What's new for 'Trypanosomatids' in PubMed

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Sent on Thursday, 2010 Jun 10
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 - 7 of 7

1.	Org Biomol Chem. 2010 Jun 7. [Epub ahead of print] Rationally designed squaryldiamides - a novel class of sugar-nucleotide mimics? Niewiadomski S, Beebeejaun Z, Denton H, Smith TK, Morris RJ, Wagner GK. School of Pharmacy, University of East Anglia, Norwich, UKNR4 7TJ. g.wagner@uea.ac.uk. Abstract Sugar-nucleotides such as GDP-mannose, GDP-fucose and UDP-glucose are important biomolecules with a central role in carbohydrate and glycoconjugate biosynthesis, metabolism and cell signalling. Analogues and mimics of naturally occurring sugar-nucleotides are sought after as chemical tools and inhibitor candidates for sugar-nucleotide-dependent enzymes including glycosyltransferases. Many sugar-nucleotides bind to their target glycosyltransferases via coordination of the diphosphate group to a divalent metal cofactor in the active site. The identification of uncharged, chemically stable surrogates for the diphosphate group, with the ability to coordinate to a divalent metal, is therefore an important design criteria for the development of sugar-nucleotide mimics. Here, we describe the rational design and synthesis of a novel class of sugar-nucleotide mimics based on a squaryldiamide scaffold, an uncharged phosphate isostere. We demonstrate by comprehensive NMR titration experiments that the new sugar-nucleotide mimics coordinate efficiently to Mg(2+), and provide results from biological studies with a therapeutically relevant mannosyltransferase from Trypanosoma brucei. Our findings suggest that squaryldiamides are a promising template for the development of sugar-nucleotide mimics, and illustrate the considerable potential of the squarylamide group as a fragment for inhibitor design.
	PMID: 20532300 [PubMed - as supplied by publisher]

2.	PLoS Pathog. 2010 Jun 3;6(6):e1000926. Trypanosoma brucei Modifies the Tsetse Salivary Composition, Altering the Fly Feeding Behavior That Favors Parasite Transmission. Van Den Abbeele J, Caljon G, De Ridder K, De Baetselier P, Coosemans M. Department of Animal Health, Unit of Veterinary Protozoology, Institute of Tropical Medicine Antwerp (ITM), Antwerp, Belgium. Abstract Tsetse flies are the notorious transmitters of African trypanosomiasis, a disease caused by the Trypanosoma parasite that affects humans and livestock on the African continent. Metacyclic infection rates in natural tsetse populations with Trypanosoma brucei, including the two human-pathogenic subspecies, are very low, even in epidemic situations. Therefore, the infected fly/host contact frequency is a key determinant of the transmission dynamics. As an obligate blood feeder, tsetse flies rely on their complex salivary potion to inhibit host haemostatic reactions ensuring an efficient feeding. The results of this experimental study suggest that the parasite might promote its transmission through manipulation of the tsetse feeding behavior by modifying the saliva composition. Indeed, salivary gland Trypanosoma brucei-infected flies display a significantly prolonged feeding time, thereby enhancing the likelihood of infecting multiple hosts during the process of a single blood meal cycle. Comparison of the two major anti-haemostatic activities i.e. anti-platelet aggregation and anti-coagulation activity in these flies versus non-infected tsetse flies demonstrates a significant suppression of these activities as a result of the trypanosome-infection status. This effect was mainly related to the parasite-induced reduction in salivary gland gene transcription, resulting in a strong decrease in protein content and related biological activities. Additionally, the anti-thrombin activity and inhibition of thrombin-induced coagulation was even more severely hampered as a result of the trypanosome infection. Indeed, while naive tsetse saliva strongly inhibited human thrombin activity and thrombin-induced blood coagulation, saliva from T. brucei-infected flies showed a significantly enhanced thrombinase activity resulting in a far less potent anti-coagulation activity. These data clearly provide evidence for a trypanosome-mediated modification of the tsetse salivary composition that results in a drastically reduced anti-haemostatic potential and a hampered feeding performance which could lead to an increase of the vector/host contact and parasite transmission in field conditions.
	PMID: 20532213 [PubMed - as supplied by publisher]

