What's new for 'Trypanosomatids' in PubMed

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Sent on Friday, 2012 March 02
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 54

1.	PLoS Comput Biol. 2012 Jan;8(1):e1002352. Epub 2012 Jan 19. Dynamic Modelling under Uncertainty: The Case of Trypanosoma brucei Energy Metabolism. Achcar F, Kerkhoven EJ; The SilicoTryp Consortium, Bakker BM, Barrett MP, Breitling R. Source Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom. Abstract Kinetic models of metabolism require detailed knowledge of kinetic parameters. However, due to measurement errors or lack of data this knowledge is often uncertain. The model of glycolysis in the parasitic protozoan Trypanosoma brucei is a particularly well analysed example of a quantitative metabolic model, but so far it has been studied with a fixed set of parameters only. Here we evaluate the effect of parameter uncertainty. In order to define probability distributions for each parameter, information about the experimental sources and confidence intervals for all parameters were collected. We created a wiki-based website dedicated to the detailed documentation of this information: the SilicoTryp wiki (http://silicotryp.ibls.gla.ac.uk/wiki/Glycolysis). Using information collected in the wiki, we then assigned probability distributions to all parameters of the model. This allowed us to sample sets of alternative models, accurately representing our degree of uncertainty. Some properties of the model, such as the repartition of the glycolytic flux between the glycerol and pyruvate producing branches, are robust to these uncertainties. However, our analysis also allowed us to identify fragilities of the model leading to the accumulation of 3-phosphoglycerate and/or pyruvate. The analysis of the control coefficients revealed the importance of taking into account the uncertainties about the parameters, as the ranking of the reactions can be greatly affected. This work will now form the basis for a comprehensive Bayesian analysis and extension of the model considering alternative topologies.
	PMID: 22379410 [PubMed - as supplied by publisher]

2.	New Microbiol. 2012 Jan;35(1):93-5. Epub 2012 Jan 10. Acute liver failure: a rare clinical presentation of visceral leishmaniasis. Sagnelli C, Di Martino F, Coppola N, Crisci A, Sagnelli E. Source Department of Clinical nd Experimental Medicine and Surgery �F. Magrassi e A. Lanzara, Second University of Naples, Italy. Abstract We recently re-examined a case of Visceral Leishmaniasis, in a 36-year-old caucasian immune-competent men with an unusual clinical presentation. Together with symptoms and signs of a severe acute liver involvement, he presented weight loss, huge spleen enlargement, pancytopenia and increased ?-globulin serum level with a high polyclonal peak. He had no fever, but over-abundant night sweats were frequent. The patient was considered to have liver cirrhosis, and the diagnosis of visceral leishmaniosis was made with a year�s delay. From this case report we may learn that, despite an unusual clinical presentation, the diagnosis of visceral leishmaniasis should not be excluded when other characteristic signs and symptoms and laboratory abnormalities are present.
	PMID: 22378560 [PubMed - in process]

3.	Bioorg Med Chem Lett. 2012 Feb 9. [Epub ahead of print] Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 2. Tadalafil analogs. Ochiana SO, Gustafson A, Bland ND, Wang C, Russo MJ, Campbell RK, Pollastri MP. Source Northeastern University Department of Chemistry and Chemical Biology, 417 Egan Research Center, 360 Huntington Avenue, Boston, MA 02115, United States. Abstract In this Letter we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1. Copyright © 2012 Elsevier Ltd. All rights reserved.
	PMID: 22377518 [PubMed - as supplied by publisher]

4.	J Med Chem. 2012 Mar 1. [Epub ahead of print] Synthesis and Structure-Activity Relationships of New Quinolone-type Molecules against <i>Trypanosoma brucei</i> Hiltensperger G, Jones NG, Niedermeier S, Stich A, Kaiser M, Jung J, Puhl S, Damme A, Braunschweig H, Meinel L, Engstler M, Holzgrabe U. Abstract Human African trypanosomiasis (HAT)a or sleeping sickness is caused by two subspecies of <i>T. brucei</i>, <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i> and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because apart from limited access to health services only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure <b>29</b>, which exhibits promising <i>in vitro</i> activity against <i>T. b. brucei</i> (IC<sub>50</sub> = 47 nM) and <i>T. b. rhodesiense</i> (IC<sub>50</sub> = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds <b>19</b> and <b>29</b> suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however topoisomerase II is probably not the main drug target.
	PMID: 22376072 [PubMed - as supplied by publisher]

