Wednesday, July 22, 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 -10 of 12

1: Parasitol Res. 2009 Jul 21. [Epub ahead of print]Click here to read

An orally effective dihydropyrimidone (DHPM) analogue induces apoptosis-like cell death in clinical isolates of Leishmania donovani overexpressing pteridine reductase 1.

Singh N, Kaur J, Kumar P, Gupta S, Singh N, Ghosal A, Dutta A, Kumar A, Tripathi R, Siddiqi MI, Mandal C, Dube A.

Drug Target Discovery & Development Division, Central Drug Research Institute, Lucknow, 226001, India, neeloo888@yahoo.com.

The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis. The enzyme pteridine reductase 1 (PTR1) of L. donovani acts as a metabolic bypass for drugs targeting dihydrofolate reductase (DHFR); therefore, for successful antifolate chemotherapy to be developed against Leishmania, it must target both enzyme activities. Leishmania cells overexpressing PTR1 tagged at the N-terminal with green fluorescent protein were established to screen for proprietary dihydropyrimidone (DHPM) derivatives of DHFR specificity synthesised in our laboratory. A cell-permeable molecule with impressive antileishmanial in vitro and in vivo oral activity was identified. Structure activity relationship based on homology model drawn on our recombinant enzyme established the highly selective inhibition of the enzyme by this analogue. It was seen that the leishmanicidal effect of this analogue is triggered by programmed cell death mediated by the loss of plasma membrane integrity as detected by binding of annexin V and propidium iodide (PI), loss of mitochondrial membrane potential culminating in cell cycle arrest at the sub-G0/G1 phase and oligonucleosomal DNA fragmentation. Hence, this DHPM analogue [(4-fluoro-phenyl)-6-methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylic acid ethyl ester] is a potent antileishmanial agent that merits further pharmacological investigation.

PMID: 19621245 [PubMed - as supplied by publisher]

2: PLoS Negl Trop Dis. 2009 Jul 21;3(7):e479.Click here to read

Protease activated receptor signaling is required for african trypanosome traversal of human brain microvascular endothelial cells.

Grab DJ, Garcia-Garcia JC, Nikolskaia OV, Kim YV, Brown A, Pardo CA, Zhang Y, Becker KG, Wilson BA, de A Lima AP, Scharfstein J, Dumler JS.

Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

BACKGROUND: Using human brain microvascular endothelial cells (HBMECs) as an in vitro model for how African trypanosomes cross the human blood-brain barrier (BBB) we recently reported that the parasites cross the BBB by generating calcium activation signals in HBMECs through the activity of parasite cysteine proteases, particularly cathepsin L (brucipain). In the current study, we examined the possible role of a class of protease stimulated HBMEC G protein coupled receptors (GPCRs) known as protease activated receptors (PARs) that might be implicated in calcium signaling by African trypanosomes. METHODOLOGY/PRINCIPAL FINDINGS: Using RNA interference (RNAi) we found that in vitro PAR-2 gene (F2RL1) expression in HBMEC monolayers could be reduced by over 95%. We also found that the ability of Trypanosoma brucei rhodesiense to cross F2RL1-silenced HBMEC monolayers was reduced (39%-49%) and that HBMECs silenced for F2RL1 maintained control levels of barrier function in the presence of the parasite. Consistent with the role of PAR-2, we found that HBMEC barrier function was also maintained after blockade of Galpha(q) with Pasteurella multocida toxin (PMT). PAR-2 signaling has been shown in other systems to have neuroinflammatory and neuroprotective roles and our data implicate a role for proteases (i.e. brucipain) and PAR-2 in African trypanosome/HBMEC interactions. Using gene-profiling methods to interrogate candidate HBMEC pathways specifically triggered by brucipain, several pathways that potentially link some pathophysiologic processes associated with CNS HAT were identified. CONCLUSIONS/SIGNIFICANCE: Together, the data support a role, in part, for GPCRs as molecular targets for parasite proteases that lead to the activation of Galpha(q)-mediated calcium signaling. The consequence of these events is predicted to be increased permeability of the BBB to parasite transmigration and the initiation of neuroinflammation, events precursory to CNS disease.

