Tuesday, April 21, 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 10

1: Int J Dev Biol. 2009 Apr 2. [Epub ahead of print]

The conserved role of sirtuins in chromatin regulation.

Vaquero A.

Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program (PEBC), ICREA and Catalan Institute of Oncology (ICO)/IDiBELL, Barcelona, Spain.

The members of the Sir2 family, or Sirtuins, have garnered considerable attention because of their key roles as metabolic sensors and mediators of cell survival under stress. Sirtuins may play roles in myriad human pathologies such as cancer, neurological diseases, malaria, leishmaniasis and hormone-related disorders. They are present from prokaryotes to humans and show a high degree of functional diversification that has led to two different enzymatic activities, a wide range of substrates and a highly diversified pattern of cellular localization. Throughout chromatin evolution, Sirtuins have maintained an intimate functional relationship in regulating its structure and function via their targeting of histones, particularly H4K16Ac, as well as other non-histone chromatin proteins. This link permitted fast communication from metabolic fluctuations to chromatin allowing efficient adaptation to environmental stimuli. Therefore, understanding the common path of Sirtuins and chromatin development over the course of evolution might be important for understanding not only the remarkable diversity of functions of these proteins in mammals, but also the path followed by chromatin evolution. Herein is provided an overview of current knowledge of Sirtuin function, from bacteria to humans, including a discussion on its implications for chromatin dynamics, organization and integrity.

PMID: 19378253 [PubMed - as supplied by publisher]

2: J Antimicrob Chemother. 2009 Apr 17. [Epub ahead of print]

Quinacrine and a novel apigenin dimer can synergistically increase the pentamidine susceptibility of the protozoan parasite Leishmania.

Wong IL, Chan KF, Zhao Y, Chan TH, Chow LM.

Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR.

Objectives The aim of this study was to investigate the synergistic effect of quinacrine and a novel apigenin dimer (compound 9d) on reversing pentamidine resistance of Leishmania parasites. Methods Pentamidine-resistant cell lines, LePentR50 and LdAG83PentR50, were generated by gradually increasing pentamidine pressure on wild-type promastigotes. We tested the effects of different combinations of quinacrine and an apigenin dimer on modulating the pentamidine resistance levels of LePentR50 and LdAG83PentR50 using an MTS proliferation assay. We then measured the accumulation level of pentamidine using HPLC. The fractional inhibitory concentration index (FICI) method was used to evaluate the interaction between quinacrine and the apigenin dimer on reversing pentamidine resistance in Leishmania. Results LePentR50 and LdAG83PentR50 promastigotes were approximately 8.6- and 4.6-fold more resistant to pentamidine than their wild-type parents. Amastigotes derived from LePentR50 and LdAG83PentR50 were also pentamidine-resistant. We found that quinacrine can increase the susceptibility of Leishmania to pentamidine. Quinacrine, when used at 6 microM, can increase the IC(50) of pentamidine by 3.8-, 3.4-, 3.5- and 6.3-fold in wild-type Leishmania enriettii Le, LePentR50, wild-type Leishmania donovani LdAG83 and LdAG83PentR50, respectively. Quinine, quinidine and verapamil did not show any sensitizing effect. The sensitizing effect of quinacrine was: (i) dose-dependent; (ii) not associated with an increase in pentamidine accumulation; and (iii) only observed in pentamidine-resistant but not sodium stibogluconate-resistant or vinblastine-resistant parasites. Other than quinacrine, we also found that an apigenin dimer (compound 9d), previously shown to be able to inhibit ABCB1-mediated cancer drug resistance in mammalian cells, can also increase the pentamidine susceptibility of Leishmania. 9d, when used at 6 microM, can increase the IC(50) of pentamidine by 2.5-, 4.2-, 1.6- and 1.9-fold in Le, LePentR50, LdAG83 and LdAG83PentR50, respectively. Unlike quinacrine, sensitization by 9d was accompanied by an increase in pentamidine accumulation, presumably due to the inhibition of an ABC transporter. Using the FICI method, we found that quinacrine and 9d can act synergistically. When they are used in a 1:1 ratio, they sensitize LePentR50 to pentamidine by 19-fold, with an FICI of 0.48 (P < 0.005), indicating that they might act synergistically. Conclusions Our findings support the notion that the pentamidine susceptibility of Leishmania is mediated by multiple targets. Quinacrine and apigenin dimer 9d, each inhibiting its own target, can have a synergistic effect when used together to sensitize Leishmania to pentamidine.

