What's new for 'Trypanosomatids' in PubMed

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Sent on Saturday, 2012 May 12
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 - 8 of 8

1.	J Antimicrob Chemother. 2012 May 10. [Epub ahead of print] Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine. Dorlo TP, Balasegaram M, Lima MA, de Vries PJ, Beijnen JH, Huitema AD. Source Division Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Abstract OBJECTIVES: Use of miltefosine in the treatment of visceral leishmaniasis (VL) is hampered by its potential teratogenicity. The duration of adequate contraceptive cover in females of child-bearing potential after cessation of a potentially teratogenic drug therapy remains debated. The objective of this study was to provide a rational approach to suggest durations of contraceptive cover for various miltefosine regimens. METHODS: A human reproductive safety threshold exposure limit was derived using animal-to-human dose conversion. Pharmacokinetic (PK) data for miltefosine in females are lacking; a previously developed population PK model and a comprehensive anthropometric dataset were used to simulate PK data for Indian female VL patients receiving miltefosine for 5, 7, 10 or 28 days. Probability of supra-threshold miltefosine exposure was used to evaluate adequate durations of post-treatment contraceptive cover for the various regimens. RESULTS: PK data were simulated for 465 treated Indian female VL patients of child-bearing potential with a median age of 25 years (IQR 16-31 years) and median weight of 38 kg (IQR 34-42 kg). From animal reproductive toxicity studies, a human reproductive safety threshold exposure limit was derived of 24.5 μg · day/mL. Probability of 'unprotected' supra-threshold miltefosine exposure was very low (<0.2%) for a post-treatment contraceptive cover period of 4 months for the standard 28 day regimen, and of 2 months for the shorter regimens. CONCLUSIONS: To our knowledge, this is the first study providing rational suggestions for contraceptive cover for a teratogenic drug based on animal-to-human dose conversion. For the 28 day miltefosine regimen, post-treatment contraceptive cover may be extended to 4 months, whereas for all shorter regimens 2 months may be adequate.
	PMID: 22577099 [PubMed - as supplied by publisher]
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2.	Planta Med. 2012 May 10. [Epub ahead of print] Leishmanicidal Compounds from the Fruits of Piper longum. Ghosal S, Deb A, Mishra P, Vishwakarma R. Source Amity Institute of Biotechnology, Amity University, Noida, India. Abstract One new alkaloid amide, piperlongumide (1) [N-isobutyl-19-(3',4'-methylenedioxyphenyl)-2E,4E nonadecadienamide], and six known compounds with leishmanicidal activity against promastigotes and axenic amastigotes of Leishmania donovani were isolated from the n-hexane fraction of the fruits of Piper longum. The structure of 1 was elucidated by spectroscopic evidences. Georg Thieme Verlag KG Stuttgart · New York.
	PMID: 22576441 [PubMed - as supplied by publisher]
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3.	Asian Pac J Trop Med. 2012 Jun;5(6):485-97. Leishmaniasis: Current status of available drugs and new potential drug targets. Singh N, Kumar M, Singh RK. Source Molecular Immunology Laboratory, Department of Biochemistry, Faculty of Science, Banaras Hindu University, Varanasi-221 005, India. Abstract The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericin B, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs. Copyright © 2012 Hainan Medical College. Published by Elsevier B.V. All rights reserved.
