Saturday, May 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: PLoS Pathog. 2009 May;5(5):e1000441. Epub 2009 May 22.Click here to read

Sand fly salivary proteins induce strong cellular immunity in a natural reservoir of visceral leishmaniasis with adverse consequences for Leishmania.

Collin N, Gomes R, Teixeira C, Cheng L, Laughinghouse A, Ward JM, Elnaiem DE, Fischer L, Valenzuela JG, Kamhawi S.

Vector Molecular Biology Unit, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Immunity to a sand fly salivary protein protects against visceral leishmaniasis (VL) in hamsters. This protection was associated with the development of cellular immunity in the form of a delayed-type hypersensitivity response and the presence of IFN-gamma at the site of sand fly bites. To date, there are no data available regarding the cellular immune response to sand fly saliva in dogs, the main reservoirs of VL in Latin America, and its role in protection from this fatal disease. Two of 35 salivary proteins from the vector sand fly Lutzomyia longipalpis, identified using a novel approach termed reverse antigen screening, elicited strong cellular immunity in dogs. Immunization with either molecule induced high IgG(2) antibody levels and significant IFN-gamma production following in vitro stimulation of PBMC with salivary gland homogenate (SGH). Upon challenge with uninfected or infected flies, immunized dogs developed a cellular response at the bite site characterized by lymphocytic infiltration and IFN-gamma and IL-12 expression. Additionally, SGH-stimulated lymphocytes from immunized dogs efficiently killed Leishmania infantum chagasi within autologous macrophages. Certain sand fly salivary proteins are potent immunogens obligatorily co-deposited with Leishmania parasites during transmission. Their inclusion in an anti-Leishmania vaccine would exploit anti-saliva immunity following an infective sand fly bite and set the stage for a protective anti-Leishmania immune response.

PMID: 19461875 [PubMed - in process]

2: Exp Parasitol. 2009 May 18. [Epub ahead of print]Click here to read

Leishmania (Viannia) peruviana (MHOM/PE/LCA08) Comparison of THP-1 cell and murine macrophage susceptibility to axenic amastigotes for the screening of leishmanicidal compounds.

González G, Castillo D, Estevez Y, Grentzinger T, Deharo E.

Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofi a, Universidad Peruana Cayetano Heredia (UPCH), Av. Honorio Delgado 430, SMP, Lima, Peru.

This study, undertaken to compare the susceptibility of THP-1 cells and murine peritoneal macrophages to Leishmania peruviana amastigotes, obtained THP-1 infection with 10 parasites/cell compared to 2 parasites/murine macrophage. The parasite burden was maximal at 72 hours post infection (h.p.i.) for THP-1 cells, while it was still increasing at 120 h.p.i. for murine macrophages. Since in both cases the infection with L. peruviana affected cell viability, we recommend evaluating any leishmanicidal activity at 72 h.p.i. Amphotericin B reduced Leishmania infection by 50% at concentrations of 0.1 muM in THP-1 and murine macrophages at 72 h.p.i. Our results demonstrate that amastigotes of L. peruviana can infect THP-1 cells and murine macrophages and indicate the suitability of this model to screen compounds for leishmanicidal activity.

PMID: 19460378 [PubMed - as supplied by publisher]

3: Exp Parasitol. 2009 May 18. [Epub ahead of print]Click here to read

Antiplasmodial and antileishmanial activities of phylloseptin-1, an antimicrobial peptide from the skin secretion of Phyllomedusa azurea (Amphibia).

S Kückelhaus SA, S A Leite JR, Muniz-Junqueira MI, Sampaio RN, Jr Bloch C, Tosta CE.

Laboratory of Cellular Immunology, Department of Pathology, Faculdade de Medicina, Universidade de Brasília, 70910-900 Brasília, DF, Brazil.

The development of drug resistance by infectious agents represents a major hindrance for controlling parasitic diseases and has stimulated the search for new compounds. We have previously shown that phylloseptin-1 (PS-1), a cationic peptide from the skin secretion of Phyllomedusa azurea, exhibited potent antimicrobial activity. Now we evaluate the effect of PS-1 on Leishmania amazonensis and Plasmodium falciparum. Concentrations as low as 0.5 mug/mL of PS-1 exhibited antileishmanial activity comparable to that of antimoniate of N-metilglucamine, while the antiplasmodial effect of PS-1 was evident at the concentration of 16 mug/mL, and reached an activity comparable to that of artesunate, at the concentration of 64 mug/mL. The high antiparasitic activity of PS-1, together with the unrelatedness of its chemical structure to any present antimicrobial drug, which prevents the development of cross-resistance, together with its non-toxicity to mammalian cells make this peptide a promising candidate for the treatment of malaria and leishmaniasis.

