Friday, October 9, 2009

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: Muscle Nerve. 2009 Oct 7. [Epub ahead of print]

Syrian hamster infected with Leishmania infantum: A new experimental model for inflammatory myopathies.

Paciello O, Wojcik S, Gradoni L, Oliva G, Trapani F, Iovane V, Politano L, Papparella S.

Department of Pathology and Animal Health, University of Naples Federico II, Via Delpino 1, 80137 Naples, Italy.

Idiopathic inflammatory myopathies (IIMs) are inflammatory disorders of unknown origin. On the basis of clinical, histopathological, and immunological features, they can be differentiated into three major and distinct subsets: dermatomyositis; polymyositis; and inclusion-body myositis. Although a few animal models for IIM are currently available, they lack several characteristic aspects of IIMs. The aim of our study was to examine skeletal muscle involvement in an experimental animal model of visceral leishmaniasis, a disseminated infection caused by the protozoan parasite Leishmania infantum, and to compare features of associated inflammation with those of human IIM. Syrian hamsters infected intraperitoneally with amastigotes of L. infantum were killed at 3 or 4 months post-infection, and the skeletal muscles were studied. Focal inflammation was predominantly observed in the endomysium and, to a lesser extent, in perivascular areas. Degenerating muscle fibers were also found, as well as myonecrosis. Immunofluorescence with confocal laser scanning microscopy was used to characterize the phenotype of inflammatory infiltrates and the distribution of MHC class I and II in muscle biopsies. The infiltrating inflammatory cells consisted mainly of T cells, and CD8(+) T cells were found in non-necrotic muscle fibers that expressed MHC class I on the sarcolemma. In addition to T cells, several macrophages were present. The model we are proposing closely resembles polymyositis and may be useful in studying certain aspects of this disease such as the role of T cells in muscle inflammation and myocytotoxicity, while also providing novel therapeutic targets. Muscle Nerve, 2009.

PMID: 19813199 [PubMed - as supplied by publisher]

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2: FASEB J. 2009 Oct 7. [Epub ahead of print]

Novel role for the double-stranded RNA-activated protein kinase PKR: modulation of macrophage infection by the protozoan parasite Leishmania.

Pereira RM, Teixeira KL, Barreto-de-Souza V, Calegari-Silva TC, De-Melo LD, Soares DC, Bou-Habib DC, Silva AM, Saraiva EM, Lopes UG.

*Laboratório de Parasitologia Molecular, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, andLaboratório de Imunobiologia de Leishmanioses, Instituto de Microbiologia Paulo Góes, Universidade Federal do Rio Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil;Laboratório de Pesquisas sobre o Timo, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil; andDepartamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal do Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.

The evolution of Leishmania infection depends on the balance between microbicidal and suppressor macrophage functions. Double-stranded RNA (dsRNA)-activated protein kinase R (PKR), a classic antiviral protein, is able to regulate a number of signaling pathways and macrophage functions. We investigated the possible role of PKR in the modulation of Leishmania infection. Our data demonstrated that Leishmania amazonensis infection led to PKR activation and increased PKR levels. Consistently, in macrophages from PKR knockout 129Sv/Ev mice and RAW-264.7 cells stably expressing a dominant-negative (DN) construct of PKR (DN-PKR), L. amazonensis infection was strongly reduced. The treatment of infected macrophages with the synthetic double-stranded RNA poly(I:C), a potent PKR inductor, increased L. amazonensis intracellular proliferation. This effect was reversed by 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, as well as by the expression of DN-PKR. NO release induced by dsRNA treatment was inhibited by L. amazonensis through NF-kappaB modulation. PKR activation induced by dsRNA also resulted in IL-10 production, whose neutralization with specific antibody completely abrogated L. amazonensis proliferation. Our data demonstrated a new role of PKR in protozoan parasitic infection through IL-10 modulation.-Pereira, R. M. S., Teixeira, K. L. D., Barreto-de-Souza, V. Calegari-Silva, T. C., De-Melo, D. B., Soares, D. C., Bou-Habib, D. C., Silva, A. M., Saraiva, E. M., Lopes, U. G. Novel role for the double-stranded RNA-activated protein kinase PKR: modulation of macrophage infection by the protozoan parasite Leishmania.

PMID: 19812373 [PubMed - as supplied by publisher]

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3: Clin Vaccine Immunol. 2009 Oct 7. [Epub ahead of print]

Specific serodiagnosis of canine visceral leishmaniasis using Leishmania ribosomal protein extracts.

Coelho EA, Ramírez L, Costa MA, Coelho VT, Martins VT, Chávez-Fumagalli MA, Oliveira DM, Tavares CA, Bonay P, Nieto CG, Abánades DR, Alonso C, Soto M.

