The Experts below are selected from a list of 570 Experts worldwide ranked by ideXlab platform
Cheng Chi Lee - One of the best experts on this subject based on the ideXlab platform.
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amp Deaminase 3 deficiency enhanced 5 amp induction of hypometabolism
PLOS ONE, 2013Co-Authors: Isadora Susan Daniels, William G O Brien, Vinay Nath, Zhaoyang Zhao, Cheng Chi LeeAbstract:A hypometabolic state can be induced in mice by 5′-AMP administration. Previously we proposed that an underlying mechanism for this hypometabolism is linked to reduced erythrocyte oxygen transport function due to 5′-AMP uptake altering the cellular adenylate equilibrium. To test this hypothesis, we generated mice deficient in Adenosine Monophosphate Deaminase 3 (AMPD3), the key catabolic enzyme for 5′-AMP in erythrocytes. Mice deficient in AMPD3 maintained AMPD activities in all tissues except erythrocytes. Developmentally and morphologically, the Ampd3−/− mice were indistinguishable from their wild type siblings. The levels of ATP, ADP but not 5′-AMP in erythrocytes of Ampd3−/− mice were significantly elevated. Fasting blood glucose levels of the Ampd3−/− mice were comparable to wild type siblings. In comparison to wild type mice, the Ampd3−/− mice displayed a deeper hypometabolism with a significantly delayed average arousal time in response to 5′-AMP administration. Together, these findings demonstrate a central role of AMPD3 in the regulation of 5′-AMP mediated hypometabolism and further implicate erythrocytes in this behavioral response.
Nagaraju Kanneboyina - One of the best experts on this subject based on the ideXlab platform.
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Daily Supplementation of D-ribose Shows No Therapeutic Benefits in the MHC-I Transgenic Mouse Model of Inflammatory Myositis
Public Library of Science, 2013Co-Authors: Coley William, Rayavarapu Sree, Van Der Meulen Jack H., Duba Ayyappa S., Nagaraju KanneboyinaAbstract:Current treatments for idiopathic inflammatory myopathies (collectively called myositis) focus on the suppression of an autoimmune inflammatory response within the skeletal muscle. However, it has been observed that there is a poor correlation between the successful suppression of muscle inflammation and an improvement in muscle function. Some evidence in the literature suggests that metabolic abnormalities in the skeletal muscle underlie the weakness that continues despite successful immunosuppression. We have previously shown that decreased expression of a purine nucleotide cycle enzyme, Adenosine Monophosphate Deaminase (AMPD1), leads to muscle weakness in a mouse model of myositis and may provide a mechanistic basis for muscle weakness. One of the downstream metabolites of this pathway, D-ribose, has been reported to alleviate symptoms of myalgia in patients with a congenital loss of AMPD1. Therefore, we hypothesized that supplementing exogenous D-ribose would improve muscle function in the mouse model of myositis. We treated normal and myositis mice with daily doses of D-ribose (4 mg/kg) over a 6-week time period and assessed its effects using a battery of behavioral, functional, histological and molecular measures.Treatment with D-ribose was found to have no statistically significant effects on body weight, grip strength, open field behavioral activity, maximal and specific forces of EDL, soleus muscles, or histological features. Histological and gene expression analysis indicated that muscle tissues remained inflamed despite treatment. Gene expression analysis also suggested that low levels of the ribokinase enzyme in the skeletal muscle might prevent skeletal muscle tissue from effectively utilizing D-ribose.Treatment with daily oral doses of D-ribose showed no significant effect on either disease progression or muscle function in the mouse model of myositis
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Daily supplementation of D-ribose shows no therapeutic benefits in the MHC-I transgenic mouse model of inflammatory myositis
Health Sciences Research Commons, 2013Co-Authors: Coley William, Rayavarapu Sree, Van Der Meulen Jack H., Duba Ayyappa S., Nagaraju KanneboyinaAbstract:Background Current treatments for idiopathic inflammatory myopathies (collectively called myositis) focus on the suppression of an autoimmune inflammatory response within the skeletal muscle. However, it has been observed that there is a poor correlation between the successful suppression of muscle inflammation and an improvement in muscle function. Some evidence in the literature suggests that metabolic abnormalities in the skeletal muscle underlie the weakness that continues despite successful immunosuppression. We have previously shown that decreased expression of a purine nucleotide cycle enzyme, Adenosine Monophosphate Deaminase (AMPD1), leads to muscle weakness in a mouse model of myositis and may provide a mechanistic basis for muscle weakness. One of the downstream metabolites of this pathway, D-ribose, has been reported to alleviate symptoms of myalgia in patients with a congenital loss of AMPD1. Therefore, we hypothesized that supplementing exogenous D-ribose would improve muscle function in the mouse model of myositis. We treated normal and myositis mice with daily doses of D-ribose (4 mg/kg) over a 6-week time period and assessed its effects using a battery of behavioral, functional, histological and molecular measures. Results Treatment with D-ribose was found to have no statistically significant effects on body weight, grip strength, open field behavioral activity, maximal and specific forces of EDL, soleus muscles, or histological features. Histological and gene expression analysis indicated that muscle tissues remained inflamed despite treatment. Gene expression analysis also suggested that low levels of the ribokinase enzyme in the skeletal muscle might prevent skeletal muscle tissue from effectively utilizing D-ribose. Conclusions Treatment with daily oral doses of D-ribose showed no significant effect on either disease progression or muscle function in the mouse model of myositis
Cheryl A Hillery - One of the best experts on this subject based on the ideXlab platform.
