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Validation of Poly(Propylene Imine) Glycodendrimers Towards Their Anti-prion Conversion Efficiency.

聚丙烯亚胺糖树枝状大分子对其抗朊病毒转化效率的验证。

  • 影响因子:4.05
  • DOI:10.1007/s12035-019-01837-w
  • 作者列表:"Schmitz M","Candelise N","Kanata E","Llorens F","Thüne K","Villar-Piqué A","da Silva Correia SM","Dafou D","Sklaviadis T","Appelhans D","Zerr I
  • 发表时间:2020-04-01
Abstract

:Prion diseases, such as the sporadic Creutzfeldt-Jakob disease (sCJD), are a class of fatal neurodegenerative disorders. Currently, there is no efficient treatment or therapy available. Hence, the search for molecules that may inhibit the conversion of the cellular prion protein (PrPC) into its pathological counterpart PrPScrapie (PrPSc) is of great urgency. Here, we report the generation- and dose-dependent biological action of dense-shell poly(propylene imine) (PPI) glycodendrimers by using scrapie-infected neuroblastoma (ScN2a) cells and the real-time quaking-induced conversion assay (RT-QuIC) for validation of anti-prion efficiencies. Whereas the 2nd and 3rd generation of PPI glycodendrimers exhibited anti-prion conversion efficiency in ScN2a cells validated by RT-QuIC analysis, we observed that the 4th generation of glycodendrimers had shown no significant effect. Translational RT-QuIC studies conducted with human prions derived from sCJD patients indicated an anti-prion conversion effect (not on PrPRes degradation) of PPI glycodendrimers against human prions with the highest inhibitory activity of the 4th generation of PPI glycodendrimers towards prion aggregation compared to the 2nd and 3rd generation. In conclusion, our study highlights the potential of PPI glycodendrimers as therapeutic compounds due to their anti-conversion activity on human prions in a PrPSc strain depending manner.

摘要

: 朊病毒疾病,如散发性克雅氏病 (sCJD),是一类致命的神经退行性疾病。目前,没有有效的治疗或疗法可用。因此,寻找可能抑制细胞朊蛋白 (PrPC) 转化为其病理对应物 PrPScrapie (PrPSc) 的分子迫在眉睫。在此,我们报道了通过使用羊瘙痒感染的神经母细胞瘤 (ScN2a) 的致密壳聚 (丙烯亚胺) (PPI) 糖树枝状大分子的产生和剂量依赖性生物作用细胞和实时抖动诱导转化试验 (RT-QuIC) 用于验证抗朊病毒效率。而在 RT-QuIC 分析验证的 ScN2a 细胞中,第2 和第3 代 PPI 糖树枝状分子表现出抗朊病毒转化效率,我们观察到 4 代糖树枝状分子没有表现出显著影响。用来自 sCJD 患者的人朊病毒进行的翻译 RT-QuIC 研究表明抗朊病毒转换作用 (而不是对 PrPRes 降解) PPI 糖树状大分子对人朊病毒的抑制活性最高,与第2 代和第3 代相比,第 4 代 PPI 糖树状大分子对朊病毒聚集的抑制活性最高。总之,我们的研究强调了 PPI 糖树枝状分子作为治疗化合物的潜力,因为它们以 PrPSc 菌株依赖的方式对人朊病毒具有抗转化活性。

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相关文献
影响因子:3.85
发表时间:2020-01-14
来源期刊:Neurology
DOI:10.1212/WNL.0000000000008680
作者列表:["Maddox RA","Person MK","Blevins JE","Abrams JY","Appleby BS","Schonberger LB","Belay ED"]