PMID: 19621073 [PubMed - in process]

3: PLoS Negl Trop Dis. 2009 Jul 21;3(7):e486.Click here to read

Bioluminescent Imaging of Trypanosoma brucei Shows Preferential Testis Dissemination Which May Hamper Drug Efficacy in Sleeping Sickness.

Claes F, Vodnala SK, van Reet N, Boucher N, Lunden-Miguel H, Baltz T, Goddeeris BM, Büscher P, Rottenberg ME.

Institute of Tropical Medicine Antwerp, Department of Parasitology, Antwerp, Belgium.

Monitoring Trypanosoma spread using real-time imaging in vivo provides a fast method to evaluate parasite distribution especially in immunoprivileged locations. Here, we generated monomorphic and pleomorphic recombinant Trypanosoma brucei expressing the Renilla luciferase. In vitro luciferase activity measurements confirmed the uptake of the coelenterazine substrate by live parasites and light emission. We further validated the use of Renilla luciferase-tagged trypanosomes for real-time bioluminescent in vivo analysis. Interestingly, a preferential testis tropism was observed with both the monomorphic and pleomorphic recombinants. This is of importance when considering trypanocidal drug development, since parasites might be protected from many drugs by the blood-testis barrier. This hypothesis was supported by our final study of the efficacy of treatment with trypanocidal drugs in T. brucei-infected mice. We showed that parasites located in the testis, as compared to those located in the abdominal cavity, were not readily cleared by the drugs.

PMID: 19621071 [PubMed - in process]

4: J Clin Invest. 2009 Jul 13. pii: 38813. doi: 10.1172/JCI38813. [Epub ahead of print]Click here to read

IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani.

Pitta MG, Romano A, Cabantous S, Henri S, Hammad A, Kouriba B, Argiro L, El Kheir M, Bucheton B, Mary C, El-Safi SH, Dessein A.

IL-17 and IL-22 have been shown to increase protection against certain bacteria and fungal pathogens in experimental models. However, no human studies have demonstrated a crucial role of IL-17 and IL-22 in protection against infections. We show here that Leishmania donovani, which can cause the lethal visceral disease Kala Azar (KA), stimulates the differentiation of Th17 cells, which produce IL-17, IL-22, and IFN-gamma. Analysis of Th1, Th2, and Th17 cytokine responses by cultured PBMCs from individuals in a cohort of subjects who developed KA or were protected against KA during a severe outbreak showed that IL-17 and IL-22 were strongly and independently associated with protection against KA. Our results suggest that, along with Th1 cytokines, IL-17 and IL-22 play complementary roles in human protection against KA, and that a defect in Th17 induction may increase the risk of KA.

PMID: 19620772 [PubMed - as supplied by publisher]

5: Antimicrob Agents Chemother. 2009 Jul 20. [Epub ahead of print]Click here to read

New treatment option for second stage African sleeping sickness: In vitro and in vivo efficacy of aza analogs of DB289.

Wenzler T, Boykin DW, Ismail MA, Hall JE, Tidwell RR, Brun R.

Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basel, Switzerland; Department of Chemistry, Center for Biotechnology and Drug Design, Georgia State University, Atlanta, Georgia, USA; Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina, USA.

African sleeping sickness is a fatal parasitic disease and all drugs currently in use for treatment have strong liabilities. It is essential to find new, effective and less toxic drugs ideally with oral application to control the disease. In this study, the aromatic diamidine DB75 (furamidine), two aza analogs DB820 and DB829 (CPD-0801), as well as their methoxyamidine prodrugs and amidoxime metabolites were evaluated against African trypanosomes. The active parent diamidines did show similar in vitro profiles against different Trypanosoma brucei strains, melarsoprol and pentamidine resistant lines and against a P2 transporter knockout strain (AT1KO), with DB75 as the most trypanocidal molecule. In the T. b. rhodesiense STIB900 acute mouse model, the aza analogs DB820 and DB829 demonstrated superior activity over DB7The aza prodrugs DB844 and DB868 as well as two metabolites of DB844 were orally more potent in the T. b. brucei GVR35 CNS mouse model than DB289 (pafuramidine maleate). Unexpectedly, the parent diamidine DB829 showed high activity in the CNS mouse model by the intraperitoneal route. In conclusion, DB868 with oral or DB829 with parenteral application are potential candidates for further development for a 2(nd) stage African sleeping sickness drug.

