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 - 10 of 18

1.	Eur J Med Chem. 2010 May 21. [Epub ahead of print] Synthesis and Antileishmanial activity of Piperoyl-Amino Acid Conjugates. Singh IP, Jain SK, Kaur A, Singh S, Kumar R, Garg P, Sharma SS, Arora SK. Department of Natural Products, National Institute of Pharmaceutical Education and Research (NIPER)(1), Sector 67, S.A.S. Nagar, Punjab 160062, India. Abstract Based on reported antileishmanial activity of naturally occurring alkaloid piperine and amino acid esters, their conjugates were synthesized by the hydrolysis of piperine to piperic acid followed by reaction with amino acid methyl esters. These conjugates were further converted to compounds with free carboxyl group and those with reduced double bonds. The synthesized compounds were evaluated for activity against promastigote and amastigote forms of L. donovani in vitro. All the compounds showed better activity than either piperine or the amino acid methyl esters. Piperoyl-valine methyl ester was the most active compound showing an IC(50) of 0.075mM against the amastigotes. Two active compounds were evaluated for in vivo activity in golden hamster model of leishmaniasis. Copyright © 2010 Elsevier Masson SAS. All rights reserved.
	PMID: 20546981 [PubMed - as supplied by publisher]
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2.	Vet Immunol Immunopathol. 2010 Apr 21. [Epub ahead of print] Systemic and compartmentalised immune responses in a Leishmania braziliensis-macaque model of self-healing cutaneous leishmaniasis. de-Campos SN, Souza-Lemos C, Teva A, Porrozzi R, Grimaldi G Jr. Laboratório de Pesquisa em Leishmaniose, Instituto Oswaldo Cruz/Fiocruz, Rio de Janeiro, Brazil. Abstract We have recently introduced a macaque (Macaca mulatta) model of Leishmania braziliensis-induced chronic granulomatous cutaneous lesions affecting the nasal mucosa. Using an L. braziliensis strain that produces self-healing dermal lesions in macaques, here we characterises the systemic and local cell-mediated immune responses that led to controlled growth of granulomas in the infected host. As detected using flow cytometry, more cytokine-producing T-cell subsets were observed in granuloma-derived leukocytes that were analysed directly ex vivo than in the in vitro-restimulated cells from the peripheral blood and skin-draining lymph nodes (dLNs). We demonstrate that antigen-specific interferon-gamma (IFN-gamma)- or tumour necrosis factor alpha (TNF-alpha)-producing CD4(+) and CD8(+) cells are likely important for the immunological effectiveness of granulomas. However, their resolution can be ascribed to the concomitant recruitment of interleukin (IL)-10-producing CD4(+)CD25(+) regulatory T (Treg) cells that suppress the effector T-cell-mediated inflammatory response. The findings confirm that the macaque model can be used to fully elucidate the regulatory mechanisms that may render granulomas inadequate for fighting intracellular pathogens, which will need to be considered in the development of any therapeutic strategy designed to prevent immune pathology. Copyright © 2010 Elsevier B.V. All rights reserved.
	PMID: 20546932 [PubMed - as supplied by publisher]
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3.	Mol Biochem Parasitol. 2010 May 20. [Epub ahead of print] Complete set of mitochondrial pan-edited mRNAs in Leishmania mexicana amazonensis LV78. Maslov DA. Department of Biology, University of California, Riverside, CA 92521, USA. Abstract Editing of mRNA transcribed from the mitochondrial cryptogenes ND8 (G1), ND9 (G2), G3, G4, ND3 (G5), RPS12 (G6) was investigated in Leishmania mexicana amazonensis, strain LV78, by amplification of the cDNA, cloning and sequencing. For each of these genes, extensively and partially edited transcripts were found to be relatively abundant compared to the respective pre-edited molecules. Moreover, the editing patterns observed in a majority of transcripts of each gene were consistent among themselves which allowed for inferring consensus editing sequences. The open reading frames contained in the consensus sequences were predicted to encode polypeptides that were highly similar to their counterparts in other species of Trypanosomatidae. Several kinetoplast DNA minicircles from this species available in the public domain were found to contain genes for guide RNAs which mediate editing of some of the mRNAs. The results indicate that the investigated strain of L. m. amazonensis has preserved its full editing capacity in spite of the long-term maintenance in culture. This property differs drastically from the other Leishmania species which lost some or all of the G1-G5 mRNA editing ability in culture. Copyright © 2010. Published by Elsevier B.V.
