Tuesday, August 4, 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 -10 of 11

1: J Mol Model. 2009 Aug 2. [Epub ahead of print]

Homology modeling and atomic level binding study of Leishmania MAPK with inhibitors.

Awale M, Kumar V, Saravanan P, Mohan CG.

Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062, Punjab, India.

The current therapy for leishmaniasis is not sufficient and it has two severe drawbacks, host-toxicity and drug resistance. The substantial knowledge of parasite biology is not yet translating into novel drugs for leishmaniasis. Based on this observation, a 3D structural model of Leishmania mitogen-activated protein kinase (MAPK) homologue has been developed, for the first time, by homology modeling and molecular dynamics simulation techniques. The model provided clear insight in its structure features, i.e. ATP binding pocket, phosphorylation lip, and common docking site. Sequence-structure homology recognition identified Leishmania CRK3 (LCRK3) as a distant member of the MAPK superfamily. Multiple sequence alignment and 3D structure model provided the putative ATP binding pocket of Leishmania with respect to human ERK2 and LCRK3. This analysis was helpful in identifying the binding sites and molecular function of the Leishmania specific MAPK homologue. Molecular docking study was performed on this 3D structural model, using different classes of competitive ATP inhibitors of LCRK3, to check whether they exhibit affinity and could be identified as Leishmania MAPK specific inhibitors. It is well known that MAP kinases are extracellular signal regulated kinases ERK1 and ERK2, which are components of the Ras-MAPK signal transduction pathway which is complexed with HDAC4 protein, and their inhibition is of significant therapeutic interest in cancer biology. In order to understand the mechanism of action, docking of indirubin class of molecules to the active site of histone deacetylase 4 (HDAC4) protein is performed, and the binding affinity of the protein-ligand interaction was computed. The new structural insights obtained from this study are all consistent with the available experimental data, suggesting that the homology model of the Leishmania MAPK and its ligand interaction modes are reasonable. Further the comparative molecular electrostatic potential and cavity depth analysis of Leishmania MAPK and human ERK2 suggested several important differences in its ATP binding pocket. Such differences could be exploited in the future for designing Leishmania specific MAPK inhibitors.

PMID: 19649663 [PubMed - as supplied by publisher]

2: Nat Biotechnol. 2009 Aug 2. [Epub ahead of print]Click here to read

Species-independent translational leaders facilitate cell-free expression.

Mureev S, Kovtun O, Nguyen UT, Alexandrov K.

Institute for Molecular Bioscience and Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.

Cell-free protein synthesis enables the rapid production and engineering of recombinant proteins. Existing cell-free systems differ substantially from each other with respect to efficiency, scalability and the ability to produce functional eukaryotic proteins. Here we describe species-independent translational sequences (SITS) that mediate efficient cell-free protein synthesis in multiple prokaryotic and eukaryotic systems, presumably through bypassing the early translation initiation factors. We use these leaders in combination with targeted suppression of the endogenous Leishmania tarentolae mRNAs to create a cell-free system based on this protozoan. The system can be directly programmed with unpurified PCR products, enabling rapid generation of large protein libraries and protein variants. L. tarentolae extract can produce up to 300 mug/ml of recombinant protein in 2 h. We further demonstrate that protein-protein and protein-small molecule interactions can be quantitatively analyzed directly in the translation mixtures using fluorescent (cross-) correlation spectroscopy.

PMID: 19648909 [PubMed - as supplied by publisher]

3: Exp Parasitol. 2009 Jul 30. [Epub ahead of print]Click here to read

Leishmania donovani: A glycosyl dihydropyridine analogue induces apoptosis like cell death via targeting pteridine reductase 1 in promastigotes.

Kaur J, Singh BK, Tripathi RP, Singh P, Singh N.

Drug Target Discovery & Development Division, Central Drug Research Institute, Chattar Manzil Palace, P.O. Box No. 173, Lucknow-226001, India.

