Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ethanol impairs insulin-stimulated survival and mitochondrial function in immature proliferating neuronal cells due to marked inhibition of downstream signaling through P13 kinase. The present study demonstrates that, in contrast to immature neuronal cells, the major adverse effect of chronic ethanol exposure (50 mM) in post-mitotic rat cerebellar granule neurons is to inhibit insulin-stimulated mitochondrial function (MTT activity, MitoTracker Red fluorescence, and cytochrome oxidase immunoreactivity). Ethanol-impaired mitochondrial function was associated with increased expression of the p53 and CD95 pro-apoptosis genes, reduced Calcein AM retention (a measure of membrane integrity), increased SYTOX Green and propidium iodide uptake (indices of membrane permeability), and increased oxidant production (dihydrorosamine fluorescence and H2O2 generation). The findings of reduced membrane integrity and mitochondrial function in short-term (24 h) ethanol-exposed neurons indicate that these adverse effects of ethanol can develop rapidly and do not require chronic neurotoxic injury. A role for caspase activation as a mediator of impaired mitochondrial function was demonstrated by the partial rescue observed in cells that were pre-treated with broad-spectrum caspase inhibitors. Finally, we obtained evidence that the inhibitory effects of ethanol on mitochondrial function and membrane integrity were greater in insulin-stimulated compared with nerve growth factor-stimulated cultures. These observations suggest that activation of insulin-independent signaling pathways, or the use of insulin sensitizer agents that enhance insulin signaling may help preserve viability and function in neurons injured by gestational exposure to ethanol.
Cell Mol Life Sci 2001 Nov
PMID:Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons. 1176 90

This study describes the effects of short- and long-term ethanol treatment and withdrawal on the biosynthesis of the phospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in hepatocytes isolated from rats, using isotopically labelled choline and ethanolamine as exogenous precursors. Our results demonstrate that short-term ethanol consumption increases the incorporation of exogenous polar bases into PC and PE, whereas long-term ethanol administration provokes a differential effect in both PC and PE biosynthesis via cytidine diphosphate derivatives (CDP-derivatives), decreasing PC synthesis and increasing the biosynthesis of PE. We suggest that the increased biosynthesis of PE after ethanol treatment results from changes in lipogenic substrates produced as a consequence of ethanol metabolism, whilst the specific inhibition of PC biosynthesis seems to be a consequence of alterations of enzymes involved in the CDP-choline pathway. With regard to the influence of ethanol on PE methylation to give PC, our results demonstrate that ethanol activates this pathway in short-term, as well as chronic ethanol treatment. Ethanol withdrawal returns the activity of the PC and PE pathways to control levels. The alterations in the biosynthesis of the main phospholipids, PC and PE, demonstrated in this study could be of a great physiological interest in determining the pathology of alcoholism.
Comp Biochem Physiol B Biochem Mol Biol 2002 Mar
PMID:Comparative study of the effects of short- and long-term ethanol treatment and alcohol withdrawal on phospholipid biosynthesis in rat hepatocytes. 1195 31

The human alcohol dehydrogenase system is comprised of multiple forms that catalyse the oxidation/reduction of a large variety of alcohols and aldehydes. A transition that results in an Ile308Val substitution was identified in the human ADH2 gene by single-strand conformation polymorphism analysis. Screening a Swedish population revealed that Val308 was the most frequent allele (73%), and site-directed mutagenesis was used to obtain both allelozymes, which were expressed in Escherichia coli for characterisation. Thermostability was assayed by activity measurements and circular dichroism spectroscopy. The results showed that the 308Val substitution decreases protein stability, as compared to the Ile308 variant, an effect also demonstrated during prolonged storage. Ethanol, octanol, 12-hydroxydodecanoic acid and all-trans retinol were used as model substrates and, generally, slightly higher Km values were observed with Val at position 308. Finally, homology modelling, from mouse ADH2, further supported the decreased stability of the Val308 variant and located position 308 in the subunit interface of the molecule and in the vicinity of the active-site pocket entrance. In conclusion, the Ile308Val substitution represents a novel functional polymorphism within the human alcohol dehydrogenase gene cluster that may affect the metabolism of ethanol and other substrates.
Cell Mol Life Sci 2002 Mar
PMID:Identification and characterisation of two allelic forms of human alcohol dehydrogenase 2. 1196 33

