The Experts below are selected from a list of 10617 Experts worldwide ranked by ideXlab platform
K. Michael Hambidge - One of the best experts on this subject based on the ideXlab platform.
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Zinc Metabolism and homeostasis: The application of tracer techniques to human Zinc physiology
Biometals, 2001Co-Authors: Nancy F. Krebs, K. Michael HambidgeAbstract:Tracer kinetic techniques based on Zinc stable isotopes have a vital role in advancing knowledge of human Zinc physiology and homeostasis. These techniques have demonstrated the complexity of Zinc Metabolism, and have been critical to estimating the size and interrelationships of those pools of Zinc that exchange rapidly with Zinc in plasma and which are likely to be especially important for Zinc dependent biology. This paper presents findings from recent research linking a steady state compartmental model with non-steady state post-prandial sampling from the intestine, utilizing a combination of intestinal intubation/perfusion and stable isotope tracer kinetic techniques. The gastrointestinal tract has a central role in maintaining whole body Zinc homeostasis. While the fractional absorption of Zinc from a meal depends on the quantity of exogenous Zinc and on such dietary factors as phytic acid, the fractional absorption does not appear to be dependent on the size of the rapidly exchanging pool of the host. In contrast, the quantity of endogenous Zinc excreted via the intestine is positively correlated with both the amount of absorbed Zinc and the Zinc `status' of the host, and thus this process has an equally critical role in maintaining Zinc homeostasis. The observed alterations in Zinc Metabolism in some disease states can be understood in the context of known homeostatic processes. In other conditions, however, such alterations as inflammation-associated hyperZincuria and Zinc redistribution, the links between homeostatic perturbation and cellular biology are yet to be explained. Thus the challenge remains for research at the whole body level to carefully characterize Zinc distribution and exchange under diverse circumstances, while research at the cellular level must elucidate the regulatory processes and the factors to which they respond.
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Development of a compartmental model of human Zinc Metabolism: identifiability and multiple studies analyses.
American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 2000Co-Authors: Leland V. Miller, Nancy F. Krebs, K. Michael HambidgeAbstract:A compartmental model of Zinc Metabolism has been developed from stable isotope tracer studies of five healthy adults. Multiple isotope tracers were administered orally and intravenously, and the resulting enrichment was measured in plasma, erythrocytes, urine, and feces for as long as 3 wk. Data from total Zinc measurements and model-independent calculations of various steady-state parameters were also modeled with the kinetic data. A structure comprised of 14 compartments and as many as 25 unknown kinetic parameters was developed to adequately model the data from each of the individual studies. The structural identifiability of the model was established using the GLOBI2 identifiability analysis software. Numerical identifiability of parameter estimates was evaluated using statistical data provided by SAAM. A majority of the model parameters was estimated with sufficient statistical certainty to be considered well determined. After the fitting of the model and data from the individual studies using SAAM/CONSAM, results were submitted to SAAM extended multiple studies analysis for aggregation into a single set of population parameters and statistics. The model was judged to be valid based on criteria described elsewhere.
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The use of stable isotope techniques to assess Zinc Metabolism
Journal of Nutritional Biochemistry, 1995Co-Authors: Nancy F. Krebs, Leland V. Miller, Vernon L. Naake, Jamie E. Westcott, Paul V. Fennessey, K. Michael HambidgeAbstract:The refinement of techniques that can accurately measure small changes in Zinc stable isotope ratios in biological samples provides new opportunities for advancing our understanding of human Zinc Metabolism. The feasibility of utilizing more than one Zinc stable isotope label simultaneously is invaluable for more complex kinetic studies. These techniques are especially valuable for investigations of the regulation of Zn homeostasis in infants and in women during the reproductive cycle in whom problems with Zinc nutriture may be relatively frequent and of concern for preand postnatal growth and development. Initially, these techniques have been applied to studying the role of the intestine in the maintenance of Zinc homeostasis and have served to emphasize the importance of the modulation of fecal excretion of endogenous Zinc. Application of stable isotope techniques to explore Zinc Metabolism beyond the intestinal tract is still limited but has considerable potential for advancing our understanding of Zinc Metabolism in health and disease.
Daniel Mansuy - One of the best experts on this subject based on the ideXlab platform.
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A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Paris Laskaris, Rocío Vicentefranqueira, Olivier Helynck, Grégory Jouvion, José Antonio Calera, Laurence Du Merle, Franck Suzenet, Frédéric Buron, Rodolphe Alves De Sousa, Daniel MansuyAbstract:Aspergillus fumigatus can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to a lack of reliable treatment options. This opportunistic pathogen requires Zinc in order to grow and cause disease. Novel compounds that interfere with fungal Zinc Metabolism may therefore be of therapeutic interest. We screened chemical libraries containing 59,223 small molecules using a resazurin assay that compared their effects on an A. fumigatus wild-type strain grown under Zinc-limiting conditions and on a Zinc transporter knockout strain grown under Zinc-replete conditions to identify compounds affecting Zinc Metabolism. After a first screen, 116 molecules were selected whose inhibitory effects on fungal growth were further tested by using luminescence assays and hyphal length measurements to confirm their activity, as well as by toxicity assays on HeLa cells and mice. Six compounds were selected following a rescreening, of which two were pyrazolones, two were porphyrins, and two were polyaminocarboxylates. All three groups showed good in vitro activity, but only one of the polyaminocarboxylates was able to significantly improve the survival of immunosuppressed mice suffering from pulmonary aspergillosis. This two-tier screening approach led us to the identification of a novel small molecule with in vivo fungicidal effects and low murine toxicity that may lead to the development of new treatment options for fungal infections by administration of this compound either as a monotherapy or as part of a combination therapy.