Targeting of pteridine reductase1 (PTR1) in Leishmania is essential for development of successful antifolate chemotherapy. In search for specific inhibitors of PTR1 we have previously reported phenyl 1, 4-dihydropyridine ring as the lead structure showing antileishmanial efficacy in vitro and by the oral route in vivo. In this study we present programmed cell death inducing potential of this glycosyl dihydropyridine analogue (2, 6-dimethyl-4-(3-O-benzyl-1, 2-O-isopropylidene-beta-L-threo-pentofuranos-4-yl)-1-phenyl-1, 4-dihydro-pyridine-3, 5-dicarboxylic acid diethyl ester). Flow cytometric analysis revealed that this analogue induces cell cycle arrest at G2/M phase with subsequent increase in sub-G1 peak. Incubation of Leishmania promastigotes with this analogue causes exposure of phosphatidylserine to the outer leaflet of plasma membrane, formation of reactive oxygen species, depolarization of mitochondrial membrane potential and concomitant nuclear alterations that included DNA fragmentation. The results from this study on promastigotes give important lead to investigate further in intracellular amastigotes, the biologically relevant parasite stage in host macrophages.

PMID: 19647734 [PubMed - as supplied by publisher]

4: Exp Parasitol. 2009 Jul 30. [Epub ahead of print]Click here to read

Trypanosoma brucei AMP-Activated Kinase Subunit Homologs Influence Surface Molecule Expression.

Clemmens CS, Morris MT, Lyda TA, Acosta-Serrano A, Morris JC.

Department of Genetics and Biochemistry, Clemson University, Clemson South Carolina 29634.

The African trypanosome, Trypanosoma brucei, can gauge its environment by sensing nutrient availability. For example, procyclic form (PF) trypanosomes monitor changes in glucose levels to regulate surface molecule expression, which is important for survival in the tsetse fly vector. The molecular connection between glycolysis and surface molecule expression is unknown. Here we partially characterize T. brucei homologs of the beta and gamma subunits of the AMP-activated protein kinase (AMPK), and determine their roles in regulating surface molecule expression. Using flow cytometry and mass spectrometry, we found that TbAMPKbeta or TbAMPKgamma-deficient parasites express both of the major surface molecules, EP- and GPEET-procyclin, with the latter being a form that is expressed when glucose is low such as in the tsetse fly. Last, we have found that the putative scaffold component of the complex, TbAMPKbeta, fractionates with organellar components and colocalizes in part with a glycosomal marker as well as the flagellum of PF parasites.

PMID: 19647733 [PubMed - as supplied by publisher]

5: Vet Parasitol. 2009 Jul 15. [Epub ahead of print]Click here to read

Tissue distribution of Leishmania chagasi and lesions in transplacentally infected fetuses from symptomatic and asymptomatic naturally infected bitches.

Pangrazio KK, Costa EA, Amarilla SP, Cino AG, Silva TM, Paixão TA, Costa LF, Dengues EG, Diaz AA, Santos RL.

Departamento de Ciencias Patológicas, Facultad de Ciencias Veterinarias, Universidad Nacional de Asunción, Ruta Mcal. Estigarribia km 10, San Lorenzo, Paraguay.

Visceral leishmaniasis (VL) is primarily transmitted by an invertebrate vector, but transmission in the absence of the vector has been reported. Vertical transmission of VL has been described in man and dogs. The aim of this study was to evaluate the distribution of Leishmania amastigotes in fetal organs and histopathologic changes associated with parasitism and to determinate the frequency of transplacental transmission and potential of vertical transmission by symptomatic and asymptomatic pregnant bitches. Symptomatic (n=4) and asymptomatic (n=4) pregnant bitches, serologically and parasitologically positive for Leishmania sp., carrying a total of 53 fetuses (26 from symptomatic and 27 from asymptomatic bitches) were selected at the Veterinary Hospital of the National University of Asuncion, Paraguay. Samples of placenta and fetal organs such as liver, spleen, lymph nodes, bone marrow, kidney and heart were histologically evaluated and processed for immunodetection of amastigotes and PCR. There were no lesions compatible with VL in fetal tissues in spite of the presence of amastigotes, particularly in lymphoreticular tissues. However, fetal hepatocytes had marked degenerative changes that were independent of the presence of amastigotes in liver. Twenty-six out of 53 placentas (13 symptomatic and 13 asymptomatic) and a total of 17 fetuses out of 53 (nine symptomatic and eight asymptomatic) were PCR positive. Together these findings indicate a high frequency of transplacental transmission and no differences in the potential of transmission when symptomatic were compared to asymptomatic pregnant bitches.

