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Sent on Saturday, 2010 Apr 03Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | PLoS Negl Trop Dis. 2010 Mar 30;4(3):e642.Nelfinavir, an HIV-1 Protease Inhibitor, Induces Oxidative Stress-Mediated, Caspase-Independent Apoptosis in Leishmania Amastigotes.Kumar P, Lodge R, Trudel N, Ouellet M, Ouellette M, Tremblay MJ.Centre de Recherche en Infectiologie, Centre Hospitalier de l'Université Laval, and Département de Microbiologie et Immunologie, Université Laval, Québec, Canada. BACKGROUND: Visceral leishmaniasis has now emerged as an important opportunistic disease in patients coinfected with human immunodeficiency virus type-1 (HIV-1). Although the effectiveness of HIV-1 protease inhibitors, such as nelfinavir, in antiretroviral therapies is well documented, little is known of the impact of these drugs on Leishmania in coinfected individuals. METHODOLOGY AND PRINCIPAL FINDINGS: Here, we show that nelfinavir generates oxidative stress in the parasite, leading to altered physiological parameters such as an increase in the sub-G1 DNA content, nuclear DNA fragmentation and loss of mitochondrial potential, which are all characteristics of apoptosis. Pretreatment of axenic amastigotes with the caspase inhibitor z-VAD-fmk did not inhibit the increase in sub-G1 DNA content in nelfinavir-treated parasites, suggesting therefore that this antiviral agent does not kill Leishmania amastigotes in a caspase-dependent manner. Furthermore, we observed that the mitochondrial resident protein endonuclease G is involved. We also demonstrate that parasites overexpressing GSH1 (the rate limiting enzyme of glutathione biosynthesis) were more resistant to nelfinavir when compared to untransfected controls. CONCLUSIONS AND SIGNIFICANCE: These data suggest that nelfinavir induces oxidative stress in Leishmania amastigotes, culminating in caspase-independent apoptosis, in which DNA is degraded by endonuclease G. This study provides a rationale for future, long-term design of new therapeutic strategies to test nelfinavir as a potential antileishmanial agent as well as for possible future use in Leishmania/HIV-1 coinfections. |
| PMID: 20361030 [PubMed - in process] | |
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| 2. | PLoS Negl Trop Dis. 2010 Mar 30;4(3):e648.Delineation of diverse macrophage activation programs in response to intracellular parasites and cytokines.Zhang S, Kim CC, Batra S, McKerrow JH, Loke P.Department of Pathology, University of California, San Francisco, California, United States of America. BACKGROUND: The ability to reside and proliferate in macrophages is characteristic of several infectious agents that are of major importance to public health, including the intracellular parasites Trypanosoma cruzi (the etiological agent of Chagas disease) and Leishmania species (etiological agents of Kala-Azar and cutaneous leishmaniasis). Although recent studies have elucidated some of the ways macrophages respond to these pathogens, the relationships between activation programs elicited by these pathogens and the macrophage activation programs elicited by bacterial pathogens and cytokines have not been delineated. METHODOLOGY/PRINCIPAL FINDINGS: To provide a global perspective on the relationships between macrophage activation programs and to understand how certain pathogens circumvent them, we used transcriptional profiling by genome-wide microarray analysis to compare the responses of mouse macrophages following exposure to the intracellular parasites T. cruzi and Leishmania mexicana, the bacterial product lipopolysaccharide (LPS), and the cytokines IFNG, TNF, IFNB, IL-4, IL-10, and IL-17. We found that LPS induced a classical activation state that resembled macrophage stimulation by the Th1 cytokines IFNG and TNF. However, infection by the protozoan pathogen L. mexicana produced so few transcriptional changes that the infected macrophages were almost indistinguishable from uninfected cells. T. cruzi activated macrophages produced a transcriptional signature characterized by the induction of interferon-stimulated genes by 24 h post-infection. Despite this delayed IFN response by T. cruzi, the transcriptional response of macrophages infected by the kinetoplastid pathogens more closely resembled the transcriptional response of macrophages stimulated by the cytokines IL-4, IL-10, and IL-17 than macrophages stimulated by Th1 cytokines. CONCLUSIONS/SIGNIFICANCE: This study provides global gene expression data for a diverse set of biologically significant pathogens and cytokines and identifies the relationships between macrophage activation states induced by these stimuli. By comparing macrophage activation programs to pathogens and cytokines under identical experimental conditions, we provide new insights into how macrophage responses to kinetoplastids correlate with the overall range of macrophage activation states. |
| PMID: 20361029 [PubMed - in process] | |
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| 3. | Nature. 2010 Apr 1;464(7289):728-32.N-myristoyltransferase inhibitors as new leads to treat sleeping sickness.Frearson JA, Brand S, McElroy SP, Cleghorn LA, Smid O, Stojanovski L, Price HP, Guther ML, Torrie LS, Robinson DA, Hallyburton I, Mpamhanga CP, Brannigan JA, Wilkinson AJ, Hodgkinson M, Hui R, Qiu W, Raimi OG, van Aalten DM, Brenk R, Gilbert IH, Read KD, Fairlamb AH, Ferguson MA, Smith DF, Wyatt PG.Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK. Comment in: African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis. |