	PMID: 22575984 [PubMed - in process]
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4.	Microbiology. 2012 May 10. [Epub ahead of print] A highly basic sequence at the N-terminal region is essential for targeting the DNA replication protein ORC1 to the nucleus in Leishmania donovani. Kumar D, Kumar D, Saha S. Source University of Delhi South Campus. Abstract The conserved eukaryotic DNA replication protein ORC1 is one of the constituents of pre-replication complexes that assemble at or very near origins prior to replication initiation. ORC1 has been shown to be constitutively nuclear in Leishmania major. This study investigates the sequences involved in nuclear localization of ORC1 in Leishmania donovani, the causative agent of visceral leishmaniasis. Nuclear localization signals (NLSs) have been reported in only a few Leishmania proteins. Functional analyses have delineated NLSs to regions ~ 60 amino acids in length in tyrosyl DNA phosphodiesterase I and Type II DNA topoisomerase of L.donovani, and in the L.major kinesin KIN13-1. Using a panel of site-directed mutations we have identified a sequence essential for nuclear import of LdORC1. This sequence at the N-terminus of the protein, comprises residues 2-5 (KRSR), with K2, R3 and R5 being crucial. Independent mutation of the K2 residue causes exclusion of the protein from the nucleus, while mutating the R5 residue leads to diffusion of the protein throughout the cell. This sequence, however, is insufficient for targeting a heterologous protein (β-galactosidase) to the nucleus. Analysis of additional ORC1 mutations and reporter constructs reveals that while the highly basic tetra-amino acid sequence at the N-terminus is essential for nuclear localization, the ORC1 NLS in its entirety is more complex, and of a distributive character. Our results suggest that nuclear localization signaling sequences in Leishmania nuclear proteins are more complex than what is typically seen in higher eukaryotes.
	PMID: 22575896 [PubMed - as supplied by publisher]
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5.	Mol Biochem Parasitol. 2012 Apr 28. [Epub ahead of print] Characterization of the M32 metallocarboxypeptidase of Trypanosoma brucei: Differences and similarities with its orthologue in Trypanosoma cruzi. Frasch AP, Carmona AK, Juliano L, Cazzulo JJ, Niemirowicz GT. Source Instituto de Investigaciones Biotecnológicas "Dr. Rodolfo Ugalde"-Instituto Tecnológico Chascomús, UNSAM-CONICET, Campus Miguelete, Av. 25 de Mayo y Francia, 1650 San Martín, Buenos Aires, Argentina. Abstract Metallocarboxypeptidases (MCP) of the M32 family of peptidases have been identified in a number of prokaryotic organisms but they are absent from eukaryotic genomes with the remarkable exception of those of trypanosomatids. The genome of Trypanosoma brucei, the causative agent of Sleeping Sickness, encodes one such MCP which displays 72% identity to the characterized TcMCP-1 from Trypanosoma cruzi. As its orthologue, TcMCP-1, Trypanosoma brucei MCP is a cytosolic enzyme expressed in both major stages of the parasite. Purified recombinant TbMCP-1 exhibits a significant hydrolytic activity against the carboxypeptidase B substrate FA (furylacryloil)-Ala-Lys at pH 7.0-7.8 resembling the T. cruzi enzyme. Several divalent cations had little effect on TbMCP-1 activity but increasing amounts of Co(2+) inhibited the enzyme. Despite having similar tertiary structure, both protozoan MCPs display different substrate specificity with respect to P1 position. Thus, TcMCP-1 enzyme cleaved Abz-FVK-(Dnp)-OH substrate (where Abz: o-aminobenzoic acid and Dnp: 2,4-dinitrophenyl) whereas TbMCP-1 had no activity on this substrate. Comparative homology models and sequence alignments using TcMCP-1 as a template led us to map several residues that could explain this difference. To verify this hypothesis, site-directed mutagenesis was undertaken replacing the TbMCP-1 residues by those present in TcMCP-1. We found that the substitution A414M led TbMCP-1 to gain activity on Abz-FVK-(Dnp)-OH, thus showing that this residue is involved in specificity determination, probably being part of the S1 sub-site. Moreover, the activity of both protozoan MCPs was explored on two vasoactive compounds such as bradykinin and angiotensin I resulting in two different hydrolysis patterns. Copyright © 2012. Published by Elsevier B.V.