PMID: 19377065 [PubMed - as supplied by publisher]

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3: Microbes Infect. 2009 Apr 16. [Epub ahead of print]

The paraphyletic composition of Leishmania donovani zymodeme MON-37 revealed by multilocus microsatellite typing.

Alam MZ, Haralambous C, Kuhls K, Gouzelou E, Sgouras D, Soteriadou K, Schnur L, Pratlong F, Schönian G.

Institut für Mikrobiologie und Hygiene, Charité Universitätsmedizin Berlin, Dorotheenstr. 96, 10117 Berlin, Germany; Department of Parasitology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh.

Multilocus microsatellite typing (MLMT) was employed to compare strains of Leishmania donovani belonging to the MON-37 zymodeme (MON-37 strains) from Cyprus and Israel to MON-37 strains from the Indian subcontinent, the Middle East, China and East Africa as well as strains of other zymodemes. The MLMT data were processed with a distance-based method for construction of phylogenetic trees, factorial correspondence analysis and a Bayesian model-based clustering algorithm. All three approaches assigned the MON-37 strains to different distantly related genetically defined subgroups, corresponding to their geographical origin. Specifically, the Kenyan, Sri Lankan and Indian MON-37 strains were genetically closer to strains of other zymodemes from the same regions than to MON-37 strains from other areas. MON-37 strains from Cyprus and Israel were clearly different not only among themselves, but also compared to all the other MON-37 strains studied and could, therefore, be autochthonous. This study showed that the zymodeme MON-37 is paraphyletic and does not reflect the genetic relationship between strains of different geographical origin.

PMID: 19376262 [PubMed - as supplied by publisher]

4: Indian J Biochem Biophys. 2009 Feb;46(1):86-92.

Functionality of drug efflux pumps in antimonial resistant Leishmania donovani field isolates.

Mandal G, Sarkar A, Saha P, Singh N, Sundar S, Chatterjee M.

Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, 244B Acharya JC Bose Road, Kolkata 700 020 India.

The recent upsurge of antimony (Sb) resistance is a major impediment to successful chemotherapy of visceral leishmaniasis (VL). Mechanisms involved in antimony resistance have demonstrated an upregulation of drug efflux pumps; however, the biological role drug efflux pumps in clinical isolates remains to be substantiated. Thus, in this study, the functionality of drug efflux pumps was measured in promastigotes and axenic amastigotes isolated from VL patients, who were either Sb-sensitive (AG83, 2001 and MC9) or resistant (NS2, 41 and GE1) using rhodamine123 as a substrate for multidrug resistant (MDR) pumps and calcein as a substrate for multidrug resistance-associated proteins (MRP) respectively; their specificity was confirmed using established blockers. Sb-resistant (Sb-R) isolates accumulated higher amounts of R123, as compared to Sb-sensitive (Sb-S) isolates. Verapamil, a MDR inhibitor failed to alter R123 accumulation, suggesting absence of classical MDR activity. In Sb-R isolates, both promastigotes and axenic amastigotes accumulated significantly lower amounts of calcein than Sb-S isolates and probenecid, an established pan MRP blocker, marginally increased calcein accumulation. Depletion of ATP dramatically increased calcein accumulation primarily in Sb-R isolates, indicating existence of a MRP-like pump, which was more active in Sb-R isolates. In conclusion, our data suggested that overfunctioning of a MRP-like pump contributed towards generation of Sb-R phenotype in L. donovani field isolates.

