Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PI 3-kinase, an enzyme that selectively phosphorylates the 3-position of the inositol ring, is acutely activated by insulin and other growth factors. The physiological significance of PI 3-kinase activation and, more specifically, its role in insulin action is an area under intense investigation. In this study, we have examined the role of PI 3-kinase activation in mediating selected metabolic and mitogenic effects of insulin employing the fungal metabolite wortmannin, a potent inhibitor of PI 3-kinase activity. In isolated rat and cultured 3T3-L1 adipocytes, wortmannin inhibited insulin-stimulated glucose transport (IC50 = 9 nM) without a significant effect on basal transport. Insulin-stimulated translocation of GLUT4 in isolated rat adipocytes was markedly inhibited by wortmannin. Wortmannin had no effect on either basal or insulin-stimulated glucose utilization in L6 myocytes, a skeletal muscle cell line in which GLUT1 is the predominant transporter isoform. Wortmannin also partially antagonized the antilipolytic effect of insulin on adenosine deaminase-stimulated lipolysis in isolated rat adipocytes. Furthermore, wortmannin caused a significant reduction in insulin-stimulated DNA synthesis in Fao rat hepatoma cells. We conclude that PI 3-kinase activation is necessary for maximum insulin-stimulated glucose transport, translocation of GLUT4, antilipolysis and DNA synthesis.
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PMID:The effects of wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, on insulin-stimulated glucose transport, GLUT4 translocation, antilipolysis, and DNA synthesis. 852 5

A typical clinical feature of patients with fasting hyperglycemia in diabetes is well correlated with accelerated hepatic glucose production which is determined by elevated FFA-induced gluconeogenesis. Therefore, to treat fasting hyperglycemia, inhibition of both FFA release and fatty acid oxidation in the liver may be efficient modalities of treatment. (1) Inhibitor of FFA release: a novel selective adenosine A1 agonist, SDZ WAG 994 is a potent inhibitor of adenosine deaminase-induced lipolysis. Twenty-three-week old, male GK rats showing glucose intolerance were treated with WAG 994 (1000 micrograms/kg body weight) for 16 days. Plasma glucose level at 0 time in WAG group was significantly (P < 0.01) less than that of the control. Both plasma FFA and triglyceride concentrations also decreased by 54% and 74%, respectively (vs. control GK rats). (2) Inhibition of hepatic fatty acid oxidation: beta-aminobetaine (emeriamine) is a water-soluble carnitine analog and inhibition of CPT-1 in isolated hepatocytes is 100 times more sensitive than that in isolated cardiocytes and it suppresses both gluconeogenesis and ketogenesis by 60-80%. However, it may be possible that this drug may induce fat deposition in the liver. An inhibitor of elevated fatty acid release from adipose tissue in concomitant with liver-specific and reversible inhibition of fatty acid oxidation may be an effective agent with hypoglycemic and hypolipidemic action for the treatment of diabetes mellitus.
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PMID:Rationale and hurdles of inhibitors of hepatic gluconeogenesis in treatment of diabetes mellitus. 852 14

We selected the common shrew (Sorex araneus) to generate the first insectivore gene map. Shrew-Chinese hamster and shrew- mouse somatic cell hybrid cells were constructed. When the 119 shrew-rodent clones were characterized, only shrew chromosomes were found to have segregated. A panel of hybrid clones was selected for gene assignment. The genes for hypoxanthine phosphoribosyl transferase (HPRT), glucose-6- phosphate dehydrogenase (G6PD), and malate dehydrogenase 1 (MDH1) were assigned to shrew Chromosome (Chr) de [which is the product of a tandem fusion between the 'original' mammalian X Chromosome (Chr) and an autosome], the gene for adenosine deaminase (ADA) and 6-phosphogluconate dehydrogenase se (PGD) to Chromosome jl, the gene for thymidine kinase (TK) to Chromosome hn, and the gene for lactate dehydrogenase (LDHA) to chromosome ik. Further studies in progress.
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PMID:Gene mapping in the common shrew (Sorex araneus; Insectivora) by shrew-rodent cell hybrids: chromosome localization of the loci for HPRT, TK, LDHA, MDH1, G6PD, PGD, and ADA. 859 34

