What's new for 'Trypanosomatids' in PubMed

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Sent on Wednesday, 2010 Jul 28
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 15

1.	Parasitol Res. 2010 Jul 27. [Epub ahead of print] Activity of the julocrotine, a glutarimide alkaloid from Croton pullei var. glabrior, on Leishmania (L.) amazonensis. Guimarães LR, Rodrigues AP, Marinho PS, Muller AH, Guilhon GM, Santos LS, do Nascimento JL, Silva EO. Laboratório de Parasitologia e Biologia Estrutural, Instituto de Ciências Biológicas, Universidade Federal do Pará, Av. Augusto Corrêa no.01, Bairro Guamá, 66075-110, Belém, Pará, Brazil. Abstract The antiproliferative effect of julocrotine, an alkaloid isolated from Croton pullei var. glabrior (Euphorbiaceae), was studied in the macrophage amastigote and promastigote stages of the protozoan Leishmania (L.) amazonensis, which causes cutaneous leishmaniasis in the New World. Julocrotine showed a dose-dependent effect against the amastigote and promastigote forms, where 79 muM julocrotine inhibited promastigote growth by 54%, with an IC50 of 67 muM. To analyze the antiamastigote activity of the drug, murine peritoneal macrophages infected with L. amazonensis promastigotes were treated with different concentrations of julocrotine. An 80% inhibition of amastigote development was observed using 79 muM julocrotine for 72 h, with an IC50 of 19.8 muM. In addition, ultrastructural observation of the parasites showed a significant reduction in the number of amastigotes in the parasitophorous vacuoles and morphological changes in promastigotes, such as swelling of the mitochondrion, chromatin condensation, presence of membranous structures near the Golgi complex, and some vesicle bodies in the flagellar pocket. A colorimetric assay (MTT), which measures cytotoxic metabolic activity, showed that macrophages maintain their viability after treatment with the drug. These results suggest that julocrotine effectively inhibits the growth of parasites and does not have any cytototoxic effects on the host cell.
	PMID: 20661748 [PubMed - as supplied by publisher]
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2.	Antimicrob Agents Chemother. 2010 Jul 26. [Epub ahead of print] Discovery of Novel Orally Bioavailable Ox aborole 6-carboxamides that Demonstrate Cure in a Murine Model of Late Stage Central Nervous System African Trypanosomiasis. Nare B, Wring S, Bacchi C, Beaudet B, Bowling T, Brun R, Chen D, Ding C, Freund Y, Gaukel E, Hussain A, Jarnagin K, Jenks M, Kaiser M, Mercer L, Mejia E, Noe A, Orr M, Parham R, Plattner J, Randolph R, Rattendi D, Rewerts C, Sligar J, Yarlett N, Don R, Jacobs R. SCYNEXIS Inc., Research Triangle Park, NC, Haskins Laboratory, Pace University, New York, NY; Anacor Pharmaceuticals Inc., Palo Alto, CA; Swiss Tropical Institute and Public Health, Basel, Switzerland; University of Basel, Switzerland; Drugs for Neglected Disease Initiative, Geneva, Switzerland. Abstract We report the discovery of novel boron-containing molecules, exemplified by N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl-2-trifluoromethylbenzamide (AN3520) and 4-Fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (SCYX-6759), as potent compounds against Trypanosoma brucei in vitro, including the two species responsible for human disease T. b. rhodesiense and T. b. gambiense. These oxaborole carboxamides cured stage 1 (hemolymphatic) trypanosomiasis infection in mice when administered orally at 2.5 to10 mg/kg for 4 consecutive days. In stage 2 disease (central nervous system (CNS) involvement), mice infected with Trypanosoma brucei brucei (T. b. brucei) were cured when AN3520 or SCYX-6759 were administered intraperitoneally or orally (50 mg/kg) twice daily for 7 days. Oxaborole treated animals did not exhibit gross signs of compound-related acute or sub-chronic toxicity. Metabolism and pharmacokinetic studies in several species, including non-human primates, demonstrate that both SCYX-6759 and AN3520 are low clearance compounds. Both compounds were well absorbed following oral dosing in multiple species and also demonstrated ability to cross the blood-brain barrier with no evidence of interaction with P-glycoprotein transporter. Overall, SCYX-6759 demonstrated superior pharmacokinetics, and this was reflected in better efficacy against stage 2 disease in the mouse model. On the whole, oxaboroles demonstrate potent activity against all T. brucei subspecies, excellent physicochemical profiles, in vitro metabolic stability, low potential for CYP450 inhibition, lack of active efflux by the P-glycoprotein transporter, and high permeability. These properties strongly suggest that these novel chemical entities are suitable leads for development of new and effective orally administered treatments for human African trypanosomiasis.