PMID: 19460376 [PubMed - as supplied by publisher]

4: BMC Mol Biol. 2009 May 21;10(1):48. [Epub ahead of print]Click here to read

Key role of the 3' untranslated region in the cell cycle regulated expression of the Leishmania infantum histone H2A genes: minor synergistic effect of the 5' untranslated region.

Abanades DR, Ramirez L, Iborra S, Soteriadou K, Gonzalez VM, Bonay P, Alonso C, Soto M.

ABSTRACT: BACKGROUND: Histone synthesis in Leishmania is tightly coupled to DNA replication by a post-transcriptional mechanism operating at the level of translation. RESULTS: In this work we have analyzed the implication of the 5' and 3' untranslated regions (UTR) in the cell cycle regulated expression of the histone H2A in Leishmania infantum. For that purpose, L. infantum promastigotes were stably transfected with different plasmid constructs in which the CAT coding region used as a reporter was flanked by the 5' and 3' UTR regions of the different H2A genes. We report that in spite of their sequence differences, histone H2A 5' and 3' UTRs conferred a cell cycle dependent pattern of expression on the CAT reporter since de novo synthesis of CAT increased when parasites enter the S phase. Using one established L. infantum cell line we showed that CAT expression is controlled by the same regulatory events that control the endogenous histone gene expression. Thus, although we did not detect changes in the level of CAT mRNAs during cell cycle progression, a drastic change in the polysome profiles of CAT mRNAs was observed during the progression from G1 to S phase. In the S phase CAT mRNAs were on polyribosomal fractions, but in the G1 phase the association of CAT transcripts with ribosomes was impaired. Furthermore, it was determined that the addition of just the H2A 3' UTR to the CAT reporter gene is sufficient to achieve a similar pattern of post-transcriptional regulation indicating that this region contains the major regulatory sequences involved in the cell cycle dependent expression of the H2A genes. On the other hand, although CAT transcripts bearing the H2A 5' alone were translated both in the G1 and S phase, higher percentages of transcripts were detected on polyribosomes in the S phase correlating with an increase in the de novo synthesis of CAT. Thus, it can be concluded that this region also contributes, although to a minor extent than the 3' UTR, in the enhancement of translation in the S phase relative to the G1 phase. CONCLUSIONS: Our findings indicate that both, the 5' and the 3' UTRs contain sequence elements that contribute to the cell cycle expression of L. infantum H2A. The 3' UTR region is essential for cell cycle dependent translation of the L. infantum H2A transcripts whereas the 5' UTR has a minor contribution in their S phase dependent translation.

PMID: 19460148 [PubMed - as supplied by publisher]

5: FEBS J. 2009 May 1;276(10):2822-2832.Click here to read

Structure of a trypanosomatid mitochondrial cytochrome c with heme attached via only one thioether bond and implications for the substrate recognition requirements of heme lyase.

Fülöp V, Sam KA, Ferguson SJ, Ginger ML, Allen JW.

Department of Biological Sciences, University of Warwick, Coventry, UK.

The principal physiological role of mitochondrial cytochrome c is electron transfer during oxidative phosphorylation. c-Type cytochromes are almost always characterized by covalent attachment of heme to protein through two thioether bonds between the heme vinyl groups and the thiols of cysteine residues in a Cys-Xxx-Xxx-Cys-His motif. Uniquely, however, members of the evolutionarily divergent protist phylum Euglenozoa, which includes Trypanosoma and Leishmania species, have mitochondrial cytochromes c with heme attached through only one thioether bond [to an (A/F)XXCH motif]; the implications of this for the cytochrome structures are unclear. Here we present the 1.55 A resolution X-ray crystal structure of cytochrome c from the trypanosomatid Crithidia fasciculata. Despite the fundamental difference in heme attachment and in the cytochrome c biogenesis machinery of the Euglenozoa, the structure is remarkably similar to that of typical (CXXCH) mitochondrial cytochromes c, both in overall fold and, other than the missing thioether bond, in the details of the heme attachment. Notably, this similarity includes the stereochemistry of the covalent heme attachment to the protein. The structure has implications for the maturation of c-type cytochromes in the Euglenozoa; it also hints at a distinctive redox environment in the mitochondrial intermembrane space of trypanosomes. Surprisingly, Saccharomyces cerevisiae cytochrome c heme lyase (the yeast cytochrome c biogenesis system) cannot efficiently mature Trypanosoma brucei cytochrome c or a CXXCH variant when expressed in the cytoplasm of Escherichia coli, despite their great structural similarity to yeast cytochrome c, suggesting that heme lyase requires specific recognition features in the apocytochrome.

