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Sent on Tuesday, 2011 May 31Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | Front Biosci. 2011 Jun 1;17:2069-85.Lights and shadows on gene organization and regulation of gene expression in Leishmania.Requena JM.SourceCentro de Biologia Molecular Severo Ochoa (CSIC-UAM), Universidad Autonoma de Madrid, Madrid, Spain. AbstractRegulation of gene expression is one of the most intriguing aspects of Leishmania biology. This review deals with current knowledge concerning gene organization and regulation of gene expression in this protozoan parasite, which cause serious illness and death in humans living in tropical and subtropical regions. Post-transcriptional regulation is especially important for Leishmania, and other trypanosomatids, due to the unusual features related to transcription and mRNA maturation. In these organisms, genes are organized into polycistronic transcription units, whereby many genes are cotranscribed by RNA polymerase II from not well characterized, upstream promoters. These organisms represent an extreme in which the expression of their genome is almost exclusively controlled post-transcriptionally. Because the regulatory needs of these parasites are considerable as they undergo complex developmental transitions, post-transcriptional mechanisms that involve RNA and protein regulatory processes are of paramount importance for these protozoa. This review summarizes recent results on the post-transcriptional mechanisms in Leishmania that regulate protein abundance through influencing RNA splicing, nuclear-cytoplasmic mRNA stability, translation, or post-translational events such as protein stability and modification. |
| 2. | Biochim Biophys Acta. 2011 May 19. [Epub ahead of print]The peptidases of Trypanosoma cruzi: Digestive enzymes, virulence factors, and mediators of autophagy and programmed cell death.Alvarez VE, Niemirowicz GT, Cazzulo JJ.AbstractTrypanosoma cruzi, the agent of the American Trypanosomiasis, Chagas disease, contains cysteine, serine, threonine, aspartyl and metallo peptidases. The most abundant among these enzymes is cruzipain, a cysteine proteinase expressed as a mixture of isoforms, some of them membrane-bound. The enzyme is an immunodominant antigen in human chronic Chagas disease and seems to be important in the host/parasite relationship. Inhibitors of cruzipain kill the parasite and cure infected mice, thus validating the enzyme as a very promising target for the development of new drugs against the disease. In addition, a 30kDa cathepsin B-like enzyme, two metacaspases and two autophagins have been described. Serine peptidases described in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca(2+)-signaling during mammalian cell invasion; a prolyl endopeptidase (Tc80), against which inhibitors are being developed, and a lysosomal serine carboxypeptidase. Metallopeptidases homologous to the gp63 of Leishmania spp. are present, as well as two metallocarboxypeptidases belonging to the M32 family, previously found only in prokaryotes. The proteasome has properties similar to those of other eukaryotes, and its inhibition by lactacystin blocks some differentiation steps in the life cycle of the parasite. This article is part of a Special Issue entitled: SI: Proteolysis 50 years after lysosome. Copyright © 2011. Published by Elsevier B.V. |
| 3. | Int J Infect Dis. 2011 May 26. [Epub ahead of print]Detection of Leishmania parasites in the blood of patients with isolated cutaneous leishmaniasis.Nakkash-Chmaisse H, Makki R, Nahhas G, Knio K, Nuwayri-Salti N.SourceDepartment of Physiology, Faculty of Medicine, Beirut Arab University, Beirut, Lebanon. AbstractBACKGROUND:The consequences of the spread of Leishmania parasites to the blood from lesions in patients with cutaneous leishmaniasis are numerous. To assess the magnitude of this invasion we conducted the present study on patients referred to the American University of Beirut Medical Center for cutaneous leishmaniasis. METHODS:Patients referred for the management of cutaneous leishmaniasis were included in the study. Skin and blood cultures for Leishmania were taken from these patients. RESULTS:One hundred sixty-two patients were proven to have cutaneous leishmaniasis by pathology; 52% were males and 44% females (gender information was missing for 4%). Patient age ranged from 5 months to 70 years. None of the patients had received treatment for Leishmania. We obtained parasite isolates from 85 patients (52.5%), proven by cultures from skin and blood/blood components. Interestingly, the parasite was isolated in the blood and blood components of 50 patients (30.9%). Isoenzyme analysis confirmed the fact that the organisms in blood and skin were the same; from the 28 isolates that were positive in both skin and blood, eight isolates were Leishmania major and two were Leishmania tropica. The remaining isolates, whether positive in both blood and skin or in either of these tissues, skin or blood and its products, were Leishmania infantum sensu lato. CONCLUSIONS:In the current study, the detection rate of parasites in the blood of patients with cutaneous leishmaniasis was high. This illustrates the invasive characteristic of the parasite that has escaped the skin. Testing should be considered in areas other than Lebanon, especially around the Mediterranean basin. Whether these findings support the administration of systemic treatment for cutaneous leishmaniasis or not needs to be confirmed in larger prospective studies. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved. |
| 4. | J Proteomics. 2011 May 19. [Epub ahead of print]Contribution of proteomics of Leishmania spp. to the understanding of differentiation, drug resistance mechanisms, vaccine and drug development.Paape D, Aebischer T.SourceCentre for Immunology and Infection, Department of Biology/Hull York Medical School, University of York, YO10 5DD, UK. AbstractLeishmania spp., protozoan parasites with a digenetic life cycle, cause a spectrum of diseases in humans. Recently several Leishmania spp. have been sequenced which significantly boosted the number and quality of proteomic studies conducted. Here a historic review will summarize work of the pre-genomic era and then focus on studies after genome information became available. Firstly works comparing the different life cycle stages, in order to identify stage specific proteins, will be discussed. Identifying post-translational modifications by proteomics especially phosphorylation events will be discussed. Further the contribution of proteomics to the understanding of the molecular mechanism of drug resistance and the investigation of immunogenic proteins for the identification of vaccine candidates will be summarized. Approaches of how potentially secreted proteins were identified are discussed. So far 30-35% of the total predicted proteome of Leishmania spp. have been identified. This comprises mainly the abundant proteins, therefore the last section will look into technological approaches on how this coverage may be increased and what the gel-free and gel-based proteomics have to offer will be compared. Copyright © 2011 Elsevier B.V. All rights reserved. |
| 5. | Free Radic Biol Med. 2011 May 14. [Epub ahead of print]Leishmania-macrophage interactions: Insights into the redox biology.Van Assche T, Deschacht M, da Luz RA, Maes L, Cos P.AbstractLeishmaniasis is a neglected tropical disease that affects about 350 million individuals worldwide. The protozoan parasite has a relatively simple life cycle with two principal stages: the flagellated mobile promastigote living in the gut of the sandfly vector and the intracellular amastigote within phagolysosomal vesicles of the vertebrate host macrophage. This review presents a state-of-the-art overview of the redox biology at the parasite-macrophage interface. Although Leishmania species are susceptible in vitro to exogenous superoxide radical, hydrogen peroxide, nitric oxide, and peroxynitrite, they manage to survive the endogenous oxidative burst during phagocytosis and the subsequent elevated nitric oxide production in the macrophage. The parasite adopts various defense mechanisms to cope with oxidative stress: the lipophosphoglycan membrane decreases superoxide radical production by inhibiting NADPH oxidase assembly and the parasite also protects itself by expressing antioxidant enzymes and proteins. Some of these enzymes could be considered potential drug targets because they are not expressed in mammals. In respect to antileishmanial therapy, the effects of current drugs on parasite-macrophage redox biology and its involvement in the development of drug resistance and treatment failure are presented. Copyright © 2011 Elsevier Inc. All rights reserved. |