PMID: 19647368 [PubMed - as supplied by publisher]

6: Parasitology. 2009 Aug 3:1-8. [Epub ahead of print]Click here to read

Leishmania major H-line attenuated under pressure of gentamicin, induces a Th1 response which protects susceptible BALB/c mice against infection with virulent L. major.

Daneshvar H, Burchmore R, Hagan P, Phillips RS.

Medical School, University of Kerman, Kerman, Iran.

SUMMARYAn attenuated line of Leishmania major (L. major H-line) has been established by culturing promastigotes in vitro under gentamicin pressure. A modification of the previously described method for the generation of attenuated L. major is described, giving rise to attenuated parasites after 8 rather than 12 subpassages. No lesions developed in BALB/c mice infected with L. major H-line, whereas L. major wild-type (WT) induced a Th2 like response with progressive lesions. Analysis of splenocyte IFN-gamma and IL-4 production following stimulation with promastigotes shows that the L. major H-line preferentially induces Th1-like responses and possibly down-regulates Th2 responses in BALB/c mice. L. major H-line parasites remained localized in the skin and draining lymph node, whereas L. major WT parasites disseminated into the visceral organs of BALB/c mice. Mice infected with L. major H-line acquired some resistance against L. major WT. These results show that the attenuated cell line of L. major is not only avirulent but that it may also modulate the host immune response.

PMID: 19646303 [PubMed - as supplied by publisher]

7: Parasite Immunol. 2009 Aug;31(8):432-9.Click here to read

Recruitment of CD8(+) T cells expressing granzyme A is associated with lesion progression in human cutaneous leishmaniasis.

Faria DR, Souza PE, Durães FV, Carvalho EM, Gollob KJ, Machado PR, Dutra WO.

Department of Morphology, ICB, Universidade Federal de Minas Gerais, CEP 31-270-901, Belo Horizonte, Minas Gerais, Brazil.

Human infection with Leishmania braziliensis leads to the establishment of cutaneous leishmaniasis (CL), characterized by the appearance of skin lesions that progress from nonulcerated to ulcerated forms. Our goal was to characterize the immunological kinetics associated with this progression, comparing the cellular composition, cytokines and granzyme expression between lesions of patients with early (E-CL) and late stages (L-CL) of CL. Histopathological analysis showed that lesions from L-CL had more exuberant inflammatory infiltrate as compared to E-CL. Although E-CL and L-CL lesions were predominantly mononuclear, lesions from E-CL patients presented higher neutrophil and eosinophil counts than L-CL. While percentages of CD4(+) and of CD68(+) cells were slightly higher in L-CL, a fivefold increase of CD8(+) cells was observed in L-CL, as compared to E-CL. Moreover, CD8(+) T-cells from L-CL expressed significantly higher levels of granzyme A than E-CL. Interestingly, granzyme A expression was positively correlated with intensity of the inflammatory infiltrate in L-CL but not E-CL. Lastly, percentages of IFN-gamma(+) and IL-10(+) cells were higher in L-CL as compared to E-CL, with CD4(+) T-cells and CD68(+) monocytes as the main sources of these cytokines, respectively. These results suggest that recruitment of CD8(+) granzyme A(+) T cells is involved in lesion progression in human CL.

PMID: 19646207 [PubMed - in process]

8: Parasite Immunol. 2009 Aug;31(8):423-31.Click here to read

Immunopathogenic competences of Leishmania (V.) braziliensis and L. (L.) amazonensis in American cutaneous leishmaniasis.

Silveira FT, Lainson R, De Castro Gomes CM, Laurenti MD, Corbett CE.