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ca2 cam activation of amp Deaminase contributes to adenine nucleotide dysregulation and phosphatidylserine externalization in human sickle erythrocytes
British Journal of Haematology, 2009Co-Authors: Richard L Sabina, Nancy J Wandersee, Cheryl A HilleryAbstract:Ca2+-calmodulin (Ca2+-CaM) activates erythrocyte Adenosine Monophosphate Deaminase (AMPD) in conditions of disturbed calcium homeostasis, prompting us to investigate adenine nucleotide metabolic dysregulation in sickle cell disease (SCD). However, higher ATP concentrations in reticulocytes, compared to erythrocytes, confound a comparative evaluation of SCD and normal RBCs. Therefore, a combination of centrifugation and antiCD71-labelled magnetic bead selection was used to prepare reticulocyte-poor fractions (reticulocytes <4% of total RBCs) of SCD RBCs. ATP and total adenine nucleotide concentrations were 12% lower in sickle erythrocytes compared to normal erythrocytes and inosine Monophosphate (IMP) concentrations were threefold elevated (all P < 0.05). Furthermore, preincubation with a diffusible CaM antagonist slowed IMP accumulation in sickle erythrocytes during an experimental period of energy imbalance, thus showing that Ca2+-CaM activates AMPD in SCD. Finally, adenine treatment (100 micromol/l) of ex vivo SCD RBCs significantly expanded ATP levels (16% higher) and reduced phosphatidylserine (PS)-exposure, specifically those cells with the highest levels of PS externalization (46% fewer events) (both P-values <0.05 compared to untreated samples). We conclude that Ca2+-CaM activation of AMPD contributes to increased turnover of the adenine nucleotide pool in sickle erythrocytes and that this metabolic dysregulation promotes PS exposure that may contribute to the pathogenesis of SCD.
A A M Morris - One of the best experts on this subject based on the ideXlab platform.
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mutation and biochemical analysis in carnitine palmitoyltransferase type ii cpt ii deficiency
Journal of Inherited Metabolic Disease, 2003Co-Authors: S E Olpin, A Afifi, S Clark, N J Manning, J R Bonham, A Dalton, J V Leonard, J M Land, Brage S Andresen, A A M MorrisAbstract:Carnitine palmitoyltransferase type II (CPT II) deficiency has three basic phenotypes, late-onset muscular (mild), infantile/juvenile hepatic (intermediate) and severe neonatal. We have measured fatty acid oxidation and CPT II activity and performed mutation studies in 24 symptomatic patients representing the full clinical spectrum of disease. Severe and intermediate phenotypes show a clear correlation with biochemical indices and genetic analysis revealed causative mutations in most patients. Studies of mild phenotypes suggest a more complex interaction, with higher residual fatty acid oxidation, a wider range of CPT II activity (10–60%) but little evidence of genotype-phenotype correlation. Residual CPT II mutant protein from myopathic patients shows thermal instability at 41°C. The common 'polymorphisms' V3681 and M647V are strikingly overrepresented in the myopathic patients, the implication being that they may significantly influence the manifestation of clinical disease and could therefore potentially be considered as a susceptibility variants. Among myopathic individuals, males comprised 88! of patients, suggesting increased susceptibility to clinical disease. A small number of symptomatic patients appear to have significant residual CPT II activity (42–60%) The synergistic interaction of partial deficiencies of CPT II, muscle Adenosine Monophosphate Deaminase and possibly other enzymes of muscle energy metabolism in the aetiology of episodic myopathy deserves wider consideration.
C. Luccioni - One of the best experts on this subject based on the ideXlab platform.
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Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations.
British Journal of Cancer, 1994Co-Authors: V. Bardot, Anne-marie Dutrillaux, Jean Yves Delattre, Vega F, M. Poisson, Bernard Dutrillaux, C. LuccioniAbstract:Chromosomal aberrations in human gliomas are principally numerical. In tumours of low malignancy, karyotypes are frequently normal, but occasionally an excess of chromosome 7 and a loss of sex chromosome are observed. In highly malignant tumours, the most frequent aberrations are gain of chromosome 7, loss of chromosome 10 and less frequently losses or deletions of chromosomes 9, 22, 6, 13 and 14 or gains of chromosomes 19 and 20. To understand the meaning of these chromosome imbalances, the relationships between chromosome abnormalities and metabolic disturbances were studied. The losses or deletions observed affected principally chromosomes carrying genes encoding enzymes involved in purine metabolism. The activities of ten enzymes were measured: Adenosine kinase, adenine phosphoribosyltransferase, adenylate kinase, methylthioAdenosine phosphorylase, hypoxanthine phosphoribosyltransferase, adenylosuccinate lyase, inosine Monophosphate dehydrogenase, Adenosine Deaminase, nucleoside phosphorylase and Adenosine Monophosphate Deaminase. In parallel, two enzymes involved in pyrimidine metabolism, thymidine kinase and thymidylate synthase (TS), were studied. The activities of all these enzymes were measured on samples from 30 human primary glial tumours with low or high malignancy, six xenografted tumours at different passages, four portions of normal brain tissue and four non-glial brain neoplasms. As suggested by cytogenetic data, the enzymatic results showed a relatively low activity of purine metabolism in glial tumours when compared with normal brain and non-glial brain neoplasms. Considering the two enzymes involved in pyrimidine metabolism, only TS had higher activity in glial tumours of high malignancy than in normal brain. In comparison with normal brain, the balance between salvage and de novo pathways changes in gliomas, and even more in grafted tumours, in favour of de novo synthesis. The relation between chromosomes and metabolic imbalances does not correspond to a simple gene dosage effect in these tumours. These data suggest that the decrease of Adenosine metabolism occurs before chromosomal aberrations appear, since it is observed in tumours of low malignancy when most karyotypes are still normal, and that the de novo pathway increases with tumour progression.