What's new for 'Trypanosomatids' in PubMed

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Sent on Friday, 2012 June 08
Search: kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"

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Items 1 - 4 of 4

1.	Chemistry. 2012 Jun 1. doi: 10.1002/chem.201200482. [Epub ahead of print] Parasite-Based Screening and Proteome Profiling Reveal Orlistat, an FDA-Approved Drug, as a Potential Anti Trypanosoma brucei Agent([) (]). Yang PY, Wang M, Liu K, Ngai MH, Sheriff O, Lear MJ, Sze SK, He CY, Yao SQ. Source Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543 (Singapore), Fax: (+65) 6779-1691. Abstract Trypanosoma brucei is a parasite that causes African sleeping sickness in humans and nagana in livestock and is transmitted by the tsetse fly. There is an urgent need for the development of new drugs against African trypanosomiasis due to the lack of vaccines and effective drugs. Orlistat (also called tetrahydrolipstatin or THL) is an FDA-approved antiobesity drug targeting primarily the pancreatic and gastric lipases within the gastrointestinal tract. It shows potential activities against tumors, mycobacteria, and parasites. Herein, we report the synthesis and evaluation of an expanded set of orlistat-like compounds, some of which showed highly potent trypanocidal activities in both the bloodstream form (BSF) and the procyclic form (PCF) of T. brucei. Subsequent in situ parasite-based proteome profiling was carried out to elucidate potential cellular targets of the drug in both forms. Some newly identified targets were further validated by the labeling of recombinantly expressed enzymes in Escherichia coli lysates. Bioimaging experiments with a selected compound were carried out to study the cellular uptake of the drug in T. brucei. Results indicated that orlistat is much more efficiently taken up by the BSF than the PCF of T. brucei and has clear effects on the morphology of mitochondria, glycosomes, and the endoplasmic reticulum in both BSF and PCF cells. These results support specific effects of orlistat on these organelles and correlate well with our in situ proteome profiling. Given the economic challenges of de novo drug development for neglected diseases, we hope that our findings will stimulate further research towards the conversion of orlistat-like compounds into new trypanocidal drugs. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
	PMID: 22674877 [PubMed - as supplied by publisher]
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2.	Vet Immunol Immunopathol. 2012 May 11. [Epub ahead of print] Canine cerebral leishmaniasis: Potential role of matrix metalloproteinase-2 in the development of neurological disease. Melo GD, Marcondes M, Machado GF. Source UNESP - Univ Estadual Paulista, College of Veterinary Medicine, Araçatuba, São Paulo, Brazil. Abstract Matrix metalloproteinases (MMPs) are a group of calcium- and zinc-dependent endopeptidases that are involved in maintaining the extracellular matrix. MMP-2 and MMP-9 are thought to be related to the disruption of the blood-brain-barrier (BBB) by their ability to cleave type IV collagen, the main component of the basal membrane. To establish the presence of MMP-2 and MMP-9 in the pathogenesis of canine cerebral leishmaniasis, we examined the levels of these metalloproteinases in the cerebrospinal fluid (CSF) and serum of dogs with visceral leishmaniasis and neurological symptoms (n=16) and in the CSF and serum of uninfected healthy dogs (n=10) using zymography. In the CSF of dogs with cerebral leishmaniasis there was a massive presence of active MMP-2, whereas only the levels of both proMMP-2 and proMMP-9 were elevated in the serum. Although the detected MMP activity in the CSF might merely be related to CNS inflammation, these enzymes may also play a collaborative role in the disease progression. Both MMP-2 and MMP-9 are known to target critical constituents of the BBB, and once activated, they may promote cerebral barrier breakdown, allowing the entrance of inflammatory cells and proteins within the nervous system milieu. Copyright © 2012 Elsevier B.V. All rights reserved.
	PMID: 22673195 [PubMed - as supplied by publisher]
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3.	Parasite Immunol. 2012 Jun 6. doi: 10.1111/j.1365-3024.2012.01372.x. [Epub ahead of print] Are the severe injuries of cutaneous leishmaniasis caused by an exacerbated Th1 response? Nicodemo A, Amato V, Miranda A, Floeter-Winter L, Zampieri R, Fernades E, Duarte M. Source Department of Infectious Diseases, University of São Paulo, Medical School, São Paulo, Brazil Infectious and Parasitic Diseases Clinic, Hospital das Clínicas and Laboratory of Medical Investigation and Parasitology (LIM 46), University of Sao Paulo, Medical School; São Paulo, SP, Brazil Laboratory of Trypanosomatids, Physiology Department, Biosciences Institute, University of São Paulo, São Paulo, Brazil Laboratory of the Discipline of Pathology of Transmissible Disease, Medical School, University of Sao Paulo, Sao Paulo, Brazil. Abstract American Tegumentary Leishmaniasis (ATL) is a disease whose clinical features are strongly related to the type of immune response it induces. Herein we report an atypical presentation of cutaneous leishmaniasis (CL) in a woman with a severe and extensive sore located in her leg, and we describe the differences between the usual local immune response in ATL and the local immune response in this patient. We observed an intense inflammatory response characterized by Th1 cells and cytokines with conspicuous expression of Toll-like receptor 3 (TLR-3). Few parasites were present, but there was an extensive tissue damage. We also discuss the immunological factors that could be related to the atypical presentation. © 2012 Blackwell Publishing Ltd. © 2012 Blackwell Publishing Ltd.
	PMID: 22670842 [PubMed - as supplied by publisher]
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4.	Development. 2012 May;139(10):1842-50. Epub 2012 Apr 4. A new asymmetric division contributes to the continuous production of infective trypanosomes in the tsetse fly. Rotureau B, Subota I, Buisson J, Bastin P. Source Trypanosome Cell Biology Unit, Institut Pasteur & CNRS, URA 2581, 25 rue du Docteur Roux, 75015 Paris, France. Abstract African trypanosomes are flagellated protozoan parasites that cause sleeping sickness and are transmitted by the bite of the tsetse fly. To complete their life cycle in the insect, trypanosomes reach the salivary glands and transform into the metacyclic infective form. The latter are expelled with the saliva at each blood meal during the whole life of the insect. Here, we reveal a means by which the continuous production of infective parasites could be ensured. Dividing trypanosomes present in the salivary glands of infected tsetse flies were monitored by live video-microscopy and by quantitative immunofluorescence analysis using molecular markers for the cytoskeleton and for surface antigens. This revealed the existence of two distinct modes of trypanosome proliferation occurring simultaneously in the salivary glands. The first cycle produces two equivalent cells that are not competent for infection and are attached to the epithelium. This mode of proliferation is predominant at the early steps of infection, ensuring a rapid colonization of the glands. The second mode is more frequent at later stages of infection and involves an asymmetric division. It produces a daughter cell that matures into the infective metacyclic form that is released in the saliva, as demonstrated by the expression of specific molecular markers - the calflagins. The levels of these calcium-binding proteins increase exclusively in the new flagellum during the asymmetric division, showing the commitment of the future daughter cell to differentiation. The coordination of these two alternative cell cycles contributes to the continuous production of infective parasites, turning the tsetse fly into an efficient and long-lasting vector for African trypanosomes.
	PMID: 22491946 [PubMed - indexed for MEDLINE]
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