Departamento de Bioquímica e Imunologia, ICB and Departmento de Patologia Clínica, Coltec, Universidade Federal de Minas Gerais, 31.270-901, Belo Horizonte, Minas Gerais, Brazil; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, 28049 Madrid, Spain; Unidad de Parasitología y Enfermedades Parasitarias, Universidad de Extremadura, Cáceres, Spain; Departamento de Farmacologia Bioquímica e Molecular, ICB, Universidade Federal de Minas Gerais, 31.270-901, Belo Horizonte, Minas Gerais, Brazil.

In the present work we have analyzed the antigenicity of the Leishmania ribosomal proteins (LRP). To accomplish this, Leishmania infantum ribosomes were biochemically purified from promastigotes cytosolic extracts and their reactivity was analyzed using the sera from dogs naturally infected with L. infantum. Since antibodies reacting against different ribosomal proteins were observed in all the tested sera obtained from dogs having symptomatic visceral leishmaniasis, we have analyzed the potential usefulness of the LRP extracts in the development of an enzyme-linked immunosorbent assay (ELISA) for the serodiagnosis of canine visceral leishmaniasis (CVL) in an area of Brazil that is endemic for VL due to infection by Leishmania chagasi. A comparative ELISA test using crude soluble Leishmania chagasi antigen (SLA) and L. infantum LPR was performed. LRP and SLA based ELISAs gave similar sensitivity for diagnosis of symptomatic CVL, but the LRP extract provided a very high sensitivity for the detection of oligosymptomatic and asymptomatic dogs. In addition, a LRP based ELISA test showed higher specificity when the sera from dogs harbouring other infections were included in the analysis. LRP antigen displayed no cross reactivity with sera from dogs that had any of the other diseases tested, notably, Chagas disease. Our findings suggest that LRP are a potential tool for the diagnosis of CVL and will be particularly useful for diagnosis of asymptomatic CVL.

PMID: 19812259 [PubMed - as supplied by publisher]

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4: Bioorg Med Chem. 2009 Sep 20. [Epub ahead of print]

In vivo and in vitro anti-leishmanial activities of 4-nitro-N-pyrimidin- and N-pyrazin-2-ylbenzenesulfonamides, and N(2)-(4-nitrophenyl)-N(1)-propylglycinamide.

Dea-Ayuela MA, Castillo E, Gonzalez-Alvarez M, Vega C, Rolón M, Bolás-Fernández F, Borrás J, González-Rosende ME.

Department of Chemistry, Biochemistry and Molecular Biology, University CEU Cardenal Herrera, Edificio Seminario s/n, 46113-Moncada, Valencia, Spain; Department of Parasitology, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040-Madrid, Spain.

A series of compounds containing the nitrobenzene and sulfonamido moieties were synthesized and their leishmanicidal effect was assessed in vitro against Leishmaniainfantum promastigotes. Among the compounds evaluated, the p-nitrobenzenesulfonamides 4Aa and 4Ba, and the p-nitroaniline 5 showed significant activity with a good selectivity index. In a Balb/c mice model of L. Infantum, administration of compounds 4Aa, 4Ba or 5 (5mg/kg/day for 10days, injected ip route) led to a clear-cut parasite burden reduction (ca. 99%). In an attempt to elucidate their mechanism of action, the DNA interaction of 4Aa and 5 was investigated by means of viscosity studies, thermal denaturation and nuclease activity assay. Both compounds showed nuclease activity in the presence of copper salt. The results suggest that compounds 4Aa, 4Ba and 5 represent possible candidates for drug development in the therapeutic control of leishmaniasis.

PMID: 19811921 [PubMed - as supplied by publisher]

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5: Eur J Med Chem. 2009 Sep 15. [Epub ahead of print]

A new series of amodiaquine analogues modified in the basic side chain with in vitro antileishmanial and antiplasmodial activity.

Guglielmo S, Bertinaria M, Rolando B, Crosetti M, Fruttero R, Yardley V, Croft SL, Gasco A.

Dipartimento di Scienza e Tecnologia del Farmaco, Via P. Giuria 9, I-10125 Torino, Italy.

The synthesis and the study of new amodiaquine derivatives bearing modified lateral basic chains as new agents with both antimalarial and antileishmanial activities are reported. The compounds were tested in vitro against Leishmania donovani MHOM/ET/67/HU3 and 2 strains of Plasmodium falciparum, 3D7 and K1. All the compounds show complex ionisation profiles. At physiological pH the ionised form(s) are in equilibrium with the uncharged form, while at acid pH all the products exist largely as protonated forms. The antiprotozoal profile indicates that all derivatives are endowed with both antimalarial and antileishmanial activity. Interestingly amodiaquine, together with some synthesised derivatives (11, 12, 15, 27, 34), displayed antileishmanial activity in the low micromolar range, although these compounds were also cytotoxic and have a narrow therapeutic window, most of the synthesised compounds proved to be potent antimalarials, a few of them showing a good activity against the chloroquine resistant K1 strain.

