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Raymond R Russell - One of the best experts on this subject based on the ideXlab platform.
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changes in citric acid cycle flux and anaplerosis antedate the functional decline in isolated rat hearts utilizing Acetoacetate
Journal of Clinical Investigation, 1991Co-Authors: Raymond R Russell, Heinrich TaegtmeyeAbstract:To determine the temporal relationship between changes in contractile performance and flux through the citric acid cycle in hearts oxidizing Acetoacetate, we perfused isolated working rat hearts with either glucose or Acetoacetate (both 5 mM) and freeze-clamped the tissue at defined times. After 60 min of perfusion, hearts utilizing Acetoacetate exhibited lower systolic and diastolic pressures and lower cardiac outputs. The oxidation of Acetoacetate increased the tissue content of 2-oxoglutarate and glutamate and decreased the content of succinyl-CoA suggesting inhibition of citric acid cycle flux through 2-oxoglutarate dehydrogenase. Whereas hearts perfused with either Acetoacetate or glucose were similar with respect to their function for the first 20 min, changes in tissue metabolites were already observed within 5 min of perfusion at near-physiological workloads. The addition of lactate or propionate, but not acetate, to hearts oxidizing Acetoacetate improved contractile performance, although inhibition of 2-oxoglutarate dehydrogenase was probably not diminished. If lactate or propionate were added, malate and citrate accumulated indicating utilization of anaplerotic pathways for the citric acid cycle. We conclude that a decreased rate of flux through 2-oxoglutarate dehydrogenase in hearts oxidizing Acetoacetate precedes, and may be responsible for, contractile failure and is not the result of decreased cardiac work. Further, anaplerosis play an important role in the maintenance of contractile function in hearts utilizing Acetoacetate.
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Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing Acetoacetate.
The American journal of physiology, 1991Co-Authors: Raymond R Russell, H TaegtmeyerAbstract:Acetoacetate, when present as the only fuel for respiration in rat hearts, causes an impairment in contractile function that is reversible with the addition of substrates that can contribute to anaplerosis. To determine the importance of pyruvate carboxylation via NADP(+)-dependent malic enzyme on metabolism and function in hearts oxidizing Acetoacetate, isolated working rat hearts were perfused with [1-14C]pyruvate and Acetoacetate. While the cardiac power output after 60 min of perfusion in hearts utilizing Acetoacetate alone had fallen to 44% of the initial value, the addition of pyruvate resulted in a stable performance with no fall in the work output. When hydroxymalonate, an inhibitor of NADP(+)-dependent malic enzyme and malate dehydrogenase, was added to the two substrates, function at 60 min was similar to the value for hearts oxidizing Acetoacetate alone. Measurements of the specific activities of malate, aspartate, and citrate confirm inhibition of both pyruvate carboxylation and malate oxidation. The findings are consistent with a mechanism in which the enrichment of malate by pyruvate improves function by increasing the production of reducing equivalents by the malate dehydrogenase and the isocitrate dehydrogenase reactions increase flux through the span of the tricarboxylic acid cycle from malate to 2-oxoglutarate. The present study demonstrates the physiological importance of anaplerotic pathways in maintaining contractile function in the heart.
Sébastien Tremblay - One of the best experts on this subject based on the ideXlab platform.
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Automated synthesis of 1-[11C]Acetoacetate on a TRASIS AIO module.
Applied radiation and isotopes : including data instrumentation and methods for use in agriculture industry and medicine, 2017Co-Authors: Kiran Kumar Solingapuram Sai, Sébastien Tremblay, Stephen C. Cunnane, H. Donald Gage, Frankis Almaguel, Bryan J. Neth, Timothy M. Hughes, Christian-alexandre Castellano, Matthew J. Jorgensen, Suzanne CraftAbstract:Abstract We automated radiochemical synthesis of 1-[ 11 C]Acetoacetate in a commercially available radiochemistry module, TRASIS AllInOne by [ 11 C]carboxylation of the corresponding enolate anion generated in situ from isopropenylacetate and MeLi, and purified by ion-exchange column resins.1-[ 11 C]Acetoacetate was synthesized with high radiochemical purity (95%) and specific activity (~ 66.6 GBq/µmol, n = 30) with 35% radiochemical yield, decay corrected to end of synthesis. The total synthesis required ~ 16 min. PET imaging studies were conducted with 1-[ 11 C]Acetoacetate in vervet monkeys to validate the radiochemical synthesis. Tissue uptake distribution was similar to that reported in humans.