	PMID: 20660666 [PubMed - as supplied by publisher]
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3.	Nucleic Acids Res. 2010 Jul 26. [Epub ahead of print] The Trypanosoma brucei MitoCarta and its regulation and splic ing pattern during development. Zhang X, Cui J, Nilsson D, Gunasekera K, Chanfon A, Song X, Wang H, Xu Y, Ochsenreiter T. Department of Biomedical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu 210016 China, Computational Systems Biology Lab, Department of Biochemistry and Molecular Biology and Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA, Institute of Cell Biology, University of Bern, Switzerland and College of Computer Science and Technology, Jilin University, Changchun, Jilin 130000 China. Abstract It has long been known that trypanosomes regulate mitochondrial biogenesis during the life cycle of the parasite; however, the mitochondrial protein inventory (MitoCarta) and its regulation remain unknown. We present a novel computational method for genome-wide prediction of mitochondrial proteins using a support vector machine-based classifier with approximately 90% prediction accuracy. Using this method, we predicted the mitochondrial localization of 468 proteins with high confidence and have experimentally verified the localization of a subset of these proteins. We then applied a recently developed parallel sequencing technology to determine the expression profiles and the splicing patterns of a total of 1065 predicted MitoCarta transcripts during the development of the parasite, and showed that 435 of the transcripts significantly changed their expressions while 630 remain unchanged in any of the three life stages analyzed. Furthermore, we identified 298 alternatively splicing events, a small subset of which could lead to dual localization of the corresponding proteins.
	PMID: 20660476 [PubMed - as supplied by publisher]
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4.	J Immunol. 2010 Jul 21. [Epub ahead of print] Proinflammatory Clearance of Apoptotic Neutrophils Induces an IL-12lowIL-10high Regulatory Phenotype in Macrophages. Filardy AA, Pires DR, Nunes MP, Takiya CM, Freire-de-Lima CG, Ribeiro-Gomes FL, Dosreis GA. Instituto de Biofísica Carlos Chagas Filho and. Abstract Clearance of apoptotic exudate neutrophils (efferocytosis) induces either pro- or anti-inflammatory responses in mouse macrophages depending on host genetic background. In this study, we investigated whether neutrophil efferocytosis induces a stable macrophage phenotype that could be recalled by late restimulation with LPS. Bone marrow-derived macrophages previously stimulated by pro- but not anti-inflammatory neutrophil efferocytosis expressed a regulatory/M2b phenotype characterized by low IL-12 and high IL-10 production following restimulation, increased expression of LIGHT/TNF superfamily 14, Th2-biased T cell responses, and permissive replication of Leishmania major. Induction of regulatory/M2b macrophages required neutrophil elastase activity and was partially dependent on TLR4 signaling. These results suggested that macrophage differentiation to a regulatory phenotype plays a role in resolution of inflammation but could contribute to increased humoral Ab responses and parasite persistence in the infected host.