Parasitology Department, Evandro Chagas Institute (Surveillance Secretary of Health, Ministry of Health), 66090-000, Belém, Pará State, Brazil. silveiraft@lim50.fm.usp.br

The immunopathogenic competences of Leishmania (V.) braziliensis and L. (L.) amazonensis were reviewed in the light of more recent features found in the clinical and immunopathological spectrum of American cutaneous leishmaniasis. It was shown a dichotomy in the interaction between these Leishmania species and human T-cell immune response; while L. (V.) braziliensis shows a clear tendency to lead infection from the localized cutaneous leishmaniasis (LCL), a moderate T-cell hypersensitivity form at the centre of the spectrum, toward to the mucocutaneous leishmaniasis (MCL) at the T-cell hypersensitivity pole and with a prominent Th1-type immune response, L. (L.) amazonensis shows an opposite tendency, leading infection to the anergic diffuse cutaneous leishmaniasis (ADCL) at the T-cell hyposensitivity pole and with a marked Th2-type immune response. Between the central LCL and the two polar MCL and ADCL, the infection can present an intermediary form known as borderline disseminated cutaneous leishmaniasis, characterized by an incomplete inhibition of T-cell hypersensitivity but with a evident supremacy of Th1 over Th2 immune response (Th1 > or = Th2). These are probably the main immunopathogenic competences of L. (V.) braziliensis and L. (L.) amazonensis regarding the immune response dichotomy that modulates human infection outcome by these Leishmania parasites.

PMID: 19646206 [PubMed - in process]

9: Expert Rev Vaccines. 2009 Jul;8(7):921-35.Click here to read LinkOut

Vaccination approaches against Trypanosoma cruzi infection.

Cazorla SI, Frank FM, Malchiodi EL.

Cátedra de Inmunología & Instituto de Estudios de la Inmunidad Humoral (IDEHU), CONICET-UBA, Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina.

In natural infection, the survival of Trypanosoma cruzi, despite the complex immune response elicited including several humoral and cellular components of innate and acquired immunity, suggests that the immune system's natural responses are inherently inadequate. Consequently, it is of paramount importance to find alternatives to direct the immune system before infection, and redirect it after infection, to obtain a prophylactic and therapeutic vaccine. Herein, we review the recent advances in vaccine research and the development of the major antigen candidates, including cruzipain, trans-sialidase, amastigote surface protein, paraflagellar rod protein, among others. In the last 5 years, experimental works have been conducted to analyze DNA delivery systems, including viruses and bacteria, as well as immunomodulators such as CpG-oligodeoxynucleotide, macrophage-activating lipopeptide from Mycoplasma fermentans, glycolipid alpha-galactosylceramide, granulocyte-macrophage colony-stimulating factor, IL-12 and other cytokines and chemokines. The review also covers articles that shed light on some mechanisms of innate and adaptive immunity against T. cruzi, which improved our knowledge and provided potentially useful tools to fight infection. A better understanding of the protective immune responses that can effectively arrest T. cruzi survival in the mammalian host is critical for the development of vaccines against Chagas disease.

PMID: 19538117 [PubMed - indexed for MEDLINE]

10: Parasitol Res. 2009 Aug;105(2):519-28. Epub 2009 Apr 4.Click here to read LinkOut

ITS-RFLP- and RAPD-based genetic variability of Trypanosoma cruzi I, human and vector strains in Santander, Colombia.

Luna-Marín KP, Jaramillo-Londoño CL, Hernández-Torres J, Gutiérrez-Marín R, Vallejo GA, Angulo-Silva VM.

Centro de Investigaciones en Enfermedades Tropicales, (CINTROP), Universidad Industrial de Santander, Bucaramanga, Colombia. katluna23@tux.uis.edu.co

Chagas disease is a severe public health problem in Latin-American countries. In Colombia, the predominance of Trypanosoma cruzi I has been described in the literature, with a broad heterogeneity between strains. However, most of the studies carried out centered on isoenzyme analysis, with a smaller number that focus on other molecular methods. In this report, we discuss the results of a molecular analysis of T. cruzi I strains, isolated from the domestic cycle, from the department of Santander, one of the territorial divisions where the prevalence of infection is highest. Internal transcribed spacer-restriction fragment length polymorphism and random amplification of polymorphic DNA were used to characterize 16 strains from human and vector (Triatominae) hosts. The data reveal a clustering based on the biological origin. Human and vector strains grouped separately; however, three vector strains clustered together with human strains. These results indicate that genetic differences exist in the strains that infect both hosts. We conclude that T. cruzi I populations in the domestic cycle of transmission of Chagas disease in Santander are heterogeneous and are composed of different clones. The epidemiological and biological implications are discussed.

PMID: 19347363 [PubMed - indexed for MEDLINE]

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