	PMID: 20546801 [PubMed - as supplied by publisher]
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4.	J Infect. 2010 May 20. [Epub ahead of print] Amphotericin B Regulates the Host Immune Response in Visceral Leishmaniasis: Reciprocal Regulation of Protein Kinase C isoforms. Mukherjee A, Gupta G, Bhattacharjee S, Guha SK, Majumder S, Adhikari A, Bhattachrya P, Majumdar SB, Majumdar S. Div. of Molecular Medicine, Bose Institute, Kolkata, India; Employees State Insurance Hospital, Maniktala, Kolkata, India. Abstract OBJECTIVES: Treatment of visceral leishmaniasis (VL) is marked by the failure of pentavalent antimonials which has brought amphotericin B (AmpB) to the forefront. In this study we have focused on signaling pathway regulating AmpB triggered effector response. METHODS: AmpB triggered effector response in the form of free radicals and proinflammatory cytokines was determined by FACS, colorimetric estimation or Real-Time PCR (RT-PCR). Specific peptide inhibitors for classical and atypical protein kinase C (PKC) were used to investigate the role of PKC isoforms in the functioning of AmpB during VL. RESULTS: In vitro studies with THP1 cells showed that 2 mug/ml dose of AmpB could mediate effective parasite clearance due to strong induction of free radicals and proinflammatory cytokines. This induction of proinflammatory response paralleled with antagonistic regulation of classical and atypical PKC. Further confirmation was provided by RT-PCR of (peripheral blood mononuclear cells) PBMC isolated from VL infected patients undergoing AmpB treatment. CONCLUSIONS: Overall our results suggest that classical and atypical PKC signaling pathways are involved in the modulation of proinflammatory response triggered by AmpB against Leishmania donovani. These observations may contribute to the understanding of the mechanism responsible for the initiation of protective response induced by AmpB during VL. Copyright © 2010 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
	PMID: 20546775 [PubMed - as supplied by publisher]
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5.	Clin Exp Dermatol. 2010 Jun 7. [Epub ahead of print] Cutaneous sporotrichoid leishmaniasis resistant to pentavalent antimonial therapy: complete resolution with itraconazole. Cozzani E, Satta R, Fausti V, Cottoni F, Parodi A. Section of Dermatology, Di.S.E.M., University of Genoa, Genoa, Italy. Abstract Summary Sporotrichoid leishmaniasis is a sporadic form of cutaneous leishmaniasis, a protozoal infection, reported particularly in the Middle East. Clinically it occurs as nontender, subcutaneous, slightly erythematous nodules, often associated with lymphangitis, usually on exposed areas of the skin. Sometimes it occurs after treatment with a single dose of antimonials, and in older lesions, the biopsy can be negative for amastigotes. We report a case of cutaneous sporotrichoid leishmaniasis unresponsive to intralesional pentavalent antimonial therapy, which completely resolved after treatment with oral itraconazole. To our knowledge, this is only the third such case reported. We discuss the causes of dissemination of the nodular lesions and the negative results for amastigotes on re-biopsed lesions.