PMID: 19811859 [PubMed - as supplied by publisher]

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6: Autoimmunity. 2009 May;42(4):331-3.

Lipoxin A4 receptor dependent leishmania infection.

Wenzel A, Van Zandbergen G.

Institute for Medical Microbiology and Hygiene, University Clinic of Ulm, Ulm, Albert Einstein Allee 11, D-89081, Germany.

The lipoxin A4 receptor (ALX) is an important target of LxA4 in synovial tissues of patients with inflammatory arthritis. Previously this receptor was known as the FPRL-1 on PMN and shown to interact with acute phase proteins and a variety of peptides. ALX signalling can either activate or deactivate PMN functions. In this study, we found that both LxA4 and a chemotactic lipid leishmania chemotactic factor released by the parasite leishmania increased infectivity of this pathogen in an ALX dependent fashion. This functional characterization of ALX could lead to development of novel, therapeutic targets for treatment inflammatory diseases.

PMID: 19811292 [PubMed - in process]

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7: Parasite. 2009 Jun;16(2):153-9.LinkOut

[Spatial variation of risk for pigs to contract trypanosomosis in farms situated in the peri-urban area of Kinshasa]

[Article in French]

Sumbu J, De Deken R, Deckers N, Mpiana S, Kabambi P, Tshilenge G, Boelaert M.

Laboratoire Vétérinaire de Kinshasa, Kinshasa, République Démocratique du Congo.

In an effort to understand better the transmission risk as well for the animal African trypanosomosis (AAT) as for the human trypanosomosis (HAT) in the peri-urban zone of Kinshasa, a serologic study was carried out in local pig farms from 2003 to 2005. An indirect ELISA was used to detect the presence of trypanosome antibodies in 1,240 pigs originating from 404 farms. Seropositivity was recorded in 155 farms (38%), but varied considerably according to the district. In 6% of the farms TAA could be confirmed by parasitological examination. Trapping sites (n = 367) established in the neighbourhood of pig farms made it possible to capture 1,935 tsetse flies (Glossina fuscipes quanzensis). Among 562 dissected flies 23 were found to harbour trypanosomes resulting in an infection rate of 4.1%. In the majority of the districts the transmission risk for animal trypanosomosis anticipated from the apparent vector densities was corroborated by the serology. Zones with strong indications of local AAT transmission were identified in several quarters of three peri-urban districts of Kinshasa: Mount-Ngafula, Ngaliema and N'Sele. An intensification of tsetse control activities in those sites of increased transmission risk is essential.

PMID: 19585895 [PubMed - indexed for MEDLINE]

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8: Bioorg Med Chem. 2009 Jul 15;17(14):5038-43. Epub 2009 Jun 17.Click here to read LinkOut

Ruthenium complexes endowed with potent anti-Trypanosoma cruzi activity: Synthesis, biological characterization and structure-activity relationships.

Donnici CL, Araújo MH, Oliveira HS, Moreira DR, Pereira VR, de Assis Souza M, de Castro MC, Leite AC.

LASELORG-QUIM-Laboratório de Síntese, Eletrossíntese Orgânica e Química Medicinal, Departamento de Química, ICEX, Universidade Federal de Minas Gerais (UFMG), 31270-901, Belo Horizonte-MG, Brazil. cdonnici@terra.com.br

Although effective against epimastigotes (proliferative form) and of low cytotoxicity in mammals, the aryl-4-oxothiazolylhydrazones (ATZ) display only limited activity against trypomastigotes (bloodstream form) of Trypanosoma cruzi. Considering the metal complexation approach with bioactive ligands as one possible strategy for improving the biological efficacy of ATZ, a set of eight new ruthenium-ATZ complexes (RuCl(2)ATZCOD, COD is 1,5-cyclooctadiene) were prepared, chemically and biologically characterized, including in vitro assays against epimastigotes and trypomastigote forms of the parasite and also assessment of cytotoxicity in mammals. Two of these complexes presented antitrypanosomal activity at non-cytotoxic concentrations on mammalian cells and of higher potency than its metal-free ligands, while the metallic precursor [RuCl(2)COD(MeCN)(2)] showed only moderate antitrypanosomal activity. Comparative analysis between the ruthenium complexes and metal-free ligands demonstrated the usefulness of this approach, with the establishment of new SAR data. Additional pharmacological tests, including a DNA bond assay, gave rise to the proposal of a single preliminary explanation for the molecular origin of the bioactivity.

PMID: 19539479 [PubMed - indexed for MEDLINE]

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