Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immune system derangement in cirrhotic patients with evidence of malnutrition is a well-recognized characteristic of chronic alcohol abuse. However, in vitro studies on cellular immune function performed with lectin mitogens have produced conflicting results. The recent development of more accurate immunological techniques for studying lymphocyte transformation, that use monoclonal antibodies directed against surface structures (CD3 and CD2) involved in antigen recognition, as well in adhesion functions, prompted us to study discrete in vitro T-cell hypo-responsiveness in a series of alcoholic liver disease (ALD) patients with no evidence of malnutrition or hepatic cirrhosis. The results indicated that the CD2 pathway is markedly defective in ALD T lymphocytes, accompanied by reduced interleukin-2 (IL-2) receptor expression upon in vitro activation. This defect cannot be reversed by the addition of recombinant IL-2 (rIL-2) or rIL-1. Faulty intracellular signal transduction by protein kinase C (PKC) and defective intracellular Ca2+ mobilization may be responsible for the CD2 pathway impairment. The addition of small amounts of phorbol 12-myristate, 13-acetate, but not Ca2+ ionophore A23187, is able to overcome the defect, thereby suggesting a direct PKC involvement. The hypothesis of a direct ethanol effect on transmembrane signal transduction systems is suggested by the demonstration of an expansion of circulating virgin (naive) T cells (CD3+/UCHL1-low) that binds tyrosine phosphatase (CD45RA antigen) on their surface.
 ...
PMID:T-lymphocyte activation pathways in alcoholic liver disease. 167 85

Phosphatidylethanol, whose synthesis is catalyzed by a phospholipase D in a transphosphatidylation reaction, is a unique metabolite of ethanol. Phorbol 12-tetradecanoate 13-acetate, a tumor-promoting phorbol ester and stimulator of protein kinase C, activates this enzyme in peripheral blood lymphocytes. This system has been developed into an assay for measuring the potential of this pathway in human subjects. A pilot study of phosphatidylethanol synthesis in lymphocytes of adult males who have both an alcohol dependency and a family history of alcoholism has revealed that the average potential for phosphatidylethanol synthesis in this population is significantly elevated over that of control subjects.
 ...
PMID:Synthesis of phosphatidylethanol--a potential marker for adult males at risk for alcoholism. 320 Aug 56

The effects of alcohol exposure on human peripheral circulating lymphocyte protein kinase C (PKC) activity were characterized in lymphocytes harvested from two sample groups. The first group (control) consisted of 30 nonalcoholic male subjects and the second group consisted of nine male subjects with chronic alcoholism. Alcoholic subjects were admitted for detoxification to a substance abuse unit located in a nonprofit community hospital. In this group of subjects, blood was sampled on admission for detoxification (pre-A), and after 5 days (post-A). Subjects received chlordiazepoxide for treatment of alcohol withdrawal symptoms. PKC activities measured in the control, pre-A, and post-A groups expressed as pmol/microgram/min +/- SEM were 5.09 +/- 0.50, 1.81 +/- 0.43, and 3.95 +/- 0.44. Control PKC was significantly higher than pre-A PKC (p < or = 0.05) and post-A PKC was significantly higher than pre-A PKC (p < or = 0.05). Total lymphocyte PKC activity was also found to be inversely related to age, expressed by the relationship log(PKC) = 0.870-0.005(Age), with R = 0.433.
 ...
PMID:Effects of chronic alcohol use and age on human lymphocyte protein kinase C activity. 797 7

The effect of variation of the degree of cis-unsaturation on cell membrane protein functioning was investigated using a model lipid bilayer system and protein kinase C (PKC). This protein is a key element of signal transduction. Furthermore it is representative of a class of extrinsic membrane proteins that show lipid dependent interactions with cell membranes. To test for dependence of activity on the phospholipid unsaturation, experiments were devised using a vesicle assay system consisting of phosphatidylcholine (PC) and phosphatidylserine (PS) in which the unsaturation was systematically varied. Highly purified PKC alpha and epsilon were obtained using the baculovirus-insect cell expression system. It was shown that increased PC unsaturation elevated the activity of PKC alpha. By contrast, increasing the unsaturation of PS decreased the activity of PKC alpha, and to a lesser extent PKC epsilon. This result immediately rules out any single lipid bilayer physical parameter, such as lipid order, underlying the effect. It is proposed that while PC unsaturation effects are explainable on the basis of a contribution to membrane surface curvature stress, the effects of PS unsaturation may be due to specific protein-lipid interactions. Overall, the results indicate that altered phospholipid unsaturation in cell membranes that occurs in certain disease states such as chronic alcoholism, or by dietary manipulations, are likely to have profound effects on signal transduction pathways involving PKC and similar proteins.
 ...
PMID:Polyunsaturation in cell membranes and lipid bilayers and its effects on membrane proteins. 872 17

