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Sent on Thursday, 2010 Jun 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. | Exp Parasitol. 2010 May 29. [Epub ahead of print]Leishmania major: Anti-leishmanial activity of Nuphar lutea extract mediated by the activation of transcription factor NF-kappaB.Ozer L, El-On J, Golan-Goldhirsh A, Gopas J.The Shraga Segal Dept. of Microbiology and Immunology, Faculty of Health Sciences, Ben-Gurion University of the Negev and Laboratory of Parasitology, Soroka University Medical Center, Beer Sheva, Israel. AbstractHere we report the effect of a partially purified alkaloid fraction (NUP) of Nuphar lutea on NF-kappa-B (NF-kappaB) expression and studied its mechanism of toxicity against Leishmania major in C3H mice peritoneal macrophages. NUP was found to be a mixture of thermo-stable dimeric sesquiterpene thioalkaloids containing mainly thionupharidines. The anti-leishmanial activity was shown to be mediated through the activation of NF-kappaB and increased iNOS production. Additionally, the nitric oxide inhibitor, N(G)-monomethyl-L-arginine (0.5mM) totally reverted the anti-leishmanial effect of NUP (0.25 and 0.5mug/ml). NUP was also shown to act as an anti-oxidant, almost completely inhibiting the macrophage respiratory burst activity. However, no elevated lysozyme (EC3.2.1.17) or beta-galactosidase (EC3.2.1.23) activities were demonstrated in macrophages treated with NUP. The present study suggests, that the activity of NUP is mediated by NF-kappaB activation and the production of nitric oxide which is dependent on the L-arginine:NO pathway. Copyright © 2010. Published by Elsevier Inc. |
| PMID: 20515684 [PubMed - as supplied by publisher] | |
| 2. | Br J Pharmacol. 2010 May;160(2):258-9.New drugs for neglected infectious diseases: Chagas' disease.Machado FS, Tanowitz HB, Teixeira MM.Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil. Comment on: AbstractChagas' disease (CD) is caused by the protozoan Trypanosoma cruzi (Tc) and remains an important cause of morbidity and mortality. Most researchers in the field now agree that chronic low grade parasite persistence in tissue drives tissue damage and the autoimmune component of CD. Current therapy relies on two compounds: benznidazole and nifurtimox. Despite their long history in the treatment of CD, both compounds induce significant side-effects. In the current issue of the BJP, two contributions demonstrate that NO-donors are active, especially in combination with benznidazole, against Tc in vitro and in experimental models in vivo. The basic concept used by the authors to develop novel anti-Tc compounds relied on the demonstrated ability of nitric oxide to kill the parasite. There are several issues still to be resolved but the reported studies are a clear advance to the field and should be considered for further pre-clinical development. |
| PMID: 20423339 [PubMed - indexed for MEDLINE] | |
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| 3. | Exp Parasitol. 2010 Aug;125(4):315-24. Epub 2010 Feb 26.Cysteamine, the natural metabolite of pantetheinase, shows specific activity against Plasmodium.Min-Oo G, Ayi K, Bongfen SE, Tam M, Radovanovic I, Gauthier S, Santiago H, Rothfuchs AG, Roffê E, Sher A, Mullick A, Fortin A, Stevenson MM, Kain KC, Gros P.Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, QC, Canada. AbstractIn mice, loss of pantetheinase activity causes susceptibility to infection with Plasmodium chabaudi AS. Treatment of mice with the pantetheinase metabolite cysteamine reduces blood-stage replication of P. chabaudi and significantly increases survival. Similarly, a short exposure of Plasmodium to cysteamine ex vivo is sufficient to suppress parasite infectivity in vivo. This effect of cysteamine is specific and not observed with a related thiol (dimercaptosuccinic acid) or with the pantethine precursor of cysteamine. Also, cysteamine does not protect against infection with the parasite Trypanosoma cruzi or the fungal pathogen Candida albicans, suggesting cysteamine acts directly against the parasite and does not modulate host inflammatory response. Cysteamine exposure also blocks replication of P. falciparum in vitro; moreover, these treated parasites show higher levels of intact hemoglobin. This study highlights the in vivo action of cysteamine against Plasmodium and provides further evidence for the involvement of pantetheinase in host response to this infection. Copyright (c) 2010 Elsevier Inc. All rights reserved. |
