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Sent on Friday, 2009 Mar 27Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
- 1: Parasitol Res. 2009 Mar 26. [Epub ahead of print]
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Identification and chromosomal localization of one locus of Leishmania (L.) major related with resistance to itraconazole.
Instituto de Medicina Tropical, Depto de Moléstias Infecciosas e Parasitárias, Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 470, 4 masculine andar, São Paulo, SP, 05403-000, Brazil.
Ergosterol is an important compound responsible to maintain integrity and fluidity of Leishmania spp. membranes. Starting from an overexpression/selection method, our group has isolated and mapped nine different loci of Leishmania (L.) major related to resistance against two inhibitors of the ergosterol biosynthesis pathway, terbinafine (TBF) and itraconazole (ITZ). Individual functional analysis after overexpression induction of these loci in the presence of TBF and/or ITZ [or the ITZ analog ketoconazole (CTZ)] have shown low but significant levels of resistance after transfection into L. major wild-type parasites. In this work, we have shown the insert mapping and chromosomal identification of one of these loci (cosItz2). Functional analysis experiments associated with chromosomal localization by comparison at genomic database allowed us to identify two prospective gene-protein systems not related to the ergosterol biosynthesis and capable to confer wild-type cells resistance to ITZ-CTZ after transfection. We expected that this approach can open new insights for a better understanding of mechanisms of ITZ-CTZ action and resistance in Leishmania resulting in new strategies for the leishmaniasis treatment.
PMID: 19322586 [PubMed - as supplied by publisher]
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Related Articles
- Isolation of genes mediating resistance to inhibitors of nucleoside and ergosterol metabolism in Leishmania by overexpression/selection. [J Biol Chem. 1999]
- Mapping of a Leishmania major gene/locus that confers pentamidine resistance by deletion and insertion of transposable element. [Rev Inst Med Trop Sao Paulo. 2004]
- Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major. [Mol Biochem Parasitol. 2003]
- ReviewAntiparasitic chemotherapy: tinkering with the purine salvage pathway. [Adv Exp Med Biol. 2008]
- ReviewOverview of resistance to systemic therapy in patients with breast cancer. [Adv Exp Med Biol. 2007]
- Patient Drug Information
- Ketoconazole (Nizoral® ) Ketoconazole is used to treat fungal infections. Ketoconazole is most often used to treat fungal infections that can spread to different parts of the body through the bloodstream such as yeast infections of the mouth, sk...
- Itraconazole (Sporanox® ) Itraconazole capsules are used to treat fungal infections that begin in the lungsand can spread through the body. Itraconazole capsules are also used to treat fungal infections of the fingernails and/or toenails. Itracon...
- Terbinafine (Lamisil® , Lamisil® AT) Terbinafine is used to treat fungal infections of the toenail and fingernail. Terbinafine is in a class of medications called antifungals. It works by stopping the growth of fungi.
Source: AHFS Consumer Medication Information -
- 2: Nucleic Acids Res. 2009 Mar 24. [Epub ahead of print]
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Evolutionary changes in the Leishmania eIF4F complex involve variations in the eIF4E-eIF4G interactions.
Department of Life Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA and Department of Biophysics, Institute for Experimental Physics, University of Warsaw, Warsaw, Poland.
Translation initiation in eukaryotes is mediated by assembly of the eIF4F complex over the m(7)GTP cap structure at the 5'-end of mRNAs. This requires an interaction between eIF4E and eIF4G, two eIF4F subunits. The Leishmania orthologs of eIF4E are structurally diverged from their higher eukaryote counterparts, since they have evolved to bind the unique trypanosomatid cap-4 structure. Here, we characterize a key eIF4G candidate from Leishmania parasites (LeishIF4G-3) that contains a conserved MIF4G domain. LeishIF4G-3 was found to coelute with the parasite eIF4F subunits from an m(7)GTP-Sepharose column and to bind directly to LeishIF4E. In higher eukaryotes the eIF4E-eIF4G interaction is based on a conserved peptide signature [Y(X(4))L], where X is any amino acid and Phi is a hydrophobic residue. A parallel eIF4E-binding peptide was identified in LeishIF4G-3 (20-YPGFSLDE-27). However, the binding motif varies extensively: in addition to Y20 and L25, binding strictly requires the presence of F23, whereas the hydrophobic amino acid (Phi) is dispensable. The LeishIF4E-LeishIF4G-3 interaction was also confirmed by nuclear magnetic resonance (NMR) studies. In view of these diversities, the characterization of the parasite eIF4E-eIF4G interaction may not only serve as a novel target for inhibiting Leishmaniasis but also provide important insight for future drug discovery.
