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Sent on Friday, 2011 Nov 11Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
| 1. | PLoS One. 2011;6(11):e26835. Epub 2011 Nov 3.Determinants of the differential antizyme-binding affinity of ornithine decarboxylase.Liu YC, Hsu DH, Huang CL, Liu YL, Liu GY, Hung HC.SourceDepartment of Life Sciences and Institute of Genomics and Bioinformatics, National Chung-Hsing University, Taichung, Taiwan. AbstractOrnithine decarboxylase (ODC) is a ubiquitous enzyme that is conserved in all species from bacteria to humans. Mammalian ODC is degraded by the proteasome in a ubiquitin-independent manner by direct binding to the antizyme (AZ). In contrast, Trypanosoma brucei ODC has a low binding affinity toward AZ. In this study, we identified key amino acid residues that govern the differential AZ binding affinity of human and Trypanosoma brucei ODC. Multiple sequence alignments of the ODC putative AZ-binding site highlights several key amino acid residues that are different between the human and Trypanosoma brucei ODC protein sequences, including residue 119, 124,125, 129, 136, 137 and 140 (the numbers is for human ODC). We generated a septuple human ODC mutant protein where these seven bases were mutated to match the Trypanosoma brucei ODC protein sequence. The septuple mutant protein was much less sensitive to AZ inhibition compared to the WT protein, suggesting that these amino acid residues play a role in human ODC-AZ binding. Additional experiments with sextuple mutants suggest that residue 137 plays a direct role in AZ binding, and residues 119 and 140 play secondary roles in AZ binding. The dissociation constants were also calculated to quantify the affinity of the ODC-AZ binding interaction. The K(d) value for the wild type ODC protein-AZ heterodimer ([ODC_WT]-AZ) is approximately 0.22 μM, while the K(d) value for the septuple mutant-AZ heterodimer ([ODC_7M]-AZ) is approximately 12.4 μM. The greater than 50-fold increase in [ODC_7M]-AZ binding affinity shows that the ODC-7M enzyme has a much lower binding affinity toward AZ. For the mutant proteins ODC_7M(-Q119H) and ODC_7M(-V137D), the K(d) was 1.4 and 1.2 μM, respectively. These affinities are 6-fold higher than the WT_ODC K(d), which suggests that residues 119 and 137 play a role in AZ binding. |
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| 2. | PLoS One. 2011;6(11):e26508. Epub 2011 Nov 2.An Essential Farnesylated Kinesin in Trypanosoma brucei.Engelson EJ, Buckner FS, Van Voorhis WC.SourceDepartment of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, United States of America. AbstractKinesins are a family of motor proteins conserved throughout eukaryotes. In our present study we characterize a novel kinesin, Kinesin(CaaX), orthologs of which are only found in the kinetoplastids and not other eukaryotes. Kinesin(CaaX) has the CVIM amino acids at the C-terminus, and CVIM was previously shown to be an ideal signal for protein farnesylation in T. brucei. In this study we show Kinesin(CaaX) is farnesylated using radiolabeling studies and that farnesylation is dependent on the CVIM motif. Using RNA interference, we show Kinesin(CaaX) is essential for T. brucei proliferation. Additionally RNAi Kinesin(CaaX) depleted T. brucei are 4 fold more sensitive to the protein farneysltransferase (PFT) inhibitor LN-59, suggesting that Kinesin(CaaX) is a target of PFT inhibitors' action to block proliferation of T. brucei. Using tetracycline-induced exogenous tagged Kinesin(CaaX) and Kinesin(CVIMdeletion) (non-farnesylated Kinesin) expression lines in T. brucei, we demonstrate Kinesin(CaaX) is farnesylated in T. brucei cells and this farnesylation has functional effects. In cells expressing a CaaX-deleted version of Kinesin, the localization is more diffuse which suggests correct localization depends on farnesylation. Through our investigation of cell cycle, nucleus and kinetoplast quantitation and immunofluorescence assays an important role is suggested for Kinesin(CaaX) in the separation of nuclei and kinetoplasts during and after they have been replicated. Taken together, our work suggests Kinesin(CaaX) is a target of PFT inhibition of T. brucei cell proliferation and Kinesin(CaaX) functions through both the motor and farnesyl groups. |
