The Experts below are selected from a list of 216 Experts worldwide ranked by ideXlab platform
Anthony E. Pegg - One of the best experts on this subject based on the ideXlab platform.
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Putrescine activated S-adenosylmethionine decarboxylase from Trypanosoma Brucei Brucei
Molecular and Cellular Biochemistry, 1992Co-Authors: Babu L. Tekwani, Cyrus J. Bacchi, Anthony E. PeggAbstract:Trypanosoma Brucei Brucei contained a S-adenosyl-L-methionine decarboxylase (AdoMetDC) strongly activated by putrescine. The enzyme was also activated to a lesser extent by cadaverine and 1,3-diaminopropane. Spermidine and spermine had no effect on basal activity of the enzyme. However, they interfered with putrescine activation of Trypanosomal AdoMetDC. The Trypanosomal enzyme could not be precipitated with antiserum against human AdoMetDC. The Trypanosomal AdoMetDC enzyme subunit was labeled by reaction with ^35S-decarboxylated AdoMet in the presence of NaCNBH_4, and found to have a molecular weight of 34 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The subunit was readily degraded on storage to a form with a molecular weight of 26 kDa. The specificity of labeling of AdoMetDC by this procedure was confirmed by the prevention of ^35S-decarboxylated S-adenosylmethionine (AdoMet) binding in the presence of specific AdoMetDC inhibitors [either methylglyoxal bis(guanylhydrazone (MGBG), a reversible inhibitor, or 5′-deoxy-5′-[(2-hydrazinoethyl)methylamino]adenosine (MHZEA), an irreversible inactivator]. As compared to human AdoMetDC, the Trypanosomal enzyme showed weaker binding to a column of MGBG-Sepharose and also was significantly less sensitive to inhibition by MGBG and its congener ethylglyoxal bis(guanylhydrazone) (EGBG). Thus, the Trypanosomal AdoMetDC differs significantly from its mammalian and bacterial counterparts and may therefore be exploited as a specific target for chemotherapy of trypanosomiasis.
Elaine Holmes - One of the best experts on this subject based on the ideXlab platform.
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global metabolic responses of mice to Trypanosoma Brucei Brucei infection
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Yulan Wang, Jurg Utzinger, Jasmina Saric, Jia V Li, Jean Burckhardt, Stephan Dirnhofer, Jeremy K Nicholson, Burton H Singer, Reto Brun, Elaine HolmesAbstract:Human African trypanosomiasis (HAT) is transmitted by tsetse flies and, if untreated, is fatal. Treatment depends on infection stage, and early diagnosis is crucial for effective disease management. The systemic host biochemical changes induced by HAT that enable biomarker discovery or relate to therapeutic outcome are largely unknown. We have characterized the multivariate temporal responses of mice to Trypanosoma Brucei Brucei infection, using 1H nuclear magnetic resonance (NMR) spectroscopic metabolic phenotyping of urine and plasma. Marked alterations in plasma metabolic profiles were detected already 1 day postinfection. Elevated plasma concentrations of lactate, branched chain amino acids, and acetylglycoprotein fragments were noted. T. Brucei Brucei-infected mice also had an imbalance of plasma alanine and valine, consistent with differential gluconeogenesis (parasite)-ketogenesis (host) pathway counterflux, involving stimulated host glycolysis, ketogenesis, and enhanced lipid oxidation in the host. Histopathologic evidence of T. Brucei Brucei-induced extramedullary hepatic hemopoiesis, renal interstitial nephritis, and a provoked inflammatory response was also noted. Metabolic disturbance of gut microbiotal activity was associated with infection, as indicated by changes in the urinary concentrations of the microbial co-metabolites, including hippurate. Concluding, parasite infection results in multiple systemic biochemical effects in the host and disturbance of the symbiotic gut microbial metabolic interactions. Investigation of these transgenomic metabolic alterations may underpin the development of new diagnostic criteria and metrics of therapeutic efficacy.
R Kaminsky - One of the best experts on this subject based on the ideXlab platform.
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The effect of verapamil alone and in combination with trypanocides on multidrug-resistant Trypanosoma Brucei Brucei.
Acta Tropica, 1991Co-Authors: R Kaminsky, E ZweygarthAbstract:Abstract Following previous studies of verapamil reversal of multidrug resistance in cancer cells and chloroquine resistance in malaria, the effect of the calcium channel blocker verapamil was investigated on multidrug-resistant and susceptible Trypanosoma Brucei Brucei . Resistance of cloned parasites to diminazene aceturate (Berenil R ) and isometamidium chloride (Samorin R ) was expressed in a cell-free in vitro culture system. Verapamil showed antiTrypanosomal activity against both, multidrug-resistant and susceptible trypanosomes at concentrations above 1 μg/ml. Verapamil did not reverse multidrug resistance when used at concentrations of 0.1 or 1.0 μg/ml in combination with diminazene aceturate or isometamidium chloride. Results obtained in vitro correlate with observations in mice. It is suggested that multidrug resistance in African trypanosomes is due to mechanisms other than those occurring in cancer cells, malaria or South-American trypanosomiasis.
