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Nanotechnology-based gene therapy as a credible tool in the treatment of Alzheimer’s disease 被引量:5
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作者 Aziz Unnisa Nigel H.Greig Mohammad Amjad Kamal 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第10期2127-2133,共7页
Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has ev... Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease. 展开更多
关键词 Alzheimer’s disease amyloid-β bace1 gene silencing gene therapy nanoparticle NEUROTROPHINS small interfering ribonucleic acid
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Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer’s disease 被引量:3
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作者 Qian Guo Xiaoyao Zheng +10 位作者 Peng Yang Xiaoying Pang Kang Qian Pengzhen Wang Shuting Xu Dongyu Sheng Liuchang Wang Jinxu Cao Wei Lu Qizhi Zhang Xinguo Jiang 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2019年第3期590-603,共14页
Gene therapy represents a promising treatment for the Alzheimer’s disease(AD). However,gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have deve... Gene therapy represents a promising treatment for the Alzheimer’s disease(AD). However,gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood–brain barrier(BBB)penetration and QSH peptide for β-amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against β-site amyloid precursor protein-cleaving enzyme 1(BACE1), the rate-limiting enzyme of Aβ production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the Aβ deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels,as well as Aβ and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome. 展开更多
关键词 siRNA delivery NEURONS AMYLOID PLAQUES bace1 gene Alzheimer’s disease
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醒脑液对PAP双转基因痴呆小鼠NEP和BACE1 mRNA表达的影响 被引量:3
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作者 张子洋 常富业 +6 位作者 张允岭 王新祥 郑宏 马涛 刘雪梅 闫妍 单媛莉 《中华中医药学刊》 CAS 2014年第5期1016-1018,I0007,I0008,共5页
目的:探讨中药醒脑液(XNY)对PAP双转基因痴呆小鼠大脑组织中中性内肽酶(NEP)和β分泌酶(BACE1)mRNA表达的影响。方法:采用实时荧光定量PCR技术分别观测正常对照组、模型组、西药对照组、XNY高剂量组、XNY中剂量组和XNY低剂量组小鼠大脑... 目的:探讨中药醒脑液(XNY)对PAP双转基因痴呆小鼠大脑组织中中性内肽酶(NEP)和β分泌酶(BACE1)mRNA表达的影响。方法:采用实时荧光定量PCR技术分别观测正常对照组、模型组、西药对照组、XNY高剂量组、XNY中剂量组和XNY低剂量组小鼠大脑组织中NEP和BACE1 mRNA的表达。结果:与模型组相比,XNY高剂量组脑内NEP mRNA含量表达上调(P<0.05);XNY高、中剂量组BACE1 mRNA含量表达下降(P<0.01)。结论:醒脑液对双转基因痴呆小鼠大脑组织中NEP和BACE1 mRNA表达有较好的调控作用,说明醒脑液对防治老年性痴呆能起到良好效果。 展开更多
