Abstract:
BACKGROUND:The options for treating the fatal disease human African trypanosomiasis are limited to a few drugs that are toxic or facing increasing resistance. New drugs that kill the causative agents, subspecies of Trypanosoma brucei, are therefore urgently needed. Little is known about the cellular mechanisms that lead to death of the pathogenic bloodstream stage. METHODOLOGY/PRINCIPAL FINDINGS:We therefore conducted the first side by side comparison of the cellular effects of multiple death inducers that target different systems in bloodstream form parasites, including six drugs (pentamidine, prostaglandin D(2), quercetin, etoposide, camptothecin, and a tetrahydroquinoline) and six RNAi knockdowns that target distinct cellular functions. All compounds tested were static at low concentrations and killed at high concentrations. Dead parasites were rapidly quantified by forward and side scatter during flow cytometry, as confirmed by ethidium homodimer and esterase staining, making these assays convenient for quantitating parasite death. The various treatments yielded different combinations of defects in mitochondrial potential, reactive oxygen species, cell cycle, and genome segregation. No evidence was seen for phosphatidylserine exposure, a marker of apoptosis. Reduction in ATP levels lagged behind decreases in live cell number. Even when the impact on growth was similar at 24 hours, drug-treated cells showed dramatic differences in their ability to further proliferate, demonstrating differences in the reversibility of effects induced by the diverse compounds. CONCLUSIONS/SIGNIFICANCE:Parasites showed different phenotypes depending on the treatment, but none of them were clear predictors of whether apparently live cells could go on to proliferate after drugs were removed. We therefore suggest that clonal proliferation assays may be a useful step in selecting anti-trypanosomal compounds for further development. Elucidating the genetic or biochemical events initiated by the compounds with the most profound effects on subsequent proliferation may identify new means to activate death pathways.
journal_name
PLoS Negl Trop Disjournal_title
PLoS neglected tropical diseasesauthors
Worthen C,Jensen BC,Parsons Mdoi
10.1371/journal.pntd.0000678subject
Has Abstractpub_date
2010-05-04 00:00:00pages
e678issue
5eissn
1935-2727issn
1935-2735journal_volume
4pub_type
杂志文章abstract::Cystic echinococcosis (CE) is distributed worldwide, extending from China to the Middle East and from Mediterranean countries to the sub-Saharan Africa and South America. According to WHO, one million people around the world are suffering from CE with an estimated burden of 183,573 DALYs. The annual monetary burden of...
journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
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pub_type: 杂志文章
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abstract::We briefly review cysteine proteases (orthologs of mammalian cathepsins B, L, F, and C) that are expressed in flatworm and nematode parasites. Emphasis is placed on enzyme activities that have been functionally characterized, are associated with the parasite gut, and putatively contribute to degrading host proteins to...
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pub_type: 杂志文章,评审
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abstract::During the recent Ebola outbreak in West Africa several international mobile laboratories were deployed to the mainly affected countries Guinea, Sierra Leone and Liberia to provide ebolavirus diagnostic capacity. Additionally, imported cases and small outbreaks in other countries required global preparedness for Ebola...
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pub_type: 杂志文章,多中心研究
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abstract:BACKGROUND:Soil-transmitted helminth (STH) infection leads to malnutrition and anemia, and has been linked to impaired child development. Previous research on this topic is limited and mostly conducted in school-age children. The goal of this study was to determine the effect of the number of detected STH infections be...
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doi:10.1371/journal.pntd.0003984
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0001668
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章,评审
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更新日期:2013-06-06 00:00:00
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pub_type: 杂志文章,评审
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更新日期:2015-06-25 00:00:00
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更新日期:2015-02-10 00:00:00
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更新日期:2019-02-21 00:00:00
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pub_type: 杂志文章
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更新日期:2017-12-21 00:00:00