There are numerous reports of the effect of ethanol on protein kinase C (PKC) in animals or with in vitro systems. However, the effect of ethanol on PKC in humans has not been extensively investigated despite the large number of studies involving PKC and human platelets. In this study, we administered ethanol to human volunteers and determined the level of PKC before and after a 0.4 g/kg dose of ethanol. We studied Native Americans and Caucasians of both sexes. There was an increases in PKC activity 60 min after ethanol administration. There were no ethnic, age, nor gender differences detected, nor was there any correlation between family history of alcoholism and the basal or stimulated platelet PKC levels. Neither was there any correlation of basal or stimulated PKC activity with the genotypes for ADH2, ADH3, ALDH2, CYP2E1, and CYP1A2.
 ...
PMID:Effect of administered ethanol on protein kinase C in human platelets. 898 94

This work tests the hypothesis that chronic alcohol intoxication suppresses the microbicidal activity of Kupffer cells by modulating the expression of cell surface receptors associated with respiratory burst and the release of potent microbicidal agents [i.e., reactive oxygen species (ROS)]. Because alcohol is also a potential risk factor in human immunodeficiency virus-1 (HIV-1) infection, this study examines the effect of HIV-1 glycoprotein 120 (gp120)-induced ROS release by isolated Kupffer cells. After 16 weeks of ethanol feeding, Kupffer cells from male Sprague-Dawley rats were isolated and assayed for HIV-1 gp120-induced superoxide release. Fluorescein isothiocyanate (FITC)-HIV-1 gp120 binding, NADPH oxidase, and protein kinase C activity in Kupffer cells were measured. Results show that HIV-1 gp120 induced the release of superoxide anion in a dose-dependent manner in normal rats. Mannosylated-bovine serum albumin inhibited FITC-HIV-1 gp120-mediated superoxide release in normal Kupffer cells by 85%. Moreover, 83 +/- 6% of Kupffer cells were FITC-HIV 1 gp120-positive, whereas <30% were CD4-positive. In alcohol-fed rats, HIV-1 gp120-induced ROS release was reduced by 70% and FITC-HIV-1 gp120 binding (in terms of fluorescence intensity per 10[6] Kupffer cells) by 44% in Kupffer cells, without any change in percent positive cells for this ligand. Concomitantly, HIV-1 gp120-induced translocation of NADPH oxidase to the plasma membranes of Kupffer cells in alcohol-fed rats was suppressed by 60%. In contrast, alcohol consumption significantly increased total protein kinase C activity and phorbol ester-induced superoxide release by Kupffer cells. These studies demonstrate that Kupffer cells are likely targets of HIV-1 whose binding sites on macrophages could also include mannose-specific receptors. These observations further suggest that suppression of HIV-1 gp120-mediated ROS production in chronic alcoholics is due to altered cell surface receptor expression for gp120, and defective postreceptor signaling mechanisms, which in turn could lead to attenuated microbicidal activity of hepatic macrophages.
 ...
PMID:Chronic alcohol intoxication attenuates human immunodeficiency virus-1 glycoprotein 120-induced superoxide anion release by isolated Kupffer cells. 958 56