Electron paramagnetic resonance (EPR) has been used to investigate the adsorption capability and the surface interacting ability towards Cu(II) solutions (CuCl2, Cu(NO3)2, CuSO4 in water or ethanol) of various carbon blacks, both graphitized and ungraphitized, selected on the basis of the surface area, namely, Carbograph1 (area = 100 m2/g), Carbograph4 (area = 210 m2/g), and Carbograph5 (area = 560 m2/g), which were indicated as C1g, C4g, C5g (g = graphitized), and C1ng, C4ng, C5ng (ng = ungraphitized). The EPR analysis was supported by surface analysis, for evaluating the surface area, the pore volume and the porosity, and by atomic absorption to obtain the adsorbed Cu(II) amounts. Graphitization provokes a decrease in surface area, but C1g, at low surface area, showed a unexpected increase of the adsorption ability ascribed to the formation of new surface porosity closed by graphite layers. The carbon samples showed a broad unresolved EPR signal due to mobile unpaired electrons in the carbon matrix. Graphitized samples presented a narrower signal than ungraphitized samples, which increases in width with the increase in surface area (with the exception of C5ng due to the high exposition of the wide surface to oxydizing external agents) and upon prolonged thermal treatment. The signal intensity of the carbon paramagnetic centers decreases upon Cu(II) adsorption. Computer aided analysis of the EPR spectra of the solids after Cu(II) adsorption allowed to extract structural information on the Cu-surface site complexes. The Cu2+ ions coordinated with surface polar sites, mainly oxygenated. Adsorption depends on the different Cu(II) salts, caused by the salt solubility and the interacting ability of the counter-ion. In several cases the solutions concentrated in the carbon porosity leading to precipitation of the salt. Ethanol solutions are more adsorbed at the carbon surface than water solutions; Cu(II) partially retains its solvation shell and partially presents electron transfer to the carbon surface. Adsorption is favored to ungraphitized carbons with respect to the graphitized ones due to both the higher surface area, and the higher hydrophilicity of the surface. In summary, these carbon powders, widely used for chromatographic applications, show an adsorption capability towards Cu(II) solutions higher than expected due to both a definite porosity, and the presence of polar groups which are not eliminated with chemical surface treatments.
Spectrochim Acta A Mol Biomol Spectrosc 2002 Apr
PMID:Characterization of the surface interacting ability of carbon black by means of electron paramagnetic resonance analysis of adsorbed Cu2+, supported by surface analysis and atomic absorption. 1199 61

The aims of this study were to test if ethanol induces thyrotropin-releasing hormone (TRH) secretion in vitro from the posterior pituitary and hypothalamic explants by a mechanism involving cell swelling, and to characterize the pathway of stimulated secretion. Ethanol, at a concentration of 80 mM, stimulated the release of TRH from the posterior pituitary, the hypothalamic paraventricular nucleus, the median eminence, and the brain septum, when administered only in isosmolar but not in hyperosmolar medium. This indicates the involvement of a cell swelling-inducing mechanism. L-canavanine in a concentration of 3 mM, increased the basal and hyposmosis-induced TRH secretion from the posterior pituitary and the paraventricular nucleus, and both basal and ethanol-induced TRH secretion from isolated pancreatic islets. This indicates the presence of both constitutive and regulatory secretory pathways. Our results suggest that cell swelling induces exocytosis from clathrin coated granules.
Cell Mol Neurobiol 2002 Feb
PMID:Cell swelling induced secretion of TRH by posterior pituitary, hypothalamic paraventricular nucleus and pancreatic islets: effect of L-canavanine. 1206 16