5.	Mol Microbiol. 2012 Feb 29. doi: 10.1111/j.1365-2958.2012.08026.x. [Epub ahead of print] The de novo and salvage pathways of GDP-mannose biosynthesis are both sufficient for the growth of bloodstream form Trypanosoma brucei. Kuettel S, Wadum MC, Güther ML, Mariño K, Riemer C, Ferguson MA. Source Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom. Abstract The sugar nucleotide GDP-mannose is essential for Trypanosoma brucei. Phosphomannose isomerase occupies a key position on the de novo pathway to GDP-mannose from glucose, just before intersection with the salvage pathway from free mannose. We identified the parasite phosphomannose isomerase gene, confirmed that it encodes phosphomannose isomerase activity and localized the endogenous enzyme to the glycosome. We also created a bloodstream form conditional null mutant of phosphomannose isomerase to assess the relative roles of the de novo and salvage pathways of GDP-mannose biosynthesis. Phosphomannose isomerase was found to be essential for parasite growth. However, supplementation of the medium with low concentrations of mannose, including that found in human plasma, relieved this dependency. Therefore, we do not consider phosphomannose isomerase to be a viable drug target. We further established culture conditions where we can control glucose and mannose concentrations and perform steady-state [U-(13) C]-D-glucose labelling. Analysis of the isotopic sugar composition of the parasites variant surface glycoprotein synthesized in cells incubated in 5 mM [U-(13) C]-D-glucose in the presence and absence of unlabelled mannose showed that, under physiological conditions, about 80% of GDP-mannose synthesis comes from the de novo pathway and 20% from the salvage pathway. © 2012 Blackwell Publishing Ltd. © 2012 Blackwell Publishing Ltd.
	PMID: 22375793 [PubMed - as supplied by publisher]

