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阿尔茨海默病(Alzheimer’s disease, AD)是一种具有复杂病理学特征的老年失智症.淀粉样蛋白级联假说与寡聚体毒性假说在解释AD病理机制方面占据主导地位. AD患者数量庞大,但目前尚未发现治疗AD的有效疗法,多数药物在Ⅲ期临床试验的结果不够理想.本文对影响β-淀粉样肽(β-amyloid, Aβ)聚集的国内外相关研究进展进行总结,并阐述小分子化合物加速Aβ纤维形成过程的可能机理.这一过程与传统疗法相悖却在动物模型中取得了相当好的疗效,意味着促进Aβ聚集可能成为AD治疗的新策略,为新药开发指明了新方向. 相似文献
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阿尔茨海默病 (Alzheimerdisease ,AD)是一种中枢神经系统退行性疾病 ,主要病理特征是大脑皮层和海马区域出现斑块及神经元纤维缠结 ,斑块以淀粉样肽 (β amyloidpep tide ,Aβ)为核心成分。近年来研究证明Aβ与AD的发病直接相关。1 .淀粉样蛋白质前体与Aβ结构和生物功能中枢神经系统神经元、星形细胞、小胶质细胞、少突胶质细胞和内皮细胞均能表达淀粉样蛋白质前体 (amyloidpeptideprecursor,APP)。APP基因位于 2 1号染色体的长臂中段部分 (2 1q2 1 .2 ) ,它编码一组… 相似文献
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淀粉样β肽(Aβ)在阿尔茨海默病(AD)病理过程中发挥重要致病作用。部分非类固醇抗炎药(NSAID)不依赖于抑制环氧合酶(COX)特异性降低Aβ42水平,并不影响r-分泌酶的重要生理功能,可作为新一代抗淀粉样蛋白药物。 相似文献
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目的:建立β淀粉样肽(Aβ1-40)诱导激活小胶质细胞的上清致海马神经元损伤的细胞模型,并初步研究神经元损伤的机制。方法:用不同浓度的可溶性Aβ1-40诱导激活小胶质细胞,光镜下观察不同时间点的细胞形态,ELISA检测其分泌的肿瘤坏死因子仪;用激活后的小胶质细胞条件培养基刺激海马神经元,光镜下观察细胞形态,Western blot检测刺激后海马神经元内诱导型一氧化氮合酶(iNOS)和硝基酪氨酸(NT)的表达水平,ELISA检测海马神经元内胱冬蛋白酶-3(caspase-3)活性来评价神经元的损伤程度。结果:终浓度为10μmol/L的Aβ1-40与小胶质细胞孵育24h后,取上清液加到培养的海马神经元,孵育24-72h,海马神经元较对照组形态有明显变化;经Western blot检测,神经元内iNOS、NT表达明显增加;ELISA检测神经元内caspase-3活性明显增高。结论:小胶质细胞被Aβ1-40激活后,其释放物有明显的致神经元损伤效应,表明建立了神经元损伤模型。 相似文献
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神经介素S(neuromedin S,NMS)是一种由36个氨基酸组成的新的神经肽。Takanori Ida等在2005年Endocrinology上报道在大鼠脑中发现NMS,主要在视交叉神经核上表达,是G蛋白偶联受体FM-3/GPR66和FM-4/TGR—l的配体,这些受体分别是神经介素U(neuromedin U,NMU)1型和2型。他们研究发现NMS是一种新的食欲调节肽。给大鼠侧脑室内注射NMS后,NMS可以剂量依赖性地降低大鼠夜间12小时的食物和水的摄入量.其摄含抑制作用较相同剂量的NMU的抑制作用强,持续时间久, 相似文献
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胰高血糖素样肽1:阿尔茨海默病治疗新策略 总被引:3,自引:0,他引:3
2型糖尿病(type2diabetes mellitus,T2DM)与阿尔茨海默病(Alzheimer’s disease,AD)的病理生理过程具有密切的相关性。人们正在逐步深入研究治疗T2DM的最新药物——胰高血糖素样肽1(glucagon-likepe ptide1,GLP-1)的神经保护作用,并大胆地提出了利用GLP-1治疗AD的设想。本文对T2DM与AD的发病相关性、GLP-1的合成与分泌、GLP-1受体的中枢分布及其生理效应,特别是GLP-1与AD治疗策略相关的研究进展作一综述。 相似文献
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Humanin (HN) has been proved to be an extensive neuroprotective peptide against AD-related and unrelated insults, but little is know about the effect of HN in inflammation response. Current studies indicated the receptors of HN have a close relationship with immune system, which led us to hypothesize HN might have a role in inflammatory response. In this study, we used lipopolysaccharide (LPS) to induce astrocyte inflammation response. This model in vitro allowed us to study the effect of HN on the pure response of astrocyte without the exogenous influence between cells in vivo. Our results showed that 1.0 μg/ml LPS induced a significant activation of astrocyte, shown as the marked increase in the glial fibrillary acidic protein (GFAP) expression, the cell viability and the number of 5-bromo-2′-deoxyuridine (BrdU)-positive living cells. Pretreatment with HN (5, 10, 20 μM) led to a significant inhibition in astrocyte overactivation in a concentration dependent manner. We also found pretreatment with HN decreased the level of proinflammatory cytokines, interleukin (IL)-6, IL-1β and tumor necrosis factor α (TNFα) induced by LPS. Furthermore, we noticed HN couldn’t completely reverse the above inflammatory injury. Our findings imply that HN partly antagonizes inflammation injury induced by LPS and the protective effect of HN on astrocyte is concentration-dependent. 相似文献
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Humanin(HN)是近年来在人体内发现的内源性多肽,能够保护神经细胞免于各种阿尔采默病病相关因素诱导的凋亡,HN肽链第14位氨基酸被Gly取代的突变体[Gly14]-Humanin(HNG),神经保护活性比HN高近1 000倍。但由于HNG天然获取的途径有限,限制了对其功能的进一步研究。本课题组构建了HNG的表达质粒pET32a/HNG,并将其转化大肠杆菌BL21 trxB (DE3),诱导表达后HNG以可溶性融合蛋白的形式出现并用镍离子亲和层析纯化,纯化的融合蛋白用肠激酶切割后经反相层析得到纯化的HNG多肽(23 mg每1 L细菌培养液),重组HNG多肽的分子量经电喷雾电离质谱(ESI-MS)检测为2876.5道尔顿,其N末端8个氨基酸残基的序列经Edman降解法测定为A-M-M-A-P-R-G-F,均与理论值一致。神经细胞保护实验表明,重组HNG多肽的神经保护作用与天然的HNG相近 相似文献