METHODS:OBJECTIVE:To report the incidence of prion disease in the United States. METHODS:Prion disease decedents were retrospectively identified from the US national multiple cause-of-death data for 2003-2015 and matched with decedents in the National Prion Disease Pathology Surveillance Center (NPDPSC) database through comparison of demographic variables. NPDPSC decedents with neuropathologic or genetic test results positive for prion disease for whom no match was found in the multiple cause-of-death data were added as cases for incidence calculations; those with cause-of-death data indicating prion disease but with negative neuropathology results were removed. Age-specific and age-adjusted average annual incidence rates were then calculated. RESULTS:A total of 5,212 decedents were identified as having prion disease, for an age-adjusted average annual incidence of 1.2 cases per million population (range 1.0 per million [2004 and 2006] to 1.4 per million [2013]). The median age at death was 67 years. Ten decedents were <30 years of age (average annual incidence of 6.2 per billion); only 2 of these very young cases were sporadic forms of prion disease. Average annual incidence among those ≥65 years of age was 5.9 per million. CONCLUSIONS:Prion disease incidence can be estimated by augmenting mortality data with the results of neuropathologic and genetic testing. Cases <30 years of age were extremely rare, and most could be attributed to exogenous factors or the presence of a genetic mutation. Continued vigilance for prion diseases in all age groups remains prudent.

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影响因子:2.78
发表时间:2020-01-08
DOI:10.1080/07391102.2019.1708794
作者列表:["Soto P","Claflin IA","Bursott AL","Schwab-McCoy AD","Bartz JC"]

METHODS::The conformational conversion of the cellular prion protein (PrPC) to the misfolded and aggregated isoform, termed scrapie prion protein (PrPSc), is key to the development of a group of neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). Although the conversion mechanism is not fully understood, the role of gene polymorphisms in varying susceptibilities to prion diseases is well established. In ovine, specific gene polymorphisms in PrPC alter prion disease susceptibility: the Valine136-Glutamine171 variant (Susceptible structure) displays high susceptibility to classical scrapie while the Alanine136-Arginine171 variant (Resistant structure) displays reduced susceptibility. The opposite trend has been reported in atypical scrapie. Despite the differentiation between classical and atypical scrapie, a complete understanding of the effect of polymorphisms on the structural dynamics of PrPC is lacking. From our structural bioinformatics study, we propose that polymorphisms locally modulate the network of residue interactions in the globular C-terminus of the ovine recombinant prion protein while maintaining the overall fold. Although the two variants we examined exhibit a densely connected group of residues that includes both β-sheets, the β2-α2 loop and the N-terminus of α-helix 2, only in the Resistant structure do most residues of α-helix 2 belong to this group. We identify the structural role of Valine136Alanine and Glutamine171Arginine: modulation of residue interaction networks that affect the connectivity between α-helix 2 and α-helix 3. We propose blocking interactions of residue 171 as a potential target for the design of therapeutics to prevent efficient PrPC misfolding. We discuss our results in the context of initial PrPC conversion and extrapolate to recently proposed PrPSc structures.Communicated by Ramaswamy H. Sarma.

影响因子:4.10
发表时间:2020-01-09
DOI:10.1093/infdis/jiz646
作者列表:["Espinosa JC","Marín-Moreno A","Aguilar-Calvo P","Benestad SL","Andreoletti O","Torres JM"]

METHODS::Although experimental transmission of bovine spongiform encephalopathy (BSE) to pigs and transgenic mice expressing pig cellular prion protein (PrPC) (porcine PrP [PoPrP]-Tg001) has been described, no natural cases of prion diseases in pig were reported. This study analyzed pig-PrPC susceptibility to different prion strains using PoPrP-Tg001 mice either as animal bioassay or as substrate for protein misfolding cyclic amplification (PMCA). A panel of isolates representatives of different prion strains was selected, including classic and atypical/Nor98 scrapie, atypical-BSE, rodent scrapie, human Creutzfeldt-Jakob-disease and classic BSE from different species. Bioassay proved that PoPrP-Tg001-mice were susceptible only to the classic BSE agent, and PMCA results indicate that only classic BSE can convert pig-PrPC into scrapie-type PrP (PrPSc), independently of the species origin. Therefore, conformational flexibility constraints associated with pig-PrP would limit the number of permissible PrPSc conformations compatible with pig-PrPC, thus suggesting that pig-PrPC may constitute a paradigm of low conformational flexibility that could confer high resistance to the diversity of prion strains.

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