Friday, February 5, 2010

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 -8 of 8

1. Bioorg Med Chem Lett. 2010 Jan 11. [Epub ahead of print]

Podophyllotoxin analogues active versus Trypanosoma brucei.

Uddin MJ, Smithson DC, Brown KM, Crews BC, Connelly M, Zhu F, Marnett LJ, Guy RK.

Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via de-polymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with LogP values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell. Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20129783 [PubMed - as supplied by publisher]
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2. Trans R Soc Trop Med Hyg. 2010 Feb 1. [Epub ahead of print]

PCR-based detection of Leishma nia major kDNA within naturally infected Phlebotomus papatasi in southern Iran.

Azizi K, Rassi Y, Moemenbellah-Fard MD.

Department of Medical Entomology, Research Centre for Health Sciences, School of Health and Nutrition, Shiraz University of Medical Sciences, P.O. Box 71645-111, Shiraz, Iran; Tropical & Infectious Diseases Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. P.O. Box 79199-16753.

The annual incidence of cutaneous leishmaniasis (CL) in Iran rose by 43% over a five year period, from 2002 to 2006; most of these cases were caused by Leishmania major. Two complementary standard and nested polymerase chain reactions (PCRs) were used to detect parasites within their natural vector, Phlebotomus papatasi. Twelve different sand fly species were morphologically identified. The most abundant species (31.3%) was P. papatasi. Leptomonads were found in nine (2.4%) phlebotomines. Twenty (5.3%) sand fly species were found positive for Leishmania-genus DNA using standard PCR. The infection rate of this species was 5% and 7% by microscopic and molecular methods, respectively. Copyright © 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

PMID: 20129635 [PubMed - as supplied by publisher]
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3. J Med Chem. 2010 Feb 3. [Epub ahead of print]

New Benzophenone-Derived Bisphosphonium Salts as Leishmanicidal Leads Targe ting Mitochondria through Inhibition of Respiratory Complex II.

Luque-Ortega JR, Reuther P, Rivas L, Dardonville C.

Centro de Investigaciones Biologicas, CSIC, Ramiro de Maeztu 9, E-28040 Madrid, Spain.

A set of benzophenone-derived bisphosphonium salts was synthesized and assayed for lethal activity on the human protozoan parasite Leishmania. A subset of them, mostly characterized by phosphonium substituents with an intermediate hydrophobicity, inhibited parasite proliferation at low micromolar range of concentrations. The best of this subset, 4,4'-bis((tri-n-pentylphosphonium)methyl)benzophenone dibromide, showed a very scarce toxicity on mammalian cells. This compound targets complex II of the respiratory chain of the parasite, based on (i) a dramatically swollen mitochondrion in treated parasites, (ii) fast decrease of cytoplasmic ATP, (iii) a decrease of the electrochemical mitochondrial potential, and (iv) inhibition of the oxygen consumption rate using succinate as substrate. Thus, this type of compounds represents a new lead in the development of leishmanicidal drugs.

PMID: 20128602 [PubMed - as supplied by publisher]
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4. Int J Exp Pathol. 2010 Feb;91(1):72-86. Epub 2009 Oct 28.

Perforin-expressing cytotoxic cells contribute to chronic cardiomyopathy in Trypanosoma cruzi infecti on.

Silverio JC, de-Oliveira-Pinto LM, da Silva AA, de Oliveira GM, Lannes-Vieira J.

Laboratório de Biologia das Interações, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.

Understanding the dual participation of the immune response in controlling the invader and at the same time causing tissue damage might contribute to the design of effective new vaccines and therapies for Chagas disease. Perforin, a cytolytic protein product of killer cells, is involved in resistance to acute Trypanosoma cruzi infection. However, the contribution of perforin in parasite control and chronic chagasic cardiomyopathy is unclear. Perforin-positive cells were detected in the heart tissue during the acute and chronic phases of infection of C57BL/6 mice inoculated with low dose (10(2) parasites) of the Colombian T. cruzi strain. This protocol led to acute phase survival in both wild-type and perforin null (pfp(-/-)) mice lineages. During the chronic infection, parasitism and inducible nitric oxide synthase (iNOS) as well as interleukin (IL)-4+ and, mainly, interferon (IFN)-gamma+ cells were more elevated in the heart tissue of pfp(-/-) mice. Higher levels of circulating NO and anti-parasite immunoglobulin (Ig)G2c and IgG3, paralleled by a prominent frequency of IFN-gamma+ and IL-10+ splenocytes, were present in pfp(-/-)-infected mice. Therefore, although the perforin-dependent pathway plays a role, it is not crucial for anti-T. cruzi immunity and acute phase survival of mice infected with a low inoculum. Further, perforin deficiency resulted in lower activity of creatine kinase-muscle brain isoform (CK-MB) isoenzyme in serum and a more restricted connexin 43 loss, both of which are markers of the cardiomyocyte lesion. Moreover, perforin deficiency hampered the development of severe electrocardiographic abnormalities. Hence, our results corroborate that perforin-bearing cytotoxic cells might contribute to cardiomyocyte lesion and heart dysfunction during chronic T. cruzi infection, shedding light on immunopathogenesis of chronic chagasic cardiomyopathy.

