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 18

1.	Eur J Immunol. 2011 Feb 14. doi: 10.1002/eji.201040981. [Epub ahead of print] Leishmania donovani glycosphingolipid facilitates antigen presentation by inducing relocation of CD1d into lipid rafts in infected macrophages. Karmakar S, Paul J, De T. Division of Infectious Disease and Immunology, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, India. Abstract NKT cells respond to presentation of specific glycolipids with release of both Th1- and Th2-type cytokines. Leishmania donovani (LD)-infected splenic macrophages (sMϕ(I)) and bone marrow-derived dendritic cells (BMDC(I)) failed to activate NKT cells in response to α-galactosyl ceramide (α-GalCer). The defective antigen presentation could be corrected by treating the cells with the immunostimulating glycosphingophospholipid (GSPL) of LD parasites. In vitro pulsing of BMDC(I) or sMϕ(I) with GSPL, caused the activation of the Vα14(+) CD1d1-specific NKT cell hybridoma DN32.D3. Localization of MHC II and CD1d molecules to membrane lipid rafts has been suggested to play an important role in antigen presentation. Confocal analysis clearly demonstrated that LD infection changed the pattern of CD1d distribution to the non-lipid raft regions and this change could be reversed by GSPL treatment. Isoelectric focusing gel shift assay indicated that GSPL binds to CD1d. GSPL-treated but not untreated BMDC(I) formed immune synapses with NKT cells and this was associated with calcium mobilization. In conclusion, GSPL treatment was associated with modification of BMDC(I)/sMϕ(I) lipid raft structure, which is a site for immune regulation. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
	PMID: 21425159 [PubMed - as supplied by publisher]

2.	PLoS One. 2011 Mar 10;6(3):e17376. Therapy with Sodium Stibogluconate in Stearylamine-Bearing Liposomes Confers Cure against SSG-Resistant Leishmania donovani in BALB/c Mice. Roychoudhury J, Sinha R, Ali N. Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Jadavpur, Kolkata, India. Abstract BACKGROUND: Resistance of Leishmania donovani to pentavalent antimonials, the first-line treatment of visceral leishmaniasis (VL), has become a critical issue worldwide. Second-line and new drugs are also not devoid of limitations. Suitable drug-delivery systems can improve the mode of administration and action of the existing antimonials, thus increasing their clinical life. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the efficacy of sodium stibogluconate (SSG) in phosphatidylcholine (PC)-stearylamine-bearing liposomes (PC-SA-SSG), PC-cholesterol liposomes (PC-Chol-SSG) and free amphotericin B (AmB) against SSG-resistant L. donovani strains in 8-wk infected BALB/c mice. Animals were sacrificed and parasites in liver, spleen and bone marrow were estimated 4-wk post-treatment by microscopic examination of stamp smears and limiting dilution assay. A set of PC-SA-SSG and AmB treated mice were further studied for protection against reinfection. Serum antibodies and cytokine profiles of ex-vivo cultured splenocytes were determined by ELISA. Uptake of free and liposomal SSG in intracellular amastigotes was determined by atomic absorption spectroscopy. Rhodamine 123 and 5-carboxyfluorescein, known substrates of Pgp and MRP transporter proteins, respectively, were used in free and liposomal forms for efflux studies to estimate intracellular drug retention. Unlike free and PC-Chol-SSG, PC-SA-SSG was effective in curing mice infected with two differentially originated SSG-unresponsive parasite strains at significantly higher levels than AmB. Successful therapy correlated with complete suppression of disease-promoting IL-10 and TGF-β, upregulation of Th1 cytokines and expression of macrophage microbicidal NO. Cure due to elevated accumulation of SSG in intracellular parasites, irrespective of SSG-resistance, occurs as a result of increased drug retention and improved therapy when administered as PC-SA-SSG versus free SSG. CONCLUSIONS/SIGNIFICANCE: The design of this single-dose combination therapy with PC-SA-SSG for VL, having reduced toxicity and long-term efficacy, irrespective of SSG-sensitivity may prove promising, not only to overcome SSG-resistance in Leishmania, but also for drugs with similar resistance-related problems in other diseases.
	PMID: 21423750 [PubMed - in process]

3.	Immunol Cell Biol. 2011 Mar 22. [Epub ahead of print] TGF-β-regulated tyrosine phosphatases induce lymphocyte apoptosis in Leishmania donovani-infected hamsters. Banerjee R, Kumar S, Sen A, Mookerjee A, Roy S, Pal S, Das P.
	PMID: 21423262 [PubMed - as supplied by publisher]