	PMID: 20660352 [PubMed - as supplied by publisher]
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5.	J Clin Microbiol. 2010 Jul 21. [Epub ahead of print] Diagnosis of canine vector-borne diseases in young dogs: a longitudinal study. Otranto D, Testini G, Dantas-Torres F, Latrofa MS, Paulo P, de Paiva Diniz V, de Caprariis D, Lia RP, Mencke N, Stanneck D, Capelli G, Breitschwerdt EB. Department of Veterinary Public Health and Animal Sciences, Faculty of Veterinary Medicine, Bari, Italy; College of Veterinary Medicine, Western University of Health Sciences, Pomona, California, USA; Bayer Health Care AG, Animal Health Division Leverkusen, Germany; Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro (PD), Italy; and Intracellular Pathogens Research Laboratory, Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA. Abstract Canine vector-borne diseases (CVBDs) pose a diagnostic challenge, particularly when a dog is co-infected with more than one pathogen. The purpose of this study was to generate information about the diagnosis of CVBDs in young dogs following their first exposure to flea, tick, sand fly, lice and mosquito vectors. From March 2008 to May 2009, 10 purpose-bred young naïve beagle dogs and a cohort of 48 mixed-breed dogs living in a CVBD endemic area in southern Italy were monitored using different diagnostic tests (cytology, serology, and PCR). Overall, PCR detected the highest number of dogs infected with Anaplasma platys, Babesia vogeli, and Ehrlichia canis whereas serconversion was a more sensitive indicator of exposure to Leishmania infantum. For A. platys infection, combining blood and buffy coat cytology in parallel enhanced the relative sensitivity (SErel; 87.3%). For B. vogeli, the best diagnostic combination was buffy coat cytology and serology used in parallel (SErel, 67.5%) whereas serology and PCR used in parallel (SErel, 100%) was the best combination for L. infantum. Overall, 12 (20.7%) dogs were co-infected, however, the percentage of new co-infections decreased from baseline (50%) to the first (33.3%) and second (16.6%) follow-up time points. Co-infections with A. platys and B. vogeli were significantly higher (p<0.05) than co-infections with other pathogen combinations. The data generated in this study provide insights on the incidence of certain pathogens infecting young dogs in southern Italy, highlight important diagnostic testing limitations and support the use of multiple diagnostic modalities when attempting to confirm a tick-borne infection in an individual dog or in a canine population.
	PMID: 20660218 [PubMed - as supplied by publisher]
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6.	Mol Biochem Parasitol. 2010 Jul 23. [Epub ahead of print] Role of Tob55 on mitochondrial protein biogenesis in Trypanosoma bru cei. Sharma S, Singha UK, Chaudhuri M. Department of Microbiology and Immunology, School of Medicine, Meharry Medical College, Nashville, Tennessee 37208. Abstract Mitochondrial outer membrane (MOM) proteins in parasitic protozoa like Trypanosoma brucei are poorly characterized. In fungi and higher eukaryotes, Tob55 is responsible for the assembly of beta-barrel proteins in the MOM. Here we show that T. brucei Tob55 (TbTob55) has considerable similarity in its primary and secondary structure to Tob55 from other species. TbTob55 is localized in T. brucei MOM and is essential for procyclic cell survival. Induction of Tob55 RNAi decreased the level of the voltage-dependent anion channel (VDAC) within 48h. Although the primary effect is on VDAC, induction of TbTob55 RNAi for a longer time period also decreased the levels of other nucleus encoded mitochondrial proteins. In addition, the mitochondrial membrane potential was reduced at this later time point possibly due to a reduction in the level of the proteins involved in oxidative phosphorylation. However, mitochondrial structure was not altered due to depletion of Tob55. In vitro protein import of VDAC into mitochondria with a 50-60% reduction of TbTob55 was reduced about 40% in comparison to uninduced control. In addition, the import of presequence-containing proteins such as, cytochrome oxidase subunit 4 (COIV) and trypanosome alternative oxidase (TAO) was affected by about 20 % under this condition. Depletion of VDAC levels by RNAi did not affect the import of either COIV or TAO. Furthermore, TbTob55 over expression increased the steady state level of VDAC as well as the level of the assembled protein complex of VDAC, suggesting that similar to other eukaryotes TbTob55 is involved in assembly of MOM beta-barrel proteins and plays an indirect role in the biogenesis of mitochondrial preproteins destined for the mitochondrial inner membrane. Copyright © 2010 Elsevier B.V. All rights reserved.
