What's new for 'Trypanosomatids' in PubMed

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Sent on Saturday, 2010 Dec 18
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 - 5 of 5

1.	ChemMedChem. 2010 Dec 16. [Epub ahead of print] Improved Inhibitors of Trypanothione Reductase by Combination of Motifs: Synthesis, Inhibitory Potency, Binding Mode, and Antiprotozoal Activities. Eberle C, Lauber BS, Fankhauser D, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F. Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zürich (Switzerland), Fax: (+41) 44-632-1109. Abstract Trypanothione reductase (TR) is an essential enzyme in the trypanothione-based redox metabolism of trypanosomatid parasites. This system is absent in humans and, therefore, offers a promising target for the development of selective new drugs against African sleeping sickness and Chagas' disease. Over the past two decades, a variety of nonpeptidic small-molecule ligands of the parasitic enzyme were discovered. A current goal is to decipher the binding mode of these known inhibitors in order to optimize their structures. We analyzed the binding mode of recently reported 1-(1-(benzo[b]thiophen-2-yl)cyclohexyl)piperidine (BTCP) analogues using computer modeling methods. This led us to conclude that the analogues occupy a different region of the active site than the diaryl sulfide-based class of inhibitors. A combination of the two motifs significantly increased affinity for the enzyme compared to the respective parent compounds. The newly synthesized conjugates exhibit K(ic) values for TR as low as 0.51±0.1 μM and high selectivity for the parasitic enzyme over the related human glutathione reductase (hGR), as was predicted by our molecular modeling studies. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense, often in combination with low cytotoxicity against mammalian cells. Interestingly, even stronger activities were found against Plasmodium falciparum.
	PMID: 21165935 [PubMed - as supplied by publisher]
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2.	Mol Cell Biochem. 2010 Dec 17. [Epub ahead of print] Leishmania-induced repression of selected non-coding RNA genes containing B-box element at their promoters in alternatively polarized M2 macrophages. Farrow AL, Rana T, Mittal MK, Misra S, Chaudhuri G. Department of Microbiology and Immunology, Meharry Medical College, 1005 D. B. Todd Jr. Blvd, Nashville, TN, 37208, USA. Abstract Leishmania is a group of parasitic protozoa that infect blood and tissue phagocytes including macrophages. We hypothesize that Leishmania is capable of establishing infection inside the macrophages because (a) they infect a subpopulation of macrophages; and (b) they "renovate" the macrophages before the establishment of infection. We found that only alternatively activated polarized M2 macrophages support Leishmania growth. Exposure of M2 macrophages to Leishmania promastigotes represses several selected RNA polymerase III (PolIII)-transcribed non-coding RNA (ncRNA) genes including those of 7SL RNA, vault RNA, and B2 RNA which have B-box element at their promoters. The B-box-binding transcription factor TFIIIC110 is down-regulated in Leishmania-exposed macrophages. Both the surface protease gp63 and the surface glycolipid LPG are required for the down-regulation of the ncRNAs in the M2 macrophages. We conclude that Leishmania surface gp63 collaborates with LPG to down-regulate TFIIIC110 in M2 macrophages to repress B-box containing ncRNA gene promoters.
	PMID: 21165676 [PubMed - as supplied by publisher]
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3.	J Am Anim Hosp Assoc. 2010 Dec 16. [Epub ahead of print] First Report of the Use of Meglumine Antimoniate for Treatment of Canine Leishmaniasis in a Pregnant Dog. Spada E, Proverbio D, Groppetti D, Perego R, Grieco V, Ferro E. Department of Veterinary Clinical Science, Faculty of Veterinary Medicine, University of Milan, Italy. Abstract Canine leishmaniasis during pregnancy is rarely reported, even in countries where the infection in dogs is endemic. The authors report a case of a 4 yr old bitch with leishmaniasis treated with meglumine antimoniate during pregnancy. The pregnancy and delivery were normal and the bitch presented improvement of the infection during treatment. Three puppies died within 2 days of birth and tested negative via real-time PCR for L. infantum. The two surviving puppies were followed clinically, serologically, and by real-time PCR until 1 yr of age with no evidence of congenital leishmaniasis. L. infantum DNA was detected with real-time PCR analysis of uterine tissue from the bitch at the time of ovariohysterectomy. PCR analysis was performed after an ovariohysterectomy of the bitch that was performed two months after parturition. Meglumine antimoniate use in the pregnant bitch may have prevented vertical transmission of leishmaniasis.
