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Sent on Saturday, 2011 Oct 22Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| 1. | Microbiology. 2011 Oct 20. [Epub ahead of print]The histone H4 lysine 14 acetylation in Leishmania donovani is mediated by the MYST family protein HAT4.Kumar D, Rajanala K, Minocha N, Saha S.SourceUniversity of Delhi; AbstractPost-translational modifications (PTMs) of histones regulate almost all facets of DNA metabolism in eukaryotes, such as replication, repair, transcription and chromatin condensation. While histone PTMs have been exhaustively examined in yeast and higher eukaryotes, less is known of their functional consequences in trypanosomatids. Trypanosome histones are highly divergent from other eukaryotes, and specific PTMs have been identified in histones of Trypanosoma species. The characterization of three MYST family histone acetyltransferases (HATs) in Trypanosoma brucei has earlier identified the HATs responsible for acetylation of two lysine residues, K4 and K10, in the N-terminal tail of histone H4. This report presents results of the first study of a histone acetyltransferase in a Leishmania species. The HAT4 gene of Leishmania donovani, the causative pathogen of Visceral Leishmaniasis, has been cloned and expressed in fusion with GFP in Leishmania promastigotes. We find that HAT4-GFP behaves differently from typical eukaryotic MYST family HATs that are usually constitutively nuclear, in that it is cytosolic throughout the cell cycle, though the protein is also present in the nucleus in post-mitotic cells. Substrate specificity analyses reveal that LdHAT4 acetylates the N-terminus of histone H4, but not of H2A, H2B or H3. Nor does it acetylate the C-terminus of H2A. The primary target of HAT4-mediated acetylation is the K14 residue of H4, though K2 might be a minor site as well. H4K14 acetylation in Leishmania may either occur in the cytoplasm prior to histone deposition, or may occur soon after mitosis in the nucleus. |
| 2. | Clin Infect Dis. 2011 Oct 19. [Epub ahead of print]Limited Effectiveness of High-Dose Liposomal Amphotericin B (AmBisome) for Treatment of Visceral Leishmaniasis in an Ethiopian Population With High HIV Prevalence.Ritmeijer K, Ter Horst R, Chane S, Aderie EM, Piening T, Collin SM, Davidson RN.SourcePublic Health Department, Médecins Sans Frontières, Amsterdam, the Netherlands. AbstractBackground. Due to unacceptably high mortality with pentavalent antimonials, Médecins Sans Frontières in 2006 began using liposomal amphotericin B (AmBisome) for visceral leishmaniasis (VL) patients in Ethiopia who were severely ill or positive for human immunodeficiency virus (HIV).Methods. We used clinical data obtained from January 2007 to January 2009 to compare outcomes by HIV status and VL episode (primary vs relapse) and to identify risk factors for treatment failure among patients treated with AmBisome monotherapy at a total dose of 30 mg/kg in 6 doses on alternate days, a higher dose than recommended by the World Health Organization (20 mg/kg).Results. Among 94 HIV-negative severely ill VL patients, 93% had initial cure and 6% died. Among 195 HIV-positive patients (116 primary, 79 relapse VL), 60% had initial cure, 7% died, and 32% were parasitological failures. AmBisome was less effective in the 79 HIV-positive VL relapse patients (38% initial cure, 5% mortality, 56% parasitological failure) than in the 116 HIV-positive primary VL patients (74% initial cure, 8% mortality, 16% parasitological failure). Sodium stibogluconate (SSG) rescue treatment increased the overall cure rate among all HIV-positive VL patients from 60% to 83%, but 16% (9 of 59) of rescue treatment patients died, mainly due to SSG toxicity.Conclusions. High-dose AmBisome for VL is safe and effective in severely ill HIV-negative patients, and safe but less effective in HIV-positive patients. Combining AmBisome with another drug may enhance its effectiveness in HIV-positive VL patients. SSG should be avoided for treatment of VL in HIV-positive patients. |