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| 3. | Mar Drugs. 2011;9(10):1902-13. Epub 2011 Oct 14.Antiparasitic Bromotyrosine Derivatives from the Marine Sponge Verongula rigida.Galeano E, Thomas OP, Robledo S, Munoz D, Martinez A.SourceMarine Natural Products Research Group, Pharmaceutical Chemistry Faculty, University of Antioquia, Medellin AA 1226, Colombia; E-Mail: amart@farmacia.udea.edu.co. AbstractNine bromotyrosine-derived compounds were isolated from the Caribbean marine sponge Verongula rigida. Two of them, aeroplysinin-1 (1) and dihydroxyaerothionin (2), are known compounds for this species, and the other seven are unknown compounds for this species, namely: 3,5-dibromo-N,N,N-trimethyltyraminium (3), 3,5-dibromo-N,N,N, O-tetramethyltyraminium (4), purealidin R (5), 19-deoxyfistularin 3 (6), purealidin B (7), 11-hydroxyaerothionin (8) and fistularin-3 (9). Structural determination of the isolated compounds was performed using one- and two-dimensional NMR, MS and other spectroscopy data. All isolated compounds were screened for their in vitro activity against three parasitic protozoa: Leishmania panamensis, Plasmodium falciparum and Trypanosoma cruzi. Compounds 7 and 8 showed selective antiparasitic activity at 10 and 5 μM against Leishmania and Plasmodium parasites, respectively. Cytotoxicity of these compounds on a human promonocytic cell line was also assessed. |
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| 4. | Mar Drugs. 2011;9(10):1682-97. Epub 2011 Sep 26.New tetromycin derivatives with anti-trypanosomal and protease inhibitory activities.Pimentel-Elardo SM, Buback V, Gulder TA, Bugni TS, Reppart J, Bringmann G, Ireland CM, Schirmeister T, Hentschel U.SourceJulius-von-Sachs Institute for Biological Sciences, University of Würzburg, Julius-von-Sachs-Platz 3, Würzburg 97082, Germany; E-Mail: ute.hentschel@uni-wuerzburg.de. AbstractFour new tetromycin derivatives, tetromycins 1-4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001(T) cultivated from the Mediterranean sponge Axinella polypoides. Structures were assigned using extensive 1D and 2D NMR spectroscopy as well as HRESIMS analysis. The compounds were tested for antiparasitic activities against Leishmania major and Trypanosoma brucei, and for protease inhibition against several cysteine proteases such as falcipain, rhodesain, cathepsin L, cathepsin B, and viral proteases SARS-CoV M(pro), and PL(pro). The compounds showed antiparasitic activities against T. brucei and time-dependent inhibition of cathepsin L-like proteases with K(i) values in the low micromolar range. |
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| 5. | J R Soc Interface. 2011 Nov 9. [Epub ahead of print]Predicting the effect of climate change on African trypanosomiasis: integrating epidemio logy with parasite and vector biology.Moore S, Shrestha S, Tomlinson KW, Vuong H.SourceNational Center for Atmospheric Research, Boulder, CO 80307, USA. AbstractClimate warming over the next century is expected to have a large impact on the interactions between pathogens and their animal and human hosts. Vector-borne diseases are particularly sensitive to warming because temperature changes can alter vector development rates, shift their geographical distribution and alter transmission dynamics. For this reason, African trypanosomiasis (sleeping sickness), a vector-borne disease of humans and animals, was recently identified as one of the 12 infectious diseases likely to spread owing to climate change. We combine a variety of direct effects of temperature on vector ecology, vector biology and vector-parasite interactions via a disease transmission model and extrapolate the potential compounding effects of projected warming on the epidemiology of African trypanosomiasis. The model predicts that epidemics can occur when mean temperatures are between 20.7°C and 26.1°C. Our model does not predict a large-range expansion, but rather a large shift of up to 60 per cent in the geographical extent of the range. The model also predicts that 46-77 million additional people may be at risk of exposure by 2090. Future research could expand our analysis to include other environmental factors that influence tsetse populations and disease transmission such as humidity, as well as changes to human, livestock and wildlife distributions. The modelling approach presented here provides a framework for using the climate-sensitive aspects of vector and pathogen biology to predict changes in disease prevalence and risk owing to climate change. |
