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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isolated adrenal cells from Vitamin E-deficient and control rats were prepared by a trypsin digestion method. Cyclic adenosine 3',5'-monophosphate (cyclic AMP) formation was studied in response to adrenocorticotropin (ACTH) in the presence and absence of ascorbate by measuring the conversion of prelabeled adenosine 5'-triphosphate [14C]ATP to cyclic [14C]AMP. Ascorbate (0.5 mM) inhibited ACTH-induced cyclic [14C]AMP formation in adrenal cells isolated from Vitamin E-deficient rats but had no effect in the control cells. The inhibitory effect of ascorbate on ACTH-induced cyclic AMP formation in Vitamin E-deficient rats decreased as the concentration of ACTH increased. In Vitamin E-deficient rats ascorbate inhibited ACTH-induced cyclic [14C]AMP formation after 30 min of incubation. There was no further significant accumulation of cyclic [14C]AMP at 60 min or 120 min although in the absence of ascorbate cyclic [14C]AMP continued to be formed. The in vitro addition of alpha-tocopherol reduced the inhibition of ACTH-induced cyclic [14C]AMP formation by ascorbate in Vitamin E-deficient rats. These studies suggest that alpha-tocopherol and ascorbate may affect ACTH-induced cyclic AMP formation through interaction with the membrane-bound enzyme adenylate cyclase.
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PMID:Effect of ascorbic acid on ACTH-induced cyclic AMP formation and steroidogenesis in isolated adrenal cells of vitamin E-deficient rats. 16 1

The ability of adrenergic agents to promote the differentiation and especially the mitochondriogenesis of brown fat precursor cells, grown in culture, was investigated. These cells begin to differentiate during the days preceding confluence. We found here that, already during the early growth phase, the cultures (essentially precursor cells and preadipocytes at this stage) show increased cyclic AMP (cAMP) levels when acutely stimulated with norepinephrine (NE). The cultured cells were therefore chronically treated with NE up to the time of confluence, and their cytochrome-c oxidase activity was measured as an index of mitochondriogenesis. Chronic NE treatment resulted in an increased cytochrome-c oxidase activity of the cells at confluence. This effect was reproduced by selective activation of adenylate cyclase with cholera toxin, suggesting that the NE effect was exerted through an increase in cAMP. Ascorbate (added with NE as an antioxidant) had in itself a positive effect, both on final cell number and on cytochrome-c oxidase activity. It is concluded that NE, working through beta-adrenergic receptors, can stimulate mitochondriogenesis in brown fat cells through a direct effect on the cells, in accordance with the suggestion (based on in vivo experiments) that NE accelerates, rather than initiates, the differentiation process.
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PMID:Noradrenergic stimulation of mitochondriogenesis in brown adipocytes differentiating in culture. 282

The effect of heat in combination with DL-alpha-tocopheryl (vitamin E) succinate and adenosine 3', 5'-cyclic monophosphate (cAMP) stimulating agents on mouse neuroblastoma cells ( NBP2 ) in culture on the criterion of growth inhibition (due to cell death and inhibition of cell division) was studied. Heat (41 degrees-40 degrees) alone inhibited growth; however, the extent of growth inhibition was dependent upon the temperature and the time of heat treatment. Heat (41 degrees-40 degrees) in combination with vitamin E succinate (5 micrograms/ml) produced an additive effect on the criterion of growth inhibition. Vitamin C (100 micrograms/ml) failed to modify the effect of heat. Prostaglandin A2, a stimulator of adenylate cyclase, and 4 - (3-butoxy-4-methoxybenzyl)-2-imidazolidinone ( R020 -1724), an inhibitor of cyclic nucleotide phosphodiesterase, are known to induce irreversible differentiation in mouse neuroblastoma cells in culture. These agents, in combination with heat (40 degrees) produced a synergistic effect on the criterion of growth inhibition. These data suggest that the addition of vitamin E and cAMP stimulating agents may increase the effectiveness of hyperthermia protocol.
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PMID:Effect of hyperthermia in combination with vitamin E and cyclic AMP on neuroblastoma cells in culture. 632 55

In mice ascorbate, when co-administered with morphine, suppresses the development of tolerance and physical dependence on the drug, without significantly affecting its analgesic properties as inferred from unaltered ED50 values. The duration of morphine-induced analgesia, however, is progressively reduced with an increase in the amounts of ascorbate. Ascorbate at 1g/kg body weight does not alter the pH of blood, and has no effect on the levels of lipid-peroxides in blood and brain. Studies presented in this paper suggest the potential use of ascorbate in the prevention of development of tolerance in therapeutic applications of narcotics as analgesics. Cultured Neuroblastoma X Glioma hybrid cells (NG 108-15) respond to opiates in two different ways. The rapid receptor mediated inhibition of adenylate cyclase is followed by a long-lived compensatory increase in its activity (1-4). In a recent report (5) we have shown that ascorbate suppresses the delayed etorphine-induced compensatory increase in cAMP levels in NG 108-15 cells without affecting the short-term inhibitory response of cells to the drug. It has been suggested that while the former may be the basis of narcotic dependence and tolerance, the latter is responsible for the analgesic effect. These observations, based on a model system, prompted us to examine the effect of ascorbate on the pharmacological properties of morphine at the organismal level.
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PMID:Megadoses of vitamin C prevent the development of tolerance and physical dependence on morphine in mice. 668 37

