Rivo Y B, Alkarimah A, Ramadhani N N, Cahyono A W, Laksmi D A, Winarsih S, Fitri L E
Biomedical Sciences Master Study Program, Faculty of Medicine, University of Brawijaya, Jl Veteran, Malang, Indonesia.
Trop Biomed. 2013 Jun;30(2):291-300.
Streptomyces hygroscopicus Hygroscopicus, a member of family of Actinomycetes produces eponemycin a proteasome inhibitor that can inhibit Ubiquitin-Proteasome System (UPS) function in eukaryotic cell. Previous study showed that coronamycin, an active substrate isolated from Streptomyces sp. can act as anti-plasmodial, antibacterial, and antifungal, however the research did not show the mechanism of coronamycin in inhibiting the growth of Plasmodium. This research was done to reveal if eponemycin that is contained in metabolite extract of S. hygroscopicus can inhibit UPS function of Plasmodium berghei. This study was an experimental study using P. berghei infected Balb/C mice as malaria model. Samples were divided into 1 control group (group infected with P. berghei without treatment) and 3 treatment groups (mice infected with P. berghei and treated intra-peritoneal with metabolite extract of S. hygroscopicus dose 130 μg/kgBW, 580 μg/kgBW, and 2600 μg/kgBW for 5 days). The degree of parasitemia and morphology of the parasite were measured from the first day of malaria induction until the last treatment. The accumulation level of polyubiquitin was measured using Western blot and ELISA method. The degree of parasitemia on day 6 showed significant differences among treatment groups and control (p=0,000). Percentage of inhibition showed significant differences between control and group treated with metabolite extract of S. hygroscopicus 2600 μg/kgBW. An increasing dose of extract of S. hygroscopicus followed by an increasing of inhibition in parasite growth (r=0,850). Probit analysis showed that ED50 was 9.418 μg/kgBW. There was a change in morphology of the parasite after treatment. Parasite morphology became crisis form. There was an accumulation of polyubiquitinated protein in the group treated with metabolite extract of S. hygroscopicus 2600 μg/kgBW. It can be concluded that analog eponemycin in metabolite of S. hygroscopicus is a potential candidate for new malarial drug by inhibiting UPS function of the parasite and cause stress and dead of the parasite.
吸水链霉菌，放线菌家族的一员，可产生埃坡霉素，一种蛋白酶体抑制剂，能抑制真核细胞中的泛素 - 蛋白酶体系统（UPS）功能。先前的研究表明，从链霉菌属分离出的活性底物冠霉素可起到抗疟原虫、抗菌和抗真菌的作用，然而该研究并未表明冠霉素抑制疟原虫生长的机制。本研究旨在揭示吸水链霉菌代谢物提取物中所含的埃坡霉素是否能抑制伯氏疟原虫的UPS功能。本研究是以感染伯氏疟原虫的Balb/C小鼠作为疟疾模型的实验研究。样本分为1个对照组（感染伯氏疟原虫未治疗组）和3个治疗组（感染伯氏疟原虫并腹腔注射剂量为130 μg/kg体重、580 μg/kg体重和2600 μg/kg体重的吸水链霉菌代谢物提取物，持续5天）。从疟疾诱导的第一天到最后一次治疗，测量疟原虫血症程度和寄生虫形态。使用蛋白质免疫印迹法和酶联免疫吸附测定法测量多聚泛素的积累水平。第6天的疟原虫血症程度在治疗组和对照组之间显示出显著差异（p = 0.000）。抑制百分比在对照组和用2600 μg/kg体重的吸水链霉菌代谢物提取物治疗的组之间显示出显著差异。吸水链霉菌提取物剂量增加，随后寄生虫生长抑制增加（r = 0.850）。概率分析表明，半数有效剂量（ED50）为9.418 μg/kg体重。治疗后寄生虫形态发生了变化。寄生虫形态变为危机形态。在用2600 μg/kg体重的吸水链霉菌代谢物提取物治疗的组中存在多聚泛素化蛋白的积累。可以得出结论，吸水链霉菌代谢物中的类似物埃坡霉素是一种潜在的新型抗疟药物候选物，它通过抑制寄生虫的UPS功能，导致寄生虫应激和死亡。
