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Sent on Wednesday, 2011 Mar 02Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Mol Cell Biochem. 2011 Feb 26. [Epub ahead of print]Evaluation of selected antitumor agents as subversive substrate and potential inhibitor of trypanothione reductase: an alternative approach for chemotherapy of Leishmaniasis.Shukla AK, Patra S, Dubey VK.Department of Biotechnology, Indian Institute of Technology Guwahati, Assam, 781039, India. AbstractTrypanothione reductase (TryR) is a validated drug target against Leishmaniasis. Using integrated computational and experimental approaches, the authors report doxorubicin and mitomycin C, known antitumor agents, as novel inhibitors of TryR of leishmania parasite. Interestingly, these compounds also act as subversive substrates and subvert the physiological function of enzyme by converting it from an anti-oxidant to a pro-oxidant. Possible mechanism of subversive substrate is discussed. Both doxorubicin and mitomycin C show significant effect on redox homeostasis of the parasite and high-leishmanicidal activity. The toxicity studies as well as available toxicity data in literature indicate these compounds to have acceptable toxicity in limited dose. |
| PMID: 21359528 [PubMed - as supplied by publisher] | |
| 2. | PLoS Negl Trop Dis. 2011 Feb 15;5(2):e962.Identification of small molecule lead compounds for visceral leishmaniasis using a novel ex vivo splenic explant model system.Osorio Y, Travi BL, Renslo AR, Peniche AG, Melby PC.Department of Veterans Affairs Medical Center, Research Service, South Texas Veterans Health Care System, San Antonio, Texas, United States of America. AbstractBACKGROUND: New drugs are needed to treat visceral leishmaniasis (VL) because the current therapies are toxic, expensive, and parasite resistance may weaken drug efficacy. We established a novel ex vivo splenic explant culture system from hamsters infected with luciferase-transfected Leishmania donovani to screen chemical compounds for anti-leishmanial activity. METHODOLOGY/PRINCIPAL FINDINGS: THIS MODEL HAS ADVANTAGES OVER IN VITRO SYSTEMS IN THAT IT: 1) includes the whole cellular population involved in the host-parasite interaction; 2) is initiated at a stage of infection when the immunosuppressive mechanisms that lead to progressive VL are evident; 3) involves the intracellular form of Leishmania; 4) supports parasite replication that can be easily quantified by detection of parasite-expressed luciferase; 5) is adaptable to a high-throughput screening format; and 6) can be used to identify compounds that have both direct and indirect anti-parasitic activity. The assay showed excellent discrimination between positive (amphotericin B) and negative (vehicle) controls with a Z' Factor >0.8. A duplicate screen of 4 chemical libraries containing 4,035 compounds identified 202 hits (5.0%) with a Z score of <-1.96 (p<0.05). Eighty-four (2.1%) of the hits were classified as lead compounds based on the in vitro therapeutic index (ratio of the compound concentration causing 50% cytotoxicity in the HepG(2) cell line to the concentration that caused 50% reduction in the parasite load). Sixty-nine (82%) of the lead compounds were previously unknown to have anti-leishmanial activity. The most frequently identified lead compounds were classified as quinoline-containing compounds (14%), alkaloids (10%), aromatics (11%), terpenes (8%), phenothiazines (7%) and furans (5%). CONCLUSIONS/SIGNIFICANCE: The ex vivo splenic explant model provides a powerful approach to identify new compounds active against L. donovani within the pathophysiologic environment of the infected spleen. Further in vivo evaluation and chemical optimization of these lead compounds may generate new candidates for preclinical studies of treatment for VL. |
| PMID: 21358812 [PubMed - in process] | |