Adenylate cyclase in the membrane fractions of bovine and rat brains, but not in rat liver plasma membranes, was solubilized by treatment with Fe2+ (10 microM) plus dithiothreitol (5 mM). Solubilization of the enzyme by these agents was completely prevented by simultaneous addition of N,N'-diphenyl-p-phenylenediamine (DPPD), an inhibitor of lipid peroxidation. Ascorbic acid also solubilized the enzyme from the brain membranes. Lipid peroxidation of the brain membranes was characterized by a selective loss of phosphatidylethanolamine. Solubilization of membrane-bound enzymes by Fe2+ plus dithiothreitol was not specific for adenylate cyclase, because phosphodiesterase, thiaminediphosphatase and many other proteins were also solubilized. Solubilized adenylate cyclase had a high specific activity and was not activated by either NaF, 5'-guanylyl imidodiphosphate (Gpp[NH]p) or calmodulin. These results suggested that lipid peroxidation of the brain membranes significantly solubilized adenylate cyclase of high specific activity.
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PMID:Solubilization of adenylate cyclase of brain membranes by lipid peroxidation. 711 15

The relationship between adenylate cyclase activity in the synaptic membrane fraction (M1) of rat brain and lipid peroxidation of these membranes was examined. In the presence of 5 mM dithiothreitol (DTT), 1 to 10 microM Fe/+ activated adenylate cyclase 2- to 4-fold. Of several metal ions, Fe2+ was the most effective. Other enzymes in M1, such as Mg2+-ATPase, (Na+-K+)-ATPase, 5'-nucleotidase, acetylcholinesterase, and phosphodiesterase, were not activated by Fe2+ plus DTT. Activation of adenylate cyclase by Fe2+ plus DTT was accompanied by production of malondialdehyde, a product of lipid peroxidation. Formation of malondialdehyde was completely parallel with enzyme activation. Ascorbic acid or a NADPH system also stimulated enzyme activity and caused lipid peroxidation. Activation of the enzyme and lipid peroxidation induced by Fe2+ plus DTT, ascorbic acid, or NADPH was completely prevented by simultaneous addition of N,N'-diphenyl-p-phenylenediamine, an inhibitor of lipid peroxidation. This inhibitor also prevented the decrease in turbidity of the enzyme preparation induced by Fe2+ plus DTT. The stimulatory effects of NaF, guanylyl-5'-imidodiphosphate and calmodulin, respectively, and that of Fe2+ plus DTT on the enzyme activity were additive. Activation of adenylate cyclase by Fe2+ plus DTT was only observed in brain synaptic membranes, not in erythrocyte ghosts, liver plasma membranes, or cardiac sarcolemma. These results indicate that lipid peroxidation of synaptic membranes was accompanied by specific stimulation of adenylate cyclase activity.
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PMID:Activation of adenylate cyclase of rat brain by lipid peroxidation. 721 51

1alpha,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] induces differentiation to monocyte-macrophage lineage of several leukaemic cell lines such as HL-60, U937, M1 and Mono Mac 6. Ascorbate also modulates growth and differentiation of different animal cells in culture. We have previously reported the stimulating effect of ascorbate on 1, 25-(OH)2D3-induced HL-60 cell differentiation. We show here that 1, 25-(OH)2D3 induces a transient increase in cAMP levels in these cells, and ascorbate significantly increases these cAMP levels. Ascorbate alone does not have any effect. Other cAMP-increasing agents such as isobutylmethylxanthine, forskolin and prostaglandin E2 maintain high levels of cAMP at 48 h of incubation and also enhance differentiation along the monocytic pathway induced by 1, 25-(OH)2D3, as revealed by specific differentiation markers, demonstrating the importance of cAMP in the differentiation process. It is also shown that the presence of ascorbate and its free radical (AFR) during 1,25-(OH)2D3-induced differentiation significantly decreases cytoplasmic NADH levels compared with those induced by 1,25-(OH)2D3 in HL-60 cells. The results indicate that NADH is an inhibitor of adenylate cyclase in these cells. AFR is an electron acceptor of the trans-plasma-membrane electron-transport system, and NADH is the electron donor. Through this system, ascorbate and AFR keep levels of NADH low, thereby decreasing its inhibitory effect on adenylate cyclase activity and so increasing cAMP synthesis. We also demonstrate that other ascorbate derivatives, such as ascorbate 2-phosphate and dehydroascorbate, both of which are unable to produce AFR, do not alter intracellular NADH levels during 1, 25-(OH)2D3-induced differentiation. Also, ascorbate and AFR increase specific differentiation markers (CD14 and NitroBlue Tetrazolium reduction) but neither ascorbate 2-phosphate nor dehydroascorbate show this enhancing activity. In summary, we propose that the effect of ascorbate on 1,25-(OH)2D3-induced differentiation of HL-60 cells can be explained by redox regulation of the cAMP pathway.
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PMID:Redox regulation of cAMP levels by ascorbate in 1,25-dihydroxy- vitamin D3-induced differentiation of HL-60 cells. 951 57