| PMID: 20360736 [PubMed - in process] | |
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| 4. | Protist. 2010 Mar 30. [Epub ahead of print]Leishmanolysin-like Molecules in Herpetomonas samuelpessoai Mediate Hydrolysis of Protein Substrates and Interaction with Insect.Pereira FM, Dias FA, Elias CG, d'Avila-Levy CM, Silva CS, Santos-Mallet JR, Branquinha MH, Santos AL.Laboratório de Estudos Integrados em Bioquímica Microbiana, Departamento de Microbiologia Geral, Instituto de Microbiologia Prof. Paulo de Góes (IMPPG), Bloco E-subsolo, Centro de Ciências da Saúde (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Av. Carlos Chagas Filho, 373, Cidade Universitária, Rio de Janeiro, RJ 21941-902, Brazil. Herpetomonas samuelpessoai, an insect trypanosomatid, produces a 63-kDa metallopeptidase that has similar biochemical/immunological properties to Leishmania leishmanolysin, a virulence factor that participates in different stages of the parasite life cycle. Herein, we described some biochemical characteristics of the major surface metallopeptidase of H. samuelpessoai that led us to infer some probable functions for this peptidase during the parasite-invertebrate interaction. Gelatin-SDS-PAGE, flow cytometry and confocal fluorescence microscopy provided measurements for the relative levels of surface leishmanolysin-like molecules in H. samuelpessoai. Immunocytochemical analysis demonstrated the presence of leishmanolysin-like molecules on the surface and cytoplasm of the parasite. The surface metallopeptidase was active at a broad spectrum of pH and temperature, showing maximum activity at pH 6.0 at 37 degrees C, and an ability to degrade albumin, hemoglobin, IgG, mucin, casein and gut proteins obtained from Aedes aegypti. This wide substrate utilization might support parasite growth and development. Curiously, H. samuelpessoai cells were able to colonize A. aegypti guts. In an effort to implicate a possible role for the metallopeptidase from H. samuelpessoai, living parasites were treated with different compounds before the interaction with gut cells. The pre-incubation with metallopeptidase inhibitors, phospholipase C or anti-leishmanolysin antibodies promoted a significant reduction in the interaction with guts. Similarly, the pre-treatment of gut cells with purified leishmanolysin-like protein drastically diminished the adhesion process. Furthermore, the expression of surface leishmanolysin in H. samuelpessoai cells was drastically enhanced after passage in A. aegypti. These results suggest the participation of homologues of leishmanolysin in the interaction of H. samuelpessoai with the invertebrate vector. Copyright © 2010 Elsevier Ltd. All rights reserved. |
| PMID: 20359946 [PubMed - as supplied by publisher] | |
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| 5. | Phytomedicine. 2010 Mar 30. [Epub ahead of print]Trypanocidal and antileukaemic effects of the essential oils of Hagenia abyssinica, Leonotis ocymifolia, Moringa stenopetala, and their main individual constituents.Nibret E, Wink M.Institut für Pharmazie und Molekulare Biotechnologie, Universität Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany. Essential oils from three Ethiopian medicinal plants; Hagenia abyssinica (Rosaceae), Leonotis ocymifolia (Lamiaceae), and Moringa stenopetala (Moringaceae) were investigated for their chemical composition, trypanocidal, and cytotoxic activities. Twenty components were identified from the essential oil of H. abyssinica female flowers, ledol (58.57%) being the principal volatile oil component. Sixty-eight components were identified from the essential oil of L. ocymifolia aerial part, caryophyllene oxide (12.06%) being the major component. The essential oil of M. stenopetala seeds was dominated by isothiocyanates; benzyl isothiocyanate (54.30%) and isobutyl isothiocyanate (16.37%) were the major components. The trypanocidal (Trypanosoma b. brucei) and antileukaemic (HL-60) effects of the three essential oils were studied. The oil of M. stenopetala seeds and its main compound, benzyl isothiocyanate showed the most potent trypanocidal activities with IC(50) values of 5.03mug/ml and 1.20mug/ml, respectively. The oils of H. abyssinica and L. ocymifolia exhibited trypanocidal activities with IC(50) values of 42.30mug/ml and 15.41mug/ml, respectively. Individual components (28 compounds) of the essential oils bearing different functional groups were also studied for their structure-activity relationships using trypanosomes and human leukaemia cells. Cinnamaldehyde (IC(50)=2.93mug/ml) (a representative for aldehydes), nerolidol (IC(50)=15.78mug/ml) (an alcohol), cedrene (IC(50)=4.07mug/ml) (a hydrocarbon), benzyl isothiocyanate (IC(50)=1.20mug/ml) (a representative for mustard oils), 1,8-cineole (IC(50)=83.15mug/ml) (an ether), safrole (IC(50)=18.40mug/ml) (aromatics with allyl and/or methoxy side chains), carvone (IC(50)=12.94mug/ml) (a ketone), styrene oxide (IC(50)=3.76mug/ml) (an epoxide) and carvacrol (IC(50)=11.25mug/ml) (a phenol) showed the most potent trypanocidal activities from their respective groups. Of all essential oil components tested, carvone (selectivity index (SI)=17.46) and styrene oxide (SI=19.92) showed good selective indices for the parasite with minimal toxicity on the human leukaemia cells. These compounds could therefore serve as lead structures for the development of trypanocidal agents with higher potency. Copyright © 2010 Elsevier GmbH. All rights reserved. |
| PMID: 20359874 [PubMed - as supplied by publisher] | |
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| 6. | East Mediterr Health J. 2009 Nov-Dec;15(6):1624-5.Potential utility of indomethacin in enhancing the leishmanicidal activity of glucantime.Namazi MR. |
| PMID: 20218157 [PubMed - indexed for MEDLINE] | |
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| 7. | Molecules. 2010 Jan 25;15(1):545-53.Antiproliferative effect and ultrastructural alterations induced by psilostachyin on Trypanosoma cruzi.Sülsen V, Barrera P, Muschietti L, Martino V, Sosa M.Cátedra de Farmacognosia, Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, IQUIMEFA (UBA-CONICET), Junín 956 (1113), CABA, Argentina. The effect of psilostachyin, a natural sesquiterpene lactone, on the growth and viability of cultured epimastigotes of Trypanosoma cruzi (Tulahuen) is reported. The antiproliferative effect was evaluated by counting the parasites in a Neubauer chamber and measuring their viability by using the dye exclusion technique. The effect on parasite growth was irreversible at concentrations higher than 1.0 microg/mL and the addition of glutathione only partially blocked the effect of the compound. Moreover, we have studied the effects of this natural compound on parasite ultrastructure by transmission electron microscopy. Interestingly, psilostachyin induced ultrastructural alterations on the parasites at a concentration of 0.5 microg/mL, with important mitochondrial swelling and deformity of the kinetoplast. |
| PMID: 20110908 [PubMed - indexed for MEDLINE] | |
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| 8. | Carbohydr Res. 2010 Feb 11;345(3):385-96. Epub 2009 Dec 14.Synthesis of trisaccharides containing internal galactofuranose O-linked in Trypanosoma cruzi mucins.Mendoza VM, Kashiwagi GA, de Lederkremer RM, Gallo-Rodriguez C.CIHIDECAR, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Buenos Aires, Argentina. The trisaccharides beta-D-Galf-(1-->2)-beta-D-Galf-(1-->4)-D-GlcNAc (5) and beta-D-Galp-(1-->2)-beta-D-Galf-(1-->4)-D-GlcNAc (6) constitute novel structures isolated as alditols when released by reductive beta-elimination from mucins of Trypanosoma cruzi (Tulahuen strain). Trisaccharides 5 and 6 were synthesized employing the aldonolactone approach. Thus, a convenient D-galactono-1,4-lactone derivative was used for the introduction of the internal galactofuranose and the trichloroacetimidate method was employed for glycosylation reactions. Due to the lack of anchimeric assistance on O-2 of the galactofuranosyl precursor, glycosylation studies were performed under different conditions. The nature of the solvent strongly determined the stereochemical course of the glycosylation reactions when the galactofuranosyl donor was substituted either by 2-O-Galp or 2-O-Galf. (c) 2009 Elsevier Ltd. All rights reserved. |
| PMID: 20044082 [PubMed - indexed for MEDLINE] | |
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| 9. | Int J Parasitol. 2009 Feb;39(3):333-46. Epub 2008 Aug 8.Development of a mathematical model for mechanical transmission of trypanosomes and other pathogens of cattle transmitted by tabanids.Desquesnes M, Biteau-Coroller F, Bouyer J, Dia ML, Foil L.Cirad, UR Trypanosomes, Montpellier, France. marc.desquesnes@cirad.fr Mechanical transmission of pathogens by biting insects is a non-specific phenomenon in which pathogens are transmitted from the blood of an infected host to another host during interrupted feeding of the insects. A large range of pathogens can be mechanically transmitted, e.g. hemoparasites, bacteria and viruses. Some pathogens are almost exclusively mechanically transmitted, while others are also cyclically transmitted. For agents transmitted both cyclically and mechanically (mixed transmission), such as certain African pathogenic trypanosomes, the relative impact of mechanical versus cyclical transmission is essentially unknown. We have developed a mathematical model of pathogen transmission by a defined insect population to evaluate the importance of mechanical transmission. Based on a series of experiments aimed at demonstrating mechanical transmission of African trypanosomes by tabanids, the main parameters of the model were either quantified (host parasitaemia, mean individual insect burden, initial prevalence of infection) or estimated (unknown parameters). This model allows us to simulate the evolution of pathogen prevalence under various predictive circumstances, including control measures and could be used to assess the risk of mechanical transmission under field conditions. If adjustments of parameters are provided, this model could be generalized to other pathogenic agents present in the blood of their hosts (Bovine Leukemia virus, Anaplasma, etc.) or other biting insects such as biting muscids (stomoxyines) and hippoboscids. |
| PMID: 18755195 [PubMed - indexed for MEDLINE] | |
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