| 6. | Biotechnol Adv. 2011 May 19. [Epub ahead of print]The trypanothione system and the opportunities it offers to create drugs for the neglected kinetoplast diseases.Flohé L.AbstractParasitic trypanosomatids (Kinetoplastida) are the causative agents of devastating and hard-to-treat diseases such as African sleeping sickness, Chagas disease and various forms of Leishmaniasis. Altogether they affect >30Million patients, account for half a million fatalities p.a. and cause substantial economical problems in the Third World due to human morbidity and life stock losses. The design of efficacious and safe drugs is expected from inhibition of metabolic pathways that are unique and essential to the parasite and absent in the host. In this respect, the trypanothione system first detected in the insect-pathogenic trypanosomatid Crithidia fasciculata qualified as an attractive drug target area. The existence of the system in pathogenic relatives was established by homology cloning and PCR. The vital importance of the system was verified in Trypanosoma brucei by dsRNA technology or knock-out in other trypanosomatids, respectively, and is explained by its pivotal role in the parasite's antioxidant defense and DNA synthesis. The key system component is the bis-glutathionyl derivative of spermidine, trypanothione. It is the proximal reductant of tryparedoxin which substitutes for thioredoxin-, glutaredoxin- and glutathione-dependent reactions. Heterologous expression, functional characterization and crystallization of recombinant system components finally enable structure-based rational inhibitor design. Copyright © 2011. Published by Elsevier Inc. |
| 7. | Exp Parasitol. 2011 May 19. [Epub ahead of print]Leishmania major: Activity of tamoxifen against experimental cutaneous leishmaniasis.Eissa MM, Amer EI, El Sawy SM.SourceDepartment of Medical Parasitology, Faculty of Medicine, Alexandria University, Egypt. AbstractLeishmaniasis is a family of diseases caused by protozoan parasites of the genus Leishmania. Various Leishmania species can cause human infection, producing a spectrum of clinical manifestations. The current treatments are unsatisfactory, and in absence of a vaccine, there is an urgent need for effective drugs to replace/supplement those currently in use. Recent studies have shown that the antineoplastic drug, tamoxifen, had direct leishmanicidal effect on several Leishmania species in vitro. Moreover, in vivo testing was carried out on some of the species and showed promising results. The authors have carried out the present work to complement previous published studies by investigating in vivo activity of tamoxifen in an experimental model of cutaneous leishmaniasis (CL) caused by Leishmania major. Groups of infected mice were given tamoxifen, orally, at a dose of 20mg/kg/day for 15days. Efficacy was assessed clinically, parasitologically, histopathologically by light and transmission electron microscope (TEM). Results showed that untreated infected mice suffered from autoamputation of the inoculated foot pad. However, those which received tamoxifen showed marked improvement of the cutaneous lesions and reduction of parasite burden. TEM of the cutaneous lesions from infected mice revealed the fine structure of normal Leishmania amastigotes, whereas those from infected mice treated with tamoxifen showed considerable changes. All male mice that received tamoxifen showed scrotal swelling with evident histopathological changes in the testes that could seriously compromise fertility of male mice. In conclusion, although tamoxifen causes significant side effects to the male reproductive system in the mouse model, it could provide an alternative to current agents. Results of this study demonstrated in vivo activity of tamoxifen against Leishmania major, thus, suggesting that tamoxifen is a suitable lead for the synthesis of more effective and less toxic antileishmanial derivatives. Copyright © 2011 Elsevier Inc. All rights reserved. |
| 8. | Biomed Pharmacother. 2011 May 5. [Epub ahead of print]Susceptibility of Trypanosoma evansi to cordycepin.Da Silva AS, Wolkmer P, Nunes JT, Duck MR, Oliveira CB, Gressler LT, Costa MM, Zanette RA, Mazzanti CM, Lopes ST, Monteiro SG.SourceDepartment of microbiology and parasitology, universidade Federal de Santa Maria, Santa Maria, Brazil. AbstractDrugs, which are effective during the early stage of trypanosomosis, but poorly penetrate the blood-brain barrier, are ineffective when parasites reach the brain and cause encephalitis. In order to seek alternative treatments, the aim of this study was to test the susceptibility of T. evansi to cordycepin in vitro and in rats experimentally infected. In vitro, a significant decrease (P<0.01) in live trypanosomes in the concentrations of 5.0 and 10μg/mL was observed 1hour after the beginning of the study, as well as at 3, 6, 9 and 12hours in all concentrations compared to control. Although no curative effects were observed in the in vivo assay in the majority of groups, the drug was able to maintain parasitemia at low levels, therefore increasing the longevity of rats when compared to positive control group. Rats that received cordycepin alone or in combination with adenosine deaminase inhibitor (ADA: EHNA hydrochloride), did not show trypomastigote forms of the parasite in the bloodstream 24hours after the administration. These animals remained negative in blood smears on average for 8 days, but thereafter had a recurrence of parasitemia. Among all the infected animals, only three rats in the group treated with the combination of cordycepin (2mg/kg) and EHNA hydrochloride (2mg/kg) remained negative during the experimental period. The curative efficacy of 42.5% was confirmed by PCR using T. evansi-specific primers. Thus, we conclude that cordycepin has biological effect against T. evansi, as previously reported in infections by T. brucei, T. cruzi and Leishmania sp. The treatment with cordycepin, when protected by an inhibitor of ADA, can prolong the survival of T. evansi-infected rats and provide curative efficacy. Copyright © 2011 Elsevier Masson SAS. All rights reserved. |
| 9. | Curr Top Med Chem. 2011 May 26. [Epub ahead of print]Sterol 14alpha-Demethylase (CYP51) as a Therapeutic Target for Human Trypanosomiasis and Leishmaniasis.Lepesheva GI, Waterman MR.SourceG.I.L. 622 RRB, 23 & Pierce, Department of Biochemistry Vanderbilt University, Nashville, TN, USA. galina.i.lepesheva@vanderbilt.edu. AbstractPathogenic protozoa threaten lives of several hundred million people throughout the world and are responsible for large numbers of deaths globally. The parasites are transmitted to humans by insect vectors, more than a hundred of infected mammalian species forming reservoir. With human migrations, HIV-coinfections, and blood bank contamination the diseases are now spreading beyond the endemic tropical countries, being found in all parts of the world including the USA, Canada and Europe. In spite of the widely appreciated magnitude of this health problem, current treatment for sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi) and leishmaniasis (Leishmania spp.) remains unsatisfactory. The drugs are decades old, their efficacy and safety profiles are unacceptable. This review describes sterol 14α-demethylase, an essential enzyme in sterol biosynthesis in eukaryotes and clinical target for antifungal azoles, as a promising target for antiprotozoan chemotherapy. While several antifungal azoles have been proven active against Trypanosomatidae and are under consideration as antiprotozoan agents, crystal structures of sterol 14α-demethylases from three protozoan pathogens, Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum provide the basis for the development of new, highly potent and pathogen-specific drugs with rationally optimized pharmacological properties. |
| 10. | Biol Cell. 2011 Mar;103(3):145-57.Nuclear spectrin-like proteins are structural actin-binding proteins in plants.Pérez-Munive C, Moreno Díaz de la Espina S.SourceCell Proliferation and Development Department, Centro Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain. AbstractBACKGROUND INFORMATION:Although actin is a relevant component of the plant nucleus, only three nuclear ABPs (actin-binding proteins) have been identified in plants to date: cofilin, profilin and nuclear myosin I. Although plants lack orthologues of the main structural nuclear ABPs in animals, such as lamins, lamin-associated proteins and nesprins, their genome does contain sequences with spectrin repeats and N-terminal calponin homology domains for actin binding that might be distant relatives of spectrin. We investigated here whether spectrin-like proteins could act as structural nuclear ABPs in plants. RESULTS:We have investigated the presence of spectrins in Allium cepa meristematic nuclei by Western blotting, confocal and electron microscopy, using antibodies against α- and β-spectrin chains that cross-react in plant nuclei. Their role as nuclear ABPs was analysed by co-immunoprecipitation and IF (immunofluorescence) co-localization and their association with the nuclear matrix was investigated by sequential extraction of nuclei with non-ionic detergent, and in low- and high-salt buffers after nuclease digestion. Our results demonstrate the existence of several spectrin-like proteins in the nucleus of onion cells that have different intranuclear distributions in asynchronous meristematic populations and associate with the nuclear matrix. These nuclear proteins co-immunoprecipitate and co-localize with actin. CONCLUSIONS:These results reveal that the plant nucleus contains spectrin-like proteins that are structural nuclear components and function as ABPs. Their intranuclear distribution suggests that plant nuclear spectrin-like proteins could be involved in multiple nuclear functions. |
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