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Sent on Saturday, 2012 March 24Search: kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | J Leukoc Biol. 2012 Mar 21. [Epub ahead of print]Secreted virulence factors and immune evasion in visceral leishmaniasis.Lambertz U, Silverman JM, Nandan D, McMaster WR, Clos J, Foster LJ, Reiner NE.Source*Departments of Medicine (Division of Infectious Diseases and the Experimental Medicine Program). AbstractEvasion or subversion of host immune responses is a well-established paradigm in infection with visceralizing leishmania. In this review, we summarize current findings supporting a model in which leishmania target host regulatory molecules and pathways, such as the PTP SHP-1 and the PI3K/Akt signaling cascade, to prevent effective macrophage activation. Furthermore, we describe how virulence factors, secreted by leishmania, interfere with macrophage intracellular signaling. Finally, we discuss mechanisms of secretion and provide evidence that leishmania use a remarkably adept, exosome-based secretion mechanism to export and deliver effector molecules to host cells. In addition to representing a novel mechanism for trafficking of virulence factors across membranes, recent findings indicate that leishmania exosomes may have potential as vaccine candidates. |
| PMID: 22442494 [PubMed - as supplied by publisher] | |
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| 2. | J Biol Chem. 2012 Mar 21. [Epub ahead of print]Trypanosoma brucei thymidine kinase is a tandem protein consisting of two homologous parts, which together enable efficient substrate binding.Ranjbarian F, Vodnala M, Vodnala SM, Rofougaran R, Thelander L, Hofer A.SourceUmea University, Sweden; AbstractTrypanosoma brucei causes African sleeping sickness, a disease for which existing chemotherapies are limited by their toxicity or lack of efficacy. We have found that four parasites, including T. brucei, contain genes where two or four thymidine kinase (TK) sequences are fused into a single open reading frame. The T. brucei full-length enzyme as well as its two constituent parts, domain 1 and domain 2, were separately expressed and characterized. Of potential interest for nucleoside analog development, T. brucei TK was less discriminative against purines than human TK1 with the following order of catalytic efficiencies: thymidine > deoxyuridine >> deoxyinosine > deoxyguanosine. Proteins from the TK1 family are generally dimers or tetramers and the quaternary structure is linked to substrate affinity. T. brucei TK was primarily monomeric but can be considered a two-domain pseudodimer. Independent kinetic analysis of the two domains showed that only domain 2 was active. It had a similar turnover number (kcat) as the full-length enzyme but could not self-dimerize efficiently and had a five-fold reduced thymidine/deoxyuridine affinity. Domain 1, which lacks three conserved active site residues, can therefore be considered a covalently attached structural partner that enhances substrate binding to domain 2. A consequence of the non-catalytic role of domain 1 is that its active site residues are released from evolutionary pressure, which can be advantageous for developing new catalytic functions. In addition, nearly identical 89-bp sequences present in both domains suggest that the exchange of genetic material between them can further promote evolution. |
| PMID: 22442154 [PubMed - as supplied by publisher] | |
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| 3. | Biomed Pharmacother. 2012 Jan 2. [Epub ahead of print]In vitro leishmanicidal activity of N-dodecyl-1,2-ethanediamine.Silva AL, Adade CM, Shoyama FM, Neto CP, Padrón TS, de Almeida MV, Rezende CA, Silva CV, Souza MA.SourceInstituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Av. Pará, 1720, Campus Umuarama, 6T07, 38400-902 Uberlândia, MG, Brazil. AbstractPolyamine biosynthesis and inhibition in parasites have been an attractive chemotherapeutic approach in the design of novel antiparasitic drugs. We study in this work the effect of N-dodecyl-1,2-ethylenediamine (NDDE) on the morphology and replication of Leishmania using macrophages cultured from the peritoneal exudate of mice infected in vitro with three species of Leishmania: Leishmania (Leishmania) amazonensis, Leishmania (Viannia) brasiliensis and Leishmania (Leishmania) chagasi. The results showed that NDDE inhibited Leishmania amastigotes multiplication into inflammatory peritoneal cells in concentrations which were not toxic to mammalian cells (0.5-1μg/mL). An intracellular disorganization of the promastigote forms was observed by transmission electron microscopy after 3 to 24h of treatment with 1μg/mL NDDE, suggesting that this compound affects the viability of the parasite by an autophagy pathway. Copyright © 2011 Elsevier Masson SAS. All rights reserved. |
| PMID: 22440898 [PubMed - as supplied by publisher] | |