| PMID: 20219464 [PubMed - indexed for MEDLINE] | |
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| 4. | Exp Parasitol. 2010 Aug;125(4):342-7. Epub 2010 Mar 3.Trypanosoma cruzi: synergistic cytotoxicity of multiple amphipathic anti-microbial peptides to T. cruzi and potential bacterial hosts.Fieck A, Hurwitz I, Kang AS, Durvasula R.Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. AbstractThe parasite Trypanasoma cruzi is responsible for Chagas disease and its triatomine vector, Rhodnius prolixus, has a symbiotic relationship with the soil bacterium, Rhodococcus rhodnii. R. rhodnii that was previously genetically engineered to produce the anti-microbial peptide, cecropin A was co-infected with T. cruzi into R. prolixus resulting in clearance of the infectious T. cruzi in 65% of the vectors. Similar anti-microbial peptides have been isolated elsewhere and were studied for differential toxicity against T. cruzi and R. rhodnii. Of the six anti-microbial peptides tested, apidaecin, magainin II, melittin, and cecropin A were deemed potential candidates for the Chagas paratransgenic system as they were capable of killing T.cruzi at concentrations that exhibit little or no toxic effects on R. rhodnii. Subsequent treatments of T. cruzi with these peptides in pair-wise combinations resulted in synergistic killing, indicating that improvement of the 65% parasite clearance seen in previous experiments may be possible utilizing combinations of different anti-microbial peptides. Copyright (c) 2010 Elsevier Inc. All rights reserved. |
| PMID: 20206169 [PubMed - indexed for MEDLINE] | |
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| 5. | Vet Dermatol. 2009 Oct;20(5-6):397-404.Multicentric, controlled clinical study to evaluate effectiveness and safety of miltefosine and allopurinol for canine leishmaniosis.Miró G, Oliva G, Cruz I, Cañavate C, Mortarino M, Vischer C, Bianciardi P.Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain. gmiro@vet.ucm.es AbstractThe aim of this trial was to evaluate the effectiveness and safety of miltefosine-allopurinol combination therapy vs. the current reference combination therapy, meglumine antimoniate-allopurinol, for canine leishmaniosis. Dogs included in the study exhibited clinical signs of the disease, were positive by PCR and serologically positive by immunofluorescent antibody test for leishmaniosis, and negative for ehrlichiosis. Dogs were divided into two groups: Group 1 was treated with 2 mg/kg of miltefosine orally once daily for 28 days and 10 mg/kg of allopurinol orally twice daily for 7 months; Group 2 was treated with 50 mg/kg of meglumine antimoniate sub-cutaneously twice daily for 28 days and allopurinol (same dose as Group 1) for 7 months. Dogs were examined according to the following schedule: pre-inclusion, Day 0 (D0), D14, D28, D84, D140 and D196. At each visit, blood, urine and bone marrow samples were collected. Parameters monitored included haematology, biochemistry, protein electrophoresis, serology, urinary protein/creatinine ratio and RTQ-PCR performed on bone marrow aspirates. A significant reduction in total clinical score and parasite load was observed in both groups over the 7-month study period (P < 0.0001), with no significant difference between groups (P = 0.3). The safety of miltefosine-allopurinol combination therapy was confirmed by lack of effect on renal and hepatic parameters and adverse reactions. Miltefosine, in combination with allopurinol, offers a safe, convenient and effective alternative treatment option for canine leishmaniosis compared to the reference therapy. |
| PMID: 20178476 [PubMed - indexed for MEDLINE] | |
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| 6. | Br J Pharmacol. 2010 May;160(2):270-82. Epub 2010 Jan 27.Nitric oxide donor trans-[RuCl([15]aneN)NO] as a possible therapeutic approach for Chagas' disease.Guedes PM, Oliveira FS, Gutierrez FR, da Silva GK, Rodrigues GJ, Bendhack LM, Franco DW, Do Valle Matta MA, Zamboni DS, da Silva RS, Silva JS.Department of Biochemistry and Immunology, School of Medicine at Ribeirão Preto, São Paulo, Brazil. pauloguedes@usp.br <pauloguedes@usp.br> Comment in: AbstractBACKGROUND AND PURPOSE: Benznidazole (Bz) is the therapy currently available for clinical treatment of Chagas' disease. However, many strains of Trypanosoma cruzi parasites are naturally resistant. Nitric oxide (NO) produced by activated macrophages is crucial to the intracellular killing of parasites. Here, we