首页> 外文OA文献 >In Vitro and In Vivo Effects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum.
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In Vitro and In Vivo Effects of the Bumped Kinase Inhibitor 1294 in the Related Cyst-Forming Apicomplexans Toxoplasma gondii and Neospora caninum.

机译:颠簸的激酶抑制剂1294在相关的形成囊肿的蚜虫弓形虫和犬新孢子虫的体内和体外效应。

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摘要

We report on the in vitro effects of the bumped kinase inhibitor 1294 (BKI-1294) in cultures of virulent Neospora caninum isolates Nc-Liverpool (Nc-Liv) and Nc-Spain7 and in two strains of Toxoplasma gondii (RH and ME49), all grown in human foreskin fibroblasts. In these parasites, BKI-1294 acted with 50% inhibitory concentrations (IC50s) ranging from 20 nM (T. gondii RH) to 360 nM (N. caninum Nc-Liv), and exposure of intracellular stages to 1294 led to the nondisjunction of newly formed tachyzoites, resulting in the formation of multinucleated complexes similar to complexes previously observed in BKI-1294-treated N. caninum beta-galactosidase-expressing parasites. However, such complexes were not seen in a transgenic T. gondii strain that expressed CDPK1 harboring a mutation (G to M) in the gatekeeper residue. In T. gondii ME49 and N. caninum Nc-Liv, exposure of cultures to BKI-1294 resulted in the elevated expression of mRNA coding for the bradyzoite marker BAG1. Unlike in bradyzoites, SAG1 expression was not repressed. Immunofluorescence also showed that these multinucleated complexes expressed SAG1 and BAG1 and the monoclonal antibody CC2, which binds to a yet unidentified bradyzoite antigen, also exhibited increased labeling. In a pregnant mouse model, BKI-1294 efficiently inhibited vertical transmission in BALB/c mice experimentally infected with one of the two virulent isolates Nc-Liv or Nc-Spain7, demonstrating proof of concept that this compound protected offspring from vertical transmission and disease. The observed deregulated antigen expression effect may enhance the immune response during BKI-1294 therapy and will be the subject of future studies.
机译:我们报告了颠簸激酶抑制剂1294(BKI-1294)在强毒新孢子虫分离株Nc-Liverpool(Nc-Liv)和Nc-Spain7以及两种弓形虫菌株(RH和ME49)中的体外作用,全部在人包皮成纤维细胞中生长。在这些寄生虫中,BKI-1294发挥50%抑制浓度(IC50s)的作用,范围从20 nM(T. gondii RH)到360 nM(N. caninum Nc-Liv),而细胞内阶段暴露于1294导致不分离新形成的速殖子,导致形成多核复合物,类似于先前在BKI-1294处理的犬新孢子虫β-半乳糖苷酶表达寄生虫中观察到的复合物。但是,这种复合体在表达CDPK1的转基因弓形虫菌株中看不到,该CDPK1在关守残基中具有突变(从G到M)。在弓形虫ME49和犬新孢子虫Nc-Liv中,将培养物暴露于BKI-1294会导致编码缓殖子标记BAG1的mRNA表达升高。与缓殖子不同,SAG1的表达不被抑制。免疫荧光法还显示,这些多核复合物表达了SAG1和BAG1,与尚未确定的缓殖子抗原结合的单克隆抗体CC2也显示出增加的标记。在怀孕的小鼠模型中,BKI-1294有效抑制了用两种强毒分离株Nc-Liv或Nc-Spain7中的一种感染的BALB / c小鼠的垂直传播,这证明了该化合物保护后代免受垂直传播和疾病的侵害。观察到的抗原表达失调效应可能会增强BKI-1294治疗期间的免疫反应,并将成为未来研究的主题。

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