PDF(Pubmed)
Abstract：
The rapid emergence of drug resistance against the mainstream antimalarial drugs has increased the need for development of novel drugs. Recent approaches have embarked on the repurposing of existing drugs to induce cell death via programmed cell death pathways. However, little is known about the ER stress response and programmed cell death pathways of the malaria parasite. In this study, we treated ex vivo Plasmodium berghei cultures with tunicamycin, 5-fluorouracil, and chloroquine as known stress inducer drugs to probe the transcriptional changes of autophagy and apoptosis-related genes (PbATG5, PbATG8, PbATG12, and PbMCA2). Treatments with 5-fluorouracil and chloroquine resulted in the upregulation of all analyzed markers, yet the levels of PbATG5 and PbATG12 were dramatically higher in chloroquine-treated ex vivo cultures. In contrast, tunicamycin treatment resulted in the downregulation of both PbATG8 and PbATG12, and upregulation of PbMCA2. Our results indicate that the malaria parasite responds to various ER stressors by inducing autophagy- and/or apoptosis-like pathways.
摘要：
对主流抗疟药的耐药性的迅速出现增加了对新药开发的需求。最近的方法已经开始重新利用现有药物以通过程序性细胞死亡途径诱导细胞死亡。然而,对疟疾寄生虫的内质网应激反应和程序性细胞死亡途径知之甚少。在这项研究中,我们用衣霉素处理了体外培养的伯氏疟原虫，5-氟尿嘧啶,和氯喹作为已知的应激诱导药物，以探测自噬和凋亡相关基因（PbATG5，PbATG8，PbATG12和PbMCA2）的转录变化。用5-氟尿嘧啶和氯喹处理导致所有分析的标志物上调，然而,在氯喹处理的离体培养物中,PbATG5和PbATG12的水平显著升高.相比之下,衣霉素治疗导致PbATG8和PbATG12的下调和PbMCA2的上调。我们的结果表明，疟疾寄生虫通过诱导自噬和/或凋亡样途径来响应各种ER应激源。