6.	J Biol Chem. 2012 Feb 28. [Epub ahead of print] Caspar-like gene depletion reduces Leishmania infection in the sand fly host Lutzomyia longipalpis. Telleria EL, Sant'anna MR, Ortigão-Farias JR, Pitaluga AN, Dillon VM, Bates PA, Traub-Csekö YM, Dillon RJ. Source Instituto Oswaldo Cruz, Brazil; Abstract Female phlebotomine sand flies Lutzomyia longipalpis naturally harbour populations of the medically important Leishmania infantum (syn. Leishmania chagasi) parasite in the gut but the extent to which the parasite interacts with the immune system of the insect vector is unknown. To investigate the sand fly immune response and its interaction with the Leishmania parasite we identified a homologue for caspar a negative regulator of IMD immune signalling pathway. We found that feeding antibiotics to adult female Lu. longipalpis resulted in an upregulation of caspar expression relative to controls. Caspar was differentially expressed when females were fed on Gram negative and Gram positive bacterial species. Caspar expression was significantly down regulated in females between 3 and 6 days after a blood feed containing Leishmania mexicana amastigotes. RNA interference was used to deplete caspar expression in female Lu longipalpis which were subsequently fed with Leishmania in a bloodmeal. Sand fly gut populations of both Le. mexicana and Le. infantum were significantly reduced in caspar depleted females. The prevalence of Le. infantum infection in the females fell from 85% to 45%. Our results provide the first insight into the operation of immune homeostasis in phlebotomine sand flies during growth of bacterial and Leishmania populations in the digestive tract. We have demonstrated that the activation of the sand fly immune system, via depletion of a single gene, can lead to the abortion of Leishmania development and the disruption of transmission by the phlebotomine sand fly.
	PMID: 22375009 [PubMed - as supplied by publisher]
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7.	Int J Clin Pharmacol Ther. 2012 Mar;50(3):233-6. In vitro activity of green tea extract against Leishmania major pr omastigotes. Feily A, Saki J, Maraghi S, Moosavi Z, Khademvatan S, Siahpoosh A. Source Infectious Diseases and Tropical Research Center and Department of Dermatology, Department of Medical Parasitology, School of Medicine and Infectious Diseases and Tropical Research Center, Department of Medical Parasitology, School of Medicine and Cellular and Molecular Research Center and Medicinal Plant and Natural Product Research Center, Department of Pharmacognosy, School of Pharmacy, School of Medicine, Jundishapur University of Medical Sciences, Ahvaz, Iran. Abstract Background: Systemic and topical treatment options against Leishmaniasis are limited to a few drugs with inconsistent efficacy and unacceptable side effects and none of them is suitable for all forms of the disease. Objective: The aim of this study was to search the in vitro activity of green tea extract against L. major promastigotes and compare it with glucantime. Methods: Extract was prepared by percolation method. The extract was dried and dissolved in DMSO 1% solvent. Leishmania major promastigotes treated with 6 concentrations (3, 6, 12, 24, 48, 96 mg/ml) of the extract. As control positive group glucantime 85 mg/ml and additional untreated control group were included in this study. All cultures were performed in triplicate. The promastigotes were also counted and their flagellate's motilities were assessed microscopically. Results: Ethanolic extract of green tea showed significant leishmanicidal activity against L. major promastigotes in different concentrations. Notably there was a concordance in anti-leishmanial effect of the ethanol extract with the increasing of the dosage (3, 6, 12, 24, 48, 96 mg/ml). In comparison with glucantime the mean alive promastigotes in 12 mg/ml concentration of green tea was almost as same as 85 mg/ml glucantime and higher green tea extract concentrations were higher effective than glucantime. Conclusion: Our study revealed a novel pharmacological activity against promastigotes of L. major and suggests that green tea extract has the potential of being used in leishmaniasis but more studies are needed to find out its activity against amastigote and appropriate route of application.
	PMID: 22373836 [PubMed - in process]
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8.	Biochemistry. 2012 Feb 29. [Epub ahead of print] LEISHMANIA MAJOR PEROXIDASE IS A CYTOCHROME C PEROXIDASE. Jasion VS, Poulos TL. Abstract Leishmania major peroxidase (LmP) exhibits both ascorbate and cytochrome c peroxidase activity. Our previous results illustrated that LmP has much higher activity against horse heart cytochrome c than ascorbate suggesting that cytochrome c may be the biologically important substrate. In order to elucidate the biological function of LmP, we have recombinantly expressed, purified and determined the 2.08Å crystal structure of Leishmania major cytochrome c (LmCytc). Like other cytochromes c LmCytc has an electropositive surface surrounding the exposed heme edge that serves as the docking site with redox partners. LmCytc exhibits a unique UV-Visible reduced spectrum from most cytochromes because it has only one cysteine and therefore only one heme vinyl-thioether bond. Kinetic assays performed with LmCytc and LmP show that LmCytc is a much better substrate for LmP than horse heart cytochrome c. Furthermore, unlike the well-studied yeast system, the reaction follows classic Michaelis-Menten kinetics and is sensitive to increasing ionic strength. Using the yeast co-crystal as a control, protein-protein docking was performed using Rosetta to develop a model for the binding of LmP and LmCytc. These results suggest that the biological function of LmP is to act as a cytochrome c peroxidase.
	PMID: 22372542 [PubMed - as supplied by publisher]
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9.	Rev Soc Bras Med Trop. 2012 Feb;45(1):132-3. Severe coinfection of melioidosis and dengue fever in northeastern Brazil: first case report. Macedo RN, Rocha FA, Rolim DB, Vilar DC, Araújo FM, Vieira NN, Teixeira JR, Carvalho MC, Oliveira FG, Cavalcanti LP. Source Ambulatório de Doenças Infecciosas, Hospital Geral de Fortaleza, Fortaleza, CE. Abstract This report focuses on a fatality involving severe dengue fever and melioidosis in a 28-year-old truck driver residing in Pacoti in northeastern Brazil. He exhibited long-term respiratory symptoms (48 days) and went through a wide-ranging clinical investigation at three hospitals, after initial clinical diagnoses of pneumonia, visceral leishmaniasis, tuberculosis, and fungal sepsis. After death, Burkholderia pseudomallei was isolated in a culture of ascitic fluid. Dengue virus type 1 was detected by polymerase chain reaction in cerebrospinal fluid (CSF); this infection was the cause of death. This description reinforces the need to consider melioidosis among the reported differential diagnoses of community-acquired infections where both melioidosis and dengue fever are endemic.
	PMID: 22370846 [PubMed - in process]
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10.	Rev Soc Bras Med Trop. 2012 Feb;45(1):130-1. Splenectomy in a patient with treatment-resistant visceral leishmaniasi s: a case report. Dutra RA, Dutra LF, Reis Mde O, Lambert RC. Source Departamento de Cirurgia Pediátrica, Santa Casa de Franca, Franca, SP. Abstract Visceral leishmaniasis (VL), also known as Kala-azar, is a systemic infection caused by a protozoan (Leishmania) and, in its classic form, is a serious illness associated with malnutrition, anemia, hepatosplenomegaly, infectious processes and coagulopathies. The effect of splenectomy in patients with visceral leishmaniasis is not well defined; however, it is known that the spleen is the largest reservoir of infected cells belonging to the reticulo endothelial system. Therefore, the surgical procedure is an option for the debulking of parasites, providing a cure for refractory VL and minimizing the complications of hypersplenism.
	PMID: 22370845 [PubMed - in process]
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