We previously reported that adenosine A1 receptor activation protects against the cardiodepressant effects of hydrogen peroxide in isolated rat hearts. The present study examined whether a transient ischemic period of 5 min duration, which preconditions the heart against ischemic and reperfusion-induced dysfunction, can bestow protection against 30-min exposure to hydrogen peroxide in isolated rat hearts. Transient ischemia on its own failed to alter the cardiac response to hydrogen peroxide. However, when transient ischemia was carried out in the presence of the nucleoside transport inhibitor S-(4-Nitrobenzyl)-6-thioguanosine and the adenosine deaminase inhibitor erythro-9-(2-Hydroxy-3-nonyl)adenine, a significant attenuation of the hydrogen peroxide-induced loss in contractility was evident and this was associated with significant preservation of tissue glycogen content. The protective effect of the transient ischemia/drug combination on both functional changes and glycogen levels was abolished by the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine as well as by glibenclamide, a blocker of the ATP-sensitive potassium channel (KATP). To further assess the role of glycogen in the protection against hydrogen peroxide, we compared the effects of the adenosine A1 agonist N6-cyclopentyl adenosine (CPA) and insulin. While both treatments protected against hydrogen peroxide the effect of insulin was superior to any other treatment. Moreover, while all protective modalities preserved glycogen stores after hydrogen peroxide treatment, the protection afforded by insulin was also associated with significantly elevated glycogen levels prior to hydrogen peroxide administration. No protection by either CPA or insulin was evident in the absence of exogenous glucose. Taken together, our results demonstrate that a brief period of ischemia with concomitant administration of agents which increase interstitial adenosine levels protects against hydrogen peroxide toxicity. The effect is mediated by activation of adenosine A1 receptors and is linked to KATP stimulation. Moreover, our results are strongly suggestive of an important role of glycogen preservation in bestowing protective effects against hydrogen peroxide cardiotoxicity.
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PMID:Transient ischemia in the presence of an adenosine deaminase plus a nucleoside transport inhibitor confers protection against contractile depression produced by hydrogen peroxide. Possible role of glycogen. 876 52

Adenosine A1 receptor densities were increased in cultured LLC-PK1 and OK cells by chronic treatment with the adenosine receptor antagonists 1,3,7-trimethylxanthine (caffeine, 1 mM) and 1,3-dimethyl-8-cyclopentylxanthine [cyclopentyltheophylline (CPT), < or = 0.4 mM], respectively. The A1 receptor number per cell was increased twofold by 10-day treatments with 1 mM caffeine or 0.1 mM CPT, and the sodium-coupled glucose uptake was augmented twofold by 1 mM caffeine and sevenfold by 0.1 microM CPT (higher doses of CPT were progressively less stimulatory). Glucose uptake was blocked by acute (2-h) treatment with CPT, adenosine deaminase, or calphostin C. Caffeine (1 mM) or CPT (> or = 0.1 mM) inhibited cell proliferation for the first 10 days, then cell growth assumed a normal proliferative rate despite continued presence of antagonist. Cytosolic protein kinase C (PKC) beta-isoform immunoactivity and PKC-beta II mRNA were elevated at least twofold during 10 days of 0.1 mM CPT or 1 mM caffeine treatment. The sustained elevation in sodium-glucose symport and PKC activity observed with adenosine receptor antagonists was similar to acute (2-h) effects of the adenosine A1 agonist R(-)-N6-phenylisopropyladenosine (R-PIA, 0.1-1 microM). Moreover, cell proliferation was increased by adenosine (0.1 microM R-PIA), whereas Na-K-adenosinetriphosphatase activity was unaltered with chronic antagonist or acute adenosine treatments. Caffeine treatment may have some non-adenosine A1 receptor-mediated actions, because it slightly (30%) augmented protein kinase A activity. It is concluded that chronic exposure of proximal tubule cells to caffeine or CPT augments PKC and sodium-glucose transport but retards cell proliferation mainly via adenosine A1 receptor-mediated mechanisms.
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PMID:Upregulated renal adenosine A1 receptors augment PKC and glucose transport but inhibit proliferation. 877 86