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[11C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure
Nuclear medicine and biology, 2014Co-Authors: Etienne Croteau, Sébastien Tremblay, Suzanne Gascon, Veronique Dumulon-perreault, Sébastien M. Labbé, Jacques Rousseau, Stephen C. Cunnane, André C. Carpentier, Francois Benard, Roger LecomteAbstract:Abstract The ketone body Acetoacetate could be used as an alternate nutrient for the heart, and it also has the potential to improve cardiac function in an ischemic–reperfusion model or reduce the mitochondrial production of oxidative stress involved in cardiotoxicity. In this study, [ 11 C]-Acetoacetate was investigated as an early marker of intracellular damage in heart failure. Methods A rat cardiotoxicity heart failure model was induced by doxorubicin, Dox(+). [ 14 C]-Acetoacetate, a non-positron (β−) emitting radiotracer, was used to characterize the arterial blood input function and myocardial mitochondrial uptake. Afterward, [ 11 C]-Acetoacetate (β+) myocardial PET images were obtained for kinetic analysis and heart function assessment in control Dox(−) (n=15) and treated Dox(+) (n=6) rats. The uptake rate ( K 1 ) and myocardial clearance rate ( k 2 or k mono ) were extracted. Results [ 14 C]-Acetoacetate in the blood was increased in Dox(+), from 2min post-injection until the last withdrawal point when the heart was harvested, as well as the uptake in the heart and myocardial mitochondria (unpaired t -test, p 11 C]-Acetoacetate showed that rate constants K 1 , k 2 and k mono were decreased in Dox(+) ( p p Conclusion Radioactive Acetoacetate ex vivo analysis [ 14 C], and in vivo kinetic [ 11 C] studies provided evidence that [ 11 C]-Acetoacetate can assess heart failure Dox(+). Contrary to myocardial flow reserve (rest–stress protocol), [ 11 C]-Acetoacetate can be used to assess reduced kinetic rate constants without requirement of hyperemic stress response. The proposed [ 11 C]-Acetoacetate cardiac radiotracer in the investigation of heart disease is novel and paves the way to a potential role for [ 11 C]-Acetoacetate in cardiac pathophysiology.
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Brain glucose and Acetoacetate metabolism: a comparison of young and older adults
Neurobiology of aging, 2013Co-Authors: Scott Nugent, Sébastien Tremblay, Christian-alexandre Castellano, Kewei W. Chen, Napatkamon Ayutyanont, Auttawut Roontiva, Mélanie Fortier, Maggie Roy, Alexandre Courchesne-loyer, Christian BoctiAbstract:The extent to which the age-related decline in regional brain glucose uptake also applies to other important brain fuels is presently unknown. Ketones are the brain's major alternative fuel to glucose, so we developed a dual tracer positron emission tomography protocol to quantify and compare regional cerebral metabolic rates for glucose and the ketone, Acetoacetate. Twenty healthy young adults (mean age, 26 years) and 24 healthy older adults (mean age, 74 years) were studied. In comparison with younger adults, older adults had 8 ± 6% (mean ± SD) lower cerebral metabolic rates for glucose in gray matter as a whole (p = 0.035), specifically in several frontal, temporal, and subcortical regions, as well as in the cingulate and insula (p ≤ 0.01, false discovery rate correction). The effect of age on cerebral metabolic rates for Acetoacetate in gray matter did not reach significance (p = 0.11). Rate constants (min(-1)) of glucose (Kg) and Acetoacetate (Ka) were significantly lower (-11 ± 6%; [p = 0.005], and -19 ± 5%; [p = 0.006], respectively) in older adults compared with younger adults. There were differential effects of age on Kg and Ka as seen by significant interaction effects in the caudate (p = 0.030) and post-central gyrus (p = 0.023). The Acetoacetate index, which expresses the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake, identifies regions taking up higher or lower amounts of Acetoacetate relative to glucose. The Acetoacetate index was higher in the caudate of young adults when compared with older adults (p ≤ 0.05 false discovery rate correction). This study provides new information about glucose and ketone metabolism in the human brain and a comparison of the extent to which their regional use changes during normal aging.