3.	J Exp Med. 2010 Jun 7. [Epub ahead of print] IL-10 production differentially infl uences the magnitude, quality, and protective capacity of Th1 responses depending on the vaccine platform. Darrah PA, Hegde ST, Patel DT, Lindsay RW, Chen L, Roederer M, Seder RA. Cellular Immunology Section and 2 ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. Abstract The quality of a Th1 response can be a prospective correlate of vaccine-mediated protection against certain intracellular pathogens. Using two distinct vaccine platforms, we evaluate the influence of interleukin (IL) 10 production on the magnitude, quality, and protective capacity of CD4(+) T cell responses in the mouse model of Leishmania major infection. Multiparameter flow cytometry was used to delineate the CD4(+) T cell production of interferon (IFN) gamma, IL-2, tumor necrosis factor (TNF), and IL-10 (or combinations thereof) after vaccination. Immunization with a high dose of adenovirus (ADV) expressing leishmanial proteins (MML-ADV) elicited a limited proportion of multifunctional IFN-gamma(+)IL-2(+)TNF(+) Th1 cells, a high frequency of IL-10-producing CD4(+) T cells, and did not protect against subsequent challenge. Surprisingly, in the absence of IL-10, there was no change in the magnitude, quality, or protective capacity of the Th1 response elicited by high-dose MML-ADV. In contrast, after immunization with MML protein and CpG (MML + CpG), IL-10 limited the production of IL-12 by DCs in vivo, thereby decreasing the generation of multifunctional Th1 cells. Consequently, three immunizations with MML + CpG were required for full protection. However, inhibiting IL-10 at the time of immunization enhanced the magnitude and quality of the Th1 response sufficiently to mediate protection after only a single immunization. Overall, we delineate distinct mechanisms by which vaccines elicit protective Th1 responses and underscore the importance of multifunctional CD4(+) T cells.
	PMID: 20530206 [PubMed - as supplied by publisher]

4.	Bioorg Med Chem Lett. 2010 Jun 15;20(12):3495-3498. Epub 2010 May 6. Antitrypanosomal alkaloids from Polyalthia suaveolens (Annonaceae): Their effects on three selected glycolytic enzymes of Trypanosoma brucei. Ngantchou I, Nyasse B, Denier C, Blonski C, Hannaert V, Schneider B. Laboratory of Medicinal Chemistry & Pharmacognosy, Department of Organic Chemistry, Faculty of Sciences, University of Yaoundé I, Box 812 Yaoundé, Cameroon; UMR 5068, LSPCMIB, Université Paul Sabatier, Bât II R1, 118 Route de Narbonne, 31062 Toulouse, Cedex 4, France. Abstract In continuation of our study on medicinal plants of Cameroon, stem barks of Polyalthia suaveolens were phytochemically studied. This investigation yielded a new indolosesquiterpene alkaloid, named polysin (1) and four hitherto known alkaloids (2-5). Polysin (1) appeared as a competitive reversible inhibitor (K(i)=10muM) of phosphofructo kinase (PFK) of Trypanosoma brucei with respect to fructose-6-phosphate (K(i)/K(M)=0.05) and could be used in the design of new trypanocidal drugs. The other isolated compounds (2-5) also exhibited interesting inhibitory effects on selected glycolytic enzymes (PFK, glyceraldehyde-3-phosphate dehydrogenase and aldolase). Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.
	PMID: 20529682 [PubMed - as supplied by publisher]

