What's new for 'Trypanosomatids' in PubMed

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Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results

Items 1 - 10 of 14

1.	PLoS Negl Trop Dis. 2011 Feb 8;5(2):e956. 2,4-Diaminopyrimidines as Potent Inhibitors of Trypanosoma brucei and Identification of Molecular Targets by a Chemical Proteomics Approach. Mercer L, Bowling T, Perales J, Freeman J, Nguyen T, Bacchi C, Yarlett N, Don R, Jacobs R, Nare B. SCYNEXIS Inc., Research Triangle Park, North Carolina, United States of America. Abstract BACKGROUND: There is an urgent need to develop new, safe and effective treatments for human African trypanosomiasis (HAT) because current drugs have extremely poor safety profiles and are difficult to administer. Here we report the discovery of 2,4-diaminopyrimidines, exemplified by 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid phenylamide (SCYX-5070), as potent inhibitors of Trypanosoma brucei and the related trypanosomatid protozoans Leishmania spp. METHODOLOGY/PRINCIPAL FINDINGS: In this work we show that loss of T. brucei viability following SCYX-5070 exposure was dependent on compound concentration and incubation time. Pulse incubation of T. brucei with SCYX-5070 demonstrates that a short period of exposure (10-12 hrs) is required to produce irreversible effects on survival or commit the parasites to death. SCYX-5070 cured an acute trypanosomiasis infection in mice without exhibiting signs of compound related acute or chronic toxicity. To identify the molecular target(s) responsible for the mechanism of action of 2,4-diaminopyrimidines against trypanosomatid protozoa, a representative analogue was immobilized on a solid matrix (sepharose) and used to isolate target proteins from parasite extracts. Mitogen-activated protein kinases (MAPKs) and cdc2-related kinases (CRKs) were identified as the major proteins specifically bound to the immobilized compound, suggesting their participation in the pharmacological effects of 2,4-diaminopyrimidines against trypanosomatid protozoan parasites. CONCLUSIONS/SIGNIFICANCE: Results show that 2,4-diaminopyrimidines have a good in vitro and in vivo pharmacological profile against trypanosomatid protozoans and that MAPKs and CRKs are potential molecular targets of these compounds. The 2,4-diminipyrimidines may serve as suitable leads for the development of novel treatments for HAT.
	PMID: 21347454 [PubMed - in process]
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2.	PLoS Negl Trop Dis. 2011 Feb 8;5(2):e957. Population Vulnerability and Disability in Kenya's Tsetse Fly Habitats. Grady SC, Messina JP, McCord PF. Department of Geography, Michigan State University, East Lansing, Michigan, United States of America. Abstract BACKGROUND: Human African Trypanosomiasis (HAT), also referred to as sleeping sickness, and African Animal Trypanosomaisis (AAT), known as nagana, are highly prevalent parasitic vector-borne diseases in sub-Saharan Africa. Humans acquire trypanosomiasis following the bite of a tsetse fly infected with the protozoa Trypanosoma brucei (T.b.) spp. -i.e., T.b. gambiense in West and Central Africa and T.b. rhodesiense in East and Southern Africa. Over the last decade HAT diagnostic capacity to estimate HAT prevalence has improved in active case-finding areas but enhanced passive surveillance programs are still lacking in much of rural sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: This retrospective-cross-sectional study examined the use of national census data (1999) to estimate population vulnerability and disability in Kenya's 7 tsetse belts to assess the potential of HAT-acquired infection in those areas. A multilevel study design estimated the likelihood of disability in individuals, nested within households, nested within tsetse fly habitats of varying levels of poverty. Residents and recent migrants of working age were studied. Tsetse fly's impact on disability was conceptualised via two exposure pathways: directly from the bite of a pathogenic tsetse fly resulting in HAT infection or indirectly, as the potential for AAT takes land out of agricultural production and diseased livestock leads to livestock morbidity and mortality, contributing to nutritional deficiencies and poverty. Tsetse belts that were significantly associated with increased disability prevalence were identified and the direct and indirect exposure pathways were evaluated. CONCLUSIONS/SIGNIFICANCE: Incorporating reports on disability from the national census is a promising surveillance tool that may enhance future HAT surveillance programs in sub-Saharan Africa. The combined burdens of HAT and AAT and the opportunity costs of agricultural production in AAT areas are likely contributors to disability within tsetse-infested areas. Future research will assess changes in the spatial relationships between high tsetse infestation and human disability following the release of the Kenya 2009 census at the local level.