PMID: 19321500 [PubMed - as supplied by publisher]
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Related Articles
- Translation initiation in Leishmania major: characterisation of multiple eIF4F subunit homologues. [Mol Biochem Parasitol. 2005]
- Binding specificities and potential roles of isoforms of eukaryotic initiation factor 4E in Leishmania. [Eukaryot Cell. 2006]
- A novel inhibitor of cap-dependent translation initiation in yeast: p20 competes with eIF4G for binding to eIF4E. [EMBO J. 1997]
- ReviewMolecular mechanisms of translation initiation in eukaryotes. [Proc Natl Acad Sci U S A. 2001]
- RevieweIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. [Annu Rev Biochem. 1999]
- 3: Bioorg Med Chem Lett. 2008 May 6. [Epub ahead of print]
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Synthesis and in vitro activity of new tetrahydronaphtho[1,2-b]azepine derivatives against Trypanosoma cruzi and Leishmania chagasi parasites.
Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, A. A. 678, Bucaramanga, Santander, Colombia.
Series of 2-exo-aryl-1,4-epoxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepines 3a-k and cis-2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepines 4a-j were synthesized and evaluated against free and intracellular live forms of Trypanosoma cruzi and Leishmania chagasi parasites using in vitro assays. Cell toxicity was also analyzed on Vero and THP-1 mammalian cell lines. The compounds 3c, 3f, and 4d were the most active against both live forms of T. cruzi parasites with low mammalian cell toxicity. Some compounds were active on free live forms of L. chagasi parasites but none was active on intracellular amastigotes of L. chagasi infecting THP-1 macrophages.
PMID: 19321339 [PubMed - as supplied by publisher]
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- In vitro evaluation of newly synthesised [1,2,4]triazolo[1,5a]pyrimidine derivatives against Trypanosoma cruzi, Leishmania donovani and Phytomonas staheli. [Comp Biochem Physiol C Toxicol Pharmacol. 2000]
- Identification of Three Classes of Heteroaromatic Compounds with Activity against Intracellular Trypanosoma cruzi by Chemical Library Screening. [PLoS Negl Trop Dis. 2009]
- Synthesis and in vitro evaluation of leishmanicidal and trypanocidal activities of N-quinolin-8-yl-arylsulfonamides. [Bioorg Med Chem. 2007]
- ReviewCell-mediated killing of protozoa. [Adv Parasitol. 1983]
- ReviewCephalostatin analogues--synthesis and biological activity. [Fortschr Chem Org Naturst. 2004]
- 4: Biomed Pharmacother. 2009 Mar 10. [Epub ahead of print]
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Inhibitory activity of limonene against Leishmania parasites in vitro and in vivo.
Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes, 1374, ICB2 - Cidade Universitaria, São Paulo, SP 05508-900, Brazil.
Limonene is a monoterpene that has antitumoral, antibiotic and antiprotozoal activity. In this study we demonstrate the activity of limonene against Leishmania species in vitro and in vivo. Limonene killed Leishmania amazonensis promastigotes and amastigotes with 50% inhibitory concentrations of 252.0+/-49.0 and 147.0+/-46.0muM, respectively. Limonene was also effective against Leishmania major, Leishmania braziliensis and Leishmania chagasi promastigotes. The treatment of L. amazonensis-infected macrophages with 300muM limonene resulted in 78% reduction in infection rates. L. amazonensis-infected mice treated topically or intrarectally with limonene had significant reduction of lesion sizes. A significant decrease in the parasite load was shown in the lesions treated topically with limonene by histopathological examination. The intrarectal treatment was highly effective in decreasing the parasite burden, healing established lesions and suppressing the dissemination of ulcers. Limonene presents low toxicity in humans and has been shown to be effective as an agent for enhancing the percutaneous permeation of drugs. Our results suggest that limonene should be tested in different experimental models of infection by Leishmania.
PMID: 19321295 [PubMed - as supplied by publisher]
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Related Articles
- Tamoxifen as a potential antileishmanial agent: efficacy in the treatment of Leishmania braziliensis and Leishmania chagasi infections. [J Antimicrob Chemother. 2009]
- Tamoxifen is effective against Leishmania and induces a rapid alkalinization of parasitophorous vacuoles harbouring Leishmania (Leishmania) amazonensis amastigotes. [J Antimicrob Chemother. 2007]
- Antileishmanial activity of the terpene nerolidol. [Antimicrob Agents Chemother. 2005]
- Antileishmanial activity of azithromycin against Leishmania (Leishmania) amazonensis, Leishmania (Viannia) braziliensis, and Leishmania (Leishmania) chagasi. [Am J Trop Med Hyg. 2008]
- Immunomodulatory effect of Canova medication on experimental Leishmania amazonensis infection. [J Infect. 2005]
- 5: Trop Med Int Health. 2009 Mar 23. [Epub ahead of print]
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Trypanosoma brucei gambiense in domestic livestock of Kogo and Mbini foci (Equatorial Guinea).
National Centre of Tropical Medicine, Institute of Health Carlos III, Madrid, Spain.
Objective To evaluate Trypanosoma brucei gambiense infection in peri-domestic livestock from Kogo and Mbini foci (Equatorial Guinea) in order to investigate its possible implication in the sleeping sickness transmission cycle in these hypoendemic foci. Methods Samples from 698 domestic animals (goats, sheep and pigs) from trypanosomiasis-endemic localities of Kogo and Mbini foci were tested for animal trypanosomes and T. b. gambiense (group I) by species-specific polymerase chain reaction. Results Trypanosoma brucei s.l., the predominant trypanosome species, was detected in 182 (52.6%) samples from Mbini and in 127 (36.1%) samples from Kogo. T. b. gambiense was only identified in seven (2%) of the Mbini samples and one co-infection (with T. vivax) was observed. Conclusion The occurrence of T. b. gambiense in peri-domestic livestock in Mbini and its absence in Kogo could explain the epidemiological differences between the two foci and could have significant implications for sleeping sickness control in Equatorial Guinea.
PMID: 19320872 [PubMed - as supplied by publisher]
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- High prevalence of Trypanosoma brucei gambiense group 1 in pigs from the Fontem sleeping sickness focus in Cameroon. [Vet Parasitol. 2006]
- Sleeping sickness in Zaire: a nested polymerase chain reaction improves the identification of Trypanosoma (Trypanozoon) brucei gambiense by specific kinetoplast DNA probes. [Trop Med Int Health. 1996]
- [Animal reservoir hosts of Trypanosoma brucei gambiense in Zaire: trypanosome infections in two foci in Bas-Zaire] [Trop Med Parasitol. 1989]
- ReviewInteractions between tsetse and trypanosomes with implications for the control of trypanosomiasis. [Adv Parasitol. 2003]
- ReviewThe challenge of Trypanosoma brucei gambiense sleeping sickness diagnosis outside Africa. [Lancet Infect Dis. 2003]
- 6: Mol Microbiol. 2009 Mar 6. [Epub ahead of print]
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The cell cycle as a therapeutic target against Trypanosoma brucei: Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms.
Department of Biological Sciences, Southern Methodist University, Dallas, TX 75275, USA.
Summary Aurora kinase family members coordinate a range of events associated with mitosis and cytokinesis. Anti-cancer therapies are currently being developed against them. Here, we evaluate whether Aurora kinase-1 (TbAUK1) from pathogenic Trypanosoma brucei might be targeted in anti-parasitic therapies as well. Conditional knockdown of TbAUK1 within infected mice demonstrated its essential contribution to infection. An in vitro kinase assay was developed which used recombinant trypanosome histone H3 (rTbH3) as a substrate. Tandem MS identified a novel phosphorylation site in the carboxyl-tail of rTbH3. Hesperadin, an inhibitor of human Aurora B, prevented the phosphorylation of substrate with IC(50) of 40 nM. Growth of cultured bloodstream forms (BF) was also sensitive to Hesperadin (IC(50) of 50 nM). Hesperadin blocked nuclear division and cytokinesis, but not other aspects of the cell cycle. Consequently, growth arrested cells accumulated multiple kinetoplasts, flagella and nucleoli; similar to the effects of RNAi-dependent knockdown of TbAUK1 in cultured BF cells. Molecular models predicted high affinity binding of Hesperadin to both conserved and novel sites in TbAUK1. Collectively, these data demonstrate that cell cycle progression is essential for infections with T. brucei, and that parasite Aurora kinases can be targeted with small-molecule inhibitors.
