Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine Nanoparticles.
Targeting Beclin1 as an Adjunctive Therapy against HIV Using Mannosylated Polyethylenimine Nanoparticles.
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DOI：
10.3390/pharmaceutics13020223
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发表时间：
2021-02-06
期刊：
影响因子：
5.4
通讯作者：
El-Hage N
中科院分区：
文献类型：
--
作者：
Rodriguez M;Soler Y;Muthu Karuppan MK;Zhao Y;Batrakova EV;El-Hage N
使用基于纳米颗粒的RNA干扰（RNAi），我们以前已经表明，沉默宿主自噬蛋白Beclin 1，在HIV感染的人小胶质细胞和星形胶质细胞限制HIV复制及其病毒相关的炎症反应。在这里，我们证实了Beclin 1小干扰RNA（siBeclin 1）作为抗病毒和抗炎治疗的有效性，在感染HIV的骨髓人类小胶质细胞和原代人类星形胶质细胞中，无论是否暴露于联合抗逆转录病毒（cART）药物。为了特异性靶向人小胶质细胞和人星形胶质细胞，我们使用了由线性阳离子聚乙烯亚胺（PEI）与甘露糖（Man）缀合并用siBeclin 1包封的纳米颗粒（NP）。PEI-Man NP的靶特异性在体外使用用异硫氰酸荧光素（FITC）包封的NP转染的人神经元和神经胶质细胞来证实。将PEI-Man-siBeclin 1 NP鼻内递送至健康C57 BL/6小鼠，以报告使用茎环RT-PCR测量的siBeclin 1在脑的不同区域中的生物分布。在用PEI-Man-siRNA NP处理后1-48小时回收的死后脑显示在活化时调节的趋化因子的分泌方面没有显著变化，正常T细胞表达和分泌（RANTES）和单核细胞趋化蛋白-1（MCP-1），并显示与磷酸盐相比，细胞因子白细胞介素6（IL-6）和肿瘤坏死因子α（TNF-α）的分泌显著降低。缓冲盐水（PBS）处理的脑。尼氏染色显示，与PBS处理的脑相比，神经元结构之间的差异最小，这与无不良行为影响相关。为了确认PEI-siBeclin 1在活小鼠中的脑和外周器官分布，我们使用体内成像系统（IVIS）并证明了通过鼻内给药的siBeclin 1的显著脑蓄积。
Using nanoparticle-based RNA interference (RNAi), we have previously shown that silencing the host autophagic protein, Beclin1, in HIV-infected human microglia and astrocytes restricts HIV replication and its viral-associated inflammatory responses. Here, we confirmed the efficacy of Beclin1 small interfering RNA (siBeclin1) as an adjunctive antiviral and anti-inflammatory therapy in myeloid human microglia and primary human astrocytes infected with HIV, both with and without exposure to combined antiretroviral (cART) drugs. To specifically target human microglia and human astrocytes, we used a nanoparticle (NP) comprised of linear cationic polyethylenimine (PEI) conjugated with mannose (Man) and encapsulated with siBeclin1. The target specificity of the PEI-Man NP was confirmed in vitro using human neuronal and glial cells transfected with the NP encapsulated with fluorescein isothiocyanate (FITC). PEI-Man-siBeclin1 NPs were intranasally delivered to healthy C57BL/6 mice in order to report the biodistribution of siBeclin1 in different areas of the brain, measured using stem-loop RT-PCR. Postmortem brains recovered at 1–48 h post-treatment with the PEI-Man-siRNA NP showed no significant changes in the secretion of the chemokines regulated on activation, normal T cell expressed and secreted (RANTES) and monocyte chemotactic protein-1 (MCP-1) and showed significant decreases in the secretion of the cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) when compared to phosphate-buffered saline (PBS)-treated brains. Nissl staining showed minimal differences between the neuronal structures when compared to PBS-treated brains, which correlated with no adverse behavioral affects. To confirm the brain and peripheral organ distribution of PEI-siBeclin1 in living mice, we used the In vivo Imaging System (IVIS) and demonstrated a significant brain accumulation of siBeclin1 through intranasal administration.
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影响因子：
--
作者：
Craft, Suzanne;Baker, Laura D.;Montine, Thomas J.;Minoshima, Satoshi;Watson, G. Stennis;Claxton, Amy;Arbuckle, Matthew;Callaghan, Maureen;Tsai, Elaine;Plymate, Stephen R.;Green, Pattie S.;Leverenz, James;Cross, Donna;Gerton, Brooke
通讯作者：
Gerton, Brooke
神经元中的自噬诱导和自噬体清除：与阿尔茨海默氏病自噬病理学的关系。
影响因子：
5.3
作者：
Boland, Barry;Kumar, Asok;Lee, Sooyeon;Platt, Frances M.;Wegiel, Jerzy;Yu, W. Haung;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
DOI：
10.1016/j.jconrel.2014.09.006
发表时间：
2014-11-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Chen P;Zhang X;Jia L;Prud'homme RK;Szekely Z;Sinko PJ
通讯作者：
Sinko PJ
影响因子：
5.3
作者：
Fields, Jerel;Dumaop, Wilmar;Masliah, Eliezer
通讯作者：
Masliah, Eliezer
DOI：
10.1212/01.con.0000423849.24900.ec
发表时间：
2012-12-01
期刊：
Continuum (Minneapolis, Minn.)
影响因子：
--
作者：
Kranick, Sarah M;Nath, Avindra
通讯作者：
Nath, Avindra