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| 4. | Immunobiology. 2012 Feb 16. [Epub ahead of print]115kDa serine protease confers sustained protection to visceral leishmaniasis caused by Leishmania donovani via IFN-γ induced down-regulation of TNF-α mediated MMP-9 activity.Choudhury R, Das P, De T, Chakraborti T.SourceDepartment of Biochemistry and Biophysics, University of Kalyani, Kalyani 741235, West Bengal, India. AbstractVisceral leishmaniasis caused by the intracellular parasite Leishmania donovani is a major public health problem in the developing world. The emergence of increasing number of L. donovani strains resistance to antimonial drugs recommended worldwide requires the intervention of effective vaccine strategy for treatment of VL. In the present study L. donovani culture derived, soluble, secretory serine protease (pSP) has been shown to be vaccine target of VL. Protection from VL could be achieved by the use of safer vaccine which generally requires an adjuvant for induction of strong Th1 response. To assess the safety, immunogenicity and efficacy of pSP as vaccine candidate in mouse model we used IL-12 as adjuvant. BALB/c mice immunized with pSP+IL-12 were protected significantly from challenged infection even after four months by reducing the parasite load in liver and spleen and suppressed the development of the disease along with an increase in IgG2a antibody level in serum, enhanced delayed type hypersensitivity and strong T-cell proliferation. Groups receiving pSP+IL-12 had an augmented pSP antigen specific Th1 cytokines like IFN-γ and TNF-α response with concomitant decrease of Th2 cytokines IL-4 and IL-10 after vaccination. In this study the vaccine efficacy of pSP was further assessed for its prophylactic potential by enumerating matrix metalloprotease-9 (MMP-9) profile which has been implicated in various diseases. MMP-9 associated with different microbial infections is controlled by their natural inhibitors (TIMPS) and by some cytokines. In this study pSP was found to regulate excessive inflammation by modulating the balance between MMP-9 and TIMP-1 expression. This modulatory effect has also been demonstrated by IFN-γ mediated down regulation of TNF-α induced MMP-9 expression in activated murine macrophages. This is the first report where a secretory L. donovani serine protease (pSP) adjuvanted with IL-12 could also act as protective imunogen by modifying cytokine mediated MMP-9 expression in experimental VL. These findings elucidate the mechanisms of regulation of MMP-9 following infection of L. donovani in vaccinated animals and thus pave the way for developing new immunotherapeutic interventions for VL. Copyright © 2012 Elsevier GmbH. All rights reserved. |
| PMID: 22440312 [PubMed - as supplied by publisher] | |
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| 5. | J Ethnopharmacol. 2012 Mar 13. [Epub ahead of print]Antiparasitic activities of two sesquiterpenic lactones isolated from Acanthospermum hispidum D.C.Ganfon H, Bero J, Tchinda AT, Gbaguidi F, Gbenou J, Moudachirou M, Frédérich M, Quetin-Leclercq J.SourcePharmacognosy Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier B1.72.03, B-1200 Brussels, Belgium; Laboratoire de Pharmacognosie et Huiles Essentielles UFR pharmacie, Faculté des Sciences de la Santé, Université d'Abomey Calavi, 01 BP 188 Cotonou, Benin; Centre de Recherche en Pharmacopée et Medecine Traditionnelle/Centre Béninois de la Recherche Scientifique et Technique (CBRST) 03 BP 1665 Cotonou, Benin. AbstractETHNOPHARMACOLOGICAL RELEVANCE:Aerial parts of Acanthospermum hispidum D.C. are often used by traditional healers in Benin for various diseases and especially for malaria. AIM OF THE STUDY:To identify active compounds from extracts of Acanthospermum hispidum D.CV. leaves previously shown to possess antimalarial properties and analyse in vivo activity and toxicity of crude extracts. MATERIALS AND METHODS:Compounds were isolated from aerial part of Acanthospermum hispidum D.C. and structurally elucidated using extensive spectroscopic analysis. Antiplasmodial activity was evaluated in vitro against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) using the measurement of the plasmodial lactate dehydrogenase activity and in vivo against Plasmodium berghei berghei by the 4-day suppressive test. Selectivity of extract and purified compounds on Plasmodium parasites were evaluated by using MTT test on J774 macrophage like murine cells and WI38 human normal fibroblasts and also against two other parasites: Trypanosoma brucei brucei and Leishmania mexicana mexicana. Acute and sub-acute toxicities of a crude extract were evaluated on mice. RESULTS:Two known sesquiterpenic lactones were isolated: 1 (15-acetoxy-8β-[(2-methylbutyryloxy)]-14-oxo-4,5-cis-acanthospermolide) and 2 (9α-acetoxy-15-hydroxy-8β-(2-methylbutyryloxy)-14-oxo-4,5-trans-acanthospermolide). 1 and 2 showed in vitro antiplasmodial activity against the chloroquine-sensitive strain (3D7) with IC(50) of 2.9±0.5 and 2.23±0.09μM respectively. Only 2 showed a high selectivity index (SI: 18.4) on Plasmodium compared to cytotoxicity against human fibroblasts cell line (WI38). 1 and 2 also showed interesting antiparasitic activities in vitro against Trypanosoma brucei brucei (IC(50) of 2.45±0.49 and 6.36±1.42μM respectively) and Leishmania mexicana mexicana (IC(50) of 0.94±0.05 and 2.54±0.19μM respectively). Furthermore, crude acidic water extract and fractions containing one of the two isolated compounds displayed a weak in vivo antimalarial activity against Plasmodium berghei berghei with a long half-life causing a delayed effect. In vivo acute (2000mg/kg) and sub-acute (1000mg/kg) toxicity tests on the crude acidic water extract did not show toxicity. CONCLUSION:Crude acidic water extract, fractions and pure isolated compounds from Acanthospermum hispidum showed promising in vitro antiplasmodial activity. Despite our study did not show in vivo acute and subacute toxicities of the crude acidic water extract, its weak in vivo antimalarial activity and the in vitro cytotoxicity of pure compounds and enriched extracts containing 1 and 2 indicate that the aerial parts of Acanthospermum hispidum should be used with caution for malaria treatments. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. |
| PMID: 22440261 [PubMed - as supplied by publisher] | |
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