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| 6. | Extremophiles. 2011 Nov 10. [Epub ahead of print]Leishmanicidal an d antitumoral activities of endophytic fungi associated with the Antarctic angiosperms Deschampsia antarctica Desv. and Colobanthus quitensis (Kunth) Bartl.Santiago IF, Alves TM, Rabello A, Sales Junior PA, Romanha AJ, Zani CL, Rosa CA, Rosa LH.SourceDepartamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, P.O. Box 486, Belo Horizonte, MG, 31270-901, Brazil. AbstractA total of 564 isolates of endophytic fungi were recovered from the plants Deschampsia antarctica and Colobanthus quitensis collected from Antarctica. The isolates were screened against parasites Leishmania amazonensis and Trypanosoma cruzi and against the human tumour cell lines. Of the 313 fungal isolates obtained from D. antarctica and 251 from C. quitensis, 25 displayed biological activity. Nineteen extracts displayed leishmanicidal activity, and six inhibited the growth of at least one tumour cell line. These fungi belong to 19 taxa of the genera Alternaria, Antarctomyces, Cadophora, Davidiella, Helgardia, Herpotrichia, Microdochium, Oculimacula, Phaeosphaeria and one unidentified fungus. Extracts of 12 fungal isolates inhibited the proliferation of L. amazonesis at a low IC(50) of between 0.2 and 12.5 μg ml(-1). The fungus Phaeosphaeria herpotrichoides displayed only leishmanicidal activity with an IC(50) of 0.2 μg ml(-1), which is equivalent to the inhibitory value of amphotericin B. The extract of Microdochium phragmitis displayed specific cytotoxic activity against the UACC-62 cell line with an IC(50) value of 12.5 μg ml(-1). Our results indicate that the unique angiosperms living in Antarctica shelter an interesting bioactive fungal community that is able to produce antiprotozoal and antitumoral molecules. These molecules may be used to develop new leishmanicidal and anticancer drugs. |
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| 7. | ISME J. 2011 Nov 10. doi: 10.1038/ismej.2011.138. [Epub ahead of print]Analysis of the community structure of abyssal kinetoplastids revealed similar communities at larger spatial scales.Salani FS, Arndt H, Hausmann K, Nitsche F, Scheckenbach F.SourceDepartment of General Ecology and Limnology, Institute for Zoology, Biocenter, University of Cologne, Cologne, Germany. AbstractKnowledge of the spatial scales of diversity is necessary to evaluate the mechanisms driving biodiversity and biogeography in the vast but poorly understood deep sea. The community structure of kinetoplastids, an important group of microbial eukaryotes belonging to the Euglenozoa, from all abyssal plains of the South Atlantic and two areas of the eastern Mediterranean was studied using partial small subunit ribosomal DNA gene clone libraries. A total of 1364 clones from 10 different regions were retrieved. The analysis revealed statistically not distinguishable communities from both the South-East Atlantic (Angola and Guinea Basin) and the South-West Atlantic (Angola and Brazil Basin) at spatial scales of 1000-3000 km, whereas all other communities were significantly differentiated from one another. It seems likely that multiple processes operate at the same time to shape communities of deep-sea kinetoplastids. Nevertheless, constant and homogenous environmental conditions over large spatial scales at abyssal depths, together with high dispersal capabilities of microbial eukaryotes, maintain best the results of statistically indistinguishable communities at larger spatial scales. |