| 3. | J Immunol. 2011 Feb 28. [Epub ahead of print]IL-27 and IL-21 Are Associated with T Cell IL-10 Respon ses in Human Visceral Leishmaniasis.Ansari NA, Kumar R, Gautam S, Nylén S, Singh OP, Sundar S, Sacks D.Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; AbstractIL-10 is believed to underlie many of the immunologic defects in human visceral leishmaniasis (VL). We have identified CD4(+)CD25(-)Foxp3(-) T cells as the major source of IL-10 in the VL spleen. IL-27, a member of the IL-6/IL-12 cytokine family, has been shown to promote development of IL-10-producing T cells, in part by upregulating their production of autocrine IL-21. We investigated whether IL-27 and IL-21 are associated with human VL. IL-27 was elevated in VL plasma, and at pretreatment, spleen cells showed significantly elevated mRNA levels of both IL-27 subunits, IL-27p28 and EBI-3, as well as IL-21, compared with posttreatment biopsies. CD14(+) spleen cells were the main source of IL-27 mRNA, whereas CD3(+) T cells were the main source of IL-21. IL-27 mRNA could be strongly upregulated in normal donor macrophages with IFN-γ and IL-1β, conditions consistent with those in the VL spleen. Last, a whole-blood assay revealed that most VL patients could produce Ag-specific IFN-γ and IL-10 and that the IL-10 could be augmented with recombinant human IL-21. Thus, proinflammatory cytokines acting on macrophages in the VL spleen have the potential to upregulate IL-27, which in turn can induce IL-21 to expand IL-10-producing T cells as a mechanism of feedback control. |
| PMID: 21357266 [PubMed - as supplied by publisher] | |
| 4. | Parasit Vectors. 2011 Feb 28;4(1):26. [Epub ahead of print]Are protozoan metacaspases potential parasite killers?Meslin B, Zalila H, Fasel N, Picot S, Bienvenu AL.AbstractABSTRACT: Mechanisms concerning life or death decisions in protozoan parasites are still imperfectly understood. Comparison with higher eukaryotes has led to the hypothesis that caspase-like enzymes could be involved in death pathways. This hypothesis was reinforced by the description of caspase-related sequences in the genome of several parasites, including Plasmodium, Trypanosoma and Leishmania. Although several teams are working to decipher the exact role of metacaspases in protozoan parasites, partial, conflicting or negative results have been obtained with respect to the relationship between protozoan metacaspases and cell death. The aim of this paper is to review current knowledge of protozoan parasite metacaspases within a drug targeting perspective. |
| PMID: 21356053 [PubMed - as supplied by publisher] | |
| 5. | J Proteome Res. 2011 Feb 28. [Epub ahead of print]Analysis of <i>Leishmania chagasi</i> by 2-D Difference Gel Eletrophoresis (2-D DIGE) and Immunoproteomic: identification of novel candidate antigens for diagnostic tests and vaccine.Costa MM, Andrade HM, Bartholomeu DC, Freitas L, Pires SF, Chapeaurouge A, Perales J, Ferreira AT, Melo MN, Giusta MS, Gazzinelli R.AbstractIdentification of novel antigens is essential for developing new diagnostic tests and vaccines. We used DIGE to compare protein expression in amastigote and promastigote forms of Leishmania chagasi. Nine hundred amastigote and promastigote spots were visualized. Five amastigote-specific, 25 promastigote-specific, and 10 proteins shared by the two parasite stages were identified. Furthermore, 41 proteins were identified in the Western blot employing 2-DE and sera from infected dogs. From these proteins, 3 and 38 were reactive with IgM and total IgG, respectively. The proteins recognized by total IgG presented different patterns in terms of their recognition by IgG1 and/or IgG2 isotypes. All the proteins selected by Western blot were mapped for B-cell epitopes. One hundred and eighty peptides were submitted to SPOT synthesis and immunoassay. A total of 25 peptides were shown of interest for serodiagnosis to visceral leishmaniasis. In addition, all proteins identified in this study were mapped for T cell epitopes by using the NetCTL software, and candidates for vaccine development selected. Therefore, a large-scale screening of L. chagasi proteome was performed to identify new B and T cell epitopes with potential use for developing diagnostic tests and vaccines. |
| PMID: 21355625 [PubMed - as supplied by publisher] | |
| 6. | Harefuah. 2010 Nov;149(11):708-11.[708 IMAJ 2009--toward the next decade].[Article in Hebrew] Israeli E. |
| PMID: 21250411 [PubMed - indexed for MEDLINE] | |