4.	Bioorg Med Chem. 2011 Mar 1. [Epub ahead of print] Exploration of larger central ring linkers in furamidine analogues: Synthesis and evaluation of their DNA binding, antiparasitic and fluorescence properties. Farahat AA, Paliakov E, Kumar A, Barghash AE, Goda FE, Eisa HM, Wenzler T, Brun R, Liu Y, Wilson WD, Boykin DW. Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Abstract The effects of replacing the central furan ring of furamidine with indole and benzimidazole on their DNA binding affinity, antiparasitic activity and fluorescence are reported. The bis-cyanophenylindoles required to make the corresponding amidines were prepared by sequential Stille and/or Suzuki coupling reactions. The bis-cyanophenylbenzimidazoles were obtained by coupling 4-cyanobenzaldehydes with the appropriate cyano substituted phenylenediamine. The bis-nitriles were converted to the diamidines by reaction with LiN[Si(CH(3))(3)](2) or by Pinner methodology. Specifically, we have prepared new series of 2,6- and 2,5-diaryl indoles (6a,b, 12 and 17a-d) and the related benzimidazoles (24, 30 and 35). The new compounds bind in the DNA minor groove in DNA AT base pair sequences and eight of the ten new analogues exhibit ΔT(m) values comparable to or higher than that of furamidine. Six of ten of the new compounds exhibit lower IC(50) values against Trypanosoma brucei rhodesiense (T. b. r.) and eight of ten exhibit lower IC(50) values against Plasmodium falciparum (P. f.) than furamidine. Four of the ten show greater efficacy than furamidine in the rigorous T. b. r. STIB900 mouse model for African trypanosomiasis. Generally, the fluorescence properties of the new analogues are similar to that of DAPI. Copyright © 2011 Elsevier Ltd. All rights reserved.
	PMID: 21421317 [PubMed - as supplied by publisher]

5.	Eur J Med Chem. 2011 Mar 5. [Epub ahead of print] Lipid-like sulfoxides and amine oxides as inhibitors of mast cell activation. Batista J, Schlechtingen G, Friedrichson T, Braxmeier T, Bajorath J. Department of Life Science Informatics, B-IT, LIMES, Program Unit Medicinal Chemistry and Chemical Biology, Rheinische Friedrich-Wilhelms-Universität Bonn, Dahlmannstr. 2, D-53113 Bonn, Germany; JADO Technologies GmbH, Tatzberg 47-51, D-01307 Dresden, Germany. Abstract The drug miltefosine is a prototypic lipid-like compound thought to modulate membrane environments and thereby indirectly prevent receptor-mediated signaling events. In addition to its primary therapeutic indications in cancer and leishmaniasis, miltefosine has also been shown to block immunoglobulin E receptor-dependent mast cell activation. Miltefosine and other alkylphospholipids that are active in mast cell degranulation assays contain a positively charged nitrogen and a phosphate group that are important for activity. In addition to alkylphospholipids, ceramides are also known to act on membrane environments and inhibit mast cell activation. We have systematically searched a very large compound collection for other lipid-like inhibitors of mast cell activation. Analogs of an initially identified screening hit were synthesized and preliminary SAR information was collected, leading to the identification of sulfoxide and amine oxide containing lipid-like compounds as new inhibitors of mast cell activation. Sulfoxide and amine oxide derivatives were found to be only slightly less active than miltefosine. Copyright © 2011 Elsevier Masson SAS. All rights reserved.
	PMID: 21421276 [PubMed - as supplied by publisher]

6.	Parasitol Int. 2011 Mar 18. [Epub ahead of print] In vitro antileishmanial activity and cytotoxicity of essential oil from Lippia sidoides Cham. de Medeiros MD , da Silva AC, Citó AM, Borges AR, de Lima SG, Lopes JA, Figueiredo RC. Programa de Pós-graduação em Biotecnologia -RENORBIO, Universidade Federal do Piaui, Brazil; Departamento de Química, Universidade Federal do Piaui, Campus Universitário Ministro Petrônio Portela - Ininga, Teresina, PI, Brazil, 64049-550. Abstract Leishmaniasis is a widespread tropical infection caused by different species of Leishmania protozoa. There is no vaccine available for Leishmania infections and conventional treatments are very toxic to the patients. Therefore, antileishmanial drugs are urgently needed. In this study we have analyzed the effects of essential oils from Lippia sidoides (LSEO) and its major compound thymol on the growth, viability and ultrastructure of Leishmania amazonensis. The essential oil and thymol showed significant activity against promastigote forms of Leishmania amazonensis, with IC(50/)48h of 44.38 and 19.47μg/mL respectively. However, thymol showed toxicity against peritoneal macrophages and low selectivity against the promastigotes when compared with the crude LSEO. On the other hand, no cytotoxic effect was observed in macrophages treated with the crude essential oil. Incubation of L. amazonensis-infected macrophages with LSEO showed a marked reduction in amastigote survival within the macrophages. Significant morphological alterations as accumulation of large lipid droplets in the cytoplasm, disrupted membrane and wrinkled cells were usually seen in treated parasites. The LSEO´s activity against both promastigote and the amstigote forms of L. amazonensis, together with its low toxicity to mammalian cells, point to LSEO as a promising agent for the treatment of cutaneous leishmaniasis. Copyright © 2010. Published by Elsevier Ireland Ltd.
	PMID: 21421075 [PubMed - as supplied by publisher]