To examine a possible metabolic regulatory role for adenosine, infusions of adenosine and adenosine deaminase were given to 11 near-term fetal sheep during the simulation of birth in utero. Fetal arterial blood gases, the concentration of a number of metabolites, insulin, and whole body O2 consumption (VO2) were measured. After intrauterine ventilation and cord occlusion, fetal/neonatal VO2, measured by closed-circuit respirometry, averaged 11.0 +/- 1.1 (SE) ml (STPD).min-1.kg fetal wt-1 and plasma adenosine concentration ([Ado]) was 1.29 +/- 0.21 microM. Infusion of adenosine (1.5 mumol.min-1.kg-1) during the next 30-min interval increased [Ado] to 1.57 +/- 0.28 microM (not significant) and decreased VO2 to 7.7 +/- 0.5 ml.min-1.kg-1 (P < 0.05). The infusion reduced systolic blood pressure by 19% (P < 0.01) and diastolic blood pressure by 25% (P < 0.01) and increased heart rate by 19% (P < 0.01). At the highest rate of adenosine infusion studied (6 mumol.min-1.kg-1), [Ado] increased to 4.27 +/- 0.46 microM (P < 0.001) and VO2 did not measurably decline further, although there were further decreases in blood pressure and increases in heart rate. After administration of adenosine deaminase, [Ado] decreased to 0.58 +/- 0.13 microM (P < 0.05), whereas VO2 increased to 11.2 +/- 0.8 ml.min-1.kg-1 (P < 0.05); blood pressure and heart rate returned to basal levels. The dependence of VO2 on [Ado] is described by the relationship VO2 = 6.14 + 4.89 exp(-0.45[Ado]) (n = 144; r = 0.34; P < 0.001). Throughout the experiment, arterial O2 content and plasma glucose, lactate, glycerol, and fatty acid concentrations were normal or elevated, and, therefore, O2 lack and substrate deficiency were unlikely to have caused the reduction in VO2. We conclude that plasma adenosine may act as a messenger of energy status for the ovine fetus/neonate and may contribute thereby to a maintenance of a balance between O2 supply and O2 demand.
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PMID:Exogenous infusion of adenosine depresses whole body O2 use in fetal/neonatal sheep. 887 16

Eight diurnally active (06:00-23:00 h) subjects were adapted for 2 days to the room conditions where the experiments were performed. Blood sampling for adenosine metabolites and metabolizing enzymes was done hourly during the activity span and every 30 min during sleep. The results showed that adenosine and its catabolites (inosine, hypoxanthine, and uric acid), adenosine synthesizing (S-adenosylhomocysteine hydrolase and 5'-nucleotidase), degrading (adenosine deaminase) and nucleotide-forming (adenosine kinase) enzymes as well as adenine nucleotides (AMP, ADP, and ATP) undergo statistically significant fluctuations (ANOVA) during the 24 h. However, energy charge was invariable. Glucose and lactate chronograms were determined as metabolic indicators. The same data analyzed by the chi-square periodogram and Fourier series indicated ultradian oscillatory periods for all the metabolites and enzymatic activities determined, and 24-h oscillatory components for inosine, hypoxanthine, adenine nucleotides, glucose, and the activities of SAH-hydrolase, 5'-nucleotidase, and adenosine kinase. The single cosinor method showed significant oscillatory components exclusively for lactate. As a whole, these results suggest that adenosine metabolism may play a role as a biological oscillator coordinating and/or modulating the energy homeostasis and physiological status of erythrocytes in vivo and could be an important factor in the distribution of purine rings for the rest of the organism.
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PMID:Temporal variations of adenosine metabolism in human blood. 887 80

