What's new for 'Trypanosomatids' in PubMed

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Sent on Thursday, 2009 Dec 24
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 13

1.	Antimicrob Agents Chemother. 2009 Dec 22. [Epub ahead of print] Exploiting the drug-activating properties of a novel trypanosomal nitroreductase. Hall BS, Wu X, Hu L, Wilkinson SR. Queen Mary Pre-Clinical Drug Discovery Group, School of Biological & Chemical Sciences, Queen Mary University of London, Mile End Road, London, E1 4NS, UK; Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854. Nitroheterocyclic prodrugs have been used to treat trypanosomal diseases for more than forty years. Recently the key step involved in the activation of these compounds has been elucidated and shown to be catalyzed by a type I nitroreductase (NTR). This class of enzyme is normally associated with bacteria and is absent from most eukaryotes, with trypanosomes being a major exception. Here we exploit this difference by evaluating the trypanocidal activity of a library of nitrobenzylphosphoramide mustards against bloodstream form T. brucei. Biochemical screening against purified enzyme revealed that a subset of halogenated nitroaromatic compounds were effective substrates for TbNTR having apparent Kcat/KM values approximately 100 times greater than nifurtimox. When tested against T. brucei, cytotoxicity mirrored enzyme activity with IC50 values of the most potent substrates being less than 10 nM. T. brucei NTR plays a key role in parasite killing: heterozygous lines displayed resistance to the compounds while parasites over-expressing the enzyme showed hypersensitivity. We also evaluated the cytotoxicity of substrates with highest trypanocidal activity, using mammalian THP-1 cells. The relative toxicity of these newly identified compounds was much lower than nifurtimox. We conclude that halogenated nitrobenzylphosphoramide mustards represent a novel class of anti-trypanosomal agents and their efficacy validates the strategy of specifically targeting NTR activity to develop new therapeutics.
	PMID: 20028822 [PubMed - as supplied by publisher]

2.	Chem Biol Drug Des. 2009 Dec 17. [Epub ahead of print] Synthesis and Antileishmanial Activity of Lipidic Amino Alcohols. Coimbra ES, de Almeida MV, Júnior CO, Taveira AF, da Costa CF, de Almeida AC, Reis EF, da Silva AD. Departamento de Parasitologia, Microbiologia e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Juiz de Fora, Cidade Universitária, 36036-900 Juiz de Fora, MG, Brazil. In this work, a number of lipidic amino alcohols wereas synthesized and evaluated in vitro on cultures of Leishmania amazonensis and Leishmania chagasi. Nine amino alcohols showed inhibition of L. chagasi growth, and seven of them showed inhibition of L. amazonensis with IC(50) below 10 mum. Compound 11f was more active than the reference drug amphotericin B against L. chagasi promastigote forms.
	PMID: 20028395 [PubMed - as supplied by publisher]