| 3. | Int Microbiol. 2011 Mar;14(1):1-11.Genome-wide gene expression profile induced by exposure to cadmium acetate in Leishmania infantum promastigotes.Alcolea PJ.SourceDepartm ent of Molecular Microbiology and Infection Biology, Biological Research Center (CIB), CSIC, Madrid, Spain. AbstractLeishmania infantum is the etiological agent of visceral leishmaniasis in Mediterranean areas. The life cycle of the protist is dimorphic and heteroxene, as promastigotes develop inside the gut of sand-fly vectors and amastigotes multiply inside mammalian phagocytic cells. In previous studies, we analyzed the expression profiles of these stages and the modulation of gene expression triggered by temperature increase and acidification, both of which are crucial in the differentiation of promastigotes to amastigotes. Differential expression profiles of translation initiation and elongation factors were detected. Here we report that the presence of 1 mM cadmium acetate in the culture medium leads to a shock response consisting of growth arrest, morphological changes, the absence of motility, and the up-regulation of genes that code for: a heavy metal transporter, trypanothione reductase, a haloacid-dehalogenase-like hydrolase, and a metalloexopeptidase from the M20 family, among others. This response is probably controlled by the differential expression of regulatory genes such as those encoding initiation factors 4E, eukaryotic translation initiation factor 3 subunits 8 and 2α, and elongation factor 1β. The initiation factor 2α gene is induced in anomalous environments, i.e., those outside of the protist's normal life-cycle progression, for example, in response to the presence of cadmium ions, acidification without temperature increase, and vice versa. Our results suggest that the regulation of gene expression is a key component of the shock response. |
| 4. | Acta Trop. 2011 Oct 12. [Epub ahead of print]Genotyping of sand fly species in Peruvian Andes where leishmaniasis is endemic.Fujita M, Kato H, Cáceres AG, Gomez EA, Mimori T, Zhang F, Iwata H, Korenaga M, Sakurai T, Katakura K, Hashiguchi Y.SourceLaboratory of Veterinary Hygiene, Faculty of Agriculture, Yamaguchi University, Yamaguchi, Japan. AbstractGenotyping of sand fly species circulating in Peru was established on the basis of PCR-restriction fragment length polymorphisms (RFLPs) of the 18S ribosomal RNA (rRNA) gene. The sequences of 18S rRNA gene fragments from 12 Lutzomyia and 1 Warileya species were determined and their RFLP-patterns were analyzed. Consequently, RFLP analysis with the restriction enzyme AfaI and then HapII or KpnI, followed by XspI successfully differentiated them. Intraspecific genetic diversity affecting RFLP-patterns was not detected in the specimens collected from 24 areas of 8 departments. The genotyping was applied to the surveillance of sand flies collected from Andean areas where leishmaniasis is endemic, and its usability was verified. The present method promises to be a powerful tool for the classification and surveillance of sand flies circulating in Peru. Copyright © 2011. Published by Elsevier B.V. |
| 5. | Acta Med Port. 2011 May;24(3):399-404. Epub 2011 Aug 12.[Paediatric visceral leishmaniasis: experience of a paediatric referral center 1990-2009]. [Article in Portuguese] Dionísio MT, Dias A, Rodrigues F, Félix M, Estêvão MH.SourceServiços de Cardiologia Pediátrica e de Pediatria. Hospital Pediátrico de Coimbra. (C.H.C.). Coimbra. AbstractIntroduction: Visceral Leishmaniasis (VL) is a systemic infection, endemic in many parts of the world, including Portugal. The aim is to review all cases of VL admitted to our hospital. Patients and Methods: Retrospective analysis of all cases of VL admitted to a Level III Paediatric Hospital, between January 1990 and December 2009 (20 years). Demographic, epidemiological, clinical, laboratorial, therapeutic and follow-up data were analysed. Results: During the study period, 54 children were admitted with VL, three of which were excluded from the study due to incomplete clinical records. The mean age was 27 months (seven months - twelve years) and 53% were female. Two thirds of the cases were diagnosed during Spring and Summer. The mean time for diagnosis was 31 days (2-188 days). The most common