	PMID: 21164165 [PubMed - as supplied by publisher]
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4.	Vet Parasitol. 2010 Nov 19. [Epub ahead of print] Cytokine and transcription factor profiles in the skin of dogs naturally infected by Leishmania (Leishmania) chagasi presenting distinct cutaneous parasite density and clinical status. Menezes-Souza D, Corrêa-Oliveira R, Guerra-Sá R, Giunchetti RC, Teixeira-Carvalho A, Martins-Filho OA, Oliveira GC, Reis AB. Laboratório de Imunopatologia, Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, 35400-000, Ouro Preto, Minas Gerais, Brazil; Laboratório de Imunologia Celular e Molecular, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, 30190-002, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Bioquímica e Biologia Molecular, Núcleo de Pesquisas em Ciências Biológicas, Universidade Federal de Ouro Preto, 35400-000, Ouro Preto, Minas Gerais, Brazil. Abstract The immune response in the skin of dogs infected with Leishmania chagasi and its association with distinct levels of tissue parasitism and clinical progression of canine visceral leishmaniasis (CVL) are poorly understood and limited studies are available. A detailed analysis of the profiles of cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-12, IL-13, TGF-β1 and TNF-α) and transcription factors (T-bet, GATA-3 and FOXP3) in the skin of 35 naturally infected dogs was carried out using real-time PCR alongside determinations of skin parasite density and the clinical status of CVL. A mixed cytokine profile with high levels of expression of IFN-γ, TNF-α and IL-13 was determined in asymptomatic dogs. Additionally, the levels of transcription factors GATA-3 and FOXP3 were correlated with the asymptomatic disease. A mixed cytokine profile was also observed during active CVL. Moreover, high levels of IL-10 and TGF-β1, concomitant with the low expression of IL-12, may represent a key condition that allows persistence of parasite replication in the skin. The results obtained indicate that in asymptomatic disease or lower levels of skin parasite density, a mixed inflammatory, regulatory immune response profile may be of major relevance for both the maintenance of the clinical status of the dogs as well as for parasite persistence and replication at low levels. Copyright © 2010 Elsevier B.V. All rights reserved.
	PMID: 21163578 [PubMed - as supplied by publisher]
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5.	Int J Parasitol. 2010 Dec 13. [Epub ahead of print] Glycosomal ABC transporters of Trypan osoma brucei: Characterization of their expression, topology and substrate specificity. Igoillo-Esteve M, Mazet M, Deumer G, Wallemacq P, Michels PA. Research Unit for Tropical Diseases, de Duve Institute and Laboratory of Biochemistry, Université catholique de Louvain, TROP 74.39, Avenue Hippocrate 74, B-1200 Brussels, Belgium. Abstract Metabolism in trypanosomatids is compartmentalized with major pathways, notably glycolysis, present in peroxisome-like organelles called glycosomes. To date, little information is available about the transport of metabolites through the glycosomal membrane. Previously, three ATP-binding cassette (ABC) transporters, called GAT1-3 for Glycosomal ABC Transporters 1 to 3, have been identified in the glycosomal membrane of Trypanosoma brucei. Here we report that GAT1 and GAT3 are expressed both in bloodstream and procyclic form trypanosomes, whereas GAT2 is mainly or exclusively expressed in bloodstream-form cells. Protease protection experiments showed that the nucleotide-binding domain of GAT1 and GAT3 is exposed to the cytosol, indicating that these transporters mediate the ATP-dependent uptake of solutes from the cytosol into the glycosomal lumen. Depletion of GAT1 and GAT3 by RNA interference in procyclic cells grown in glucose-containing medium did not affect growth. Surprisingly, GAT1 depletion enhanced the expression of the very different GAT3 protein. Expression knockdown of GAT1, but not GAT3, in procyclic cells cultured in glucose-free medium was lethal. Depletion of GAT1 in glucose-grown procyclic cells caused a modification of the total cellular fatty-acid composition. No or only minor changes were observed in the levels of most fatty acids, including oleate (C18:1), nevertheless the linoleate (C18:2) abundance was significantly increased upon GAT1 silencing. Furthermore, glycosomes purified from procyclic wild-type cells incorporate oleoyl-CoA in a concentration- and ATP-dependent manner, while this incorporation was severely reduced in glycosomes from cells in which GAT1 levels had been decreased. Together, these results strongly suggest that GAT1 serves to transport primarily oleoyl-CoA, but possibly also other fatty acids, from the cytosol into the glycosomal lumen and that its depletion results in a cellular linoleate accumulation, probably due to the presence of an active oleate desaturase. The role of intraglycosomal oleoyl-CoA and its essentiality when the trypanosomes are grown in the absence of glucose, are discussed. Copyright © 2010. Published by Elsevier Ltd.
	PMID: 21163262 [PubMed - as supplied by publisher]
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