5.	J Med Chem. 2010 Jun 9. [Epub ahead of print] Computer-Aided Identification of Trypanosoma brucei Uridine Diphosphate Galactose 4'-Epimerase Inhibitors: Toward the Development of Novel Therapies for African Sleeping Sickness. Durrant JD, Urbaniak MD, Ferguson MA, McCammon JA. Biomedical Sciences Program, University of California San Diego, 9500 Gilman Drive, Mail Code 0365, La Jolla, California 92093-0365. Abstract Trypanosoma brucei, the causative agent of human African trypanosomiasis, affects tens of thousands of sub-Saharan Africans. As current therapeutics are inadequate due to toxic side effects, drug resistance, and limited effectiveness, novel therapies are urgently needed. UDP-galactose 4'-epimerase (TbGalE), an enzyme of the Leloir pathway of galactose metabolism, is one promising T. brucei drug target. We here use the relaxed complex scheme, an advanced computer-docking methodology that accounts for full protein flexibility, to identify inhibitors of TbGalE. An initial hit rate of 62% was obtained at 100 muM, ultimately leading to the identification of 14 low-micromolar inhibitors. Thirteen of these inhibitors belong to a distinct series with a conserved binding motif that may prove useful in future drug design and optimization.
	PMID: 20527952 [PubMed - as supplied by publisher]

6.	J Pak Med Assoc. 2010 Jun;60(6):489-91. Use of miltefosine in the treatment of visceral leishmaniasis in children at a tertiary care hospital of Karachi. Humayun KN, Saleem T, Khalid U, Jehan F, Soofi S. Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan. Abstract Existing standard treatment options for visceral leishmaniasis are less than optimal. We report here the use of oral miltefosine in the treatment of two paediatric cases of visceral leishmaniasis at a tertiary care hospital in Karachi, Pakistan. One patient came from Balochistan while the second patient was from Northern Pakistan. Both presented with a prolonged history of fever, massive hepatosplenomegaly, anaemia and thrombocytopenia. Visceral leishmaniasis was diagnosed with bone marrow studies. Amphotericin B was first started in the first patient; however severe hypokalaemia and allergic reaction occurred. Oral miltefosine was then administered. The child showed clinical improvement with regards to signs of leishmania infection but succumbed to a nosocomial infection during the hospital stay. In the second patient, miltefosine was started in the first instance. He showed remarkable clinical improvement. At 2 months follow-up, the child showed adequate weight gain along with successful resolution of hepatosplenomegaly and fever. Miltefosine has the potential to be considered a first line therapy for visceral leishmaniasis in developing countries; however larger studies are warranted to validate the trends observed in this small case series.
	PMID: 20527651 [PubMed - in process]

7.	J Pak Med Assoc. 2010 Jun;60(6):464-9. Sero-epidemiological study of visceral leishmaniasis in Basrah, Southern Iraq. Gani ZH, Hassan MK, Jassim AM. Department of Microbiology, Basrah Medical College, Iraq. Abstract OBJECTIVES: To study selected epidemiological aspects of visceral leishmaniasis, assess direct agglutination test (DAT) as a diagnostic method and the sero-epidemiological prevalence of the disease among apparently healthy children in Basrah, Iraq. METHODS: This prospective study included 146 children suspected of visceral leishmaniasis who were admitted to Basrah Maternity and Children Hospital and Basrah General Hospital from November 2004 till November 2005 and 37 serum samples that were collected from patients with different diseases considered in the differential diagnosis of visceral leishmaniasis. In addition, 1000 apparently healthy children were randomly selected for the sero-epidemiological survey. Direct agglutination test was done for all of them. RESULTS: Out of 146 suspected visceral leishmaniasis cases, 124 (84.9%) were proved by the examination of bone marrow aspirate, 132 (91.1%) were positive by direct agglutination test (DAT) and only 3 (2%) were positive by immunochromatographic strip test. The sensitivity and specificity of DAT were (100%), with a cut-off point of 1:800. In the in-patient group children less than 2 years of age were mainly affected. The highest frequency of disease was reported in July, 24 cases (18.8%). Sand flies were recorded in the environment of all sero-positive cases (100%) in each group, stray dogs and wild canines were present in (75.7% and 15.5%) in in-patients group compared to (69% and 22.5%) in sero-epidemiological group, respectively. Low maternal education was present in a significantly higher frequency among sero-positive cases. CONCLUSIONS: Direct agglutination test can be used as a screening tool for visceral leishmaniasis on a wide range in endemic areas, with a high sensitivity and specificity.
	PMID: 20527645 [PubMed - in process]