PMID: 19620327 [PubMed - as supplied by publisher]

6: Mol Cell Biol. 2009 Jul 20. [Epub ahead of print]Click here to read

Distinct and Overlapping Functions of MRP1/2 and RBP16 in Mitochondrial RNA Metabolism.

Fisk JC, Presnyak V, Ammerman ML, Read LK.

Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14124.

Mitochondrial RNA metabolism in Trypanosoma brucei is a complex process involving both extensive RNA editing and control of RNA stability. MRP1/2 and RBP16 are two factors that have been implicated in regulating editing and stability of specific mRNAs. These two factors exhibit similar non-specific RNA binding and RNA annealing activities, suggesting that some of their actions may have been previously masked by functional redundancy. Here, we examined the functional interaction of MRP1/2 and RBP16 by separate and simultaneous RNAi, and by overexpressing RBP16 in an MRP1/2 depleted background. Simultaneous depletion of these factors results in synthetic lethality in procyclic trypanosomes. Analysis of mitochondrial RNAs in procyclic cells reveals distinct functions for MRP1/2 and RBP16 towards edited CYb mRNA, redundant functions in stabilization of edited A6 and COIII mRNAs, and concentration dependent positive and negative functions for RBP16 towards edited RPS12 mRNAs. While simultaneous MRP1/2 - RBP16 depletion had no effect on growth of bloodstream form cells, massive adverse effects on the levels of almost all mitochondrial RNAs were observed. These studies greatly expand our knowledge regarding the functions of MRP1/2 and RBP16, and suggest that both RNA specific and life cycle stage specific factors impact MRP1/2 and RBP16 function.

PMID: 19620277 [PubMed - as supplied by publisher]

7: Bioorg Med Chem. 2009 Jul 3. [Epub ahead of print]Click here to read

SAR studies on azasterols as potential anti-trypanosomal and anti-leishmanial agents.

Gigante F, Kaiser M, Brun R, Gilbert IH.

Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK; Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.

There is an urgent need for the development of new drugs for the treatment of neglected tropical diseases such as human African trypanosomiasis, Chagas disease and leishmaniasis. Azasterols, have been shown to have activity against the parasites which cause these diseases. In this paper we report synthesis of new azasterols and subsequent analysis of the SAR. The chemistry focused on variations in the ester at the 3beta-position of the sterol and the position of the nitrogen in the side chain. The data allowed us to derive preliminary pharmacophore models for the activity of the azasterols against the parasites which cause these diseases.

PMID: 19620005 [PubMed - as supplied by publisher]

8: Vet Parasitol. 2009 Jun 24. [Epub ahead of print]Click here to read

Specific detection and identification of African trypanosomes in bovine peripheral blood by means of a PCR-ELISA assay.

Cabrera L, De Witte J, Victor B, Vermeiren L, Zimic M, Brandt J, Geysen D.

Alexander von Humboldt Institute of Tropical Medicine (IMTAvH), Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, San Martín de Porras, Lima 31, Peru; Prince Leopold Institute of Tropical Medicine (ITM), Nationalestraat 155, Antwerp B-2000, Belgium.

