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在HBV持续性小鼠中针对HBV和TGF-β的短发夹RNA的增强的抗病毒

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发表于 2017-6-22 15:59 |显示全部帖子

    Sci Rep. 2017 Jun 20;7(1):3860. doi: 10.1038/s41598-017-04170-1.
    Enhanced antiviral and antifibrotic effects of short hairpin RNAs targeting HBV and TGF-β in HBV-persistent mice.Ye L1, Kan F1, Yan T1, Cao J1, Zhang L1, Wu Z2, Li W3.
    Author information
    1MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.2Ocular Gene Therapy Core, National Eye Institute, NIH, Bethesda, Maryland, 20892, USA. [email protected].3MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China. [email protected].

    AbstractThe hepatitis B virus (HBV) causes acute and chronic liver infection, which may lead to liver cirrhosis and hepatocellular carcinoma. Current treatments including interferons and nucleotide analogs, have limited therapeutic effects, underscoring the need to identify effective therapeutic options to inhibit HBV replication and prevent complications. Previous animal models mimicking chronic HBV infection do not faithfully reflect disease progression in humans. Here, we used our established HBV-persistent mouse line with liver fibrosis to evaluate the efficacy of novel therapies. The combination of two short hairpin RNAs (dual-shRNA) against different coding regions of HBV delivered by a self-complementary AAV vector showed better antiviral effects than single shRNA both in vitro and in HBV-persistent mice. The dual-shRNA also exhibited stronger antifibrotic activity in vivo. Vector carrying shRNA against TGF-β, though did not inhibit HBV replication alone, enhanced the antiviral and antifibrotic activities of single and dual HBV shRNAs. Co-administration of TGF-β shRNA and HBV dual-shRNA decreased HBV DNA, HBV RNA, HBsAg, HBeAg, and liver fibrosis markers in serum and tissues, and improved liver morphology more effectively than single treatments. Our results suggest that the combination of shRNAs against HBV and TGF-β could be developed into a viable treatment for human HBV infection.


    PMID:28634402DOI:10.1038/s41598-017-04170-1



Rank: 8Rank: 8

现金
62111 元 
精华
26 
帖子
30441 
注册时间
2009-10-5 
最后登录
2022-12-28 

才高八斗

发表于 2017-6-22 15:59 |显示全部帖子
Sci Rep。2017 Jun 20; 7(1):3860。 doi:10.1038 / s41598-017-04170-1。
在HBV持续性小鼠中针对HBV和TGF-β的短发夹RNA的增强的抗病毒和抗纤维化作用。
叶L1,蔡Yan,严Yan,曹继1,张丽,吴泽2,李。3。
作者信息

1
    中国医学科学院北京协和医学院病原生物学研究所病原体系生物学重点实验室,北京100730。
2
    Ocular Gene Therapy Core,National Eye Institute,NIH,Bethesda,Maryland,20892,USA。 [email protected]
3
    中国医学科学院北京协和医学院病原生物学研究所病原体系生物学重点实验室,北京100730。 [email protected]

抽象

乙型肝炎病毒(HBV)引起急性和慢性肝脏感染,可能导致肝硬化和肝细胞癌。包括干扰素和核苷酸类似物在内的当前治疗具有有限的治疗效果,强调需要鉴定有效的治疗选择以抑制HBV复制并预防并发症。以前的模仿慢性HBV感染的动物模型不能忠实地反映人类的疾病进展。在这里,我们使用我们建立的HBV持续性小鼠线与肝纤维化来评估新疗法的疗效。通过自身互补的AAV载体递送的针对HBV的不同编码区的两个短发夹RNA(双重shRNA)的组合在体外和HBV持续小鼠中显示比单一shRNA更好的抗病毒作用。双重shRNA也体内抗纤维化活性更强。携带shRNA对TGF-β的载体虽然没有单独抑制HBV复制,增强了单抗和双重HBV shRNA的抗病毒和抗纤维化活性。 TGF-βshRNA和HBV双重shRNA的共同施用可以降低血清和组织中的HBV DNA,HBV RNA,HBsAg,HBeAg和肝纤维化指标,并且比单次治疗更有效地改善肝脏形态。我们的研究结果表明,shRNA与HBV和TGF-β的组合可以发展成为人类HBV感染的可行治疗。

结论:
    28634402
DOI:
    10.1038 / s41598-017-04170-1
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