	PMID: 20659504 [PubMed - as supplied by publisher]
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7.	Exp Parasitol. 2010 Jul 23. [Epub ahead of print] R egulation of the expression of nitric oxide synthase by Leishmania mexicana amastigotes in murine dendritic cells. Rodríguez AW, Montaño AE, Aguirre-García M, Becker I, Gutiérrez-Kobeh L. Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México. Dr. Balmis 148, Col. Doctores, México 06726, D.F. México. Abstract In mammalian hosts, Leishmania parasites are obligatory intracellular organisms that invade macrophages (Mvarphi) and dendritic cells (DC). In Mvarphi, the production of nitric oxide (NO) catalyzed by the inducible nitric oxide synthase (iNOS) has been implicated as a major defense against Leishmania infection. The modulation of this microbicidal mechanism by different species of Leishmania has been well studied in Mvarphi. Although DC are permissive for infection with Leishmania both in vivo and in vitro, the effect of this parasite in the expression of iNOS and NO production in these cells has not been established. To address this issue, we analyzed the regulation of iNOS by Leishmania mexicana amastigotes in murine bone marrow-derived dendritic cells (BMDC) stimulated with LPS and IFN-gamma. We show that the infection of BMDC with amastigotes down regulated NO production and diminished iNOS protein levels in cells stimulated with LPS alone or in combination with IFN- gamma. The reduction in iNOS protein levels and NO production did not correlate with a decrease in iNOS mRNA expression, suggesting that the parasite affects post-transcriptional events of NO synthesis. Although amastigotes were able to reduce NO production in BMDC, the interference with this cytotoxic mechanism was not sufficient to permit the survival of Leishmania mexicana. At 48 h post-infection, BMDC stimulated with LPS + IFN- gamma were able to eliminate the parasites. These results are the first to identify the regulation of iNOS by Leishmania mexicana amastigotes in DC. Copyright © 2010. Published by Elsevier Inc.
	PMID: 20659463 [PubMed - as supplied by publisher]
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8.	Clin Exp Rheumatol. 2010 Jul 26. [Epub ahead of print] Visceral Leishmaniasis among immunosuppressed p atients with rheumatic diseases. Erre GL, Mesina P, Tonelli N, Passiu G. Unità Operativa di Reumatologia, University of Sassari, Italy. e.gianluca@libero.it. Abstract -
	PMID: 20659417 [PubMed - as supplied by publisher]
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9.	Ann Trop Med Parasitol. 2010 Jun;104(4):347-50. Evaluation of electro-eluted antigens in the serological diagnosis of cutaneous leishmaniasis. Castellano LR, Gave TC, Lira MA, Dessein H, Dessein A, Correia D, Rodrigues V. Laboratory of Immunology, Universidade Federal do Triângulo Mineiro, Uberaba, CEP 38025-180, MG, Brazil.
	PMID: 20659396 [PubMed - in process]
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10.	Mol Microbiol. 2010 Jul 27. doi: 10.1111/j.1365-2958.2010.07318.x. [Epub ahead of print] A Tyrosyl DNA phosphodiesterase 1 from kinetoplastid parasite Leishmania donovani (LdTdp1) capable of removing Topo I-DNA covalent complexes. Banerjee B, Roy A, Sen N, Majumder HK. Molecular Parasitology Laboratory Infectious Disease and Immunology Division Indian Institute of Chemical Biology 4, Raja S. C. Mullick Road, Kokata-700032, India Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Abstract Tyrosyl DNA phosphodiesterase 1 (Tdp1) is a member of phospholipase D superfamily, which cleaves a broad range of 3'-DNA adducts, the best characterized of which is the phosphodiester bond formed between DNA and topoisomerase IB. This study describes cloning and functional characterization of the enzyme, termed as LdTdp1 in the kinetoplastid parasite Leishmania donovani. Sequence analysis confirmed conservation of the active site motifs typical for all Tdp1 proteins. LdTdp1 activity was detected in the parasite nucleus as well as in the kinetoplast. The enzyme harbors a nuclear localization signal at its C-terminus. Over expression of the active enzyme protected the parasites against topoisomerase IB inhibitor camptothecin and oxidative agent H(2) O(2) mediated cytotoxicity and its down regulation rendered the parasites hypersensitive to camptothecin. Trapping of mutant LdTdp1 on DNA takes place following camptothecin treatment in L. donovani cells. The expression level and associated activity of LdTdp1 were found to be higher in CPT resistant L. donovani parasites. Altogether, this is the first report of Tdp1 from the kinetoplastid parasite L. donovani, which actively participates in topoisomerase I mediated DNA damage repair process and thereby counteracts the cytotoxic effect of topoisomerase I inhibitors. © 2010 The Authors. Journal compilation © 2010 Blackwell Publishing Ltd.
	PMID: 20659295 [PubMed - as supplied by publisher]
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