clinical findings were splenomegaly (100%), fever (96%), pallor (90%) and hepatomegaly (82%). Bone marrow aspiration was performed in all children, with amastigotes identified in 73% of the cases. Indirect immunofluorescence was performed in 30 cases, being positive in 29 (97%). All were treated with meglumine antimoniate. Three children relapsed during the first year after the initial episode. A 17 months-old child died due to cardiac failure. Conclusions: The early diagnosis of VL is essential to carry out prompt management and prevent potential fatal complications. In our analysis, the management with meglumine antimoniate resulted in an overall favourable outcome. |
| 6. | Asian Pac J Trop Med. 2011 Oct;4(10):836-40.Antileishmanial assessment of leaf extracts from Pluchea carolinensis, Pluchea odorata and Pluchea rosea.García M, Perera WH, Scull R, Monzote L.SourceParasitology Department, Institute of Medicine Tropical "Pedro Kourí", Havana City, Cuba. AbstractOBJECTIVE:To evaluate the antileishmanial activity of different extracts from three Cuban Pluchea species. METHODS:In in vitro assays the IC(50) was calculated in the promastigotes and amastigotes forms as cytotoxicity in murine macrophages. In leishmaniasis cutanea experiment, mortality, weight loss, lesion size and burden parasite were measured. RESULTS:Extracts evaluated showed inhibitive effect on growing of promastigote form; however, active extracts caused a high toxicity. Ethanol and n-hexane extracts demonstrated specific antileishmanial activity. Ethanol and n-hexane extracts from Pluchea carolinensis (P. carolinensis) caused similar inhibition against amastigote form. The intraperitoneal administration of the ethanol extract of P. carolinensis at 100 mg/kg prevented lesion development compared with control groups. CONCLUSIONS:The antileishmanial experiment suggests that ethanol extracts from P. carolinensis is the most promising. Further studies are still needed to evaluate the potential of this plant as a source of new antileishmanial agents. Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved. |
| 7. | Asian Pac J Trop Med. 2011 Oct;4(10):757-9.Bone marrow leishmaniasis: a review of situation in Thailand.Wiwanitkit V.SourceWiwanitkit House, Bangkhae, Bangkok-10330, Thailand. AbstractLeishmaniasis is an important tropical vector-borne disease. This infection can be seen in tropical area and it is considered to be one of the most important vector-borne infections at present. The general situation of the leishmaniasis in Thailand is hereby reviewed. Although Thailand is a tropical country, the leishmaniasis is not endemic but sporadic. The imported cases are documented in some literatures. The serious form of leishmaniasis, the visceral leishmaniasis is also detectable in Thailand. Also, the author performed an in depth literature review of the reports of bone marrow leishmaniasis, a specific kind of visceral leishmaniasis, in Thailand in order to summarize the characteristics of this infection among Thai patients. According to this review, there have been at least 5 reports in the literature of 6 cases of bone marrow leishmaniasis in the Thai population, of which no case was lethal. Concerning the clinical manifestations, all except had prolonged fever with unknown origin. From physical examination, all had hepatosplenomegaly. The striking findings were active hemophagocytosis with increased proliferation of lymphoidplasma cell line in the bone marrow and amastigotes of Leishmania donovani was demonstrated. Considering the treatment, pantavalent antimony compound was used and the excellent improvement and complete recovery. Finally, the author also discussed on the importance of leishmaniasis in Thailand relating to the present globalization and good traveling system. Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved. |