PMID: 19374259 [PubMed - in process]

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5: Acta Trop. 2009 Apr;110(1):65-74.LinkOut

Unique behavior of Trypanosoma dionisii interacting with mammalian cells: invasion, intracellular growth, and nuclear localization.

Oliveira MP, Cortez M, Maeda FY, Fernandes MC, Haapalainen EF, Yoshida N, Mortara RA.

Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo, Rua Botucatu 862, São Paulo, Brazil.

The phylogenetic proximity between Trypanosoma cruzi and Trypanosoma (Schizotrypanum) dionisii suggests that these parasites might explore similar strategies to complete their life cycles. T. cruzi is the etiological agent of the life-threatening Chagas' disease, whereas T. dionisii is a bat trypanosome and probably not capable of infecting humans. Here we sought to compare mammalian cell invasion and intracellular traffic of both trypanosomes and determine the differences and similarities in this process. The results presented demonstrate that T. dionisii is highly infective in vitro, particularly when the infection process occurs without serum and that the invasion is similarly affected by agents known to interfere with T. cruzi invasion process. Our results indicate that the formation of lysosomal-enriched compartments is part of a cell-invasion mechanism retained by related trypanosomatids, and that residence and further escape from a lysosomal compartment may be a common requisite for successful infection. During intracellular growth, parasites share a few epitopes with T. cruzi amastigotes and trypomastigotes. Unexpectedly, in heavily infected cells, amastigotes and trypomastigotes were found inside the host cell nucleus. These findings suggest that T. dionisii, although sharing some features in host cell invasion with T. cruzi, has unique behaviors that deserve to be further explored.

PMID: 19283898 [PubMed - indexed for MEDLINE]

6: Acta Trop. 2009 Apr;110(1):57-64.LinkOut

Karyotype variability in KP1(+) and KP1(-) strains of Trypanosoma rangeli isolated in Brazil and Colombia.

Cabrine-Santos M, Ferreira KA, Tosi LR, Lages-Silva E, Ramirez LE, Pedrosa AL.

Departamento de Ciências Biológicas, Universidade Federal do Triângulo Mineiro, Av. Frei Paulino 30, Uberaba, Minas Gerais, Brazil.

In the present study, the molecular karyotypes of 12 KP1(+) and KP1(-) Trypanosoma rangeli strains were determined and 10 different molecular markers were hybridized to the chromosomes of the parasite, including seven obtained from T. rangeli [ubiquitin hydrolase (UH), a predicted serine/threonine protein kinase (STK), hexose transporter, hypothetical protein, three anonymous sequences] and three from Trypanosoma cruzi [ubiquitin-conjugating enzyme E2 (UBE2), ribosomal RNA methyltransferase (rRNAmtr), proteasome non-ATPase regulatory subunit 6 (PSMD6)]. Despite intraspecific variation, analysis of the karyotype profiles permitted the division of the T. rangeli strains into two groups coinciding with the KP1(+) and KP1(-) genotypes. Southern blot hybridization showed that, except for the hexose transporter probe, all other probes produced distinct patterns able to differentiate the KP1(+) and KP1(-) genotypes. The UH, STK and An-1A04 probes exclusively hybridized to the chromosomes of KP1(+) strains and can be used as markers of this group. In addition, the UBE2, rRNAmtr and PSMD6 markers, which are present in a conserved region in all trypanosomatid species sequenced so far, co-hybridized to the same T. rangeli chromosomal bands, suggesting the occurrence of gene synteny in these species. The finding of distinct molecular karyotypes in KP1(+) and KP1(-) strains of T. rangeli is noteworthy and might be used as a new approach to the study of genetic variability in this parasite. Together with the Southern blot hybridization results, these findings demonstrate that differences at the kDNA level might be associated with variations in nuclear DNA.