investigate the in vitro and in vivo activities against T. cruzi, of the NO donor, trans-[RuCl([15]aneN(4))NO](2+). EXPERIMENTAL APPROACH: Trans-[RuCl([15]aneN(4))NO](2+)was incubated with a partially drug-resistant T. cruzi Y strain and the anti-proliferative (epimastigote form) and trypanocidal activities (trypomastigote and amastigote) evaluated. Mice were treated during the acute phase of Chagas' disease. The anti-T. cruzi activity was evaluated by parasitaemia, survival rate, cardiac parasitism, myocarditis and the curative rate. KEY RESULTS: Trans-[RuCl([15]aneN(4))NO](2+) was 10- and 100-fold more active than Bz against amastigotes and trypomastigotes respectively. Further, trans-[RuCl([15]aneN(4))NO](2+) (0.1 mM) induced 100% of trypanocidal activity (trypomastigotes forms) in vitro. Trans-[RuCl([15]aneN(4))NO](2+) induced permanent suppression of parasitaemia and 100% survival in a murine model of acute Chagas' disease. When the drugs were given alone, parasitological cures were confirmed in only 30 and 40% of the animals treated with the NO donor (3.33 micromol.kg(-1).day(-1)) and Bz (385 micromol.kg(-1).day(-1)), respectively, but when given together, 80% of the animals were parasitologically cured. The cured animals showed an absence of myocarditis and a normalisation of cytokine production in the sera. In addition, no in vitro toxicity was observed at the tested doses. CONCLUSIONS AND IMPLICATIONS: These findings indicate that trans-[RuCl([15]aneN(4))NO](2+)is a promising lead compound for the treatment of human Chagas' disease. |
| PMID: 20128813 [PubMed - indexed for MEDLINE] | |
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| 7. | Br J Pharmacol. 2010 May;160(2):260-9. Epub 2010 Jan 26.Novel ruthenium complexes as potential drugs for Chagas's disease: enzyme inhibition and in vitro/in vivo trypanocidal activity.Silva JJ, Guedes PM, Zottis A, Balliano TL, Nascimento Silva FO, França Lopes LG, Ellena J, Oliva G, Andricopulo AD, Franco DW, Silva JS.Departamento de Física e Informática, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil. jjerley@usp.br <jjerley@usp.br> Comment in: AbstractBACKGROUND AND PURPOSE: The discovery of the pharmacological functions of nitric oxide has led to the development of NO donor compounds as therapeutic agents. A new generation of ruthenium NO donors, cis-[Ru(NO)(bpy)(2)L]X(n), has been developed, and our aim was to show that these complexes are able to lyse Trypanosoma cruzi in vitro and in vivo. EXPERIMENTAL APPROACH: NO donors were incubated with T. cruzi and their anti-T. cruzi activities evaluated as the percentage of lysed parasites compared to the negative control. In vivo, trypanocidal activity was evaluated by observing the levels of parasitaemia, survival rate and elimination of amastigotes in mouse myocardial tissue. The inhibition of GAPDH was monitored by the biochemical reduction of NAD(+) to NADH. KEY RESULTS: The NO donors cis-[Ru(NO)(bpy)(2)L]X(n) presented inhibitory effects on T. cruzi GAPDH (IC(50) ranging from 89 to 153 microM). The crystal structure of the enzyme shows that the inhibitory mechanism is compatible with S-nitrosylation of the active cysteine (cys166) site. Compounds cis-[Ru(NO)(bpy)(2)imN](PF(6))(3) and cis-[Ru(NO)(bpy)(2)SO(3)]PF(6), at a dose of 385 nmol.kg(-1), yielded survival rates of 80 and 60%, respectively, in infected mice, and eradicated any amastigotes from their myocardial tissue. CONCLUSIONS AND IMPLICATIONS: The ruthenium compounds exhibited potent in vitro and in vivo trypanocidal activities at doses up to 1000-fold lower than the clinical dose for benznidazole. Furthermore, one mechanism of action of these compounds is via the S-nitrosylation of Cys166 of T. cruzi GAPDH. Thus, these compounds show huge potential as candidates for the development of new drugs for the treatment of Chagas's disease. |
| PMID: 20105182 [PubMed - indexed for MEDLINE] | |