PMID: 19878357 [PubMed - indexed for MEDLINE]
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Publication Types:

  • Research Support, Non-U.S. Gov't

MeSH Terms:

  • Acute Disease
  • Animals
  • Antibodies, Protozoan/blood
  • Cells, Cultured
  • Chagas Cardiomyopathy/immunology*
  • Chagas Cardiomyopathy/parasitology
  • Chagas Cardiomyopathy/physiopathology
  • Chagas Cardiomyopathy/prevention & control
  • Chronic Disease
  • Connexin 43/metabolism
  • Creatine Kinase, MB Form/blood
  • Cytotoxicity, Immunologic*
  • Disease Models, Animal
  • Electrocardiography
  • Female
  • Immunoglobulin G/blood
  • Interferon-gamma/metabolism
  • Interleukin-10/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocarditis/immunology*
  • Myocarditis/parasitology
  • Myocarditis/physiopathology
  • Myocarditis/prevention & control
  • Myocardium/immunology*
  • Myocardium/metabolism
  • Nitric Oxide/blood
  • Nitric Oxide Synthase Type II/metabolism
  • Pore Forming Cytotoxic Proteins/deficiency
  • Pore Forming Cytotoxic Proteins/genetics
  • Pore Forming Cytotoxic Proteins/metabolism*
  • T-Lymphocytes, Cytotoxic/immunology*
  • T-Lymphocytes, Cytotoxic/parasitology
  • Time Factors
  • Trypanosoma cruzi/immunology*
  • Trypanosoma cruzi/pathogenicity

Substances:

  • Antibodies, Protozoan
  • Connexin 43
  • GJA1 protein, mouse
  • Immunoglobulin G
  • Pore Forming Cytotoxic Proteins
  • perforin, mouse
  • Nitric Oxide
  • Interleukin-10
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Creatine Kinase, MB Form
5. Exp Parasitol. 2010 Feb;124(2):219-24. Epub 2009 Sep 26.

Trypanosoma cruzi: do different sylvatic strains trigger distinct immune responses?

Caetano LC, do Prado JC Jr, Toldo MP, Abrahão AA.

Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Brazil. leony@fcfrp.usp.br

Strains of Trypanosoma cruzi are multiclonal populations that can be classified in groups or genotypes, differing in pathogenicity, virulence, and histotropism. In this experiment the distinct behavior of two strains of T. cruzi, MORC-1 and MORC-2, was documented. Blood parasitemia, spleen proliferation, nitric oxide, histopathology of the spleen and heart were used as tools to evaluate parasite persistence. Groups of male mice were separated and divided in three groups: Control (C), Infected (IM-1) and Infected (IM-2). The peak of parasitemia occurred on 10days post infection for both strains. LPS stimulated animals, infected MORC-2 group displayed significant higher concentrations of NO when compared to infected MORC-1 group (P<0.05). For ConA stimulated lymphoproliferation, infected MORC-1 group displayed higher proliferation index as compared to infected MORC-2 group. An opposite behavior for IL-4 and TNF-alpha was observed according to the strain. For MORC-1 enhanced concentrations of IL-4 were present with concomitant reduced levels of TNF-alpha, while for MORC-2 enhanced concentrations of TNF-alpha and reduced levels of IL-4 were found. The histopathology of heart and spleen showed important differences in which MORC-1 displayed statistically enhanced number of amastigote in the heart and spleen as compared to MORC-2. Concluding, each strain triggered a distinct immune response with enhanced cytokine TH-1 profile for MORC-2 and TH-2 for MORC-1. Copyright 2009 Elsevier Inc. All rights reserved.