Nancy F. Krebs - One of the best experts on this subject based on the ideXlab platform.
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Zinc Metabolism and homeostasis: The application of tracer techniques to human Zinc physiology
Biometals, 2001Co-Authors: Nancy F. Krebs, K. Michael HambidgeAbstract:Tracer kinetic techniques based on Zinc stable isotopes have a vital role in advancing knowledge of human Zinc physiology and homeostasis. These techniques have demonstrated the complexity of Zinc Metabolism, and have been critical to estimating the size and interrelationships of those pools of Zinc that exchange rapidly with Zinc in plasma and which are likely to be especially important for Zinc dependent biology. This paper presents findings from recent research linking a steady state compartmental model with non-steady state post-prandial sampling from the intestine, utilizing a combination of intestinal intubation/perfusion and stable isotope tracer kinetic techniques. The gastrointestinal tract has a central role in maintaining whole body Zinc homeostasis. While the fractional absorption of Zinc from a meal depends on the quantity of exogenous Zinc and on such dietary factors as phytic acid, the fractional absorption does not appear to be dependent on the size of the rapidly exchanging pool of the host. In contrast, the quantity of endogenous Zinc excreted via the intestine is positively correlated with both the amount of absorbed Zinc and the Zinc `status' of the host, and thus this process has an equally critical role in maintaining Zinc homeostasis. The observed alterations in Zinc Metabolism in some disease states can be understood in the context of known homeostatic processes. In other conditions, however, such alterations as inflammation-associated hyperZincuria and Zinc redistribution, the links between homeostatic perturbation and cellular biology are yet to be explained. Thus the challenge remains for research at the whole body level to carefully characterize Zinc distribution and exchange under diverse circumstances, while research at the cellular level must elucidate the regulatory processes and the factors to which they respond.
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Zinc Metabolism and Requirements
Food and Nutrition Bulletin, 2001Co-Authors: Michael Hambidge, Nancy F. KrebsAbstract:Current knowledge of the Metabolism of Zinc is summarized in relation to the clinical and public health importance of human Zinc deficiency. Zinc Metabolism is considered in relation to estimations of Zinc requirements. Special attention is focused on the role and limitations of regulation of intestinal absorption of exogenous dietary Zinc and of intestinal excretion of endogenous Zinc in the maintenance of Zinc homeostasis. The dynamic interrelationships between these variables and between each of these and readily exchangeable pools of body Zinc are highlighted, as is the impact of dietary phytate on Zinc requirements. Measurements of these variables utilizing Zinc stable isotope techniques can provide quantitative information on Zinc homeostasis and dietary Zinc requirements in different communities, as well as facilitating assessment of alternative strategies for preventing Zinc deficiency.
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Development of a compartmental model of human Zinc Metabolism: identifiability and multiple studies analyses.
American Journal of Physiology-Regulatory Integrative and Comparative Physiology, 2000Co-Authors: Leland V. Miller, Nancy F. Krebs, K. Michael HambidgeAbstract:A compartmental model of Zinc Metabolism has been developed from stable isotope tracer studies of five healthy adults. Multiple isotope tracers were administered orally and intravenously, and the resulting enrichment was measured in plasma, erythrocytes, urine, and feces for as long as 3 wk. Data from total Zinc measurements and model-independent calculations of various steady-state parameters were also modeled with the kinetic data. A structure comprised of 14 compartments and as many as 25 unknown kinetic parameters was developed to adequately model the data from each of the individual studies. The structural identifiability of the model was established using the GLOBI2 identifiability analysis software. Numerical identifiability of parameter estimates was evaluated using statistical data provided by SAAM. A majority of the model parameters was estimated with sufficient statistical certainty to be considered well determined. After the fitting of the model and data from the individual studies using SAAM/CONSAM, results were submitted to SAAM extended multiple studies analysis for aggregation into a single set of population parameters and statistics. The model was judged to be valid based on criteria described elsewhere.
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Human Zinc Metabolism: Advances in the Modeling of Stable Isotope Data
Advances in Experimental Medicine and Biology, 1998Co-Authors: Leland V. Miller, Nancy F. Krebs, K M HambidgeAbstract:Compartmental modeling is a useful tool for investigating metabolic systems and processes. We and others have applied it to the study of Zinc Metabolism in humans. Because existing models could not be accurately fitted to our data, we have developed a new model of human Zinc Metabolism based on stable isotope tracer data from studies of five healthy adults. Multiple isotope tracers were administered orally and intravenously and the resulting enrichment measurement in plasma, erythrocytes, urine, and feces. These tracer kinetic data, along with other measured and calculated tracee and steady-state data, were used to develop the model. A single model structure composed of fourteen compartments was found to be suitable for all subjects. Model development and fitting of data and model for each subject were accomplished using the SAAM/CONSAM computer programs. The model development and fitting processes are described and exemplified using data from one of the subjects. While identifiability could not be demonstrated a priori due to the model’s complexity, parameter statistics for the fitted models did show most parameters to be adequately identified a posteriori.
