Thursday, June 25, 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 -6 of 6

1: J Antimicrob Chemother. 2009 Jun 23. [Epub ahead of print]Click here to read

Anti-Acanthamoeba efficacy and toxicity of miltefosine in an organotypic skin equivalent.

Walochnik J, Obwaller A, Gruber F, Mildner M, Tschachler E, Suchomel M, Duchêne M, Auer H.

Department of Medical Parasitology, Institute of Hygiene, Medical University of Vienna, Kinderspitalgasse 15, 1095 Vienna, Austria.

Objectives Acanthamoebae can cause infections of several organs, including eye, skin, lung and brain. Except for Acanthamoeba keratitis, these infections are linked to immunodeficiency. Treatment is generally problematic, due to the lack of sufficiently effective and also easily manageable drugs. In a previous study we discovered that miltefosine (hexadecylphosphocholine) is highly active against Acanthamoeba spp. in vitro. The aim of the current study was to evaluate the suitability of miltefosine for the topical treatment of Acanthamoeba infections. Methods Storage life and time dependency, susceptibilities of opportunistic bacterial and fungal pathogens, and synergistic and adverse effects of combinations with other anti-Acanthamoeba substances were determined. Moreover, an organotypic skin equivalent was adapted for investigating the penetration of acanthamoebae into the epidermis and the human tissue tolerability of miltefosine. Results It was shown that miltefosine can be stored as a 2 mM stock solution and also as a 50 microM dilution over a period of 12 months at 4 degrees C without any loss of activity. Efficacies against staphylococci and Candida albicans were established. Acanthamoebae were able to penetrate the skin equivalent within 24 h. This penetration was prevented by treatment with miltefosine, while miltefosine treatment was well tolerated by the skin equivalent. Conclusions Miltefosine has been approved for oral and topical treatment of leishmaniasis and may also be a promising candidate for the topical treatment of Acanthamoeba infections.

PMID: 19549672 [PubMed - as supplied by publisher]

2: Parasitology. 2009 Jun 24:1-6. [Epub ahead of print]Click here to read

Identification of the agent causing visceral leishmaniasis in Uzbeki and Tajiki foci by analysing parasite DNA extracted from patients' Giemsa-stained tissue preparations.

Alam MZ, Kovalenko DA, Kuhls K, Nasyrova RM, Ponomareva VI, Fatullaeva AA, Razakov SA, Schnur LF, Schönian G.

Institut für Mikrobiologie und Hygiene, Charité Universitätsmedizin Berlin, Dorotheenstrasse 96, D-10098 Berlin, Germany.

SUMMARYOur present study is the first attempt to characterize Leishmania parasites from foci in Uzbekistan and Tajikistan endemic for visceral leishmaniasis (VL). PCR-sequencing of the ribosomal internal transcribed spacer 1 and multilocus microsatellite typing (MLMT) were applied to DNA extracted from preparations of Giemsa-stained bone marrow aspirates from 13 cases of VL. L. infantum was shown to cause VL currently occurring in this area. MLMT applying 14 microsatellite markers, previously shown to be polymorphic for strains of the L. donovani complex, revealed that microsatellite profiles of parasites causing human VL in the Namangan and Jizzakh regions in Uzbekistan, and Penjikent region in Tajikistan, basically coincide with those of strains of L. infantum MON-1. Furthermore, these parasites were assigned to a distinct cluster genetically clearly separated from the populations of L. infantum MON-1 from Europe, the Middle East and North Africa. The existence of a genetically homogeneous but distinct group of L. infantum MON-1 indicates that the parasites circulating in the Uzbeki and Tajiki foci studied have been restricted there for a long time rather than having been recently introduced from elsewhere by human or animal reservoir migration.

PMID: 19549349 [PubMed - as supplied by publisher]

3: Parasitology. 2009 Jun 24:1-8. [Epub ahead of print]Click here to read

Characterization of a leucine aminopeptidase of Babesia gibsoni.

Jia H, Terkawi MA, Aboge GO, Goo YK, Luo Y, Li Y, Yamagishi J, Nishikawa Y, Igarashi I, Sugimoto C, Fujisaki K, Xuan X.

National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido 080-8555, Japan.

SUMMARYPeptidases of parasitic protozoa are currently under intense investigation in order to identify novel virulence factors, drug targets, and vaccine candidates, except in Babesia. Leucine aminopeptidases in protozoa, such as Plasmodium and Leishmania, have been identified to be involved in free amino acid regulation. We report here the molecular and enzymatic characterization, as well as the localization of a leucine aminopeptidase, a member of the M17 cytosolic aminopeptidase family, from B. gibsoni (BgLAP). A functional recombinant BgLAP (rBgLAP) expressed in Escherichia coli efficiently hydrolysed synthetic substrates for aminopeptidase, a leucine substrate. Enzyme activity of the rBgLAP was found to be optimum at pH 8.0 and at 37 degrees C. The substrate profile was slightly different from its homologue in P. falciprum. The activity was also strongly dependent on metal divalent cations, and was inhibited by bestatin, which is a specific inhibitor for metalloprotease. These results indicated that BgLAP played an important role in free amino acid regulation.