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David G. Zacharias Sung Gyun Kim Alfonso Eirin Massat Adi R. Bachar Yun K. Oh Joerg Herrmann Martin Rodriguez-Porcel Pinchas Cohen Lilach O. Lerman Amir Lerman 《PloS one》2012,7(2)
Objective
The mechanism of atherosclerotic plaque progression leading to instability, rupture, and ischemic manifestation involves oxidative stress and apoptosis. Humanin (HN) is a newly emerging endogenously expressed cytoprotective peptide. Our goal was to determine the presence and localization of HN in carotid atherosclerotic plaques.Methods and Results
Plaque specimens from 34 patients undergoing carotid endarterectomy were classified according to symptomatic history. Immunostaining combined with digital microscopy revealed greater expression of HN in the unstable plaques of symptomatic compared to asymptomatic patients (29.42±2.05 vs. 14.14±2.13% of plaque area, p<0.0001). These data were further confirmed by immunoblot (density of HN/β-actin standard symptomatic vs. asymptomatic 1.32±0.14 vs. 0.79±0.11, p<0.01). TUNEL staining revealed a higher proportion of apoptotic nuclei in the plaques of symptomatic patients compared to asymptomatic (68.25±3.61 vs. 33.46±4.46% of nuclei, p<0.01). Double immunofluorescence labeling revealed co-localization of HN with macrophages (both M1 and M2 polarization), smooth muscle cells, fibroblasts, and dendritic cells as well as with inflammatory markers MMP2 and MMP9.Conclusions
The study demonstrates a higher expression of HN in unstable carotid plaques that is localized to multiple cell types within the plaque. These data support the involvement of HN in atherosclerosis, possibly as an endogenous response to the inflammatory and apoptotic processes within the atheromatous plaque. 相似文献14.
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Sindy Escobar-Alvarez Yehuda Goldgur Ouathek Ouerfelli David A. Scheinberg 《Journal of molecular biology》2009,387(5):1211-4532
Peptide deformylase proteins (PDFs) participate in the N-terminal methionine excision pathway of newly synthesized peptides. We show that the human PDF (HsPDF) can deformylate its putative substrates derived from mitochondrial DNA-encoded proteins. The first structural model of a mammalian PDF (1.7 Å), HsPDF, shows a dimer with conserved topology of the catalytic residues and fold as non-mammalian PDFs. The HsPDF C-terminus topology and the presence of a helical loop (H2 and H3), however, shape a characteristic active site entrance. The structure of HsPDF bound to the peptidomimetic inhibitor actinonin (1.7 Å) identified the substrate-binding site. A defined S1′ pocket, but no S2′ or S3′ substrate-binding pockets, exists. A conservation of PDF-actinonin interaction across PDFs was observed. Despite the lack of true S2′ and S3′ binding pockets, confirmed through peptide binding modeling, enzyme kinetics suggest a combined contribution from P2′and P3′ positions of a formylated peptide substrate to turnover. 相似文献
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Huo Jiaying Luo Xuelian Huang Mingquan Wu Jihong Zhang Jinglin Liu Xingxun Li Hehe Sun Xiaotao 《International journal of peptide research and therapeutics》2020,26(3):1199-1210
International Journal of Peptide Research and Therapeutics - A novel peptide, Cys-Trp-Cys (CWC), which firstly isolated from Guojing Baijiu was qualitative and quantitative studied by... 相似文献
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Radhika H. Muzumdar Derek M. Huffman Gil Atzmon Christoph Buettner Laura J. Cobb Sigal Fishman Temuri Budagov Lingguang Cui Francine H. Einstein Aruna Poduval David Hwang Nir Barzilai Pinchas Cohen 《PloS one》2009,4(7)