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen that can be found in individuals in which the immune system has been suppressed by HIV/AIDS or chronic alcoholism. We evaluated the role of inducible nitric oxide synthase (NOS II) as a modulator of lung concentrations of P. aeruginosa in normal rats and rats given a single dose of ethanol (ETOH). Rats were pretreated with either sterile saline (PBS, 0.1 ml/kg, i.v.) or the NOS II inhibitor L-N6-iminoethyl lysine (LNIL, 10 mg/kg, i.v.) 15 min before intraperitoneal administration of either PBS (4.5 ml/kg) or ETOH (4.5 g/kg). Thirty min after administration of PBS or ETOH the rats were placed in inhalation chambers and exposed to 45 min of an aerosol containing P. aeruginosa (5 x 10(4) colony forming units, CFU). A group of rats (n = 5-6/treatment/time period) were killed immediately (0 hr) or 4 hr after inhalation of P. aeruginosa. The lungs were homogenized and the P. aeruginosa were grown in nutrient broth to determine the number of viable CFU remaining in the lung. The NOS II and TNFalpha mRNA and protein content lung alveolar macrophages (AM) and neutrophils (PMN) were measured with RT-PCR and Western blot. The concentration of nitrate and nitrite anion in the bronchoalveolar lavage fluid (BALf) and ex vivo incubates of PMN were also measured. The CFU of P. aeruginosa present in the lungs of the four groups of rats at 0 hr did not differ. The CFU of P. aeruginosa in the lung increased (p < 0.05) in rats pretreated with ETOH when compared with that obtained from rats pretreated with PBS. However, pretreatment of rats with LNIL decreased (p < 0.05) the 4 hr lung content of P. aeruginosa. Coadministration of LNIL and ETOH to rats augmented the CFU of P. aeruginosa in lungs to amounts which did not differ from that of rats pretreated with ETOH. Inhalation of P. aeruginosa increased NOS II mRNA and protein in rat AM and PMN. Pretreatment of rats with ETOH alone, or in combination with LNIL, inhibited P. aeruginosa-induced NOS II transcription and translation and AM and PMN nitrate and nitrite generation whereas pretreatment with LNIL alone only inhibited nitrate and nitrite generation. Pretreatment of rats with ETOH suppressed P. aeruginosa stimulated PMN recruitment into the lung whereas LNIL enhanced (p < 0.05) P. aeruginosa-stimulated PMN recruitment into the lung. ETOH-induced increases of the lung content of P. aeruginosa were associated with increased PKC delta isozyme in the membrane of the PMN but could not be explained by altered plasma concentrations of hydrocortisone or ETOH. The data demonstrate that selective inhibition of NOS II-derived NO by LNIL decreases the lung content of P. aeruginosa whereas ETOH inhibits the lung clearance of P. aeruginosa. Speculatively, the difference between these effects of LNIL and ETOH may result from differences in drug-induced changes in lung recruitment of PMN.
 ...
PMID:Ethanol inhibits lung clearance of Pseudomonas aeruginosa by a neutrophil and nitric oxide-dependent mechanism, in vivo. 1023 11

There is increasing evidence that individual protein kinase C (PKC) isozymes mediate specific effects of ethanol on the nervous system. In addition, multiple lines of evidence suggest that the mesoaccumbens dopamine reward system is critically involved in the rewarding and reinforcing effects of ethanol. Yet little is known about the role of individual PKC isozymes in ethanol reinforcement processes or in regulation of mesolimbic systems. In this study, we report that mice lacking the epsilon isoform of PKC (PKCepsilon) show reduced operant ethanol self-administration and an absence of ethanol-induced increase in extracellular dopamine levels in the nucleus accumbens. PKCepsilon null mice exhibited a 53% decrease in alcohol-reinforced operant responses under basal conditions, as well as following ethanol deprivation. Behavioural analysis revealed that while both genotypes had the same number of drinking bouts following deprivation, PKCepsilon null mice demonstrated a 61% reduction in number of ethanol reinforcers per bout and a 57% reduction in ethanol-reinforced response rate. In vivo microdialysis experiments showed that, in contrast to wild-type mice, PKCepsilon null mice exhibited no change in extracellular levels of dopamine in the nucleus accumbens following acute administration of ethanol (1 and 2 g/kg i.p.), while mesolimbic dopamine responses to cocaine (20 mg/kg i.p.) or high potassium (100 mM) in these mice were comparable with that of wild-types. These data provide further evidence that increases in extracellular mesolimbic dopamine levels contribute to the reinforcing effects of ethanol, and indicate that pharmacological agents inhibiting PKCepsilon may be useful in the treatment of alcohol dependence.
 ...
PMID:Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol in PKCepsilon-deficient mice. 1106 9

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Jobst August-Ludwig Boening and Otto Michel Lesch. The presentations were (1) Pharmacological validation of a new animal model of alcoholism, by Rainer Spanagel; (2) Persisting loss of control as main criterion for alcohol addiction in rats and mice, by Jochen Wolffgramm; (3) Role of NMDA receptor subunits associated with protein kinase C in the prevention of alcohol dependence, by Minoru Narita; (4) Long-term follow up of continued naltrexone treatment, by David Sinclair; (5) