Tuesday, May 12, 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 24

1: Planta Med. 2009 May 8. [Epub ahead of print]Click here to read

Antiprotozoal and Cytotoxic Studies on Some Isocordoin Derivatives.

Borges-Argáez R, Vela-Catzín T, Yam-Puc A, Chan-Bacab MJ, Moo-Puc RE, Cáceres-Farfán M.

Centro de Investigación Científica de Yucatán, Mérida, Yucatán, Mexico.

Isocordoin ( 1) and 2',4'-dihydroxy-3'-(gamma,gamma-dimethylallyl)-dihydrochalcone ( 7), chalcones isolated from the root of LONCHOCARPUS XUUL, together with six analogues of 1 were tested IN VITRO against promastigotes of LEISHMANIA MEXICANA and epimastigotes of TRYPANOSOMA CRUZI. Additionally, cytotoxic studies with MDCK cells were carried out using the MTT method. Among these derivatives, 2',4'-diacetoxy-3'-(3-methylbut-2-enyl)-chalcone ( 2) and 2',4'-dimethoxy-3'-(3-methylbut-2-enyl)-chalcone ( 3) showed the strongest antiprotozoal activity and lower cytotoxicity in comparison with isocordoin at a concentration in the microM range. Derivative 3 had the strongest trypanocidal activity with IC (50) values lower than those of nifurtimox and benznidazole, the common drugs used against these parasites. The selectivity index calculated for 3 (SI 109.3) confirms the selective trypanocidal activity of this metabolite.

PMID: 19431103 [PubMed - as supplied by publisher]

2: Planta Med. 2009 May 8. [Epub ahead of print]Click here to read

The Antiprotozoal Activity of Sixteen Asteraceae Species Native to Sudan and Bioactivity-Guided Isolation of Xanthanolides from Xanthium brasilicum*

Nour AM, Khalid SA, Kaiser M, Brun R, Abdallah WE, Schmidt TJ.

Institut für Pharmazeutische Biologie und Phytochemie IPBP, Westfälische Wilhelms-Universität Münster, Münster, Germany.

IN VITRO screening of the dichloromethane extracts of 16 Asteraceae species native to Sudan for activity against major protozoan pathogens revealed that a XANTHIUM BRASILICUM Vell. [syn. X. STRUMARIUM var. BRASILICUM (Vell.) Baker in Mart.] extract was the most active against TRYPANOSOMA BRUCEI RHODESIENSE, the etiological agent of East African human trypanosomiasis (IC (50) = 0.1 microg/mL). This plant extract also exhibited noticeable activities against T. CRUZI (Chagas disease), LEISHMANIA DONOVANI (Kala-Azar) as well as PLASMODIUM FALCIPARUM (Malaria tropica). Bioactivity-guided fractionation resulted in the isolation of four bioactive sesquiterpene lactones (STL) of the xanthanolide series (4,5-seco-guaianolide-type). They were identified by spectroscopic means as 8-epixanthatin ( 1), 8-epixanthatin 1beta,5beta-epoxide ( 2), and as the dimers pungiolide A ( 4) as well as pungiolide B ( 5). Two further modified xanthanolide sesquiterpene lactones, xanthipungolide ( 3) and 4,15-dinor-1,11(13)-xanthadiene-3,5beta:12,8beta-diolide ( 6) were isolated. While xanthipungolide turned out to be inactive against the tested parasites, the dinor-xanthanlide showed significant activity against T. BRUCEI RHODESIENSE and L. DONOVANI. All isolated compounds were previously known from other XANTHIUM species but this is the first report on their occurrence in X. BRASILICUM, and, most notably, on their antiprotozoal activity. As the most active single compound from this extract, 8-epixanthatin 1beta,5beta-epoxide showed IC (50) values of 0.09, 2.95, 0.16 and 1.71 microg/mL (0.33, 11.3, 0.6 and 6.5 microM) against T. BRUCEI RHODESIENSE, T. CRUZI, L. DONOVANI and P. FALCIPARUM, respectively, while its cytotoxicity against rat myoblast cells used as control was determined at 5.8 microg/mL (22.1 microM). Besides assessment of their antiprotozoal activity, the structural assignments for the dimeric xanthanolides pungiolide A and B were reinvestigated and fully established.