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[^11C] Acetoacetate Utilization by Breast and Prostate Tumors: a PET and Biodistribution Study in Mice
Molecular Imaging and Biology, 2008Co-Authors: Simon Authier, Sébastien Tremblay, Stephen C. Cunnane, Roger Lecomte, Véronique Dumulon, Céléna Dubuc, René Ouellet, Francois BenardAbstract:Purpose A significant positive correlation has been observed between ketone body availability and their uptake by tumor cells. Our objective was to evaluate [^11C]Acetoacetate as a potential tracer of ketone body utilization by breast and prostate tumors and to compare it with [^11C]acetate. Methods Biodistribution studies were performed with [^11C]Acetoacetate and [^11C]acetate in mice bearing breast or prostate tumors. The percentage of the injected dose accumulated per gram of tissue was determined. These results were complemented by dynamic positron emission tomography (PET) imaging of the radiotracer uptake and dosimetry calculations. Results [^11C]Acetoacetate uptake was optimal between 5 and 30 min, with maximal uptake of 2.72, 2.42, 2.54, and 2.19% injected dose (%ID)/g for MC7-L1, MC4-L2, PC3, and LN-CaP tumors respectively. Tumor retention for [^11C]Acetoacetate tended to be higher than [^11C]acetate, but this did not reach statistical significance. [^11C]Acetate uptake was reached within 15 min with optimal uptake of 1.25, 2.30, and 0.96%ID/g for MC7-L1, MC4-L2, and PC-3 tumors, respectively. Conclusions We observed a moderate uptake of [^11C]Acetoacetate in breast and prostate tumors with low background activity due to rapid elimination of this tracer. Further studies are warranted to determine if this tracer can detect slow-growing breast and prostate cancers in the clinical setting.
Heinrich Taegtmeye - One of the best experts on this subject based on the ideXlab platform.
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changes in citric acid cycle flux and anaplerosis antedate the functional decline in isolated rat hearts utilizing Acetoacetate
Journal of Clinical Investigation, 1991Co-Authors: Raymond R Russell, Heinrich TaegtmeyeAbstract:To determine the temporal relationship between changes in contractile performance and flux through the citric acid cycle in hearts oxidizing Acetoacetate, we perfused isolated working rat hearts with either glucose or Acetoacetate (both 5 mM) and freeze-clamped the tissue at defined times. After 60 min of perfusion, hearts utilizing Acetoacetate exhibited lower systolic and diastolic pressures and lower cardiac outputs. The oxidation of Acetoacetate increased the tissue content of 2-oxoglutarate and glutamate and decreased the content of succinyl-CoA suggesting inhibition of citric acid cycle flux through 2-oxoglutarate dehydrogenase. Whereas hearts perfused with either Acetoacetate or glucose were similar with respect to their function for the first 20 min, changes in tissue metabolites were already observed within 5 min of perfusion at near-physiological workloads. The addition of lactate or propionate, but not acetate, to hearts oxidizing Acetoacetate improved contractile performance, although inhibition of 2-oxoglutarate dehydrogenase was probably not diminished. If lactate or propionate were added, malate and citrate accumulated indicating utilization of anaplerotic pathways for the citric acid cycle. We conclude that a decreased rate of flux through 2-oxoglutarate dehydrogenase in hearts oxidizing Acetoacetate precedes, and may be responsible for, contractile failure and is not the result of decreased cardiac work. Further, anaplerosis play an important role in the maintenance of contractile function in hearts utilizing Acetoacetate.
Roger Lecomte - One of the best experts on this subject based on the ideXlab platform.