PMID: 19320832 [PubMed - as supplied by publisher]
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- An aurora kinase homologue is involved in regulating both mitosis and cytokinesis in Trypanosoma brucei. [J Biol Chem. 2006]
- Changing roles of aurora-B kinase in two life cycle stages of Trypanosoma brucei. [Eukaryot Cell. 2006]
- Okadaic acid overcomes the blocked cell cycle caused by depleting Cdc2-related kinases in Trypanosoma brucei. [Exp Cell Res. 2006]
- ReviewThe Aurora kinases: role in cell transformation and tumorigenesis. [Cancer Metastasis Rev. 2003]
- ReviewAurora kinases: structure, functions and their association with cancer. [Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2008]
- 7: Mol Biochem Parasitol. 2009 Apr;164(2):137-46.
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Functional characterization and protein-protein interactions of trypanosome splicing factors U2AF35, U2AF65 and SF1.
Laboratorio de Biología Molecular de la Enfermedad de Chagas, INGEBI-CONICET, Buenos Aires, Argentina.
Early in the assembly of eukaryotes the branch-point binding protein (BBP, also called SF1) recognizes the branch point sequence, whereas the heterodimer U2AF, consisting of a 65 and a 35 kDa subunit, contacts the polypyrimidine tract and the AG splice site, respectively. Herein, we identified, cloned and expressed the Trypanosoma cruzi and Trypanosoma brucei U2AF35, U2AF65 and SF1. Trypanosomatid U2AF65 strongly diverged from yeast and human homologues. On the contrary, trypanosomatid SF1 was conserved but lacked the C-terminal sequence present in the mammalian protein. Yeast two hybrid approaches were used to assess their interactions. The interaction between U2AF35 and U2AF65 was very weak or not detectable. However, as in other eukaryotes, the interaction between U2AF65 and SF1 was strong. At the cellular level, these results were confirmed by fractionation and affinity-selection experiments in which SF1 and U2AF65 were affinity-selected with TAP tagged SF1, but not with TAP tagged U2AF35. Silencing one of the three factors affected growth and trans-splicing in the first step of this reaction. Trypanosomes are the first described example of eukaryotic cells in which the interaction of two expressed U2AF factors seemed to be very weak, or not detectable.
PMID: 19320097 [PubMed - in process]
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- Functional recognition of the 3' splice site AG by the splicing factor U2AF35. [Nature. 1999]
- Recognition of RNA branch point sequences by the KH domain of splicing factor 1 (mammalian branch point binding protein) in a splicing factor complex. [Mol Cell Biol. 2001]
- Multiple U2AF65 binding sites within SF3b155: thermodynamic and spectroscopic characterization of protein-protein interactions among pre-mRNA splicing factors. [J Mol Biol. 2006]
- Splicing factor SF1 from Drosophila and Caenorhabditis: presence of an N-terminal RS domain and requirement for viability. [RNA. 1999]
- FRET analyses of the U2AF complex localize the U2AF35/U2AF65 interaction in vivo and reveal a novel self-interaction of U2AF35. [RNA. 2005]
- 8: J Commun Dis. 2008 Mar;40(1):87-8.
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Two cases of Kala-azar in Haryana with no evidence of local transmission.
National Institute Communicable Diseases, Delhi. kaushalmonu@Yahoo.com
PMID: 19127677 [PubMed - indexed for MEDLINE]
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- Outbreak of kala-azar in Bombay. [J Postgrad Med. 1995]
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- Epidemiological study of kala-azar by direct agglutination test in two rural communities of eastern Nepal. [Trop Med Int Health. 2004]
- ReviewEpidemiology of visceral leishmaniasis in India. [Natl Med J India. 1999]
- ReviewOrally effective drugs for kala-azar (visceral leishmaniasis): focus on miltefosine and sitamaquine. [J Assoc Physicians India. 2003]
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