PMID: 19431098 [PubMed - as supplied by publisher]

3: Ann Clin Lab Sci. 2009 Spring;39(2):192-5.Click here to read

Anti-Tumor Necrosis Factor-alpha Therapy Provokes Latent Leishmaniasis in a Patient with Rheumatoid Arthritis.

Franklin G, Greenspan J, Chen S.

Department of Pathology, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, NY 11040, USA.

It has been reported that anti-tumor necrosis factor-alpha therapy increases the risk of opportunistic infections including rare case reports of leishmaniasis. Here we report a case of latent cutaneous leishmaniasis, which was provoked by anti-tumor necrosis factor-alpha therapy in a patient with rheumatoid arthritis.

PMID: 19429808 [PubMed - in process]

4: Eukaryot Cell. 2009 May 8. [Epub ahead of print]Click here to read

Spliceosomal proteomics in Trypanosoma brucei revealed new RNA splicing factors.

Luz Ambrósio D, Lee JH, Panigrahi AK, Nguyen TN, Cicarelli RM, Günzl A.

Department of Genetics and Developmental Biology and Department of Molecular, Microbial and Structural Biology, University of Connecticut Health Center, Farmington, CT, USA; Departamento de Ciências Biológicas, Faculdade de Ciências Farmacêuticas, UNESP, Araraquara, SP, Brazil; Seattle Biomedical Research Institute, Seattle, WA, USA.

In trypanosomatid parasites, spliced leader (SL) trans splicing is an essential nuclear mRNA maturation step which caps mRNAs post-transcriptionally and, in conjunction with polyadenylation, resolves individual mRNAs from polycistronic precursors. While all trypanosomatid mRNAs are trans spliced, intron removal by cis splicing is extremely rare and predicted to occur in only four pre-mRNAs. Trans and cis splicing reactions are carried out by the spliceosome which consists of U-rich small nuclear ribonucleoprotein particles (U snRNPs) and of non-snRNP factors. Mammalian and yeast spliceosome complexes are well-characterized and found to be associated with up to 170 proteins. Despite the central importance of trans splicing in trypanosomatid gene expression, only the core RNP proteins and a few snRNP-specific proteins are known. To characterize the trypanosome spliceosomal protein repertoire, we conducted a proteomic analysis by tagging and tandem affinity-purifying the canonical core RNP protein SmD1 in Trypanosoma brucei and by identifying co-purified proteins by mass spectrometry. The set of 47 identified proteins harbored nearly all spliceosomal snRNP factors characterized in trypanosomes so far and twenty-one proteins lacking a specific annotation. A bioinformatic analysis combined with protein pull-down assays and immunofluorescence microscopy identified nine divergent orthologues of known splicing factors including the missing U1-specific protein U1A. In addition, a novel U5-specific, and as we show, essential splicing factor was identified which shares a short, highly conserved N-terminal domain with the yeast protein Cwc21p and thus was tentatively named U5-Cwc21. Together, these data strongly indicate that most of the identified proteins are components of the spliceosome.

PMID: 19429779 [PubMed - as supplied by publisher]

5: J Biol Chem. 2009 May 8. [Epub ahead of print]Click here to read

An Ab initio structural model of a nucleoside permease predicts functionally important residues.

Valdés RM, Arastu-Kapur SA, Landfear SM, Shinde U.

Oregon Health & Science University, United States.

Permeases belonging to the equilibrative nucleoside transporter family promote uptake of nucleosides and/or nucleobases into a wide range of eukaryotes and mediate the uptake of a variety of drugs used in the treatment of cancer, heart disease, AIDS, and parasitic infections. No experimental three-dimensional structure exists for any of these permeases, and they are not present in prokaryotes, the source of many membrane proteins used in crystal structure determination. To generate a structural model for such a transporter, the LdNT1.1 nucleoside permease from the parasitic protozoan Leishmania donovani was modeled using ab initio computation. Site-directed mutations that strongly impair transport or that alter substrate specificity map to the central pore of the ab initio model, while mutations that have less pronounced phenotypes map to peripheral positions. The model suggests that aromatic residues present in transmembrane helices 1, 2, and 7 may interact to form an extracellular gate that closes the permeation pathway in the inward oriented conformation. Mutation of two of these three residues abrogated transport activity, consistent with the prediction of the model. The ab initio model is similar to one derived previously using threading analysis, a distinct computational approach, supporting the overall accuracy of both models. However, significant differences in helix orientation and residue position between the two models are apparent, and the mutagenesis data suggest that the ab initio model represents an improvement regarding structural details over the threading model. The putative gating interaction may also help explain differences in substrate specificity between members of this family.

PMID: 19429678 [PubMed - as supplied by publisher]

6: J Ethnopharmacol. 2009 Apr 21;122(3):463-467. Epub 2009 Feb 10.Click here to read

In vitro activity of Tridax procumbens against promastigotes of Leishmania mexicana.

Martín-Quintal Z, Moo-Puc R, González-Salazar F, Chan-Bacab MJ, Torres-Tapia LW, Peraza-Sánchez SR.

Centro de Investigación Científica de Yucatán, Calle 43 #130, Col. Chuburná de Hidalgo, Mérida, Yucatán 97200 (CICY), Mexico.

ETHNOPHARMACOLOGICAL RELEVANCE: Tridax procumbens is an active herb against leishmaniasis. AIM OF THE STUDY: Leishmaniasis is a group of diseases caused by Leishmania protozoa. We investigated the antileishmanial activity of Tridax procumbens extracts and a pure compound against promastigotes of Leishmania mexicana, the causative agent of cutaneous leishmaniasis in the New World. MATERIALS AND METHODS: Extracts and (3S)-16,17-didehydrofalcarinol (1) were obtained by chromatographic methods from Tridax procumbens, and the latter identified by spectroscopic analysis. The effect of these extracts and 1 on the growth inhibition of promastigotes of Leishmania mexicana was evaluated. In order to test the safety of extracts and 1, mammalian cells were treated with them, and cell viability was assessed using trypan blue and MTT. RESULTS: We demonstrated that extracts of Tridax procumbens and 1 showed a pronounced activity against Leishmania mexicana. The methanol extract inhibited promastigotes growth of Leishmania mexicana with a 50% inhibitory concentration (IC(50)) of 3mug/ml, while oxylipin 1 exhibited the highest inhibition at IC(50)=0.478mug/ml. CONCLUSIONS: In this study we report the biological activity of extracts and (3S)-16,17-didehydrofalcarinol (1), obtained from Tridax procumbens, on the promastigote form of Leishmania mexicana, with no effect upon mammalian cells.

PMID: 19429313 [PubMed - as supplied by publisher]

7: Vaccine. 2009 May 11;27(21):2884-90. Epub 2009 Mar 9.Click here to read

Leishmania infantum sterol 24-c-methyltransferase formulated with MPL-SE induces cross-protection against L. major infection.

Goto Y, Bhatia A, Raman VS, Vidal SE, Bertholet S, Coler RN, Howard RF, Reed SG.

Infectious Disease Research Institute, 1124 Columbia St, Suite 400, Seattle, WA 98104, USA.

The enzyme sterol 24-c-methyltranferase (SMT) is required for the biosynthesis of ergosterol, the major membrane sterol in Leishmania parasites. SMT and ergosterol are not found in mammals, so this protein may be an attractive target for anti-leishmanial vaccines and drugs. We have previously demonstrated that SMT from L. infantum, which causes visceral leishmaniasis, is a protective antigen against this parasite. Because this protein is highly conserved among Leishmania species, we evaluated the potential of SMT to cross-protect against a different form of leishmaniasis. Here, we show that immunization with L. infantum SMT, formulated with monophosphoryl lipid A in stable emulsion (MPL-SE), protects mice from cutaneous leishmaniasis caused by L. major. In BALB/c mice the vaccine preparation induced antigen-specific multi-functional CD4(+) T cells capable of producing IFN-gamma, IL-2, and/or TNF-alpha upon antigen re-exposure, and MPL-SE was indispensable to direct immune responses to SMT towards Th1. Mice immunized with the SMT/MPL-SE vaccine developed significantly smaller lesions following ear challenge with L. major. These results suggest that SMT is a promising vaccine antigen for multiple forms of leishmaniasis.

PMID: 19428898 [PubMed - in process]

8: Vaccine. 2009 Apr 28;27(19):2554-62. Epub 2009 Feb 10.Click here to read

Qualitative differences in the early immune response to live and killed Leishmania major: Implications for vaccination strategies against Leishmaniasis.

Okwor I, Liu D, Uzonna J.

Department of Immunology, University of Manitoba, Winnipeg, MB, Canada.

Recovery from natural or deliberate infection with Leishmania major leads to the development of lifelong immunity against rechallenge infections. In contrast, vaccination with killed parasites or defined leishmanial antigens generally induces only short-term protection. The reasons for this difference are currently not known but may be related to differences in the quality of the early immune responses to live and killed parasites. Here, we report that live and killed L. major parasites elicit comparable early inflammatory response as evidenced by influx and/or proliferation of cells in the draining lymph nodes (dLNs). In contrast, the early cytokine responses were qualitatively different. Cells from mice inoculated with killed parasites produced significantly more antigen-specific IL-4 and less IFN-gamma than those from mice injected with live parasites. Inclusion of CpG ODN into killed parasite preparations changed the early response to killed parasites from IL-4 to a predominantly IFN-gamma response, resulting in better protection following secondary high dose virulent L. major challenge. Interestingly, CpG-mediated enhancement of killed parasites-induced protection was short-lived and waned after 12 weeks. Taken together, these results suggest that the nature of primary immunity induced by killed and live parasites are qualitatively different and that these differences may account for the differential protection seen in mice following vaccination with live and killed parasites. They further suggest that modulating the early response with an appropriate adjuvant could enhance efficacy of killed parasite vaccines.

PMID: 19428861 [PubMed - in process]

9: Mol Biochem Parasitol. 2009 Jun;165(2):170-9. Epub 2009 Feb 13.Click here to read

Proline racemases are conserved mitogens: characterization of a Trypanosoma vivax proline racemase.

Chamond N, Cosson A, Coatnoan N, Minoprio P.

Institut Pasteur, Laboratoire d'Immunobiologie des Infections à Trypanosoma, Département d'Immunologie, Paris, France.

Trypanosoma cruzi proline racemases (TcPRAC) are the only eukaryotic proline racemases described so far. Except their role in the interconversion of free L- and D-proline enantiomers, parasite TcPRACs are involved in major T. cruzi biological pathways. These essential enzymes are implicated in the process of parasite differentiation and the acquisition of virulence during metacyclogenesis and are currently considered as key targets for drug development against Chagas' disease. In this study, we searched for the presence of TcPRAC gene homologues among other trypanosomatid genomes. Despite the high degree of gene synteny observed in Kinetoplastidae genomes, PRAC genes are missing in Trypanosoma brucei, Trypanosoma congolense and Leishmania spp. genomes. Interestingly, we identified a hypothetical PRAC gene in Trypanosoma vivax that is the major hemoparasite responsible for livestock trypanosomiasis, a serious economical impact for most of African and South American countries. We report here that the product of this T. vivax gene is bona fide a proline racemase with an activity comparable to the one we described previously for TcPRAC. Inhibition studies using the pyrrole-2-carboxylic acid confirmed that this compound is a competitive inhibitor for both TcPRAC and TvPRAC enzymes. Similarly to TcPRAC and all members of the racemase family studied so far in other pathogenic and nosocomial bacteria, our results show that TvPRAC is a T-cell-independent B-cell mitogen. Therefore the product of the novel TvPRAC gene identified in T. vivax and reported herein has the potential to be used as a drug target for this parasite-based trypanosomiasis.

PMID: 19428664 [PubMed - in process]

10: Mol Biochem Parasitol. 2009 Jun;165(2):142-52. Epub 2009 Feb 6.Click here to read

Selective amplification of maxicircle classes during the life cycle of Leishmania major.

Flegontov PN, Zhirenkina EN, Gerasimov ES, Ponirovsky EN, Strelkova MV, Kolesnikov AA.

Department of Molecular Biology, Lomonosov Moscow State University, Moscow, Russia.

The kinetoplast genome contains several thousands of minicircles of various sequence classes and several scores of maxicircles. We demonstrated that maxicircles are heterogeneous in clonal cultures of Leishmania major, and, therefore, probably heterogeneous (heteroplasmic) within the kinetoplast. Sequence heterogeneity was observed in a non-coding fragment upstream of the 12S rRNA gene. We identified about 20 stable variants of this fragment, which were composed of one to five non-identical repeats 200-300bp in length. Promastigote-to-amastigote and amastigote-to-promastigote differentiation was often accompanied by shifts in abundance of some maxicircle classes. Reversion to promastigote-specific maxicircle patterns was usually observed in the life cycle (promastigote-amastigote-promastigote), however there were many exceptions.

PMID: 19428661 [PubMed - in process]

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