Thursday, March 26, 2009

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 -5 of 5

1: RNA. 2009 Mar 24. [Epub ahead of print]Click here to read

Differential functions of two editosome exoUases in Trypanosoma brucei.

Ernst NL, Panicucci B, Carnes J, Stuart K.

Seattle Biomedical Research Institute, Seattle, Washington 98109, USA.

Mitochondrial RNAs in trypanosomes are edited by the insertion and deletion of uridine (U) nucleotides to form translatable mRNAs. Editing is catalyzed by three distinct editosomes that contain two related U-specific exonucleases (exoUases), KREX1 and KREX2, with the former present exclusively in KREN1 editosomes and the latter present in all editosomes. We show here that repression of KREX1 expression leads to a concomitant reduction of KREN1 in approximately 20S editosomes, whereas KREX2 repression results in reductions of KREPA2 and KREL1 in approximately 20S editosomes. Knockdown of KREX1 results in reduced cell viability, reduction of some edited RNA in vivo, and a significant reduction in deletion but not insertion endonuclease activity in vitro. In contrast, KREX2 knockdown does not affect cell growth or editing in vivo but results in modest reductions of both insertion and deletion endonuclease activities and a significant reduction of U removal in vitro. Simultaneous knockdown of both proteins leads to a more severe inhibition of cell growth and editing in vivo and an additive effect on endonuclease cleavage in vitro. Taken together, these results indicate that both KREX1 and KREX2 are important for retention of other proteins in editosomes, and suggest that the reduction in cell viability upon KREX1 knockdown is likely a consequence of KREN1 loss. Furthermore, although KREX2 appears dispensable for cell growth, the increased inhibition of editing and parasite viability upon knockdown of both KREX1 and KREX2 together suggests that both proteins have roles in editing.

PMID: 19318463 [PubMed - as supplied by publisher]

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2: J Med Chem. 2009 Mar 24. [Epub ahead of print]Click here to read

Molecular Basis of Antimony Treatment in Leishmaniasis (dagger).

Baiocco P, Colotti G, Franceschini S, Ilari A.

Istituto di Biologia e Patologia MolecolariCNR and Department of Biochemical Sciences, Sapienza University of Roma, P.le A. Moro 5, 00185 Roma, Italy.

Leishmaniasis is a disease that affects 2 million people and kills 70000 persons every year. It is caused by Leishmania species, which are human protozoan parasites of the trypanosomatidae family. Trypanosomatidae differ from the other eukaryotes in their specific redox metabolism because the glutathione/glutathione reductase system is replaced by the unique trypanothione/trypanothione reductase system. The current treatment of leishmaniasis relies mainly on antimonial drugs. The crystal structures of oxidized trypanothione reductase (TR) from Leishmania infantum and of the complex of reduced TR with NADPH and Sb(III), reported in this paper, disclose for the first time the molecular mechanism of action of antimonial drugs against the parasite. Sb(III), which is coordinated by the two redox-active catalytic cysteine residues (Cys52 and Cys57), one threonine residue (Thr335), and His461' of the 2-fold symmetry related subunit in the dimer, strongly inhibits TR activity. Because TR is essential for the parasite survival and virulence and it is absent in mammalian cells, these findings provide insights toward the design of new more affordable and less toxic drugs against Leishmaniasis.

PMID: 19317451 [PubMed - as supplied by publisher]

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3: Mol Pharm. 2009 Mar 24. [Epub ahead of print]Click here to read

Kahalalide F, an antitumor depsipeptide in clinical trial, and its analogs as effective anti-leishmanial agents.

Albericio F, Cruz LJ, Luque-Ortega J, Rivas L.