Insulin increased 2-deoxyglucose (2-DG) uptake via the translocation of glucose transporter (GLUT) 4 to the plasma membrane fraction in rat adipocytes. The stimulatory actions of insulin were accompanied by both an increase in the immunoreactive p85 subunit of phosphatidylinositol (PI) 3-kinase in the plasma membrane fractions and PI 3-kinase activation by tyrosine phosphorylation of the p85 subunit. The beta3-adrenoceptor agonist CL316243 (CL) suppressed all the insulin actions in adenosine deaminase (ADA)-treated cells, but was without effect in non-ADA-treated cells. The inhibitory effects of CL on GLUT 4 translocation and PI 3-kinase activation were abolished by the addition of N6-phenylisopropyl adenosine. Cholera toxin treatment, which markedly increased intracellular cAMP levels, suppressed increases in the levels of GLUT 4 and PI 3-kinase in the plasma membrane fractions in response to insulin. In addition, dibutyryl (Bt2) cAMP also impaired the activation of PI 3-kinase by insulin. These results indicated that CL suppressed insulin-stimulated glucose transport under conditions where cAMP levels were markedly increased (approximately 12-fold). The inhibitory actions of PI 3-kinase activation by insulin were exerted even when cAMP, 8-bromo-cAMP, or Bt2 cAMP was added to immunoprecipitates of the p85 subunit of PI 3-kinase, after treating the cells with insulin. These results suggest that CL suppressed insulin-stimulated PI 3-kinase activity via a cAMP-dependent mechanism, at least in part, direct cAMP action in ADA-treated adipocytes, by which PI 3-kinase activation was inhibited, resulting in the decrease in GLUT 4 translocation and subsequent 2-DG uptake in response to insulin.
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PMID:Suppression of insulin-stimulated phosphatidylinositol 3-kinase activity by the beta3-adrenoceptor agonist CL316243 in rat adipocytes. 903 4

When a patient with an undiagnosed pleural effusion is evaluated, the first question to answer is whether the patient has a transudate or an exudate. This is best done using Light's criteria, but these criteria occasionally misidentify a transudate as an exudate. If the patient's pleural fluid meets exudative criteria, but the patient appears clinically to have a transudative effusion, then the serum-pleural fluid albumin gradient should be measured. If this is greater than 1.2 g-dL-1, the patient probably does have a transudative effusion. If the patient has an exudative pleural effusion, additional tests are indicated to determine the aetiology of the effusion. The gross appearance and the odour of the pleural fluid should be noted and samples of all exudates should be sent for bacterial cultures. Laboratory tests that are useful in the differential diagnosis of exudative pleural effusions include: differential white cell count of the pleural fluid; cytology of the pleural fluid; and levels of adenosine deaminase, glucose, amylase and lactate dehydrogenase in the pleural fluid. If pleural tuberculosis is suspected, a needle biopsy of the pleura is indicated. Thoracoscopy is very efficient at diagnosing malignant pleural effusion and tuberculosis pleuritis, but rarely establishes any other diagnosis.
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PMID:Diagnostic principles in pleural disease. 904 52

Cryptococcosis is the commonest fungal infection of the CNS and it is an important cause of morbidity and mortality in immunodeficient patients [1]. It has been occasionally described in immunocompetent patients [2]. We report a patient with no predisposing factors who was treated with flucytosine and amphotericin B for cryptococcal meningitis. Following treatment, she developed a reversible acute cerebellar syndrome that was probably secondary to the administration of flucytosine, an adverse effect that has not previously been described [3, 4]. An 87-year old women with no relevant personal or family history was admitted to the hospital for headache, fever, and confusion over the past week. The vital signs, general and neurological examination were normal. In laboratory tests, the urine, urea nitrogen, glucose, bilirubin, electrolytes, aspartate aminotransferase, creatine kinase, alkaline phosphatase, haematocrit, white-cell count, and platelet were also normal. A lumbar puncture was performed which showed: 60 typical lymphocytes per ml, adenosine deaminase (ADA) activity 6 U.l-1 (normal under 4 U.l-1), proteins 75.7 mg.dl-1, and glucose 13 mg.dl-1 with a glycaemia of 120 mg.dl-1. The microbiology study showed staining and a positive culture for Cryptococcus neoformans, and an antigen titre of 1/2080. The serology for HIV infection was negative, and other predisposing factors for this fungal infection, such as immunological defects, a lymphoreticular malignancy and sarcoidosis were excluded. A CT scan of the cranial-thoracic-abdominal regions was normal and tumour markers were absent.
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PMID:Acute cerebellopathy as a probable toxic effect of flucytosine. 911 68


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