3.	Rev Saude Publica. 2009 Dec 18. pii: S0034-89102009005000072. [Epub ahead of print] [Distribution of Lutzomyia whitmani in phytoregions of the state of Maranhão, Northeastern Brazil.] [Article in Portuguese] Rebêlo JM, Rocha RV, Moraes JL, Alves GA, Leonardo FS. Laboratório de Entomologia e Vetores, Departamento de Patologia, Universidade Federal do Maranhão, São Luís, MA, Brasil. The study had the aim of characterizing the geographical distribution of Lutzomyia whitmani s.l. in the state of Maranhão, Northeastern Brazil. Between 1992 and 2005, 9,600 specimens (65.1% males and 34.9% females) were caught in the rural and urban zones of 35 municipalities in regions consisting of forests, savanna and mixed vegetation with coconut plantations, sandbanks and heath. Greater abundance was observed in areas surrounding dwellings (91.6%) than inside the dwellings (8.4%). The presence of the vector in different phytoregions and in rural and urban areas favors the transmission of tegumentary leishmaniasis in these environments. This taxon may constitute a complex of species in Maranhão, which can be confirmed by molecular biology studies.
	PMID: 20027495 [PubMed - as supplied by publisher]
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4.	Mem Inst Oswaldo Cruz. 2009 Nov;104(7):992-7. Genus-specific kinetoplast-DNA PCR and parasite culture for the diagnosis of localised cutaneous leishmaniasis: applications for clinical trials under field conditions in Brazil. Ampuero J, Rios AP, Carranza-Tamayo CO, Romero GA. Núcleo de Medicina Tropical, Universidade de Brasília, Brasília, DF, Brasil, 70904-970. The positivities of two methods for the diagnosis of localised cutaneous leishmaniasis (CL) were estimated in 280 patients enrolled in a clinical trial. The trial was conducted in an endemic area of Leishmania (Viannia) braziliensis and trial participants were patients with skin ulcers and positive leishmanin skin tests. Patients underwent aspirative skin punctures of the ulcerated lesions and lymph nodes for in vitro cultures, which were processed under field conditions at the local health centre. Skin lesion biopsies were tested at a reference laboratory using kinetoplastid DNA (kDNA)-PCR to detect DNA. The median time required to obtain a positive culture from the skin samples was seven days and the contamination rate of the samples was 1.8%. The positivities of the cultures from skin lesions, kDNA-PCR and the combination of the two methods were 78.2% (95% CI: 73-82.6%), 89.3% (95% CI: 85.1-92.4%) and 97.1% (95% CI: 94.5-98.5%). We conclude that parasite culture is a feasible method for the detection of Leishmania in field conditions and that the combination of culture and PCR has a potential role for the diagnosis of CL in candidates for clinical trials.
	PMID: 20027466 [PubMed - in process]
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5.	Mem Inst Oswaldo Cruz. 2009 Nov;104(7):955-9. Species structure of sand fly (Diptera: Psychodidae) fauna in the Brazilian western Amazon. Gil LH, Araújo Mda S, Villalobos JM, Camargo LM, Ozaki LS, Fontes CJ, Ribolla PE, Katsuragawa TH, Cruz RM, Silva Ade A, Silva LH. Instituto de Pesquisa de Patologias Tropicais, Porto Velho, RO, Brasil, 78912-000. We surveyed areas of the state of Rondônia in western Amazon for phlebotomine, which are potential vectors of leishmaniasis. A total of 5,998 specimens were captured, resulting in the identification of 48 species within the Lutzomyia (99.98%) and Brumptomyia (0.02%) genera. The predominant species was Lutzomyia davisi, followed by Lutzomyia umbratilis, Lutzomyia llanosmartinsi, Lutzomyia c. carrerai, Lutzomyia dendrophyla, Lutzomyia nevesi and Lutzomyia whitmani. All sand flies identified as vectors for cutaneous leishmaniasis in Brazil, i.e., Lu. davisi, Lu. umbratilis, Lu. c. carrerai and Lu. whitmani, were found in the surveyed areas.
	PMID: 20027459 [PubMed - in process]
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6.	Mem Inst Oswaldo Cruz. 2009 Nov;104(7):937-54. Proven and putative vectors of American cutaneous leishmaniasis in Brazil: aspects of their biology and vectorial competence. Rangel EF, Lainson R. Laboratório de Transmissores de Leishmanioses, Instituto Oswaldo Cruz, Rio de Janeiro, RJ, Brasil, 21045-900. The aim of the present review is to give relevant information on aspects of the biology and ecology, including the vectorial competence of Lutzomyia sand fly species suggested as vectors of American cutaneous leishmaniasis in Brazil. The disease, due to Leishmania (Viannia) braziliensis, has been registered in most municipalities in all the Brazilian states and its transmission is associated with more than one sand fly species in each geographical region. A variety of Leishmania species can be found in the Amazon basin, where different epidemiological chains have been detected with the participation of different phlebotomine vectors. Finally, a discussion is presented on some sand fly species found naturally infected by Leishmania, but for which there is as yet no evidence regarding their epidemiological importance.
	PMID: 20027458 [PubMed - in process]
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7.	Glob Health Action. 2009 Oct 22;2. doi: 10.3402/gha.v2i0.2046. Low-cost liquid medium for in vitro cultivation of Leishmania parasites in low-income countries. Tasew G, Kebede A, Wolday D, Gadisa E, Britton S, Eidsmo L, Akuffo H. Department of Infectious and Non-infectious Diseases Research, Ethiopian Health and Nutrition Research Institute (EHNRI), Addis Ababa, Ethiopia. BACKGROUND: Prompt laboratory diagnosis and initiation of treatment are effective components of leishmaniasis control. Detection of Leishmania parasites by ex-vivo culture of lesion scrapings is considered a definitive diagnostic method preceding initiation of treatment. OBJECTIVE: A pilot study to find alternative medium that could reduce the cost of culturing from patient lesions for diagnosing leishmaniasis. METHOD: GALF-1 medium was formulated in our lab from locally available inexpensive solutions and powders in the presence of urine from healthy individuals. Amastigote to promastigote transformation, recovery of parasites after cryopreservation, cost and mass cultivation was compared using the following media: GALF-1, RPMI 1640, and conventional Locke's semi-solid medium (LSSM), a modifications of Novy-MacNeal-Nicolle culture media, which uses Locke's solution as an overlay RESULTS: GALF-1 preparation was cheap and the components available in low-income countries such as Ethiopia. Preparation was simple, not requiring autoclaving and extra distilled water. GALF-1 was able to transform amastigotes from Ethiopian patients' samples and could be used to cultivate promastigotes in large quantities. GALF-1 decreased Leishmania culture costs by approximately 80-95% compared to LSSM and RPMI 1640, respectively. Promastigotes cultured with GALF-1 could be cryopreserved in liquid nitrogen with comparable re-culture potential. CONCLUSION: Affordability of diagnostic assays is a key issue for endemic resource-poor countries and the possibility to cut the cost of the efficient culture method for diagnosis through the use of inexpensive, locally formulated reagents could improve the diagnosis of leishmaniasis in Ethiopia and in other low-income countries.
	PMID: 20027250 [PubMed - in process]