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Evaluation of dl-α-difluoromethylornithine against susceptible and drug-resistant Trypanosoma Brucei Brucei
Acta Tropica, 1991Co-Authors: E Zweygarth, R KaminskyAbstract:Abstract The antiTrypanosomal activity of the ornithine decarboxylase inhibitor dl -α-difluoromethylornithine (DFMO, eflornithine) was tested in ten stocks and one clone of the hemoflagellate Trypanosoma Brucei Brucei in an in vitro system. They showed varying levels of susceptibility to DFMO, their IC 50 (the concentration which inhibited growth by 50%) values ranging from 81–691 μM. Differences in DFMO susceptibility were also demonstrated in mice. Combinations of melarsonyl potassium (mel W; trimelarsan) and DFMO showed an additive effect in vitro in a mel W-susceptible and a mel W-resistant stock, but an antagonistic effect in a mel W- and DFMO-susceptible clone. Combinations of suramin and DFMO showed an antagonistic effect in vitro in a suramin-susceptible clone, but a potentiation in a suramin-resistant stock.
Babu L. Tekwani - One of the best experts on this subject based on the ideXlab platform.
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Putrescine activated S-adenosylmethionine decarboxylase from Trypanosoma Brucei Brucei
Molecular and Cellular Biochemistry, 1992Co-Authors: Babu L. Tekwani, Cyrus J. Bacchi, Anthony E. PeggAbstract:Trypanosoma Brucei Brucei contained a S-adenosyl-L-methionine decarboxylase (AdoMetDC) strongly activated by putrescine. The enzyme was also activated to a lesser extent by cadaverine and 1,3-diaminopropane. Spermidine and spermine had no effect on basal activity of the enzyme. However, they interfered with putrescine activation of Trypanosomal AdoMetDC. The Trypanosomal enzyme could not be precipitated with antiserum against human AdoMetDC. The Trypanosomal AdoMetDC enzyme subunit was labeled by reaction with ^35S-decarboxylated AdoMet in the presence of NaCNBH_4, and found to have a molecular weight of 34 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The subunit was readily degraded on storage to a form with a molecular weight of 26 kDa. The specificity of labeling of AdoMetDC by this procedure was confirmed by the prevention of ^35S-decarboxylated S-adenosylmethionine (AdoMet) binding in the presence of specific AdoMetDC inhibitors [either methylglyoxal bis(guanylhydrazone (MGBG), a reversible inhibitor, or 5′-deoxy-5′-[(2-hydrazinoethyl)methylamino]adenosine (MHZEA), an irreversible inactivator]. As compared to human AdoMetDC, the Trypanosomal enzyme showed weaker binding to a column of MGBG-Sepharose and also was significantly less sensitive to inhibition by MGBG and its congener ethylglyoxal bis(guanylhydrazone) (EGBG). Thus, the Trypanosomal AdoMetDC differs significantly from its mammalian and bacterial counterparts and may therefore be exploited as a specific target for chemotherapy of trypanosomiasis.
E Zweygarth - One of the best experts on this subject based on the ideXlab platform.
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The effect of verapamil alone and in combination with trypanocides on multidrug-resistant Trypanosoma Brucei Brucei.
Acta Tropica, 1991Co-Authors: R Kaminsky, E ZweygarthAbstract:Abstract Following previous studies of verapamil reversal of multidrug resistance in cancer cells and chloroquine resistance in malaria, the effect of the calcium channel blocker verapamil was investigated on multidrug-resistant and susceptible Trypanosoma Brucei Brucei . Resistance of cloned parasites to diminazene aceturate (Berenil R ) and isometamidium chloride (Samorin R ) was expressed in a cell-free in vitro culture system. Verapamil showed antiTrypanosomal activity against both, multidrug-resistant and susceptible trypanosomes at concentrations above 1 μg/ml. Verapamil did not reverse multidrug resistance when used at concentrations of 0.1 or 1.0 μg/ml in combination with diminazene aceturate or isometamidium chloride. Results obtained in vitro correlate with observations in mice. It is suggested that multidrug resistance in African trypanosomes is due to mechanisms other than those occurring in cancer cells, malaria or South-American trypanosomiasis.
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Evaluation of dl-α-difluoromethylornithine against susceptible and drug-resistant Trypanosoma Brucei Brucei
Acta Tropica, 1991Co-Authors: E Zweygarth, R KaminskyAbstract:Abstract The antiTrypanosomal activity of the ornithine decarboxylase inhibitor dl -α-difluoromethylornithine (DFMO, eflornithine) was tested in ten stocks and one clone of the hemoflagellate Trypanosoma Brucei Brucei in an in vitro system. They showed varying levels of susceptibility to DFMO, their IC 50 (the concentration which inhibited growth by 50%) values ranging from 81–691 μM. Differences in DFMO susceptibility were also demonstrated in mice. Combinations of melarsonyl potassium (mel W; trimelarsan) and DFMO showed an additive effect in vitro in a mel W-susceptible and a mel W-resistant stock, but an antagonistic effect in a mel W- and DFMO-susceptible clone. Combinations of suramin and DFMO showed an antagonistic effect in vitro in a suramin-susceptible clone, but a potentiation in a suramin-resistant stock.