	PMID: 20545956 [PubMed - as supplied by publisher]
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6.	Mol Microbiol. 2010 Jun 1. [Epub ahead of print] Screening Leishmania donovani specific genes required for visceral infection. Zhang WW, Matlashewski G. Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, Canada H3A 2B4. Abstract Summary Comparison of the L. infantum genome with L. braziliensis and L. major genomes has identified 25 L. infantum species-specific genes which are absent or pseudogenes in L. major and L. braziliensis. To determine whether these L. infantum species-specific genes are involved in visceral Leishmania infection, we cloned the orthologs of 14 L. infantum species-specific genes from the genetically closely related L. donovani and introduced them into L. major. Two of these L. donovani species-specific genes were found to significantly increase L. major survival in visceral organs in BALB/c mice. One (ortholog of LinJ28_V3.0340; Ld2834) of these two genes was further investigated. The L. donovani Ld2834 null mutants displayed dramatically reduced virulence in BALB/c mice and were unable to survive in axenic amastigote culture conditions arguing that Ld2834 plays a crucial role in enabling L. donovani survive at the increased temperature typically associated with visceral organs. Ld2834 encodes a 50 kDa protein that is localized in the cytoplasma and has no significant sequence similarity with other known genes. This study validates the importance of comparative genomics for understanding Leishmania species pathology and argues that Leishmania species-specific genes play important roles in tissue tropism and virulence.
	PMID: 20545850 [PubMed - as supplied by publisher]
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7.	Mol Microbiol. 2010 Jun 1. [Epub ahead of print] Trypanosoma brucei pteridine reductase 1 is essential for survival in vitro and for virulence in mice. Sienkiewicz N, Ong HB, Fairlamb AH. Division of Biological Chemistry & Drug Discovery, College of Life Sciences, University of Dundee, Dundee United Kingdom. Abstract Summary Gene knockout and knockdown methods were used to examine essentiality of pteridine reductase (PTR1) in pterin metabolism in the African trypanosome. Attempts to generate PTR1 null mutants in bloodstream form T. brucei proved unsuccessful; despite integration of drug selectable markers at the target locus, the gene for PTR1 was either retained at the same locus or elsewhere in the genome. However, RNA interference (RNAi) resulted in complete knockdown of endogenous protein after 48 h, followed by cell death after 4 days. This lethal phenotype was reversed by expression of enzymatically active Leishmania major PTR1 in RNAi lines ((oe)RNAi) or by addition of tetrahydrobiopterin to cultures. Loss of PTR1 was associated with gross morphological changes due to a defect in cytokinesis, resulting in cells with multiple nuclei and kinetoplasts, as well as multiple detached flagella. Electron microscopy also revealed increased numbers of glycosomes, while immunofluorescence microscopy showed increased and more diffuse staining for glycosomal matrix enzymes, indicative of mis-localisation to the cytosol. Mis-localisation was confirmed by digitonin fractionation experiments. RNAi cell lines were markedly less virulent than wild-type (WT) parasites in mice and virulence was restored in the (oe)RNAi line. Thus, PTR1 may be a drug target for human African trypanosomiasis.
	PMID: 20545846 [PubMed - as supplied by publisher]
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8.	Drug Dev Ind Pharm. 2010 Jun 14. [Epub ahead of print] Barriers to treatment for visceral leishmaniasis in hyperendemic areas: India, Bangladesh, Nepal, Brazil and Sudan. Thornton SJ, Wasan KM, Piecuch A, Lynd LL, Wasan EK. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada. Abstract Context: Visceral leishmaniasis (VL) is a severe and potentially fatal infection caused by the trypanosome parasite Leishmania sp. Over 90% of reported cases occur in India, Bangladesh, Nepal, Sudan, and Brazil, affecting mainly impoverished individuals and creating a significant economic burden through direct and indirect costs of treatment. Objectives: To identify the direct and indirect costs of VL treatment, compare these costs to household income, and identify the barriers to treatment in each of the five VL-endemic countries. Methods: Articles obtained through PubMed (US National Library of Medicine), EMBASE, and Cochrane Library were selected for relevance to VL treatment, costs for all forms of amphotericin B, miltefosine, paromomycin, and antimony compounds, and healthcare costs in India, Bangladesh, Nepal, Brazil, and Sudan. Healthcare statistics were obtained from the World Health Organization Statistical Information System, Médecins Sans Frontieres, and each country's national health ministry. Results: Per capita GDP, per capita GNI, cost of drugs, and hospitalization expenses differ by up to 10-fold in each of the five countries where VL is hyperendemic, resulting in unequal barriers to treatment. We found that the cost of specific drugs influences the choice of therapy. Conclusions: Poverty and VL treatment-related costs cause potential limitations in the provision of full and efficacious treatment, which may result in further dissemination of the disease. Effective nonparenteral antileishmania drugs would provide a significant advantage in reducing the barriers to VL treatment.
