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1.
周渭  胡文辉 《科学通报》2014,59(3):232-237
阿尔茨海默症(Alzheimer’s disease,AD)的致病机制尚不明确,至今仍然缺乏有效的治疗药物,并且临床研究中的候选药物也多以失败告终. 因此,对于AD这样一种复杂的疾病,单纯依赖分子靶标的现代药物研发策略难以奏效,迫切需要结合以细胞和动物药效为重心的经典药物研发策略,方有望打破AD新药开发的瓶颈. 鉴于神经元的退化和凋亡始终是AD发生、发展的中心环节,因此通过抑制大脑小胶质细胞的过度活化,进而抑制神经炎症的发展可以阻止AD的恶化进程. 本文综述了如何通过神经免疫细胞的表型筛选,确立神经炎症抑制剂,进而辅以AD动物模型的体内药效评价,获得能够显著提高模型动物的记忆和认知能力的活性分子,并结合本课题组最新的研究进展,对本领域进行了初步的讨论和展望.  相似文献   
2.
Recent reports describe successful treatment using copper chelation therapy in neurodegenerative animal models. However, the success claimed for chelation therapy in neurodegenerative diseases is still rather controversial. To acquire new information on copper metabolism/homeostasis, we utilized cuprizone, a very sensitive and selective copper-chelating agent with well-known neurotoxic properties, as a relevant chemical model in mice. Upon cuprizone treatment, mice developed a pronounced astrocytosis, with brain oedema and spongiosis characterised by vacuolisations of the neuropil predominantly in the white matter. In addition, cuprizone treatment severely altered copper and zinc homeostasis in the central nervous system (CNS) as well as in all other tissues examined, with increasing metal ion concentrations particularly in the CNS. Concomitant with this increase in the Cu and Zn concentration in the brain, metallothionein-I and -II were also highly immunoreactive in astrocyte, consistent with the astrocytosis and demyelination observed in our and other laboratories.Received 23 February 2005; received after revision 3 May 2005; accepted 13 May 2005  相似文献   
3.
In this work, the distributions of some acid-sensitive two-pore-domain K+ channels (TASK-1, TASK-2 and TASK-3) were investigated in the rat and human cerebellum. Astrocytes situated in rat cerebellar tissue sections were positive for TASK-2 channels. Purkinje cells were strongly stained and granule cells and astrocytes were moderately positive for TASK-3. Astrocytes isolated from the hippocampus, cerebellum and cochlear nucleus expressed TASK channels in a primary tissue culture. Our results suggest that TASK channel expression may be significant in the endoplasmic reticulum of the astrocytes. The human cerebellum showed weak TASK-2 immunolabelling. The pia mater, astrocytes, Purkinje and granule cells demonstrated strong TASK-1 and TASK-3 positivities. The TASK-3 labelling was stronger in general, but it was particularly intense in the Purkinje cells and pia mater.Received 25 February 2004; received after revision 19 April 2004; accepted 28 April 2004  相似文献   
4.
rhEPO对预处理低氧损伤胶质细胞MMP-9表达的影响   总被引:1,自引:0,他引:1  
 探讨人促红细胞生成素(rhEPO)对低氧损伤胶质细胞的影响及对金属蛋白酶-9(MMP-9)表达的影响。通过体外纯化培养第3代星形胶质细胞,将其分为正常组、低氧组、rhEPO预处理组;以四唑蓝(MTT)比色法测定低氧培养12、24、36h细胞的存活率,倒置显微镜和透射电镜观察低氧对胶质细胞形态的影响;免疫荧光和逆转录-聚合酶链反应(RT-PCR)方法研究低氧对星形胶质细胞MMP-9表达的影响。结果显示:低氧组星形胶质细胞在低氧培养下出现细胞肿胀,且随时间的延长而加重,rhEPO预处理组在各时间点细胞肿胀明显轻于低氧组。rhEPO能减轻细胞超微结构的改变及降低MTT比值。RT-PCR及免疫荧光检测表明:低氧组MMP-9 mRNA及蛋白的表达在低氧各时间点均高于正常组,在24h达到最高,在36h开始降低(P<0.05);rhEPO预处理组MMP-9mRNA及蛋白的表达变化在12、24、36h较低氧组低(P<0.05)。由此得出结论:rhEPO通过抑制MMP-9的表达促进低氧条件下星形胶质细胞的存活。  相似文献   
5.
Astrocytes play an important role in the formation of glial scars. In order to investigate the effect of inhibitingGFAP gene expression on normal, reactive astrocytes and on glial scar formation, the efficiency of the recombinant antisenseGFAP retrovirus (PLBskG) on the growth, cell cycle, morphology andGFAP gene expression of astrocytesin vitro and on the formation of glial scarsin vivo has been studied by cell growth curves, flow cytometry, immunocytochemistry,in situ hybridization, RT-PCR and Southern blot. The results confirm the recombinant retrovirus (PLBskG) produced growth suppression and G1 arrest of the normal and injured astrocytes. The infected cells become round or ellipoid. The cell processes become fine or retracted. The intensity of staining ofGFAP is reduced. Expression ofGFAP mRNA is down regulated. However, in the control experiment, no obvious effects on the morphology or synthesis ofGFAP on cultured normal and scratched astrocytes infected by primary retrovirus vector (PLXSN) have been observed. The supernatant of PLBskG has been injected into an injured site by microinjectionin vivo. The number and process lengths of GFAP positive cells are obviously reduced around the injured site. The formation of the glial scar is inhibited, showing that the recombinant antisenseGFAP retrovirus can effectively inhibit the growth andGFAP expression of normal and injured astrocytesin vitro and the formation of glial scarin vivo. It is suggested thatGFAP plays an important role in glial scar formation.  相似文献   
6.