	PMID: 21347453 [PubMed - in process]
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3.	PLoS Negl Trop Dis. 2011 Feb 8;5(2):e960. Options for active case detection of visceral leishmaniasis in endemic districts of India, Nepal and bangladesh, comparing yield, feasibility and costs. Singh SP, Hirve S, Huda MM, Banjara MR, Kumar N, Mondal D, Sundar S, Das P, Gurung CK, Rijal S, Thakur CP, Varghese B, Kroeger A. Department of Community Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. Abstract BACKGROUND: The VL elimination strategy requires cost-effective tools for case detection and management. This intervention study tests the yield, feasibility and cost of 4 different active case detection (ACD) strategies (camp, index case, incentive and blanket approach) in VL endemic districts of India, Nepal and Bangladesh. METHODOLOGY/PRINCIPAL FINDINGS: First, VL screening (fever more than 14 days, splenomegaly, rK39 test) was performed in camps. This was followed by house to house screening (blanket approach). An analysis of secondary VL cases in the neighborhood of index cases was simulated (index case approach). A second screening round was repeated 4-6 months later. In another sub-district in India and Nepal, health workers received incentives for detecting new VL cases over a 4 month period (incentive approach). This was followed by house screening for undetected cases. A total of 28 new VL cases were identified by blanket approach in the 1(st) screening round, and used as ACD gold standard. Of these, the camp approach identified 22 (sensitivity 78.6%), index case approach identified 12 (sensitivity - 42.9%), and incentive approach identified 23 new VL cases out of 29 cases detected by the house screening (sensitivity - 79.3%). The effort required to detect a new VL case varied (blanket approach - 1092 households, incentive approach - 978 households; index case approach - 788 households had to be screened). The cost per new case detected varied (camp approach $21 - $661; index case approach $149 - $200; incentive based approach $50 - $543; blanket screening $112 - $629). The 2(nd) screening round yielded 20 new VL cases. Sixty and nine new PKDL cases were detected in the first and second round respectively. CONCLUSIONS/SIGNIFICANCE: ACD in the VL elimination campaign has a high yield of new cases at programme costs which vary according to the screening method chosen. Countries need the right mix of approaches according to the epidemiological profile, affordability and organizational feasibility.
	PMID: 21347452 [PubMed - in process]
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4.	PLoS Negl Trop Dis. 2011 Feb 8;5(2):e961. Phylogeography and Taxonomy of Trypanosoma brucei. Balmer O, Beadell JS, Gibson W, Caccone A. Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland. Abstract BACKGROUND: Characterizing the evolutionary relationships and population structure of parasites can provide important insights into the epidemiology of human disease. METHODOLOGY/PRINCIPAL FINDINGS: We examined 142 isolates of Trypanosoma brucei from all over sub-Saharan Africa using three distinct classes of genetic markers (kinetoplast CO1 sequence, nuclear SRA gene sequence, eight nuclear microsatellites) to clarify the evolutionary history of Trypanosoma brucei rhodesiense (Tbr) and T. b. gambiense (Tbg), the causative agents of human African trypanosomosis (sleeping sickness) in sub-Saharan Africa, and to examine the relationship between Tbr and the non-human infective parasite T. b. brucei (Tbb) in eastern and southern Africa. A Bayesian phylogeny and haplotype network based on CO1 sequences confirmed the taxonomic distinctness of Tbg group 1. Limited diversity combined with a wide geographical distribution suggested that this parasite has recently and rapidly colonized hosts across its current range. The more virulent Tbg group 2 exhibited diverse origins and was more closely allied with Tbb based on COI sequence and microsatellite genotypes. Four of five COI haplotypes obtained from Tbr were shared with isolates of Tbb, suggesting a close relationship between these taxa. Bayesian clustering of microsatellite genotypes confirmed this relationship and indicated that Tbr and Tbb isolates were often more closely related to each other than they were to other members of the same subspecies. Among isolates of Tbr for which data were available, we detected just two variants of the SRA gene responsible for human infectivity. These variants exhibited distinct geographical ranges, except in Tanzania, where both types co-occurred. Here, isolates possessing distinct SRA types were associated with identical COI haplotypes, but divergent microsatellite signatures. CONCLUSIONS/SIGNIFICANCE: Our data provide strong evidence that Tbr is only a phenotypic variant of Tbb; while relevant from a medical perspective, Tbr is not a reproductively isolated taxon. The wide distribution of the SRA gene across diverse trypanosome genetic backgrounds suggests that a large amount of genetic diversity is potentially available with which human-infective trypanosomes may respond to selective forces such as those exerted by drugs.