PMID: 19549347 [PubMed - as supplied by publisher]

4: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2009 Jun 1;65(Pt 6):641-4. Epub 2009 May 23.LinkOut

Crystallization and preliminary X-ray diffraction analysis of Q4DV70 from Trypanosoma cruzi, a hypothetical protein with a putative thioredoxin domain.

dos Santos CR, Fessel MR, Vieira Lde C, Krieger MA, Goldenberg S, Guimarães BG, Zanchin NI, Barbosa JA.

Center for Structural Molecular Biology (CeBiME), Brazilian Synchrotron Light Laboratory (LNLS), CP 6192, 13084-971 Campinas-SP, Brazil.

Q4DV70 is annotated in the Trypanosoma cruzi CL Brener genome as a hypothetical protein with a predicted thioredoxin-like fold, although the catalytic cysteine residues that are conserved in typical oxidoreductases are replaced by serine residues. Gene-expression analysis indicates that this protein is differentially expressed during the T. cruzi life cycle, suggesting that it plays an important role during T. cruzi development. The gene coding for Q4DV70 was cloned and the protein was overexpressed in Escherichia coli with an N-terminal His tag. Purification of Q4DV70 was carried out by affinity and size-exclusion chromatography and the His tag was removed by TEV protease digestion. Crystals of Q4DV70 were grown using the sitting-drop vapour-diffusion method. A diffraction data set was collected to 1.50 A resolution from a single crystal grown in 25% PEG 1500, 200 mM sodium thiocyanate pH 6.9, 10 mM phenol and 10% ethylene glycol. The crystal belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 35.04, b = 50.32, c = 61.18 A. The Q4DV70 structure was solved by molecular replacement using protein disulfide isomerase from yeast (PDB code 2b5e) as a search model. Initial refinement of the model indicated that the solution was correct. These data are being used for refinement of the model of Q4DV70.

PMID: 19478453 [PubMed - indexed for MEDLINE]

PMCID: PMC2688432 [Available on 2011/06/01]

Patient Drug Information

5: Invest Clin. 2009 Mar;50(1):77-87.LinkOut

Proliferation and bystander suppression induced by membrane and flagellar antigens of Trypanosoma cruzi.

Mosca W, Briceño L.

Laboratorio de Fisiopatología, Instituto de Biomedicina, Facultad de Medicina, Universidad Central de Venezuela, Apartado 4043, Caracas 1010A, Venezuela. wmosca@gmail.com

We have studied, in vitro, proliferation induced by flagella (FE) and membrane (ME) antigenic fractions of T. cruzi epimastigotes, as well as their regulatory effect on the proliferative response to PPD (Protein Purified Derivative). Crude flagella as well as bands from Western blots of flagella and membrane of epimastigotes were tested. Crude flagella elicited higher proliferation in mononuclear cells from patients with Chagasic cardiomyopathy (CDM) than in patients with no evidence of cardiac pathology (INF). Fractionated antigens induced a lower proliferative response, in intensity as well as in frequency, than the crude extracts. With FE, bands between 150 and 24.3 kDa (B3 to B18 with the exception of B4 and B13) induced higher CPM (Counts Per Minute) in CDM. In INF only bands B7 (87.3 to 80.1 kDa), 9 (69.8 to 64.6 kDa) and 13 (45.4 to 41.5 kDa) had high CPM. ME bands also elicited higher proliferation in CDM. However, only 5 out of 14 bands gave CPM higher than 1000 in CDM and none in INF. The mean down regulation (DR) of most bands was similar in both groups. But the frequency of relevant DR elicited by FE was significantly higher in CDM. In contrast the frequency of up regulation (UR) was higher in INF. Bands 13 and 14 of ME did not induce DR in most INF. The discordance between the frequency of relevant DR in CDM and INF was more evident with ME than with FE. The frequency of (UR) was 50% or higher with all ME bands in INF, but, lower than 12% in CDM. The higher UR in INF and of DR in CDM, suggest the presence of some balance or interaction in INF that is lost in CDM. In ME there might be antigens that could be relevant for the immunoprofilaxis of Chagas' disease. The difference in the clinical status of the two groups seems to be associated with the recognition of different groups of antigens together with variations in the nature of the regulation of the response of mononuclear cells to these antigens.

PMID: 19418729 [PubMed - indexed for MEDLINE]

6: J Am Chem Soc. 2009 Apr 15;131(14):5153-62.Click here to read Taxonomy via GenBank, Protein, Structure, 3D Domains, LinkOut

Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.

Zhang Y, Cao R, Yin F, Hudock MP, Guo RT, Krysiak K, Mukherjee S, Gao YG, Robinson H, Song Y, No JH, Bergan K, Leon A, Cass L, Goddard A, Chang TK, Lin FY, Van Beek E, Papapoulos S, Wang AH, Kubo T, Ochi M, Mukkamala D, Oldfield E.

Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.

Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.

PMID: 19309137 [PubMed - indexed for MEDLINE]

Structures reported by this article

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