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目的:建立小鼠急性乙型肝炎病毒感染动物模型,在此基础上观察慢病毒载体携带小干扰RNA (small interferingRNAs,siRNAs)对乙型肝炎病毒(HBV)复制和表达的影响.方法:36只Balb/c小鼠随机等分为3组(n=12):①空白对照组(NC组):通过尾静脉注射pTHBV2(包含HBV全基因组真核表达质粒).建立小鼠急性HBV感染模型;②干扰组(E组):将pTHBV2与pWPT-HBV-siRNA1(携带靶向HBV S区的siRNA1的慢病毒)通过尾静脉共注射小鼠;③无关干扰组(I组):pTHBV2和pWPT-HBV-siRNA2(携带非靶向HBV的无关siRNA2的慢病毒)通过尾静脉共注射小鼠.于注射后第4大和第7天取小鼠血清和肝脏组织.采用ELISA法检测血清中HBsAg(HBV表面抗原);选择逆转录聚合酶链反应方法(RT-PCR)检测肝组织HBVS-mRNA水平;用免疫组织化学法检测肝组织HBcAg(HBV核心抗原)和HBsAg.结果:与NC组比较,E组小鼠血清中HBsAg水平在第4和第7天分别下降89.76%和94.81%(P<0.01);RT-PCR结果提示E组肝组织HBV S-mRNA水平明显降低(P<0.05);免疫组织化学法检测结果显示示E组肝组织HBcAg、HBsAg阳性细胞数明显减少(P<0.05).I组与NC组比较,上述检测指标无统计学差异(P>0.05).结论:慢病毒载体携带siRNAs能够显著抑制小鼠体内HBV的复制和表达,并儿抑制作用在第7天较第4天更强.没有减弱的趋势. 相似文献
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Julie Rousseau Virginie Escriou François Lamoureux Régis Brion Julie Chesneau Séverine Battaglia Jérome Amiaud Daniel Scherman Dominique Heymann Françoise Rédini Valérie Trichet 《Journal of bone and mineral research》2011,26(10):2452-2462
The development of osteosarcoma, the most common malignant primary bone tumor is characterized by a vicious cycle established between tumor proliferation and paratumor osteolysis. This osteolysis is mainly regulated by the receptor activator of nuclear factor κB ligand (RANKL). Preclinical studies have demonstrated that Rankl blockade by soluble receptors is an effective strategy to prevent osteolytic lesions leading to osteosarcoma inhibition. A new therapeutic option could be to directly inhibit Rankl expression by small interfering RNAs (Rkl‐siRNAs) and combine these molecules with chemotherapy to counteract the osteosarcoma development more efficiently. An efficient siRNA sequence directed against both mouse and rat mRNAs coding Rankl was first validated in vitro and tested in two models of osteosarcoma: a syngenic osteolytic POS‐1 model induced in immunocompetent mice and a xenograft osteocondensant model of rat OSRGA in athymic mice. Intratumor injections of Rankl‐directed siRNAs in combination with the cationic liposome RPR209120/DOPE reduced the local and systemic Rankl production and protected bone from paratumor osteolysis. Although Rkl‐siRNAs alone had no effect on tumor development in both osteosarcoma models, it significantly blocked tumor progression when combined with ifosfamide compared with chemotherapy alone. Our results indicate that siRNAs could be delivered using cationic liposomes and thereby could inhibit Rankl production in a specific manner in osteosarcoma models. Moreover, the Rankl inhibition mediated by RNA interference strategy improves the therapeutic response of primary osteosarcoma to chemotherapy. © 2011 American Society for Bone and Mineral Research 相似文献
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《Expert opinion on drug discovery》2013,8(1):19-29
RNA interference (RNAi) and high-content screening (HCS) are powerful technologies that have converged on the early drug discovery process within the last year. RNAi emerged from basic science, where it has become a standard and accepted method for examining gene function. RNAi has achieved this level of recognition because it is a robust technology; however, it is not simple to use, and care needs to be taken to manage the sources of artifacts that can occur when using RNAi. HCS was developed for advanced drug development studies, particularly for toxicology. Recently developed HCS systems are tailored to target validation and high-throughput screening applications. These newer platforms are both faster, and capable of studying many more cellular events than previously possible. It follows that combining RNAi, particularly the screening of RNAi libraries, with HCS would be an obvious step. However, obvious is not synonymous with simple, and combining the technologies requires an understanding of strengths and challenges to each. This review describes RNAi and HCS technologies as they apply to drug target validation, and discusses efforts to integrate them. Particular focus is applied to aspects of HCS that mitigate some of the challenges inherent to RNAi. 相似文献
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RNAi在基因治疗中的应用 总被引:1,自引:0,他引:1
小RNA的作用与应用研究是近年生物学领域的研究热点,其核心技术RNA干扰(RNAi)是动物和植物界普遍存在的一种防御反应,RNAi被细胞内出现的双链RNA(dsRNA)所激活,可以高度特异地抑制同源基因的表达,已经迅速而广泛地应用到基因功能,基因表达调控机制研究等热门领域,并为基因治疗开辟了新的途径。 相似文献
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MicroRNAs(miRNAs)是一类新发现的非编码小RNA分子,是由机体内源基因转录出长约70nt的发夹结构前体,然后被Dicer酶切割后产生的长度约22nt非编码单链核苷酸片段。在翻译水平特异性抑制基因的表达,参与调控了生物的生长和发育等许多复杂的生命过程。最近的研究表明,miRNAs与肿瘤的发生和发展密切相关。该文就miRNAs的结构特点及其在肿瘤研究中的最新进展作一综述。 相似文献