PMID: 19786023 [PubMed - indexed for MEDLINE]
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Publication Types:

  • Research Support, Non-U.S. Gov't

MeSH Terms:

  • Animals
  • Brazil
  • Chagas Disease/immunology*
  • Chagas Disease/parasitology
  • Chagas Disease/pathology
  • Chiroptera
  • Heart/parasitology
  • Interleukin-4/blood
  • Lymphocyte Activation
  • Macrophages/metabolism
  • Male
  • Mice
  • Myocardium/pathology
  • Nitric Oxide/analysis
  • Parasitemia/immunology
  • Parasitemia/parasitology
  • Spleen/cytology
  • Spleen/immunology
  • Spleen/parasitology
  • Spleen/pathology
  • Trypanosoma cruzi/classification
  • Trypanosoma cruzi/immunology*
  • Tumor Necrosis Factor-alpha/blood

Substances:

  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Interleukin-4
6. Exp Parasitol. 2010 Feb;124(2):172-80. Epub 2009 Sep 9.

Trypanosoma cruzi: Immunological predictors of benznidazole efficacy during experimental infection.

Fernández MC, González Cappa SM, Solana ME.

Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Argentina.

C3H/HeN male mice were infected with a lethal population of Trypanosoma cruzi and treated with benznidazole (Bz). Parasitemia, body weight and survival rate were registered during the therapy with significant improvement for T. cruzi-infected Bz-treated animals. Besides, flow cytometry resulted a useful method to discriminate between cured animals from those not cured by monitoring IgG(1) bound to live trypomastigotes levels. At the end of Bz therapy, the LT splenocyte compartment was studied for activation/memory cell surface markers (CD(69)(+) and CD(44)(+)). Cytofluorometric analysis showed that T. cruzi-infected untreated mice increased their activated LT numbers and this effect was completely abolished only in cured mice at the end of Bz administration. The same behavior was observed for the memory LT subpopulation correlating to an effector memory (CD(62L)(-)) displayed by T. cruzi infection. Bz treatment was able to modulate the immunological response by reducing the deleterious effect of the acute phase in all T. cruzi-infected mice. Copyright 2009 Elsevier Inc. All rights reserved.

PMID: 19747482 [PubMed - indexed for MEDLINE]
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Publication Types:

  • Research Support, Non-U.S. Gov't

MeSH Terms:

  • Animals
  • Antibodies, Protozoan/blood
  • Antigens, CD/analysis
  • Antigens, CD44/analysis
  • Antigens, Differentiation, T-Lymphocyte/analysis
  • CD4 Lymphocyte Count
  • CD8-Positive T-Lymphocytes/immunology
  • Chagas Disease/drug therapy*
  • Chagas Disease/immunology
  • Chagas Disease/parasitology
  • DNA, Protozoan/analysis
  • DNA, Protozoan/blood
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Immunoglobulin G/blood
  • Immunophenotyping
  • Male
  • Mice
  • Mice, Inbred C3H
  • Muscle, Skeletal/parasitology
  • Nitroimidazoles/pharmacology
  • Nitroimidazoles/therapeutic use*
  • Parasitemia/drug therapy
  • Parasitemia/immunology
  • Parasitemia/parasitology
  • Polymerase Chain Reaction
  • Spleen/cytology
  • Spleen/immunology
  • T-Lymphocytes/immunology
  • Trypanocidal Agents/pharmacology
  • Trypanocidal Agents/therapeutic use*
  • Trypanosoma cruzi/drug effects*
  • Trypanosoma cruzi/genetics
  • Trypanosoma cruzi/immunology

Substances:

  • Antibodies, Protozoan
  • Antigens, CD
  • Antigens, CD44
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • DNA, Protozoan
  • Immunoglobulin G
  • Nitroimidazoles
  • Trypanocidal Agents
  • benzonidazole
7. Exp Parasitol. 2010 Feb;124(2):167-71. Epub 2009 Sep 6.

Trypanosoma cruzi: In vitro effect of aspirin with nifurtimox and benznidazole.

López-Muñoz R, Faúndez M, Klein S, Escanilla S, Torres G, Lee-Liu D, Ferreira J, Kemmerling U, Orellana M, Morello A, Ferreira A, Maya JD.

Program of Molecular and Clinical Pharmacology, ICBM, School of Medicine, University of Chile, Chile.