关键词 醒脑液 PAP双转基因小鼠 中性内肽酶 Β分泌酶 阿尔茨海默病 老年性痴呆 基因表达
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源于尿道上皮细胞的诱导多能干细胞构建阿尔茨海默病研究模型 被引量:2
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作者 王旎 刘舜杰 +3 位作者 孟洋阳 雷清锋 韦睿 李中 《中国病理生理杂志》 CAS CSCD 北大核心 2022年第3期487-494,共8页
目的:阿尔茨海默病(AD)是常见的神经退行性疾病之一,目前仍未有理想的研究模型,这使得其发病机制尚不完全清楚。因此,本研究将利用非侵袭性方法收集的尿道上皮细胞重编程为诱导多能干细胞(iPSC)从而构建AD疾病研究模型。方法:本研究选取... 目的:阿尔茨海默病(AD)是常见的神经退行性疾病之一,目前仍未有理想的研究模型,这使得其发病机制尚不完全清楚。因此,本研究将利用非侵袭性方法收集的尿道上皮细胞重编程为诱导多能干细胞(iPSC)从而构建AD疾病研究模型。方法:本研究选取3名男性AD患者作为实验组和2名正常男性作为对照者组,通过分离实验组和对照组的尿道上皮细胞,并将其重编程成为iPSC,利用碱性磷酸酶染色、RT-qPCR及畸胎瘤形成实验等验证其干细胞特性。随后将iPSC定向神经分化成为神经细胞,采用ELISA方法验证AD特异性标志物的表达水平。同时,将BACE1基因在iPSC细胞系中过表达,采用ELISA方法验证AD特异性标志物的表达水平,以上实验每组研究对象均进行2~3次重复实验。结果:尿道上皮细胞被成功地重编程成iPSC,且具有分化为三种不同胚层来源组织的多能性。定向分化患者来源的神经细胞分泌AD标志物的水平与正常对照比较没有显著差异(P>0.05)。但是,过表达BACE1后的iPSC细胞系和分化的神经细胞,AD相关标志物表达水平较对照组显著增高(P<0.05),说明该细胞系作为AD模型的可行性。结论:本研究成功地将AD患者的尿道上皮细胞重编程为iPSC,并将其与正常来源的iPSC进行比较,观察到患者来源的iPSC具有相对正常的蛋白表达谱,提示该细胞的临床应用价值。同时,过表达BACE1基因的iPSC能检测到高表达的AD相关标志物,提示该细胞可以作为研究AD发病机制的细胞模型。 展开更多
关键词 阿尔茨海默病 尿道上皮细胞 诱导多能干细胞 神经分化 bace1基因
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RNAi技术在阿尔采末病防治研究中的应用 被引量:2
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作者 孙琰 周文霞 张永祥 《中国药理学通报》 CAS CSCD 北大核心 2009年第11期1408-1411,共4页
阿尔采末病(Alzheimer′s disease,AD)是一种神经退行性疾病,目前已成为严重威胁老年人生活质量乃至生命的主要疾病之一。由于AD的发病机制并不清楚,因此给其治疗带来了很大困难,目前的治疗方法都只能部分改善症状,而不能逆转病理变化... 阿尔采末病(Alzheimer′s disease,AD)是一种神经退行性疾病,目前已成为严重威胁老年人生活质量乃至生命的主要疾病之一。由于AD的发病机制并不清楚,因此给其治疗带来了很大困难,目前的治疗方法都只能部分改善症状,而不能逆转病理变化或阻止病情的发展。近年来RNAi技术在体内外抑制AD相关基因表达的成功,为AD的治疗提供了新的方法。该综述主要介绍了RNAi技术在AD中的应用。 展开更多
关键词 阿尔采末病 RNAI 基因沉默 Β淀粉样蛋白 bace1 TAU
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BACE1基因RNA干扰质粒的构建及干扰效果的鉴定 被引量:1
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作者 张璇 胡海梅 《北京生物医学工程》 2013年第6期579-582,共4页
目的构建BACE1基因干扰质粒,并研究其在neuro-2a细胞中的表达,为以其为靶点的基因治疗提供稳定转染的质粒。方法选择人、小鼠和大鼠的BACE1基因共有序列为干扰靶点,设计3组连接有GFP的干扰质粒,将构建好的质粒转染neuro-2a细胞,通过Real... 目的构建BACE1基因干扰质粒,并研究其在neuro-2a细胞中的表达,为以其为靶点的基因治疗提供稳定转染的质粒。方法选择人、小鼠和大鼠的BACE1基因共有序列为干扰靶点,设计3组连接有GFP的干扰质粒,将构建好的质粒转染neuro-2a细胞,通过Real time RT-PCR及Western-blotting的方法分别在RNA及蛋白质水平上检测BACE1的表达,以分析其干扰的效率。结果经酶切及测序证实,插入的DNA片段序列与设计序列完全一致。与空质粒对照组相比,3个干扰靶点对BACE1基因的表达均有不同程度的抑制作用。其中pYr-1.1-siBACE1在mRNA水平及蛋白质水平干扰效果均最好。结论成功构建了BACE1基因的干扰质粒pYr-1.1-siBACE1,并能有效抑制neuro-2a细胞内源性BACE1基因表达,为靶向BACE1基因的治疗提供了有力的工具。 展开更多
关键词 bace1 基因 RNA干扰 neuro-2a细胞
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