Astrogliosis is a hallmark of prion disease, but the metabolic alterations of astrocytes remain poorly documented. A synthetic peptide corresponding to amino acid 106-126 of the human prion protein (PrP) has been shown to be toxic to neurons. In this study, the effects of PrP 106-126 on astrocytes were investigated in vitro. The proliferation of astrocytes was significantly (P 〈 0.05) increased when grown in media conditioned with PrP 106-126 (80 μmol/L) from microglia. The expression of laminin (LN) and fibronectin (FN) was examined at both mRNA and protein levels. The results showed that exposure of astrocytes to PrP 106-126 enhanced the expression of LN and FN. The increase of FN in astrocyte cultures required cytokines previously released by activated microglia. This study reveals the expression of LN and FN affected by PrP106-126.  相似文献   
7.
Neural stem cells (NSCs) in the adult mammalian brain proliferate and continuously produce new neurons. To date, there has been little research into the functions of lectins in adult NSCs. Recently, we reported that a lectin, galectin-1, is expressed on adult NSCs and promotes their proliferation through its carbohydrate-binding ability. This evidence raises the possibility that glycans play roles in the proliferation of adult NSCs. Received 6 November 2006; received after revision 13 December 2006; accepted 15 February 2007  相似文献   
8.
It has long been thought that astrocytes, like other glial cells, simply provide a support mechanism for neuronal function in the healthy and inflamed central nervous system (CNS). However, recent evidence suggests that astrocytes play an active and dual role in CNS inflammatory diseases such as multiple sclerosis (MS). Astrocytes not only have the ability to enhance immune responses and inhibit myelin repair, but they can also be protective and limit CNS inflammation while supporting oligodendrocyte and axonal regeneration. The particular impact of these cells on the pathogenesis and repair of an inflammatory demyelinating process is dependent upon a number of factors, including the stage of the disease, the type and microenvironment of the lesion, and the interactions with other cell types and factors that influence their activation. In this review, we summarize recent data supporting the idea that astrocytes play a complex role in the regulation of CNS autoimmunity.  相似文献   
9.
缺血性脑卒中是中老年常见的急性脑血管病,是当今世界主要的致死性疾病之一。现有治疗方案有限,仅适用于一小部分中风患者。因此,开发有效的治疗方法以减少脑损伤至关重要。星形胶质细胞(astrocyte, AS)是中枢神经系统的核心组成部分,其线粒体功能障碍是缺血性脑卒中的初始事件,在神经元存活和神经功能改善过程中发挥着重要作用。以AS细胞线粒体在缺血性脑卒中发病中的作用机制为切入点,分析讨论了缺血性脑卒中发生时AS细胞线粒体的生物能量与动力学变化、细胞之间线粒体的转移以及AS细胞线粒体对脑血流的调节作用,提出将AS细胞线粒体作为治疗缺血性脑卒中的靶点之一,以更好地了解AS细胞线粒体在缺血诱导的神经元死亡过程中的重要作用,为缺血性脑卒中的新型治疗方案提供理论基础。  相似文献   
10.
目的探讨刺参多糖对星形胶质细胞的活化作用机制.方法选取新生Wistar大鼠24只,经胰酶消化分离可得星形胶质细胞;采用MTT法检测HS-4对细胞的毒副作用;采用伊红染色与免疫荧光染色检查细胞的形态学变化;采用Western blot法检测细胞特征蛋白GFAP和细胞周期调控蛋白Cyc DI的表达;采用BrdU法检测细胞的增殖;采用Transwell法检测细胞的迁移.结果 HS-4浓度在0.1~100μg/mL,作用时间为3,5 d时,细胞数量与对照组差异不显著,HS-4浓度在100μg/mL,作用时间为7 d时,细胞存活率明显低于对照组,差异显著;体外培养的细胞与HS-4单独作用,细胞形态无明显改变,HS-4与FGF-2联合作用后,细胞形态发生明显改变;星形胶质细胞的特征蛋白GFAP表达水平显著升高,HS-4在1μg/mL和5μg/mL时,GFAP表达升高了169%和183%;对照组细胞周期调控蛋白Cyc DI表达最低,FGF-2单独作用后,Cyc DI表达略有升高,当HS-4与FGF-2联合作用后,Cyc DI表达明显升高;对照组BrdU阳性率最低,占细胞总数的12.9%,FGF-2单独作用后,BrdU阳性率略有升高,占细胞总数的16.4%,与对照组差异不显著,HS-4浓度为1μg/mL和5μg/mL时与FGF-2联合作用,BrdU阳性率明显升高,占细胞总数的28.5%和56.1%,与对照组相比差异显著;静息状态星形胶质细胞无迁移,HS-4与FGF-2作用下星形胶质细胞迁移明显.结论 HS-4与FGF-2能有效诱导星形胶质细胞的活化,其活化机制主要是强化细胞增殖与迁移.  相似文献   
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