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| 7. | Int J Health Geogr. 2010 Oct 29;9:55.Penalized likelihood and multi-objective spatial scans for the detection and inference of irregular clusters.Cançado AL, Duarte AR, Duczmal LH, Ferreira SJ, Fonseca CM, Gontijo EC.Department of Statistics, Universidade Federal de Minas Gerais, Belo Horizonte/MG, Brazil. AbstractBACKGROUND: Irregularly shaped spatial clusters are difficult to delineate. A cluster found by an algorithm often spreads through large portions of the map, impacting its geographical meaning. Penalized likelihood methods for Kulldorff's spatial scan statistics have been used to control the excessive freedom of the shape of clusters. Penalty functions based on cluster geometry and non-connectivity have been proposed recently. Another approach involves the use of a multi-objective algorithm to maximize two objectives: the spatial scan statistics and the geometric penalty function. RESULTS & DISCUSSION: We present a novel scan statistic algorithm employing a function based on the graph topology to penalize the presence of under-populated disconnection nodes in candidate clusters, the disconnection nodes cohesion function. A disconnection node is defined as a region within a cluster, such that its removal disconnects the cluster. By applying this function, the most geographically meaningful clusters are sifted through the immense set of possible irregularly shaped candidate cluster solutions. To evaluate the statistical significance of solutions for multi-objective scans, a statistical approach based on the concept of attainment function is used. In this paper we compared different penalized likelihoods employing the geometric and non-connectivity regularity functions and the novel disconnection nodes cohesion function. We also build multi-objective scans using those three functions and compare them with the previous penalized likelihood scans. An application is presented using comprehensive state-wide data for Chagas' disease in puerperal women in Minas Gerais state, Brazil. CONCLUSIONS: We show that, compared to the other single-objective algorithms, multi-objective scans present better performance, regarding power, sensitivity and positive predicted value. The multi-objective non-connectivity scan is faster and better suited for the detection of moderately irregularly shaped clusters. The multi-objective cohesion scan is most effective for the detection of highly irregularly shaped clusters. |
| PMID: 21034451 [PubMed - indexed for MEDLINE] | |
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| 8. | Curr Opin Microbiol. 2010 Dec;13(6):700-5. Epub 2010 Sep 29.Molecular mechanisms underlying the control of antigenic variation in African trypanosomes.Horn D, McCulloch R.London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. david.horn@lshtm.ac.uk AbstractAfrican trypanosomes escape the host adaptive immune response by switching their dense protective coat of Variant Surface Glycoprotein (VSG). Each cell expresses only one VSG gene at a time from a telomeric expression site (ES). The 'pre-genomic' era saw the identification of the range of pathways involving VSG recombination in the context of mono-telomeric VSG transcription. A prominent feature of the early post-genomic era is the description of the molecular machineries involved in these processes. We describe the factors and sequences recently linked to mutually exclusive transcription and VSG recombination, and how these act in the control of the key virulence mechanism of antigenic variation. Copyright © 2010 Elsevier Ltd. All rights reserved. |
| PMID: 20884281 [PubMed - indexed for MEDLINE] | |
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| 9. | Autoimmunity. 2010 Dec;43(8):664-71. Epub 2010 Apr 7.CD4+ T-cell anergy induced by lin- CD117(c-kit)+ stem cell-derived immature dendr itic cells loaded with nuclear antigen derived from Trypanosoma equiperdum.Xia Y, Zhang Y, Jiang S, Cheng H.Department of Dermatology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China. ymxia@whu.edu.cn AbstractDendritic cells (DCs) are professional antigen-presenting cells, which have the extraordinary capacity to initiate naïve T-cell-mediated primary immune responses. To investigate the role of DCs in the induction of antigen-specific tolerance, the immature DCs (imDCs) and mature DCs (mDCs) were generated in vitro from lin(-)CD117(c-kit)(+) stem cells isolated from mice bone marrow. Flow cytometry and confocal microscopy were used to characterize the phenotypes of DCs. These cells were loaded with nuclear antigen derived from Trypanosoma equiperdum and then co-cultured with naïve CD4(+) T cells. It was found that imDC-treated T cells had lower proliferation level and cytokine expression of interleukin (IL)-2, IL-4, IL-12, and interferon-γ compared with mDC-treated T cells. These results demonstrated that the maturation status of DCs is critical for preventing the production of autoantibodies. |
| PMID: 20370574 [PubMed - indexed for MEDLINE] | |
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