	PMID: 22575602 [PubMed - as supplied by publisher]
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6.	Vet Parasitol. 2012 Apr 25. [Epub ahead of print] Risk factors for canine leishmaniasis in an endemic Mediterranean region. Cortes S, Vaz Y, Neves R, Maia C, Cardoso L, Campino L. Source Unidade de Leishmanioses, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa (IHMT/UNL), Rua da Junqueira, 100, 1346-008 Lisboa, Portugal; Centro de Malária e Outras Doenças Tropicais, IHMT/UNL, Lisboa, Portugal. Abstract Human visceral leishmaniasis is an emergent/re-emergent parasitic zoonotic disease in Europe caused by Leishmania infantum, with domestic dog as its main reservoir host. This study presents the results of a canine epidemiological survey in a mediterranean region where human and canine leishmaniasis (CanL) are endemic - Portugal. The main goal was to identify risk factors, which can be relevant for Leishmania infection control. The national survey was carried out in January 2009 with a screening of 3974 dogs from all 18 districts of mainland Portugal. Direct Agglutination Test was used for the detection of anti-Leishmania antibodies in canine blood. An overall CanL true prevalence of 6.31% was observed. Apparent prevalence at district level ranged from 0.88% to 16.16%, with the highest prevalence in the interior regions. Identified risk factors for positivity were: dogs of 2 years and older (adjusted odds ratio OR=5.39); spending exclusively/most of the time outdoors (OR=2.51); origin from the interior of Portugal in comparison to littoral/coast districts (OR=2.51); not having long fur (OR=2.03); and being pure exotic (OR=1.67). The results confirm the leishmaniasis endemicity in Portugal and the dynamic character of prevalence as new foci emerged and old foci lost their importance. The dog's age, fur size, district and living outdoors as opposed to indoors were more important than dog breeds and insecticide treatment in the transmission of Leishmania infection. The future of CanL prevention and control rely on an integrated approach involving veterinarians, dog owners and health authorities in order to reduce the canine infection risk and consequently, the human zoonotic visceral leishmaniasis. Copyright © 2012 Elsevier B.V. All rights reserved.
	PMID: 22575278 [PubMed - as supplied by publisher]
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7.	Nat Prod Commun. 2012 Apr;7(4):467-70. Glucosylated sesquiterpene alcohols from Fraxinus griffithii. Macahig RA, Harinantenaina L, Sugimoto S, Matsunami K, Otsuka H, Takeda Y, Shinzato T. Source Department of Chemistry, School of Science and Engineering, Ateneo de Manila University, Katipunan Avenue, Loyola Heights, Quezon City 1108, Philippines. rmacahig@ateneo.edu Abstract Phytochemical investigation of the leaves of Fraxinus griffithii has led to the isolation of two new glucosylated acyclic sesquiterpene alcohols, griffithosides D (1) and E (2), along with iridoid and secoiridoid glycosides. The molecular structures of these compounds were elucidated using NMR, MS and other spectroscopic techniques, as well as comparison with literature data. The isolated compounds were tested for radical-scavenging activity and cytotoxicity against A549 human lung adenocarcinoma cells and Leishmania major parasites.
	PMID: 22574443 [PubMed - in process]
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8.	Bioorg Med Chem. 2012 Jan 15;20(2):942-8. Epub 2011 Dec 2. Synthesis of benzopolycyclic cage amines: NMDA receptor antagonist, trypanocidal and antiviral activities. Torres E, Duque MD, López-Querol M, Taylor MC, Naesens L, Ma C, Pinto LH, Sureda FX, Kelly JM, Vázquez S. Source Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Diagonal, 643, Barcelona E-08028, Spain. Abstract The synthesis of several 6,7,8,9,10,11-hexahydro-9-methyl-5,7:9,11-dimethano-5H-benzocyclononen-7-amines is reported. Several of them display low micromolar NMDA receptor antagonist and/or trypanocidal activities. Two compounds are endowed with micromolar anti vesicular stomatitis virus activity, while only one compound shows micromolar anti-influenza activity. The anti-influenza activity of this compound does not seem to be mediated by blocking of the M2 protein. Copyright © 2011 Elsevier Ltd. All rights reserved.
	PMID: 22178660 [PubMed - indexed for MEDLINE]
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