The aim of the present study was to develop a PCR-ELISA assay for the detection and differentiation of the main African pathogen trypanosomal species present in peripheral blood of cattle. The proposed methodology allows to specifically differentiate Trypanosoma congolense, Trypanosoma vivax and the subgenus Trypanozoon, by means of a sensitive universal PCR amplifying trypanosome DNA followed by an ELISA-based hybridization with three highly specific probes. The semi-nested PCR had a sensitivity of 15fg, 15fg, and 0.15fg of DNA from T. vivax, T. congolense, and Trypanosoma brucei brucei, respectively that is sufficient to detect parasites in blood during the chronic phase of the disease. Biotinylated second round asymmetric PCR amplification products were used in an ELISA set up using three species-specific probes for the diagnosis of T. congolense (type Riverine, Kilifi or Savannah), T. vivax and T. brucei brucei. A factor O.D. of 0.082 was determined on blood samples from bovines (n=18) from a non-endemic area in Africa. In a pilot study of blood samples of naturally and experimentally Trypanosoma infected cattle previously characterized by PCR-RFLP (n=42), a high rate of concordance (93.3%) was found between PCR-RFLP and PCR-ELISA. There is a good ratio between positive and negative O.D. values (3.00 vs. 0.1) and the technique can also be used to distinguish mixed infections.

PMID: 19619947 [PubMed - as supplied by publisher]

9: Mol Ecol. 2009 Jul 10. [Epub ahead of print]Click here to read

Evidence for a discrete evolutionary lineage within Equatorial Guinea suggests that the tsetse fly Glossina palpalis palpalis exists as a species complex.

Dyer NA, Furtado A, Cano J, Ferreira F, Odete Afonso M, Ndong-Mabale N, Ndong-Asumu P, Centeno-Lima S, Benito A, Weetman D, Donnelly MJ, Pinto J.

Vector Group, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.

Abstract Tsetse flies of the palpalis group are major vectors of Human African Trypanosomiasis in Africa. Accurate knowledge of species identity is essential for vector control. Here, we combine ribosomal internal transcribed spacer 1 (ITS1), mitochondrial Cytochrome Oxidase 1 (COI) and microsatellites to determine the population structure and phylogenetic relations of Glossina p. palpalis in Equatorial Guinea. CO1 sequence data suggest that G. p. palpalis in Equatorial Guinea is a distinct subspecies from previously described G. p. palpalis in West Africa and Democratic Republic of Congo. Glossina p. palpalis in Equatorial Guinea and DRC share a common ancestor which diverged from West African G. p. palpalis around 1.9 Ma. Previous ITS1 length polymorphism data suggested the possible presence of hybrids in Equatorial Guinea. However, ITS1 showed incomplete lineage sorting compared with clearly defined COI groups, and data from 12 unlinked microsatellites provided no evidence of hybridization. Microsatellite data indicated moderate but significant differentiation between the populations analysed (Rio Campo, Mbini and Kogo). Moreover, unlike previous studies of G. p. palpalis, there was no evidence for heterozygote deficiency, presence of migrants or cryptic population structure. Variance effective population size at Rio Campo was estimated at 501-731 assuming eight generations per year. This study of the population genetics of G. p. palpalis in central Africa provides the first estimate of genetic differentiation between geographically separated G. p. palpalis populations.

PMID: 19619197 [PubMed - as supplied by publisher]

10: Curr Pharm Biotechnol. 2009 Sep 1. [Epub ahead of print]

In silico Studies on Tryparedoxin Peroxidase of Leishmania infantum: Structural Aspects.

Singh BK, Dubey VK.

Department of Biotechnology, Indian Institute of Technology Guwahati, Assam, India. vdubey@iitg.ernet.in.

Tryparedoxin peroxidase (TryP) is a key enzyme of the trypanothione-dependent metabolism for removal of oxidative stress in leishmania. These enzymes function as antioxidants through their peroxidase and peroxynitrite reductase activities. Inhibitors of this enzyme are presumed to be antilesihmania drugs and structural studies are prerequisite of rational drug design. We have constructed three dimensional structure of TryP of Leishmania infantum using comparative modeling. Structural analysis reveals several interesting features. Moreover, it shows remarkable structural difference with human host glutathione peroxidase, an enzyme involved in similar function and TryP from Leishmania major.

PMID: 19619120 [PubMed - as supplied by publisher]

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