7.	J Mol Biol. 2011 Mar 18. [Epub ahead of print] The double-length tyrosyl-tRNA synthetase from the eukaryote Leishmania major forms an intrinsically asymmetric pseudo-dimer. Larson ET, Kim JE, Castaneda LJ, Napuli AJ, Zhang Z, Fan E, Zucker FH, Verlinde CL, Buckner FS, Van Voorhis WC, Hol WG, Merritt EA. Medical Structural Genomics of Pathogenic Protozoa(1); (Department of Biochemistry, University of Washington, Seattle, WA 98195 USA). Abstract The single tyrosyl tRNA-synthetase (TyrRS) gene in trypanosomatid genomes codes for a protein that is twice the length of TyrRS from virtually all other organisms. Each half of the double-length TyrRS contains a catalytic domain and an anticodon-binding domain, however the two halves retain only 17% sequence identity to each other. The structural and functional consequences of this duplication and divergence are un- clear. TyrRS normally forms a homodimer in which the active site of one monomer pairs with the anticodon- binding domain from the other. However, crystal structures of Leishmania major TyrRS show that instead the two halves of a single molecule form a pseudo-dimer resembling the canonical TyrRS dimer. Curiously, the C-terminal copy of the catalytic domain has lost the catalytically important HIGH and KMSKS motifs characteristic of Class I aminoacyl-tRNA synthetases. Thus the pseudo-dimer contains only one functional active site, contributed by the N-terminal half, and only one functional anticodon recognition site, con- tributed by the C-terminal half. Despite biochemical evidence for negative cooperativity between the two active sites of the usual TyrRS homodimer, previous structures have captured a crystallographically-imposed symmetric state. As the L. major TyrRS pseudo-dimer is inherently asymmetric, conformational variations observed near the active site may be relevant to understanding how the state of a single active site is commu- nicated across the dimer interface. Furthermore, substantial differences between trypanosomal TyrRS and human homologs are promising for the design of inhibitors that selectively target the parasite enzyme. Copyright © 2011. Published by Elsevier Ltd.
	PMID: 21420975 [PubMed - as supplied by publisher]

8.	Acta Trop. 2011 Mar 18. [Epub ahead of print] Systematic Review of the Adverse Effects of Cutaneous Leishmaniasis Treatment in the New World. Oliveira LF, Schubach AO, Martins MM, Passos SL, Oliveira RV, Marzochi MC, Andrade CA. Instituto de Pesquisa Clínica Evandro Chagas (IPEC)/Fiocruz. Abstract Pentavalent antimonials are first-line drugs for the treatment of the cutaneous form of American tegumentary leishmaniasis. Second-line drugs include amphotericin B and pentamidine. Although these drugs have been used for decades, there are no systematic reviews about their safety. The objective of this review was to identify and classify the main adverse effects associated with these drugs and to estimate the frequency of these effects, whenever possible. Intervention studies, case series and case reports containing information regarding clinical, laboratory or electrocardiographic adverse effects of drugs used for the treatment of cutaneous leishmaniasis were systematically retrieved from 10 databases searched between August 13, 2008 and March 31, 2009. The 65 studies included in this review had treated a total of 4,359 patients from 12 countries infected with eight different Leishmania species. Despite the small number of drugs used in these studies, a wide variability in the therapeutic regimens was observed. As a consequence, the adverse effects of pentavalent antimonials and pentamidine needed to be classified jointly according to system, irrespective of formulation, daily dose, duration of treatment, and route of administration. The frequencies of adverse effects were calculated based on the data of 32 articles involving 1,866 patients. The most frequently reported clinical adverse effects of pentavalent antimonials and pentamidine were musculoskeletal pain, gastrointestinal disturbances, and mild to moderate headache. Electrocardiographic QTc interval prolongation and a mild to moderate increase in liver and pancreatic enzymes were additional adverse effects of pentavalent antimonials. Patients treated with liposomal amphotericin B had mild dyspnea and erythema. The adverse effects associated with miltefosine were vomiting, nausea, kinetosis, headache, diarrhea, and a mild to moderate increase in aminotransferases and creatinine. Although closer surveillance is needed for the treatment of cutaneous leishmaniasis, antileishmanial drugs are basically safe and severe side effects requiring the discontinuation of treatment are relatively uncommon. Copyright © 2011. Published by Elsevier B.V.
	PMID: 21420925 [PubMed - as supplied by publisher]