	PMID: 21347445 [PubMed - in process]
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5.	PLoS One. 2011 Feb 8;6(2):e14666. Reactive Oxygen Species Production and Mitochondrial Dysfunction Contribute to Quercetin Induced Death in Leishmania amazonensis. Fonseca-Silva F, Inacio JD, Canto-Cavalheiro MM, Almeida-Amaral EE. Laboratório de Bioquímica de Tripanosomatideos, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brazil. Abstract BACKGROUND: Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania, affects more than 12 million people worldwide. Quercetin has generated considerable interest as a pharmaceutical compound with a wide range of therapeutic activities. One such activity is exhibited against the bloodstream parasite Trypanosoma brucei and amastigotes of Leishmania donovani. However, the mechanism of protozoan action of quercetin has not been studied. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we report here the mechanism for the antileishmanial activity of quercetin against Leishmania amazonensis promastigotes. Quercetin inhibited L. amazonensis promastigote growth in a dose- and time- dependent manner beginning at 48 hours of treatment and with maximum growth inhibition observed at 96 hours. The IC(50) for quercetin at 48 hours was 31.4 µM. Quercetin increased ROS generation in a dose-dependent manner after 48 hours of treatment. The antioxidant GSH and NAC each significantly reduced quercetin-induced cell death. In addition, quercetin caused mitochondrial dysfunction due to collapse of mitochondrial membrane potential. CONCLUSIONS/SIGNIFICANCE: The effects of several drugs that interfere directly with mitochondrial physiology in parasites such as Leishmania have been described. The unique mitochondrial features of Leishmania make this organelle an ideal drug target while minimizing toxicity. Quercetin has been described as a pro-oxidant, generating ROS which are responsible for cell death in some cancer cells. Mitochondrial membrane potential loss can be brought about by ROS added directly in vitro or induced by chemical agents. Taken together, our results demonstrate that quercetin eventually exerts its antileishmanial effect on L. amazonensis promastigotes due to the generation of ROS and disrupted parasite mitochondrial function.
	PMID: 21346801 [PubMed - in process]
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6.	J Biol Chem. 2011 Feb 23. [Epub ahead of print] Nifurtimox activation by trypanosomal type I nitroreductases generates cytotoxic nitrile metabol ites. Hall BS, Bot C, Wilkinson SR. Queen Mary University of London, United Kingdom. Abstract The prodrug nifurtimox has been used for more than 40 years to treat Chagas disease and forms part of a recently approved combinational therapy that targets West African trypanosomiasis. Despite this, its mode of action is poorly understood. Detection of reactive oxygen and nitrogen intermediates in nifurtimox-treated extracts led to the proposal that this drug induces oxidative stress in the target cell. Here, we outline an alternative mechanism involving reductive activation by a eukaryotic type I nitroreductase. Several enzymes proposed to metabolize nifurtimox, including prostaglandin F2alpha synthase, and cytochrome P450 reductase, were over expressed in bloodstream form Trypanosoma brucei. Only cells with elevated levels of the nitroreductase displayed altered susceptibility to this nitrofuran, implying a key role in drug action. Reduction of nifurtimox by this enzyme was shown to be insensitive to oxygen and yields a product characterized by LC/MS as an unsaturated open chain nitrile. This metabolite was shown to inhibit both parasite and mammalian cell growth at equivalent concentrations, in marked contrast to the parental prodrug. These experiments indicate that the basis for the selectivity of nifurtimox against T. brucei lies in the expression of a parasite-encoded type I nitroreductase.
