Friday, October 23, 2009

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 -7 of 7

1: ChemMedChem. 2009 Oct 21. [Epub ahead of print]

Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine-Conjugated Diaryl Sulfide Scaffolds.

Eberle C, Burkhard JA, Stump B, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F.

Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zürich (Switzerland), Fax: (+41) 44-632-1109.

Trypanothione reductase (TR) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. Various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. Herein we show that the combination of two structural motifs of known TR inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. The binding efficacy of these conjugates is enhanced over that of the respective parent inhibitors. They show K(ic) values for the parasite enzyme down to 0.9+/-0.1 mum and exhibit high selectivity for TR over human glutathione reductase (GR). Despite their considerable molecular mass and in some cases permanent positive charges, in vitro studies revealed IC(50) values in the low micromolar to sub-micromolar range against Trypanosoma brucei rhodesiense and Trypanosoma cruzi, as well as the malaria parasite Plasmodium falciparum, which lack trypanothione metabolism. The inhibitors exhibit strong fluorescence due to their aminoacridine moiety. This feature allows visualization of the drugs in the parasite where high accumulation was observed by fluorescence microscopy even after short exposure times.

PMID: 19847846 [PubMed - as supplied by publisher]

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2: Ann N Y Acad Sci. 2009 Oct;1178:285-90.

Are There Epigenetic Controls in Trypanosoma cruzi?

Elias MC, Faria M.

Laboratório de Parasitologia, Instituto Butantan, São Paulo-SP, Brazil.

RNA interference (RNAi) is defined as the mechanism through which double-stranded RNA (dsRNA) triggers degradation of homologous transcripts. Besides providing an invaluable tool to downregulate gene expression in a variety of organisms, it is now evident that RNAi acts beyond the cytoplasm and is involved in a variety of gene-silencing phenomena in the nucleus. In the present work we review the current status of the knowledge about RNAi in protozoan parasites that belong to the Trypanosoma genus and have medical relevance. While RNAi was first discovered in Trypanosoma brucei, it became evident that other members of the same genus of organisms, namely Trypanosoma cruzi, does not possess RNAi, probably due to the lack of Ago protein analogs in their genomes. We will discuss the genome organization of Trypanosoma cruzi and propose that the absence of both RNAi and gene promoters is symptomatic of alternative epigenetic controls in this parasite orchestrated by parasite-host interactions. Whereas in Trypanosoma brucei, RNAi and other epigenetic controls dictate alternative transcriptional programs critical for virulence.

PMID: 19845644 [PubMed - in process]

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3: Cytometry A. 2009 Sep;75(9):727-33.Click here to read LinkOut

Disease-specific biomarker discovery by aptamers.

Ulrich H, Wrenger C.

Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil. henning@iq.usp.br

RNA and DNA aptamers developed by an in vitro selection process, Systematic Evolution of Ligands by EXponential enrichment (SELEX), comprise a novel class of high-affinity and specific capture agents, which can be easily modified for cytometry and in vivo applications. A novel application of this technique (Cell SELEX) explores the expression of cell surface epitopes that differ between two given cell types or between healthy and diseased cells. Using whole cells as targets, aptamer libraries can be identified that bind to biomarkers expressed by target cells and not by any other cells. Aptamers have been developed that specifically interact with cell surface epitopes of trypanosomes or distinguish between the differences in molecular signature of somatic and cancer cells. Aside from its use for target cell identification by image and flow cytometry and laser-scanning microscopy, aptamers can be used for ligand-mediated purification and identification of their binding proteins in target cell membranes. In this review, we discuss an approach for the development of aptamers targeting parasite-derived surface proteins of Trypanosoma and Plasmodium.

PMID: 19565638 [PubMed - indexed for MEDLINE]

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4: Dev Comp Immunol. 2009 Oct;33(10):1128-36. Epub 2009 Jun 30.Click here to read Nucleotide, Taxonomy via GenBank, Protein, LinkOut

Trypanosoma carassii hsp70 increases expression of inflammatory cytokines and chemokines in macrophages of the goldfish (Carassius auratus L.).

Oladiran A, Belosevic M.

Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E9.

We report on the cloning and characterization of Trypanosoma carassii 70 KDa heat shock protein (hsp70). T. carassii hsp70 was secreted/excreted into culture medium in vitro and was recognized by sera from infected fish. Recombinant hsp70 (rhsp70) activated goldfish macrophages and stimulated the production of pro-inflammatory cytokines including interferon gamma (IFNgamma), tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, (IL)-12 and chemokines CCL-1 and CXCL-8 (IL-8). T. carassii hsp70-induced cytokine expression was abrogated by pronase treatment of macrophages confirming the existence of receptor(s) on goldfish macrophage surface that recognize parasite molecule. Parasite hsp70 also up-regulated the expression inducible nitric oxide synthase (iNOS) isoforms A and B and induced a strong nitric oxide response of goldfish macrophages.

PMID: 19527750 [PubMed - indexed for MEDLINE]

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5: Acta Trop. 2009 Sep;111(3):237-42. Epub 2009 May 13.Click here to read LinkOut

Incrimination of Eratyrus cuspidatus (Stal) in the transmission of Chagas' disease by molecular epidemiology analysis of Trypanosoma cruzi isolates from a geographically restricted area in the north of Colombia.