PMID: 19459937 [PubMed - as supplied by publisher]

6: Exp Parasitol. 2009 Jun;122(2):91-6. Epub 2009 Mar 11.Click here to read LinkOut

Trypanosoma cruzi: in vitro activity of Epoxy-alpha-Lap, a derivative of alpha-lapachone, on trypomastigote and amastigote forms.

Bourguignon SC, Castro HC, Santos DO, Alves CR, Ferreira VF, Gama IL, Silva FC, Seguins WS, Pinho RT.

Universidade Federal Fluminense, Departamento de Biologia Geral e Celular, Outeiro de São João Baptista, CEP 24020-150, Niterói, RJ, Brazil. saulocb@globo.com

Chagas disease is an endemic parasitic infection caused by Trypanosomacruzi that affects 18-20 million people in Central and South America. Recently we described the Epoxy-alpha-Lap, an oxyran derivative of alpha-lapachone, which presents a low toxicity profile and a high inhibitory activity against T.cruzi epimastigotes forms, the non-infective form of this parasite. In this work we described the trypanocidal effects of Epoxy-alpha-Lap on extracellular (trypomastigote) and intracellular (amastigote) infective forms of two T. cruzi strains (Y and Colombian) known by their different infective profile. Our results showed that Epoxy-alpha-Lap is lethal to trypomastigote Y and Colombian strains (97% and 84%, respectively). Interestingly, Epoxy-alpha-Lap also showed a trypanocidal effect in human macrophage infected with T. cruzi Y (85.6%) and Colombian (71.9%) strains amastigote forms. Similar effects were observed on T. cruzi amastigote infected Vero cells (96.4% and 95.0%, respectively). Our results pointed Epoxy-alpha-Lap as a potential candidate for Chagas disease chemotherapy since it presents trypanocidal activity on all T. cruzi forms with low) toxicity profile.

PMID: 19285074 [PubMed - indexed for MEDLINE]

7: Exp Parasitol. 2009 Jun;122(2):128-33. Epub 2009 Feb 13.Click here to read LinkOut

Trypanosoma cruzi: isolation and characterization of aspartyl proteases.

Pinho RT, Beltramini LM, Alves CR, De-Simone SG.

Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Imunologia Clínica, Av. Brasil 4365, Rio de Janeiro, RJ 21040-900, Brazil.

Two aspartyl proteases activities were identified and isolated from Trypanosoma cruzi epimastigotes: cruzipsin-I (CZP-I) and cruzipsin-II (CZP-II). One was isolated from a soluble fraction (CZP-II) and the other was solubilized with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CZP-I). The molecular mass of both proteases was estimated to be 120 kDa by HPLC gel filtration and the activity of the enzymes was detected in a doublet of bands (56 and 48 kDa) by substrate-sodium dodecyl sulphate-polyacrylamide-gelatin gel electrophoresis. Substrate specificity studies indicated that the enzymes consistently hydrolyze the cathepsin D substrate Phe-Ala-Ala-Phe (4-NO2)-Phe-Val-Leu-O4MP but failed to hydrolyze serine and other protease substrates. Both proteases activities were strongly inhibited by the classic inhibitor pepstatin-A (> or =68%) and the aspartic active site labeling agent, 1,2-epoxy-3-(phenyl-nitrophenoxy) propane (> or =80%). These findings show that both proteases are novel T. cruzi acidic proteases. The physiological function of these enzymes in T. cruzi has under investigation.

PMID: 19217906 [PubMed - indexed for MEDLINE]

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