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The use of stable isotope techniques to assess Zinc Metabolism
Journal of Nutritional Biochemistry, 1995Co-Authors: Nancy F. Krebs, Leland V. Miller, Vernon L. Naake, Jamie E. Westcott, Paul V. Fennessey, K. Michael HambidgeAbstract:The refinement of techniques that can accurately measure small changes in Zinc stable isotope ratios in biological samples provides new opportunities for advancing our understanding of human Zinc Metabolism. The feasibility of utilizing more than one Zinc stable isotope label simultaneously is invaluable for more complex kinetic studies. These techniques are especially valuable for investigations of the regulation of Zn homeostasis in infants and in women during the reproductive cycle in whom problems with Zinc nutriture may be relatively frequent and of concern for preand postnatal growth and development. Initially, these techniques have been applied to studying the role of the intestine in the maintenance of Zinc homeostasis and have served to emphasize the importance of the modulation of fecal excretion of endogenous Zinc. Application of stable isotope techniques to explore Zinc Metabolism beyond the intestinal tract is still limited but has considerable potential for advancing our understanding of Zinc Metabolism in health and disease.
Janet C King - One of the best experts on this subject based on the ideXlab platform.
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a compartmental model of Zinc Metabolism in healthy women using oral and intravenous stable isotope tracers
The American Journal of Clinical Nutrition, 1997Co-Authors: Nicola M Lowe, David M Shames, Leslie R Woodhouse, Julie S Matel, Raimund Roehl, Maria Pia Saccomani, Gianna Toffolo, C Cobelli, Janet C KingAbstract:A mathematical model of Zinc Metabolism in six healthy women (average age: 30 +/- 11 y) was developed by using stable isotopes of Zinc. After equilibration on a constant diet containing 7.0 mg Zn/d, an oral tracer highly enriched in 67Zn and an intravenous tracer highly enriched in 70Zn were administered simultaneously. Multiple plasma and 24-h urine samples were collected for the next 7 d with complete fecal collections for 11 d. Tracer-trace ratios in plasma, urine, and feces were calculated from isotope ratios of 67Zn to 66Zn and 70Zn to 66Zn measured by using inductively coupled plasma-mass spectrometry. An a priori identifiable model composed of seven compartments was developed to describe the kinetics of both tracers as well as that of naturally occurring Zinc. The parameters of the model were fitted to the data by using the SAAM-CONSAM modeling software and were estimated with good precision. Several important, not directly measurable Zinc variables were estimated (mean +/- SEM) from the model including the fractional absorption from the gastrointestinal tract (0.279 +/- 0.043), the rates of endogenous secretion (2.79 +/- 0.49 mg/d) and excretion (2.01 +/- 0.35 mg/d), the fractional turnover rate of the plasma pool (131 +/- 20/d), and the sizes (7.2 +/- 1.2 and 77.1 +/- 6.4 mg) and fractional turnover rates (22.3 +/- 7.1 and 1.49 +/- 0.18/d) of the fast and slow tissue pools equilibrating with the plasma, respectively.
Paris Laskaris - One of the best experts on this subject based on the ideXlab platform.
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A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Paris Laskaris, Rocío Vicentefranqueira, Olivier Helynck, Grégory Jouvion, José Antonio Calera, Laurence Du Merle, Franck Suzenet, Frédéric Buron, Rodolphe Alves De Sousa, Daniel MansuyAbstract:Aspergillus fumigatus can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to a lack of reliable treatment options. This opportunistic pathogen requires Zinc in order to grow and cause disease. Novel compounds that interfere with fungal Zinc Metabolism may therefore be of therapeutic interest. We screened chemical libraries containing 59,223 small molecules using a resazurin assay that compared their effects on an A. fumigatus wild-type strain grown under Zinc-limiting conditions and on a Zinc transporter knockout strain grown under Zinc-replete conditions to identify compounds affecting Zinc Metabolism. After a first screen, 116 molecules were selected whose inhibitory effects on fungal growth were further tested by using luminescence assays and hyphal length measurements to confirm their activity, as well as by toxicity assays on HeLa cells and mice. Six compounds were selected following a rescreening, of which two were pyrazolones, two were porphyrins, and two were polyaminocarboxylates. All three groups showed good in vitro activity, but only one of the polyaminocarboxylates was able to significantly improve the survival of immunosuppressed mice suffering from pulmonary aspergillosis. This two-tier screening approach led us to the identification of a novel small molecule with in vivo fungicidal effects and low murine toxicity that may lead to the development of new treatment options for fungal infections by administration of this compound either as a monotherapy or as part of a combination therapy.