8.	J Antimicrob Chemother. 2009 Dec 21. [Epub ahead of print] Visceral leishmaniasis affects liver and spleen concentrations of amphotericin B following administration to mice. Gershkovich P, Wasan EK, Sivak O, Li R, Zhu X, Werbovetz KA, Tidwell RR, Clement JG, Thornton SJ, Wasan KM. Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada. Objectives To assess the impact of visceral leishmaniasis (VL) on the concentration of amphotericin B (AmB) recovered in the liver and spleen following either intravenous (AmBisome((R))) or oral (iCo-009) AmB administration to mice. Methods Livers and spleens previously obtained from VL-infected BALB/c mice (following intravenous AmBisome((R)) or oral AmB treatments) were analysed for AmB concentrations. Then, non-infected BALB/c mice were divided into three treatment groups: a single dose of intravenous AmBisome((R)) (2 mg/kg, n = 5); and oral AmB every 12 h for 5 days (10 mg/kg, n = 6 and 20 mg/kg, n = 6). The animals were sacrificed 7 days after the initiation of the treatment and the livers and spleens were harvested for drug analysis by HPLC. Results The single intravenous injection of AmBisome((R)) resulted in a 77-fold lower concentration of AmB in infected compared with non-infected liver tissue, while the difference in AmB concentration in the spleen was only 5-fold. The multiple dose oral administration of AmB resulted in a 3-fold lower concentration of AmB in infected compared with non-infected livers for both oral doses, while the differences in AmB concentrations in the spleen were not statistically different for the oral treatment groups. Conclusions VL significantly lowered the concentration of AmB in the liver and the spleen when compared with uninfected animals. This effect seems to correlate with the degree of infection of the tissue. In the case of the intravenous liposomal formulation (AmBisome((R))), the differences between the infected and non-infected tissues are of a higher magnitude than in the case of orally administered AmB (iCo-009).
	PMID: 20026611 [PubMed - as supplied by publisher]
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9.	Mol Biochem Parasitol. 2009 Dec 18. [Epub ahead of print] Phospholipid and sphingolipid metabolism in Leishmania. Zhang K, Beverley SM. Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. In many eukaryotes, phospholipids (PLs) and sphingolipids (SLs) are abundant membrane components and reservoirs for important signaling molecules. In Leishmania, the composition, metabolism, and function of PLs and SLs differ significantly from those in mammalian cells. Although only a handful of enzymes have been experimentally characterized, available data suggest many steps of PL/SL metabolism are critical for Leishmania viability and/or virulence, and could be a source for new drug targets. Further studies of genes involved in the synthesis (de novo and salvage) and degradation of PLs and SLs will reveal their diverse effects on Leishmania pathogenesis. Copyright © 2009. Published by Elsevier B.V.
	PMID: 20026359 [PubMed - as supplied by publisher]
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10.	Mol Biochem Parasitol. 2009 Dec 15. [Epub ahead of print] Functional characterization of LIT1, the Leishmania amazonensis ferrous iron transporter. Jacques I, Andrews NW, Huynh C. Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven CT, 06510. Leishmania amazonensis LIT1 was identified based on homology with IRT1, a ferrous iron transporter from Arabidopsis thaliana. Deltalit1 Leishmania amazonensis are defective in intracellular replication and lesion formation in vivo, a virulence phenotype attributed to defective intracellular iron acquisition. Here we functionally characterize LIT1, directly demonstrating that it functions as a ferrous iron membrane transporter from the ZIP family. Conserved residues in the predicted transmembrane domains II, IV, V and VII of LIT1 are essential for iron transport in yeast, including histidines that were proposed to function as metal ligands in ZIP transporters. LIT1 also contains two regions within the predicted intracellular loop that are not found in Arabidopsis IRT1. Deletion of region I inhibited LIT1 expression on the surface of Leishmania promastigotes. Deletion of region II did not interfere with LIT1 trafficking to the surface, but abolished its iron transport capacity when expressed in yeast. Mutagenesis revealed two motifs within region II, HGHQH and TPPRDM, that are independently required for iron transport by LIT1. D263 was identified as a key residue required for iron transport within the TPPRDM motif, while P260 and P261 were dispensable. Deletion of proline-rich regions within region I and between regions I and II did not affect iron transport in yeast, but in Leishmania amazonensis were not able to rescue the intracellular growth of Deltalit1 parasites, or their ability to form lesions in mice. These results are consistent with a potential role of the unique intracellular loop of LIT1 in intracellular regulation by Leishmania-specific factors. Copyright © 2009. Published by Elsevier B.V.
	PMID: 20025906 [PubMed - as supplied by publisher]
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