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| 8. | Photochem Photobiol. 2011 Nov 9. doi: 10.1111/j.1751-1097.2011.01034.x. [Epub ahead of print]New Application for Expanded Porphyrins: Sapphyrin and Heterosapphyrins as Inhibitors of Leishmania Parasites.Hooker JD, Nguyen VH, Taylor VM, Cedeño DL, Lash TD, Jones MA, Robledo SM, Vélez ID.SourceDepartment of Chemistry, Illinois State University, Normal, Illinois 61790-4160 PECET, School of Medicine, Universidad de Antioquia, Medellin, Colombia. AbstractSapphyrins and a series of related porphyrinoid macrocycles have been investigated as potential agents for the treatment of leishmaniasis. The effectiveness of the compounds was evaluated in vitro upon incubation with Leishmania tarentolae or L. panamensis amastigotes and promastigotes. Their effectiveness was also assessed against intracellular L. panamensis. The cytotoxicity of the compounds was evaluated in vitro using the U937 human promonocyte cell line. Effectiveness and cytotoxicity were assessed in the presence and absence of visible light to assess the photodynamic activity of the compounds. Sapphyrin and two related heterosapphyrins were shown to be particularly effective as inhibitors of Leishmania. A photodynamic effect was observed, which may be attributed to the formation of reactive oxygen species. Yields of singlet oxygen produced were determined in ethanol solutions by direct measurement of singlet oxygen phosphorescence. Confocal microscopy demonstrated that sapphyrin and related macrocycles were taken up by the Leishmania cells and that their presence induces the formation of mitochondrial superoxide. Sapphyrins have been widely investigated as anticancer agents and we here show activity against the Leishmania parasites. Photochemistry and Photobiology © 2011 American Society for Photobiology. |
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| 9. | J Med Primatol. 2011 Nov 10. doi: 10.1111/j.1600-0684.2011.00523.x. [Epub ahead of print]Lipid metabolism and other metabolic changes in vervet monkeys experimentally infected with Trypanosoma brucei rhodesiense.Gaithuma AK, Karanja SM, Ngotho M, Maathai RG, Kagira JM, Maina NW.SourceDepartment of Biochemistry, Jomo Kenyatta University of Agriculture & Technology, Nairobi, Kenya Department of Tropical and Infectious Diseases, Institute of Primate Research, Karen, Nairobi, Kenya Department of Biochemistry, University of Nairobi, Nairobi, Kenya. AbstractBackground Human African trypanosomiasis is associated with metabolic changes which have not been well characterized. Methods Chlorocebus aethiops were experimentally infected with Trypanosoma brucei rhodesiense and late-stage disease induced at 28 days post-infection. Ear prick blood for glucose determination and blood samples were obtained at weekly intervals for 56 days. Analysis was carried out using dry chemistry analysis. Results In early infection, there was a significant increase in creatine kinase, while during early and transitional stage of infection there was a significant decrease in glucose and high-density lipoprotein and an increase in triglyceride levels. In the late stage, there was a significant increase in both total cholesterol and LDL levels. Conclusions Further investigations should focus on levels of total cholesterol during the follow-up period in curatively treated vervet monkeys. Apart from their importance in disease staging, the changes in lipids levels may also affect the pharmacokinetics of some trypanocides. © 2011 John Wiley & Sons A/S. |
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| 10. | Clin Microbiol Rev. 2011 Jul;24(3):592-630. doi: 10.1128/CMR.00063-10.Pathogenesis of chagas' disease: parasite persistence and autoimmunity.Teixeira AR, Hecht MM, Guimaro MC, Sousa AO, Nitz N.SourceChagas Disease Multidisciplinary Research Laboratory, University of Brasilia, Federal District, Brazil. ateixeir@unb.br AbstractAcute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas' disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas' disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas' disease is achieved with the cross-kingdom chicken model system, which is refractory to T. cruzi infections. The inoculation of T. cruzi into embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8(+) γδ, and CD8α(+) T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas' disease is a genetically driven autoimmune disease. |
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