Dib J, Barnabe C, Tibayrenc M, Triana O.

Grupo de Chagas, Instituto de Biología, Sede de Investigación Universitaria-SIU Universidad de Antioquia, Colombia. juandib@hotmail.com

Following the report of two cases of acute Chagas' disease and the appearance of several triatomine species in human dwellings in an area considered non-endemic for domestic transmission of Trypanosoma cruzi; a epidemiological, entomological and T. cruzi molecular epidemiology analysis was performed in order to establish the transmission dynamic of the parasite in the studied area. 2 T. cruzi isolates from human patients, 5 from Eratyrus cuspidatus, 4 from Rhodnius pallescens, 4 from Panstrongylus geniculatus and 7 reference stocks were analyzed by mini-exon gene, random amplified polymorphic DNA (RAPD) and multilocus enzyme electrophoresis (MLEE). All isolates from vectors and human resulted T. cruzi group I by mini-exon, RAPD and MLEE. While mini-exon and MLEE did not showed any differences between the studied isolates, RAPD analysis identified a common T. cruzi genotype for the E. cuspidatus isolates and human isolates and distinguished different strains from R. pallescens and P. geniculatus isolates. The presence of the same T. cruzi genotype in isolates from patients and E. cuspidatus suggests that this species can be responsible for the transmission of Chagas' disease in the study area. RAPD analysis showed better resolution and discrimination of T. cruzi strains than mini-exon and MLEE and can be considered a useful tool for molecular epidemiology studies. Incrimination of sylvatic triatomine species in the transmission of Chagas' disease indicates that more knowledge about the ecology of these vectors is necessary to improve control strategies.

PMID: 19442641 [PubMed - indexed for MEDLINE]

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6: Acta Trop. 2009 Sep;111(3):255-62. Epub 2009 May 9.Click here to read Nucleotide, Taxonomy via GenBank, Protein, LinkOut

Molecular analysis of surface glycoprotein multigene family TrGP expressed on the plasma membrane of Trypanosoma rangeli epimastigotes forms.

Peña CP, Lander N, Rodríguez E, Crisante G, Añez N, Ramírez JL, Chiurillo MA.

Laboratorio de Genética Molecular Dr. Yunis-Turbay, Decanato de Ciencias de la Salud, Universidad Centroccidental Lisandro Alvarado, Barquisimeto, Venezuela.

Trypanosoma rangeli, a non-pathogenic hemoflagelate that in Central and South America infects humans, shares with Trypanosoma cruzi reservoirs and triatomine vectors, as well as geographical distribution. Recently, we have described in T. rangeli a truncated gene copy belonging to the group II of the trans-sialidase superfamily (TrGP). This superfamily, collectively known in T. cruzi as gp85/TS, includes members that are involved in host cell invasion and infectivity. To confirm the presence of this superfamily in the genome of T. rangeli and obtain a better knowledge of its characteristics, we designed a PCR and RT-PCR cloning strategy to allow sequence analysis of both genomic and transcribed copies. We identified two full-length copies of TrGP, some pseudogenes, and N- and C-terminal sequences of several genes. We also analyzed the expression and cellular localization of these proteins in epimastigote forms of a Venezuelan T. rangeli isolate using polyclonal antibodies made against a recombinant peptide from the N-terminal region of a TrGP member. We confirmed that TrGP is a multigenic family that shares many features with T. cruzi gp85/TS, including the telomeric location of some of its members, and by immunofluorescence analysis that its location is at the surface of the parasite.

PMID: 19433050 [PubMed - indexed for MEDLINE]

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7: J Antibiot (Tokyo). 2009 Jun;62(6):303-8. Epub 2009 May 1.Click here to read Nucleotide, LinkOut
Erratum in:
J Antibiot (Tokyo). 2009 Jun;62(6):343. Iwatsuki, Masahito [corrected to Iwatsuki, Masato].

In vitro and in vivo antitrypanosomal activities of three peptide antibiotics: leucinostatin A and B, alamethicin I and tsushimycin.

Ishiyama A, Otoguro K, Iwatsuki M, Namatame M, Nishihara A, Nonaka K, Kinoshita Y, Takahashi Y, Masuma R, Shiomi K, Yamada H, Omura S.

Research Center for Tropical Diseases, Center for Basic Research, Kitasato Institute for Life Sciences and Graduate School of Infectious Control Sciences, Kitasato University, Tokyo, Japan.

In the course of our screening for antitrypanosomal compounds from soil microorganisms, as well as from the antibiotics library of the Kitasato Institute for Life Sciences, we found three peptide antibiotics, leucinostatin (A and B), alamethicin I and tsushimycin, which exhibited potent or moderate antitrypanosomal activity. We report here the in vitro and in vivo antitrypanosomal properties and cytotoxicities of leucinostatin A and B, alamethicin I and tsushimycin compared with suramin. We also discuss their possible mode of action. This is the first report of in vitro and in vivo trypanocidal activity of leucinostatin A and B, alamethicin I and tsushimycin.

PMID: 19407848 [PubMed - indexed for MEDLINE]

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