	PMID: 21345801 [PubMed - as supplied by publisher]
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7.	Vet Res. 2011 Feb 23;42(1):39. [Epub ahead of print] Mechanisms of resistance and susceptibility to experimental visceral l eishmaniosis: BALB/c mouse versus Syrian hamster model. Nieto A, Dominguez-Bernal G, Orden JA, De La Fuente R, Madrid-Elena N, Carrion J. Abstract ABSTRACT: Several animal models have been established to study visceral leishmaniosis (VL), a worldwide vector-borne disease affecting humans and domestic animals that constitutes a serious public health problem. BALB/c mice and Syrian hamsters are the most widely used experimental models. In this paper, we summarize the advantages and disadvantages of these two experimental models and discuss the results obtained using these models in different studies of VL. Studies using the BALB/c mouse model have underscored differences between the liver and spleen in the course of VL, indicating that pathological evaluation of the visceral organs is essential for understanding the immune mechanisms induced by Leishmania infantum infection. The main goal of this review is to collate the relevant literature on Leishmania pathogenesis into a sequence of events, providing a schematic view of the main components of adaptive and innate immunity in the liver and spleen after experimental infection with L. infantum or L. donovani. This review also presents several viewpoints and reflections about some controversial aspects of Leishmania research, including the choice of experimental model, route of administration, inoculum size and the relevance of pathology (intimately linked to parasite persistence): a thorough understanding of which is essential for future VL research and the successful development of efficient control strategies for Leishmania spp.
	PMID: 21345200 [PubMed - as supplied by publisher]
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8.	J Allergy Clin Immunol. 2011 Jan;127(1):279-82, 282.e1-3. Sequence variation in the IL4 gene and resistance to Trypanosoma cruzi infection in Bolivians. Alvarado Arnez LE, Venegas EN, Ober C, Thompson EE.
	PMID: 21211660 [PubMed - indexed for MEDLINE]
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9.	Microbiol Mol Biol Rev. 2010 Dec;74(4):552-69. Cell biology of the trypanosome genome. Daniels JP, Gull K, Wickstead B. University of Oxford, Oxford, United Kingdom. Abstract Trypanosomes are a group of protozoan eukaryotes, many of which are major parasites of humans and livestock. The genomes of trypanosomes and their modes of gene expression differ in several important aspects from those of other eukaryotic model organisms. Protein-coding genes are organized in large directional gene clusters on a genome-wide scale, and their polycistronic transcription is not generally regulated at initiation. Transcripts from these polycistrons are processed by global trans-splicing of pre-mRNA. Furthermore, in African trypanosomes, some protein-coding genes are transcribed by a multifunctional RNA polymerase I from a specialized extranucleolar compartment. The primary DNA sequence of the trypanosome genomes and their cellular organization have usually been treated as separate entities. However, it is becoming increasingly clear that in order to understand how a genome functions in a living cell, we will need to unravel how the one-dimensional genomic sequence and its trans-acting factors are arranged in the three-dimensional space of the eukaryotic nucleus. Understanding this cell biology of the genome will be crucial if we are to elucidate the genetic control mechanisms of parasitism. Here, we integrate the concepts of nuclear architecture, deduced largely from studies of yeast and mammalian nuclei, with recent developments in our knowledge of the trypanosome genome, gene expression, and nuclear organization. We also compare this nuclear organization to those in other systems in order to shed light on the evolution of nuclear architecture in eukaryotes. PMCID: PMC3008170 [Available on 2011/12/1]
	PMID: 21119017 [PubMed - indexed for MEDLINE]
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10.	Trans R Soc Trop Med Hyg. 2010 Nov;104(11):720-5. Epub 2010 Sep 28. Incidence of kala-azar in Nepal: estimating the effects of individual and household characteristics. Adhikari SR, Supakankunti S, Khan MM. Centre for Health Economics, Chulalongkorn University, Bangkok 10330, Thailand. sssadhikari@yahoo.com Abstract Kala-azar (KA) remains a major public health problem in Nepal. The disease is preventable, but various environmental, socioeconomic, health care and health behaviour related variables affect its transmission. Household or individual related factors determine the magnitude and direction of impacts of these factors. Data were collected from clinically diagnosed KA patients and non-KA patients from hospitals in Nepal. The hospitals are located in the highest KA incidence rate districts. Logistic regressions are used to identify individual and household characteristics affecting the probability of having KA by estimating models with and without the introduction of interaction terms. Poverty incidence, being a member of disadvantaged population group, size of family and literacy are important in explaining the likelihood of having KA. Poverty directly influences the likelihood of KA and modifies the magnitude and direction of the effects of other variables. The traditional approach of controlling KA at the community level should be complemented by poverty alleviation and other developmental activities to ensure rapid decline and eradication of KA. Poverty and illiteracy magnifies the problem of KA at the community level and simultaneous implementation of KA control interventions with effective poverty alleviation strategies is likely to be much more effective than the traditional disease control program alone. Copyright © 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
	PMID: 20875906 [PubMed - indexed for MEDLINE]
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