PMID: 19283897 [PubMed - indexed for MEDLINE]

7: Acta Trop. 2009 Apr;110(1):15-21. Epub 2008 Dec 24.Click here to read Nucleotide, LinkOut

Haplotype identification within Trypanosoma cruzi I in Colombian isolates from several reservoirs, vectors and humans.

Falla A, Herrera C, Fajardo A, Montilla M, Vallejo GA, Guhl F.

Centro de Investigaciones en Microbiología y Parasitología Tropical, Universidad de Los Andes, Bogotá, Colombia.

Genetic variability in the Trypanosoma cruzi I group has recently been revealed in Colombian isolates from humans, reservoirs and vectors. Genomic rearrangements and the polymorphic regions in taxonomic markers, such as the miniexon gene, have led to the development of molecular tools to identify phylogenetic haplotypes in T. cruzi isolates. From genetic polymorphisms found in T. cruzi I isolates, they have been classified into four haplotypes according to their epidemiologic transmission cycles. Haplotype Ia is associated with domestic isolates, from Rhodnius prolixus; haplotype Ib, with the domestic and peridomestic cycle, mainly associated with Triatoma dimidiata; haplotype Ic is a poorly characterized group, which has been associated with the peridomestic cycle; and haplotype Id has been related to the sylvatic cycle. In order to demonstrate that the circulating T. cruzi I isolates in Colombia can be classified in the four proposed haplotypes, specific primers were designed on polymorphic regions of the miniexon gene's intergenic sequences. This set of primers allowed the molecular characterization of 33 Colombian isolates, classifying them into three of the four proposed haplotypes (Ia, Ib and Id). Results obtained from maximum parsimony and maximum-likelihood-based phylogenetic analyses correlated with the molecular classification of the isolates and their transmission cycles. This study brings insights into the Chagas disease epidemiology and the parasite's transmission dynamics.

PMID: 19135020 [PubMed - indexed for MEDLINE]

8: Acta Trop. 2009 Apr;110(1):7-14. Epub 2008 Nov 20.Click here to read LinkOut

Biological activity of 1,2,3,4-tetrahydro-beta-carboline-3-carboxamides against Trypanosoma cruzi.

Valdez RH, Tonin LT, Ueda-Nakamura T, Dias Filho BP, Morgado-Diaz JA, Sarragiotto MH, Nakamura CV.

Programa de Pós-graduação em Microbiologia, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid, Campus Universitário, Londrina, Paraná, Brazil.

Several beta-carboline compounds were evaluated for in vitro trypanocidal activity against Trypanosoma cruzi and their potential toxic effects was also assessed. beta-Carboline derivative 4 showed good activity against epimastigote, trypomastigote, and amastigote forms of T. cruzi, with a dose-dependent inhibitory effect. It showed an IC(50) of 14.9 microM against the epimastigote form and an EC(50) of 45 microM and 33 microM against trypomastigote and amastigote forms, respectively. Additionally, 4 was able to be active on mammalian cell-protozoan interaction, reducing the number of infected cells and the number of internalized parasites. The compound showed low cytotoxicity, with a selective index 31 times higher to the parasite than for mammalian cells. In human red-blood cells beta-Carboline 4 at 14.9 microM not caused haemolysis. Observed at electron microscopy 4-treated epimastigotes showed abnormal swelling of the mitochondrion, a diffuse kinetoplast, and distortions of the parasite cell body. The present data support the potential effect of this class of compounds against T. cruzi and encourage further experiments in vitro to evaluate the action mechanism of this drug and also with in vivo models.

PMID: 19063858 [PubMed - indexed for MEDLINE]

9: Clin Biochem. 2009 Jan;42(1-2):12-6. Epub 2008 Nov 5.Click here to read LinkOut

Seroprevalence to Trypanosoma cruzi in rural communities of the state of Querétaro (Mexico): statistical evaluation of tests.

Villagrán ME, Sánchez-Moreno M, Marín C, Uribe M, de la Cruz JJ, de Diego JA.

Laboratorio de Tripanosomiasis Americana, Facultad de Química, UAQ, CHIVO I.S.S.S.T.E., México.