	PMID: 20545513 [PubMed - as supplied by publisher]
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9.	Oligonucleotides. 2010 Jun 14. [Epub ahead of print] In Vitro Selection of Leishmania infantum H3-Binding ssDNA Aptamers. Ramos E, Moreno M, Martín ME, Soto M, Gonzalez VM. 1 Departamento de Bioquímica-Investigación, Instituto Ramón y Cajal de Investigación Sanitaria (IRyCIS) , Madrid, Spain . Abstract Aptamers are single-stranded DNA or RNA oligonucleotides that adopt specific three-dimensional structures binding with high affinity and specificity to their targets. These molecules are being currently used with detection and diagnosis purposes. Parasites of the genus Leishmania cause leishmaniosis in humans and animals. Interestingly, Leishmania do not condense their chromatin during mitosis, and histone genes could be responsible for this fact. Although histones are extremely conserved proteins, reflecting their apparent universality of function, sequence similarity of kinetoplastid core histones with that of higher eukaryotes is found predominantly in the globular region. However, high sequence divergences in the N-terminal and C-terminal domains are found that convert them into potential diagnostic and/or therapeutics targets. We have successfully isolated a pool of DNA aptamers, named SELH3, which binds to Leishmania infantum H3 with high affinity and specificity. Thus, it appears that this novel anti-H3 aptamer population may be of potential application as a diagnostic system for leishmaniosis.
	PMID: 20545478 [PubMed - as supplied by publisher]
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10.	J Drug Target. 2010 Jun 14. [Epub ahead of print] Drug targeting to macrophages using paromomycin-loaded albumin microspheres for treatment of visceral leishmaniasis: an in vitro evaluation. < a href="http://www.ncbi.nlm.nih.gov/pubmed?term=%22Khan%20W%22%5BAuthor%5D">Khan W, Kumar N. Department of Pharmaceutics, National Institute of Pharmaceutical Education & Research (NIPER), Punjab, India. Abstract Background: Leishmania parasite is an obligate intracellular parasite of the mammalian host and lives inside resident macrophages of liver and spleen. A high dose of paromomycin (PM) is required for the treatment. Purpose: Preparation and in vitro evaluation of PM loaded albumin microspheres (MS) (of size </= 5 microm) to target macrophages for treatment of visceral leishmaniasis. Methods: PM loaded MS were prepared by spray-drying method using albumin as a polymer matrix and stabilized using heat treatment. These MS were evaluated for product yield, encapsulation efficiency, particle size, size distribution, contact angle, drug-polymer interactions, and for in vitro drug release. Fluorescent labeling and in vitro uptake of these MS was assessed in RAW 264.7 cell line. Results: PM loaded albumin MS were prepared with a mean particle size approximately 3 microm. Free albumin content and contact angle study confirmed the stabilization of these MS. Release studies showed biphasic release pattern. Interaction studies ruled out any possibility of drug-polymer interaction. Uptake study in macrophage confirmed the suitability of prepared MS for macrophage targeting. Conclusion: The proposed drug-delivery system was found suitable for targeting macrophages in vitro and may serve as an optimum carrier to target macrophages where Leishmania parasite resides.
	PMID: 20545446 [PubMed - as supplied by publisher]
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