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[11C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure
Nuclear medicine and biology, 2014Co-Authors: Etienne Croteau, Sébastien Tremblay, Suzanne Gascon, Veronique Dumulon-perreault, Sébastien M. Labbé, Jacques Rousseau, Stephen C. Cunnane, André C. Carpentier, Francois Benard, Roger LecomteAbstract:Abstract The ketone body Acetoacetate could be used as an alternate nutrient for the heart, and it also has the potential to improve cardiac function in an ischemic–reperfusion model or reduce the mitochondrial production of oxidative stress involved in cardiotoxicity. In this study, [ 11 C]-Acetoacetate was investigated as an early marker of intracellular damage in heart failure. Methods A rat cardiotoxicity heart failure model was induced by doxorubicin, Dox(+). [ 14 C]-Acetoacetate, a non-positron (β−) emitting radiotracer, was used to characterize the arterial blood input function and myocardial mitochondrial uptake. Afterward, [ 11 C]-Acetoacetate (β+) myocardial PET images were obtained for kinetic analysis and heart function assessment in control Dox(−) (n=15) and treated Dox(+) (n=6) rats. The uptake rate ( K 1 ) and myocardial clearance rate ( k 2 or k mono ) were extracted. Results [ 14 C]-Acetoacetate in the blood was increased in Dox(+), from 2min post-injection until the last withdrawal point when the heart was harvested, as well as the uptake in the heart and myocardial mitochondria (unpaired t -test, p 11 C]-Acetoacetate showed that rate constants K 1 , k 2 and k mono were decreased in Dox(+) ( p p Conclusion Radioactive Acetoacetate ex vivo analysis [ 14 C], and in vivo kinetic [ 11 C] studies provided evidence that [ 11 C]-Acetoacetate can assess heart failure Dox(+). Contrary to myocardial flow reserve (rest–stress protocol), [ 11 C]-Acetoacetate can be used to assess reduced kinetic rate constants without requirement of hyperemic stress response. The proposed [ 11 C]-Acetoacetate cardiac radiotracer in the investigation of heart disease is novel and paves the way to a potential role for [ 11 C]-Acetoacetate in cardiac pathophysiology.
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[^11C] Acetoacetate Utilization by Breast and Prostate Tumors: a PET and Biodistribution Study in Mice
Molecular Imaging and Biology, 2008Co-Authors: Simon Authier, Sébastien Tremblay, Stephen C. Cunnane, Roger Lecomte, Véronique Dumulon, Céléna Dubuc, René Ouellet, Francois BenardAbstract:Purpose A significant positive correlation has been observed between ketone body availability and their uptake by tumor cells. Our objective was to evaluate [^11C]Acetoacetate as a potential tracer of ketone body utilization by breast and prostate tumors and to compare it with [^11C]acetate. Methods Biodistribution studies were performed with [^11C]Acetoacetate and [^11C]acetate in mice bearing breast or prostate tumors. The percentage of the injected dose accumulated per gram of tissue was determined. These results were complemented by dynamic positron emission tomography (PET) imaging of the radiotracer uptake and dosimetry calculations. Results [^11C]Acetoacetate uptake was optimal between 5 and 30 min, with maximal uptake of 2.72, 2.42, 2.54, and 2.19% injected dose (%ID)/g for MC7-L1, MC4-L2, PC3, and LN-CaP tumors respectively. Tumor retention for [^11C]Acetoacetate tended to be higher than [^11C]acetate, but this did not reach statistical significance. [^11C]Acetate uptake was reached within 15 min with optimal uptake of 1.25, 2.30, and 0.96%ID/g for MC7-L1, MC4-L2, and PC-3 tumors, respectively. Conclusions We observed a moderate uptake of [^11C]Acetoacetate in breast and prostate tumors with low background activity due to rapid elimination of this tracer. Further studies are warranted to determine if this tracer can detect slow-growing breast and prostate cancers in the clinical setting.
Adolfo Alexandre - One of the best experts on this subject based on the ideXlab platform.
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The control of mitochondrial succinate-dependent H_2O_2 production
Journal of Bioenergetics and Biomembranes, 2011Co-Authors: Franco Zoccarato, Claudio Miotto, Lucia Cavallini, Adolfo AlexandreAbstract:In brain mitochondria succinate activates H_2O_2 release, concentration dependently (starting at 15 μM), and in the presence of NAD dependent substrates (glutamate, pyruvate, β-hydroxybutyrate). We report that TCA cycle metabolites (citrate, isocitrate, α-ketoglutarate, fumarate, malate) individually and quickly inhibit H_2O_2 release. When they are present together at physiological concentration (0.2, 0.01, 0.15, 0.12, 0.2 mM respectively) they decrease H_2O_2 production by over 60% at 0.1–0.2 mM succinate. The degree of inhibition depends on the concentration of each metabolite. Acetoacetate is a strong inhibitor of H_2O_2 release, starting at 10 μM and acting quickly. It potentiates the inhibition induced by TCA cycle metabolites. The action of Acetoacetate is partially removed by β-hydroxybutyrate. Removal is minimal at 0.1 mM Acetoacetate, and is higher at 0.5 mM Acetoacetate. We conclude that several inhibitors of H_2O_2 release act jointly and concentration dependently to rapidly set the required level of H_2O_2 generation at each succinate concentration.