Nifurtimox and benznidazole are the only active drugs against Trypanosoma cruzi; however, they have limited efficacy and severe side effects. During primoinfection, T. cruzi infected macrophages mount an antiparasitic response, which the parasite evades through an increase of tumor growth factor beta and PGE(2) activation as well as decreased iNOS activity. Thus, prostaglandin synthesis inhibition with aspirin might increase macrophage antiparasitic activity and increase nifurtimox and benznidazole effect. Aspirin alone demonstrated a low effect upon macrophage antiparasitic activity. However, isobolographic analysis of the combined effects of aspirin, nifurtimox and benznidazole indicated a synergistic effect on T. cruzi infection of RAW cells, with combinatory indexes of 0.71 and 0.61, respectively. The observed effect of aspirin upon T. cruzi infection was not related with the PGE(2) synthesis inhibition. Nevertheless, NO() levels were restored by aspirin in T. cruzi-infected RAW cells, contributing to macrophage antiparasitic activity improvement. Thus, the synergy of aspirin with nifurtimox and benznidazole is due to the capability of aspirin to increase antiparasitic activity of macrophages. Copyright 2009 Elsevier Inc. All rights reserved.

PMID: 19735656 [PubMed - indexed for MEDLINE]
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Publication Types:

  • Research Support, Non-U.S. Gov't

MeSH Terms:

  • Animals
  • Aspirin/pharmacology*
  • Cell Line
  • Cell Survival/drug effects
  • Cyclooxygenase Inhibitors/pharmacology*
  • Drug Synergism
  • Inhibitory Concentration 50
  • Macrophages/drug effects
  • Macrophages/immunology
  • Macrophages/parasitology
  • Mice
  • Nifurtimox/pharmacology*
  • Nitric Oxide/metabolism
  • Nitroimidazoles/pharmacology*
  • Trypanocidal Agents/pharmacology*
  • Trypanosoma cruzi/drug effects*

Substances:

  • Cyclooxygenase Inhibitors
  • Nitroimidazoles
  • Trypanocidal Agents
  • Nitric Oxide
  • benzonidazole
  • Nifurtimox
  • Aspirin
8. Exp Parasitol. 2010 Feb;124(2):147-52. Epub 2009 Aug 19.

Experimental Chagas' disease in orchiectomized Calomys callosus infected with the CM strain of Trypanosoma cruzi.

Pinto AC, Caetano LC, Levy AM, Fernandes RD, Santos CD, do Prado JC Jr.

Laboratório de Parasitologia da Faculdade de Ciências Farmacêuticas USP, Ribeirão Preto, SP, Brazil.

The incidence and progression of disorders associated with an unbalanced immune response has among many factors the gender as a contributory factor. The aims of this work were to evaluate the effects of orchiectomy and the immune response during the experimental Trypanosoma cruzi infection. Young adult, male Calomys callous were i.p. inoculated with 1 x 10(5) blood trypomastigotes of the CM strain of T. cruzi and divided in groups: Control, Sham and Castrated. Castrated group displayed significantly lower values for prostate and seminal vesicle weights indicating a drastic drop of testosterone plasmatic levels. Orchiectomized animals also displayed lesser number of blood parasites, enhanced lytic antibody percentage, splenocyte proliferation and NO concentration when compared to its sham and control counterparts, indicating that steroid gonadal ablation actually influences immune response triggering a more efficient cellular and humoral response which led animals to become more resistant against T. cruzi infection. Copyright 2009 Elsevier Inc. All rights reserved.

PMID: 19698712 [PubMed - indexed for MEDLINE]
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MeSH Terms:

  • Animals
  • Antibodies, Protozoan/biosynthesis
  • Cell Proliferation
  • Chagas Disease/immunology
  • Chagas Disease/metabolism*
  • Chagas Disease/parasitology
  • Disease Models, Animal
  • Lymphocyte Activation
  • Macrophages, Peritoneal/metabolism
  • Male
  • Nitric Oxide/analysis
  • Orchiectomy
  • Organ Size
  • Parasitemia/parasitology
  • Prostate/pathology
  • Seminal Vesicles/pathology
  • Sigmodontinae
  • Spleen/cytology
  • Spleen/immunology
  • Testosterone/physiology*
  • Trypanosoma cruzi/growth & development*
  • Trypanosoma cruzi/immunology*

Substances:

  • Antibodies, Protozoan
  • Nitric Oxide
  • Testosterone

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