOC) transports unfolded proteins to lysosomes and are degraded through autophagy. Histone deacetylase 6 (HDAC6) deacetylates α-tubulin, which is thought to be a component of the MTOC. Recently, two small molecule inhibitors of the aggresome pathway and HDAC6 have been described. One inhibitor, tubacin, prevents deacetylation of α-tubulin and produces accumulation of polyubiquitinated proteins and apoptosis. Tubacin acts synergistically with the proteasome inhibitor, bortezomib, to induce cytotoxicity in one type of hematologic malignancy, multiple myeloma. The other, LBH589, is a pan HDAC inhibitor and hydroxamic acid derivative that induces apoptosis of multiple myeloma cells resistant to conventional therapies. In this review, we summarize recent reports on targeting the aggresome pathway and HDAC6 in hematologic malignancies.     

组蛋白去乙酰化酶抑制剂罗米地辛对小鼠T细胞表型及功能的影响

目的:通过体外实验观察罗米地辛对效应T细胞和调节性T细胞的作用。方法:取CFSE标记的淋巴细胞、CD4+T细胞和CD8+T细胞作为反应细胞,实验组加入不同浓度梯度(1、3、5μmol/L)的罗米地辛及CD3/CD28单抗进行淋巴细胞培养,以仅加入CD3/CD28单抗作为阳性对照组,另设空白对照组。培养72 h后检测各组细胞的增殖情况。以淋巴细胞作为反应细胞,实验组、阳性对照组及空白对照组设定同上,72 h后检测各组中CD4+Foxp3+T细胞与CD4+T细胞的比例变化。同时采用ELISA检测培养液中相关细胞因子,如TNF-α、IL-10及TGF-β水平的变化。结果:罗米地辛剂量依赖性地抑制CD3/CD28单抗诱导的淋巴细胞、CD4+T细胞和CD8+T细胞的增殖(P0.05)。在CD3/CD28单抗存在的条件下,1μmol/L的罗米地辛不能诱导CD4+Foxp3+T细胞的比例上调(P0.05)。但提高罗米地辛的浓度至3μmol/L和5μmol/L后,CD4+Foxp3+T细胞的比例显著提高(P0.05)。随着罗米地辛浓度的增加,TNF-α和IL-10水平呈剂量依赖性降低,但各实验组明显高于空白对照组而低于阳性对照组(P0.05)。TGF-β在阳性对照组虽稍有升高,但与空白对照组相比无显著差异(P0.05)。而随着罗米地辛浓度的增加,TGF-β水平呈剂量依赖性升高,3实验组间及与空白对照组、阳性对照组间差异显著(P0.05)。结论:体外实验研究显示罗米地辛不仅能够有效抑制效应性T细胞的增殖,而且一定浓度的罗米地辛可上调调节性T细胞的比例,这可能与TGF-β升高有关,而与IL-10变化无关。     

组蛋白去乙酰化酶抑制剂与细胞周期和凋亡关系的研究进展

表观遗传学是目前遗传学研究的热点。组蛋白乙酰化修饰是一种重要的表观遗传学调控方式,参与调控染色质构象变化和转录表达过程,组蛋白乙酰化状态紊乱与肿瘤的发生发展关系密切。研究发现,组蛋白去乙酰化酶抑制剂(histone deacetylase in-hibitor,HDACi)可以纠正肿瘤细胞异常的乙酰化状态,诱导肿瘤细胞发生细胞周期停滞和凋亡,逆转肿瘤细胞恶性表型。1组蛋白乙酰化酶(histone acetyltransferase,HAT)和组蛋白去乙酰化酶(histone deacetylase,HDAC)真核生物染色体的基本单位是核小体,核小体的核心是由4种组蛋白(H2A、H2B、H3和H4)各2…     

Cytokine/neurotrophin interaction in the aged central nervous system

Age-associated neurodegenerative diseases such as Alzheimer's disease are characterised by neuronal impairment that leads to cognitive deficits. As certain affected neurons depend on trophic factors such as neurotrophins (NTs), impairment in NT function has been suggested to be a component of neuronal damage associated with such disorders. Age-related neurodegenerative diseases are also characterised by high levels of proinflammatory cytokines such as tumour necrosis factor alpha (TNFα) in the CNS. Because TNFα receptors and certain NT receptors share a high degree of homology and are capable of activating similar signalling pathways, one possibility is that altered cytokine levels may affect NT function in the aged or diseased CNS. Here we wish briefly to review the evidence suggesting a role for cytokine and NT in the onset of age-associated neurodegenerative diseases. We propose that cytokine/NT interactions may alter neuronal homeostasis, thus possibly contributing to some of the neuronal degeneration occurring during such age-associated CNS diseases.