| 8. | Chem Biol Drug Des. 2011 Oct 20. doi: 10.1111/j.1747-0285.2011.01262.x. [Epub ahead of print]Identification of Novel Inhibitors of Dipeptidylcarboxypeptidase of Leishmania donovani via Ligand Based Virtual Screening and Biological Evaluation.Gangwar S, Baig MS, Shah P, Biswas S, Batra S, Siddiqi MI, Goyal N.SourceDivisions of Biochemistry Molecular and Structural Biology Medicinal Chemistry CSIR-Central Drug Research Institute, Council of Scientific and Industrial Research, Chattar Manzil Palace, PO Box 173, Lucknow-22600, India. AbstractCurrent treatment of leishmaniasis is based on chemotherapy, which relies on a handful of drugs with serious limitations such as high cost, toxicity and lack of efficacy in endemic regions. Therefore, development of new, effective and affordable anti-leishmanial drugs is a global health priority. Dipeptidylcarboxypeptidase has been characterized and established as a drug target for antileishmanial drug discovery. We virtually screened a large chemical library of 15,452 compounds against a 3D model of dipeptidylcarboxypeptidase to identify novel inhibitors. The initial virtual screening using a ligand-based pharmacophore model identified 103 compounds. Forty-six compounds were short listed based on the docking scores and other scoring functions. Further, these compounds were subjected to biological assay, and four of them belonging to two chemical classes were identified as the lead compounds. Identification of these novel and chemically diverse inhibitors should provide leads to be optimized into candidates to treat these protozoan infections. Copyright © 2011 John Wiley & Sons A/S. |
| 9. | Br J Pharmacol. 2011 Oct 20. doi: 10.1111/j.1476-5381.2011.01723.x. [Epub ahead of print]Analysis of blood-brain barrier permeability of monovalent Nanobodies using microdialysis.Caljon G, Caveliers V, Lahoutte T, Stijlemans B, Ghassabeh GH, Van Den Abbeele J, Smolders I, De Baetselier P, Michotte Y, Muyldermans S, Magez S, Clinckers R.SourceDepartment of Pharmaceutical Chemistry and Drug Analysis, Center for Neuroscience, Vrije Universiteit Brussel, Brussels, Belgium. Unit of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium. Department of Molecular and Cellular Interactions, VIB, Brussels, Belgium. Department of Nuclear Medicine, UZ Brussel and In Vivo Cellular and Molecular Imaging, ICMI, Vrije Universiteit Brussel, Brussels, Belgium. Department of Animal Health, Unit of Veterinary Protozoology, Institute of Tropical Medicine Antwerp, Antwerp, Belgium. AbstractBACKGROUND AND PURPOSE:Nanobodies are promising antigen-binding moieties for molecular imaging and therapeutic purposes due to their favorable pharmacological and pharmacokinetic properties. However, the capability of monovalent nanobodies to reach targets in the central nervous system (CNS) remains to be demonstrated. EXPERIMENTAL APROACH: We have assessed the blood-brain barrier permeability of Nb_An33, a nanobody against the Trypanosoma brucei brucei Variant-specific Surface Glycoprotein (VSG). This analysis was performed in healthy rats and in rats that were in the encephalitic stage of African trypanosomiasis using intracerebral microdialysis, Single Photon Emission Computed Tomography (SPECT), or a combination of both methodologies. This enabled the quantification of unlabeled and (99m) Tc-labeled nanobodies using respectively a sensitive VSG-based nanobody-detection ELISA, radioactivity measurement in collected microdialysates, and SPECT image analysis. KEY RESULTS:The combined read-out methodologies demonstrate that disposition of Nb_An33 can be detected in the brain of healthy rats following intravenous injection and that inflammation-induced damage to the blood-brain barrier significantly increases the nanobody perfusion efficiency. We also illustrate the advantage of complementing SPECT analyses with intracerebral microdialysis in brain disposition studies and suggest that it is of interest to evaluate the blood-brain barrier penetrating potential of monovalent nanobodies in models of CNS-inflammation. The presented data also suggest that fast blood clearance might hamper efficient targeting of specific nanobodies to the CNS. CONCLUSIONS AND IMPLICATIONS:Nanobodies can perfuse into the brain parenchyma, especially in pathological conditions where the blood-brain barrier integrity is compromised. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
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