We have investigated the possibility that the synthesis/accumulation of neurosteroids, i.e., brain-produced steroids putatively endowed with modulatory actions in the CNS, is regulated by monoaminergic receptor-mediated mechanisms. In minces of rat brain cortex, L-ascorbic acid concentration-dependently (0.07-1.0 mM) increases the levels of pregnenolone, allotetrahydrodeoxycorticosterone, and dehydroepiandrosterone. This effect of L-ascorbic acid is region-dependent: in hippocampus, progesterone and allopregnanolone are also increased, whereas dehydroepiandrosterone is unchanged, and in corpus striatum only progesterone is increased significantly. 5-Hydroxytryptamine (10 microM), 1-(3-chlorophenyl)piperazine (1.0 microM), and 5-methoxytryptamine (0.4 microM) mimic the effect of L-ascorbic acid, whereas a pretreatment with p-chlorophenylalanine (400 mg/kg i.p., 2 days) reduces the amplitude of the L-ascorbic acid effect on brain cortical neurosteroids. The effect of L-ascorbic acid is blocked by the nonselective serotonin antagonists methiothepin, clozapine, methysergide, and pizotifen, but not mesulergine, spiperone, MDL 72222, and DL-propranolol, nor by the catecholaminergic receptor antagonists prazosin and S(-)-sulpiride. L-Ascorbic acid is not additive with dibutyryl-cyclic AMP and, furthermore, the inhibition of adenylate cyclase by MDL 12330A, but not of phospholipase C by U-73122, markedly attenuates the L-ascorbic acid-induced increase of pregnenolone in rat brain cortical minces. Together these data suggest that L-ascorbic acid plays a role in the modulation of neurosteroidogenesis, presumably by favoring the activation of the purported serotonin type 6 receptor by endogenous serotonin.
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PMID:Modulation of neurosteroid synthesis/accumulation by L-ascorbic acid in rat brain tissue: inhibition by selected serotonin antagonists. 972 35

Ascorbic acid is found in very high concentrations in cells of neural crest origin such as the central nervous system and the adrenal gland. A variety of evidence has been marshalled to support a role for ascorbate as a chemical messenger. One of the first non-biosynthetic biochemical effects ascribed to ascorate in the CNS was its ability to inhibit dopamine-stimulated adenylate cyclase (DA-ACase) in homogenates from striata of Long Evans rats (J. Neurochem.28, 663, 1977). Using an adenylate cyclase assay based on preparative HPLC, we were unable to detect any inhibition of DA-ACase by ascorbate at concentrations as high as 1 mM. Moreover, this failure to find inhibitory effects of ascorbate on DA-ACase occurred not only when striatal homogenates from Long-Evans rats were used, but also when tissue from Sprague-Dawley rats of N.C. Board of Health mice was tested. Although ascorbate may play a neuromodulatory role, it does not appear that its effects are mediated through effects on cAMP biosynthesis. Despite our inability to detect effects of ascorbate on DA-ACase, we did confirm that ascorbate significantly altered the binding of [(3)H]dopamine to striatal membranes. Thus, it is clear that the sites binding [(3)H]dopamine that are affected by ascorbate are unlikely to be the same ones coupled to aenylate cyclase.
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PMID:Ascorbic acid decreases [(3)H]dopamine binding in striatum without inhibiting dopamine-sensitive adenylate cyclase. 2048 29

Ascorbic acid (AA) is the active component of vitamin C and antioxidant activity was long considered to be the primary molecular mechanism underlying the physiological actions of AA. We recently demonstrated that AA is a competitive inhibitor of adenylate cyclase, acting as a global regulator of intracellular cyclic adenosine monophosphate (cAMP) levels. Our study, therefore, aimed to determine new targets of AA that would account for its potential effect on signal transduction, particularly during cell differentiation. We demonstrated that AA is an inhibitor of pre-adipocyte cell line differentiation, with a dose-dependent effect. Additionally, we describe the impact of AA on the expression of genes involved in adipogenesis and/or the adipocyte phenotype. Moreover, our data suggest that treatment with AA partially reverses lipid accumulation in mature adipocytes. These properties likely reflect the function of AA as a global regulator of the cAMP pool, since an analog of AA without any antioxidant properties elicited the same effect. Additionally, we demonstrated that AA inhibits adipogenesis in OP9 mesenchymal cell line and drives the differentiation of this line toward osteogenesis. Finally, our data suggest that the intracellular transporter SVCT2 is involved in these processes and may act as a receptor for AA.
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PMID:Ascorbic acid is a dose-dependent inhibitor of adipocyte differentiation, probably by reducing cAMP pool. 2536 36


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