9.	Mol Biochem Parasitol. 2011 Mar 17. [Epub ahead of print] A Gateway(®) compatible vector for gene silencing in bloodstream form Trypanosoma brucei. Kalidas S, Li Q, Phillips MA. Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Rd, Dallas, Texas 75390-9041. Abstract RNA interference is the most rapid method for generation of conditional knockdown mutants in Trypanosoma brucei. The dual T7 promoter (pZJM) and the stem-loop vectors have been widely used to generate stable inducible RNAi cell lines with the latter providing tighter regulatory control. However, the steps for cloning stem-loop constructs are cumbersome requiring either multiple cloning steps or multi-fragment ligation reactions. We report the development of a vector (pTrypRNAiGate) derived from pLEW100 that utilizes the Gateway(®) recombination system to facilitate easy production of hairpin RNA constructs. This approach allows the final stem-loop RNAi construct to be generated from a single cloning step of the PCR-derived gene fragment followed by an in vitro recombination reaction. The new vector facilitates high-throughput applications for gene silencing and provides a tool for functional genomics in T. brucei. Copyright © 2011. Published by Elsevier B.V.
	PMID: 21420443 [PubMed - as supplied by publisher]

10.	Acta Trop. 2011 Mar 17. [Epub ahead of print] Influence of trypanocidal therapy on the haematology of vervet monkeys experimentally infected with Trypanosoma brucei rhodesiense. Ngotho M, Kagira JM, Kariuki C, Maina N, Thuita JK, Mwangangi DM, Farah IO, Hau J. Institute of Primate Research, P. O. Box 24481 - 00502, Nairobi, Kenya; KARI - Trypanosomiasis Research Centre (KARI-TRC), P. O. Box 362, Kikuyu, Kenya; Department of Experimental Medicine, University of Copenhagen & University Hospital, 3B Blegdamsvej, DK-2200 Copenhagen N, Denmark. Abstract The aim of this study was to characterise the sequential haematological changes in vervet monkeys infected with Trypanosoma brucei rhodesiense and subsequently treated with sub-curative diminazene aceturate (DA) and curative melarsoprol (MelB) trypanocidal drugs. Fourteen vervet monkeys, on a serial timed-kill pathogenesis study, were infected intravenously with 10(4) trypanosomes of a stabilate T. b. rhodesiense KETRI 2537. They were treated with DA at 28days post infection (dpi) and with MelB following relapse of infection at 140 dpi. Blood samples were obtained from the monkeys weekly, and haematology conducted using a haematological analyser. All the monkeys developed a disease associated with macrocytic hypochromic anaemia characterised by a reduction in erythrocytes (RBC), haemoglobin (HB), haematocrit (HCT), mean cell volume (MCV), platelet count (PLT), and an increase in the red cell distribution width (RDW) and mean platelet volume (MPV). The clinical disease was characteristic of human African trypanosomiasis (HAT) with a pre-patent period of 3days. Treatment with DA cleared trypanosomes from both the blood and cerebrospinal fluid (CSF). The parasites relapsed first in the CSF and later in the blood. This treatment normalised the RBC, HCT, HB, PLT, MCV, and MPV achieving the pre-infection values within two weeks while RDW took up to 6weeks to attain pre-infection levels after treatment. Most of the parameters were later characterised by fluctuations, and declined at one to two weeks before relapse of trypanosomes in the haemolymphatic circulation. Following MelB treatment at 140 dpi, most values recovered within two weeks and stabilised at pre-infection levels, during the 223days post treatment monitoring period. It is concluded that DA and MelB treatments cause similar normalising changes in the haematological profiles of monkeys infected with T. b. rhodesiense, indicating the efficacy of the drugs. The infection related changes in haematology parameters, further characterise the vervet monkey as an optimal induced animal model of HAT. Serial monitoring of these parameters can be used as an adjunct in the diagnosis and prognosis of the disease outcome in the vervet monkey model. Copyright © 2011 Elsevier B.V. All rights reserved.
	PMID: 21420376 [PubMed - as supplied by publisher]