Both benzodiazepines and gamma-hydroxybutyric acid (GHB) are used to treat alcohol withdrawal syndrome. The molecular basis for this therapeutic efficacy was investigated with primary cultures of rat cerebellar granule cells. Long-term exposure of these cells to ethanol (100 mM, 5 days) reduced the abundance of mRNAs encoding the gamma(2)L and gamma(2)S subunits of the GABA type A receptor (-32 and -23%, respectively) but failed to affect that of alpha(1), alpha(4), or alpha(6) subunit mRNAs. Subsequent ethanol withdrawal resulted in decreases in the amounts of alpha(1) (-29%), alpha(6) (-27%), gamma(2)L (-64%), and gamma(2)S (-76%),subunit mRNAs that were maximal after 6 to 12 h. In contrast, 3 h after ethanol withdrawal, the abundance of the alpha(4) subunit mRNA was increased by 46%. Ethanol withdrawal did not affect neuronal morphology but reduced cellular metabolic activity. The increase in alpha(4) subunit was confirmed by functional studies showing a positive action of flumazenil in patch clamp recordings of GABA-stimulated currents after ethanol withdrawal. Diazepam (10 microM) or GHB (100 mM) prevented the increase in the amount of the alpha(4) subunit mRNA, the metabolic impairment, and the positive action of flumazenil induced by ethanol withdrawal but failed to restore the expression of the alpha(1) and gamma(2) subunits. The antagonism by GHB seems not to be mediated by a direct action at GABA(A)R because GHB failed to potentiate the effects of GABA or diazepam on Cl(-) currents mediated by GABA type A receptor.
Mol Pharmacol 2003 Apr
PMID:Gamma-hydroxybutyric acid and diazepam antagonize a rapid increase in GABA(A) receptors alpha(4) subunit mRNA abundance induced by ethanol withdrawal in cerebellar granule cells. 1264 91

The rate constants of the reactions of alcohol dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase with hydroxyl radicals were determined using the method of steady-state competitive reactions. Ethanol was used as a scavenger of hydroxyl radicals. The rate constants of the reactions of hydroxyl radicals with alcohol dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase were found to be 2.8 x 10(12) dm(3) mol(-1) s(-1), and 1.6 x 10(12) dm(3) mol(-1) s(-1), respectively.
Cell Mol Biol Lett 2003
PMID:The rate constants of the reaction of hydroxyl radicals (*OH) with alcohol dehydrogenase and Glyceraldehyde-3-phosphate dehydrogenase. 1294 23

The medium (pH, organic solvents, cyclodextrin (CD) or surfactants) effects on the fluorescence of ciprofloxacin hydrochloride (CPFX.HCl) were studied in detail. It is found that the three acid constants of ciprofloxacin (CPFX) are near to each other. Therefore the relation curve between pH and fluorescence intensity has no strident change and keeps relative stable in the pH range of 2-7. When pH was in the range of 5.5-6.0, the fluorescence intensity of CPFX reached the max. The kind and amount of organic solvent added to the luminescent system have various effects. Ethanol quenched fluorescence and the fluorescence excitation wavelength is red shift at first and then blue shift. Acetone has complicated effects on the fluorescence properties of CPFX.HCl solution. The experiment result shows that acetone is really a quencher when its volume content in the system is from 0 to 20%, but when its content is 90%, the signal intensity is unexpectedly one and a half times as much as that of no acetone. This means that there is a strong interaction between the acetone and CPFX; CPFX.H(+) could be included into the gamma-CD but the capping effect is not notable. The effect of cationic surfactant cetyltrimethylammonium bromide and non-ionic surfactant TX-100 and TX-80 on CPFX fluorescence was unimpressive, but the anionic surfactant's effect is aberrant. The fluorescence intensity of CPFX.HCl solution experiences three stages of increasing, decreasing and increasing in turn, as sodium dodecyl sulfate is adding gradually. But for sodium lauryl sulfonate, there are only two stages of decreasing and increasing with the concentration increasing. It is problematic to illustrate clearly the effect mechanism of acetone and anionic surfactant at present. Undoubtedly, the experimental results in this paper should be useful in practice works and the research is worth studying still further.
Spectrochim Acta A Mol Biomol Spectrosc 2003 Oct
PMID:Medium effects on fluorescence of ciprofloxacin hydrochloride. 1449 32

Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of the CYP2E1 form of cytochrome P450 enzymes by ethanol. CYP2E1 is of interest because of its ability to metabolize and activate many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of HepG2 cell lines developed to constitutively express the human CYP2E1 in assessing the actions of CYP2E1. Regulation of CYP2E1 is quite complex and will be briefly reviewed. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.
Curr Mol Med 2003 Sep
PMID:CYP2E1: biochemistry, toxicology, regulation and function in ethanol-induced liver injury. 1452 82

Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylation-sensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu(2+) promoted enzyme activity and methylation, while Cu(+), Pb(2+), Hg(2+) and Al(3+) were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC(50) of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.
Mol Psychiatry 2004 Apr
PMID:Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. 1511 82


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