OBJECTIVES: The detection of anti-Trypanosoma cruzi antibodies has become one of the priorities of the clinical establishments in the health sector, due both to the increase in positive cases found in transfusion centres as well as to the appearance of patients with characteristic Chagas cardiopathies that seek emergency treatment in the main hospitals of Querétaro (Mexico). DESIGN AND METHODS: The present study seeks to establish for the first time the infection level of Trypanosoma cruzi, in the rural communities of this state and implement the preventive measures necessary to control and/or eradicate this infection. A transversal study was conducted, examining seriologically 1029 blood samples of the inhabitants of rural areas of the state of Querétaro, to detect anti-Trypanosoma cruzi antibodies. RESULTS: The indirect serological diagnostic tests were indirect hemagglutination, enzymo-immunoenzymatic absorbent, recombinant ELISA, and indirect immunofluorescence. For the diagnostic evaluation of serological tests used, ELISA was considered the control test. CONCLUSIONS: The first conclusion was that the two tests with the greatest serological reactivity were ELISA and recombinant ELISA, followed by IFA and IHA, respectively, with the final percentage of positives being 6.6%, far above the national mean of seroprevalence in Mexico (1.6%). On the other hand, the sensitivity, specificity, VP+, VP-, percentage of concordance and Kappa index of the recombinant ELISA tests, IFA, and IHA were determined against the control ELISA. It was found that ELISA and recombinant ELISA presented a greater sensitivity level, as well as the highest values for the different parameters studied.

PMID: 19014924 [PubMed - indexed for MEDLINE]

10: Antimicrob Agents Chemother. 2009 Jan;53(1):174-9. Epub 2008 Nov 10.Click here to read LinkOut

Absence of CD4+ T lymphocytes, CD8+ T lymphocytes, or B lymphocytes has different effects on the efficacy of posaconazole and benznidazole in treatment of experimental acute Trypanosoma cruzi infection.

Ferraz ML, Gazzinelli RT, Alves RO, Urbina JA, Romanha AJ.

Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisa René Rachou, Belo Horizonte, MG, Brazil.

We investigated the influence of CD4(+) T lymphocytes, CD8(+) T lymphocytes, and B lymphocytes on the efficacy of posaconazole (POS) and the reference drug benznidazole (BZ) during treatment of acute Trypanosoma cruzi infection in a murine model. Wild-type mice infected with T. cruzi and treated with POS or BZ presented no parasitemia, 100% survival, and 86 to 89% cure rates, defined as the percentages of animals with negative hemocultures at the end of the observation period. CD4(+)-T-lymphocyte-knockout (KO) mice infected with T. cruzi and treated with BZ or POS controlled parasitemia during treatment, although circulating parasites reappeared after drug pressure cessation, leading to only a 6% survival rate and no cure. CD8(+)-T-lymphocyte-KO mice infected with T. cruzi and treated with POS or BZ had intermediate results, displaying discrete parasitemia after the treatment was ended, 81 and 86% survival, and cure rates of 31 and 66%, respectively. B-lymphocyte-KO mice infected with T. cruzi and treated with BZ relapsed with parasitemia 1 week after the end of treatment and had a 67% survival rate and only a 22% cure rate. In contrast, the activity of POS was much less affected in these animals, with permanent suppression of parasitemia, 100% survival, and a 71% cure rate. Our results demonstrate that abrogation of different lymphocytes' activities has distinct effects on the efficacy of POS and BZ in this experimental model, probably reflecting different parasite stages preferentially targeted by the two drugs and distinct cooperation patterns with the host immune system.

PMID: 19001113 [PubMed - indexed for MEDLINE]

PMCID: PMC2612170 [Available on 2009/07/01]

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  • Posaconazole (Noxafil® )

    Posaconazole is used to prevent serious fungal infections in people with a weakened ability to fight infection. Posaconazole is also used to treat yeast infections of the mouth and throat including yeast infections that ...

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