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| 8. | Amino Acids. 2010 Feb;38(2):645-51. Epub 2009 Dec 3.Polyamine metabolism in Trypanosoma cruzi: studies on the expression and regulation of heterologous genes involved in polyamine biosynthesis.Algranati ID.Fundación Instituto Leloir, Ave. Patricias Argentinas 435, 1405, Buenos Aires, Argentina. ialgranati@leloir.org.ar AbstractBiochemical studies have shown that Trypanosoma cruzi and Toxoplasma gondii are the only eukaryotic organisms so far described which are auxotrophic for polyamines. Both parasites are unable to carry out the de novo biosynthesis of putrescine, and therefore they need the addition of exogenous polyamines to the culture medium for their normal proliferation. Further investigations at the molecular level have demonstrated that the wild-type T. cruzi genome does not contain ornithine or arginine decarboxylase-like nucleic acid sequences, and that the corresponding genes have been presumably lost during evolution. Since T. cruzi behaves as a deletion mutant for ornithine decarboxylase (ODC) and arginine decarboxylase (ADC) genes, this parasite has been selected to study the regulation of the expression of heterologous genes involved in polyamine biosynthesis in other organisms. The resulting transgenic parasites have been useful tools to analyze the different stages of gene expression after transformation, as well as the mechanisms of drug resistance induction and the post-translational processing of enzyme precursors. |
| PMID: 19956988 [PubMed - indexed for MEDLINE] | |
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| 9. | Res Vet Sci. 2010 Apr;88(2):273-8. Epub 2009 Nov 2.Growth hormones therapy in immune response against Trypanosoma cruzi.Frare EO, Santello FH, Caetano LC, Caldeira JC, Toldo MP, Prado JC Jr.Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto FCFRP-USP, Universidade de São Paulo, Brazil. AbstractGrowth hormone (GH) is an important hypophyseal hormone that is primarily involved in body growth and metabolism. In mammals, control of Trypanosoma cruzi parasitism during the acute phase of infection is considered to be critically dependent on direct macrophage activation by cytokines. To explore the possibility that GH might be effective in the treatment of Chagas' disease, we investigated its effects on the course of T. cruzi infection in rats, focusing our analyses on its influences on parasitemia, NO, TNF-alpha and IFN-gamma concentration and on histopathological alterations and parasite burden in heart tissue. T. cruzi-infected male Wistar rats were intraperitoneally treated with 5 ng/10 g body weight/day of GH. Animals treated with GH showed a significant reduction in the number of blood trypomastigotes during the acute phase of infection compared with untreated animals (P<0.05). For all experimental days (7, 14 and 21 post infection) of the acute phase, infected and GH treated animals reached higher concentrations of TNF-alpha, IFN-gamma and nitric oxide as compared to untreated and infected counterparts (P<0.05) Histopathological observations of heart tissue revealed that GH administration also resulted in fewer and smaller amastigote burdens, and less inflammatory infiltrate and tissue disorganization, indicating a reduced parasitism of this tissue. These results show that GH can be considered as an immunomodulator substance for controlling parasite replication and combined with the current drug used may represent in the future a new therapeutic tool to reduce the harmful effects of Chagas' disease. Copyright 2009 Elsevier Ltd. All rights reserved. |
| PMID: 19883928 [PubMed - indexed for MEDLINE] | |
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| 10. | Res Vet Sci. 2010 Apr;88(2):281-4. Epub 2009 Sep 24.Influence of Trypanosoma evansi in blood, plasma, and brain cholinesterase of experimentally infected cats.Da Silva AS, Spanevello R, Stefanello N, Wolkmer P, Costa MM, Zanette RA, Lopes ST, Santurio JM, Schetinger MR, Monteiro SG.Universidade Federal de Santa Maria, Faixa de Camobi, Km 9, Campus Universitário, 97105-900 Santa Maria, RS, Brazil. aleksandro_ss@yahoo.com.br AbstractChanges in blood, plasma and brain cholinesterase activities in Trypanosoma evansi-infected cats were investigated. Seven animals were infected with 10(8) trypomastigote forms each and six were used as control. Animals were monitored for 56 days by examining daily blood smears. Blood samples were collected at days 28 and 56 post-inoculation to determine the activity of acetylcholinesterase (AChE) in blood and the activity of butyrylcholinesterase (BChE) in plasma. AChE was also evaluated in total brain. The activity of AChE in blood and brain, and the activity of BChE in plasma significantly reduced in the infected cats. Therefore, the infection by T. evansi influenced cholinesterases of felines indicating changes in the responses of the cholinergic system. Copyright 2009 Elsevier Ltd. All rights reserved. |
| PMID: 19781725 [PubMed - indexed for MEDLINE] | |
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