Leishmaniasis is a human parasitic disease caused by infection by the protozoan Leishmania spp. Chemotherapy is currently the only treatment available, but its efficacy is increasingly challenged by the rising incidence of resistance and the frequent severe side-effects associated with first-line drugs. Thus the development of leads with distinct mechanisms of action is urgently needed. A strategy often used for this purpose consists of assaying for leishmanicidal activity drugs formerly developed for other applications, such as amphotericin B (antifungal) or miltefosine (antitumor), among others, to profit from previous pharmacological and toxicological studies. Kahalalide F (KF) is a tumoricidal cyclic depsipeptide currently under phase II clinical trials for several types of cancer and psoriasis. Its mechanism of action has not been fully elucidated. Here we report the leishmanicidal activity of KF and its synthetic analogs at a micromolar range of concentrations. The lethal hit is strongly linked to the destructuration of the plasma membrane (PM) of the parasite based on (i) a rapid depolarization of the PM and uptake of the vital dye SYTOX Green upon its addition; (ii) evidence of severe morphological damage to the membrane of the parasite, as shown by transmission electron microscopy; and (iii) a rapid drop in the intracellular ATP levels, which correlates significantly with the leishmanicidal activity for active analogs. In addition to the basic information provided, this mechanism of action strongly precludes induction of resistance and fosters further studies for the optimization KF and its analogs as new anti-Leishmania leads with a new mode of action.

PMID: 19317431 [PubMed - as supplied by publisher]

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4: Mil Med. 2009 Feb;174(2):206-11.

Occurence of visceral and cutaneous leishmaniasis in Croatia.

Mulić R, Custović A, Ropac D, Tripković I, Stojanović D, Klismanić Z.

Department of Public Health, School of Medicine, University of Split, Soltanska 2, 21 000, Split, Croatia.

The purpose of this study was to show epidemiological characteristics and clinical manifestations of visceral and cutaneous leishmaniasis in Croatia. METHODS: Analysis of data on reported visceral and cutaneous leishmaniasis cases and description of the most common clinical manifestations of the disease was based on meta analysis of collected data. RESULTS: A total of 124 cases of visceral and cutaneous leishmaniasis were reported from 1954 until the end of 2006. During the 1994-2006 period, 35 people became infected: 23 with visceral and 12 with the cutaneous form of the disease. The diagnosis of cutaneous leismaniasis is based on the clinical picture, epidemiological data, and light microscopic histology. The clinical picture of visceral leishmaniasis was confirmed by detection of amastigotes in bone marrow aspirate (n=22; 95.7%) and liver (n=1; 4.3%) and by serology-indirect immunofluorescent assays (n=23; 100%). Age-specific morbidity is highest in the 0 to 4 age group (0.29%). None of the infected was human immunodeficiency virus positive. CONCLUSION: It is estimated that there have been some changes in epidemiological characteristics of the natural foci of leishmaniasis in Croatia.

PMID: 19317205 [PubMed - in process]

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5: Ann N Y Acad Sci. 2009 Feb;1153:264-71.Click here to read LinkOut

Neuroendocrine-immunology of experimental Chagas' disease.

Roggero E, Pérez AR, Bottasso OA, Besedovsky HO, Del Rey A.

Instituto de Inmunología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina.

The cytokine-mediated stimulation of the hypothalamus-pituitary-adrenal (HPA) axis is relevant for immunoregulation and survival during bacterial endotoxemia and certain viral infections. However, only limited information is available regarding the effect of endogenous glucocorticoids on parasitic diseases. Here, we discuss evidence that the increased levels of corticosterone that occur following Trypanosoma cruzi infection in mice is an endocrine response that protects the host by impeding an excessive production of pro-inflammatory cytokines. Comparative studies between susceptible C57Bl/6J and resistant Balb/c mice indicate that the predisposition to the disease depends on the appropriate timing and magnitude of the activation of the HPA axis. However, this endocrine response also results in thymus atrophy and depletion of CD4(+)CD8(+) by apoptosis. On the other hand, using tumor necrosis factor (TNF)-receptor knockout mice, we found that TNF-alpha plays a complex role during this disease; it is involved in the mediation of cardiac tissue damage but it also contributes to prolonged survival. Taken together, this evidence indicates that a subtle balance between endocrine responses and cytokine production is necessary for an efficient defense against T. cruzi infection.

PMID: 19236349 [PubMed - indexed for MEDLINE]

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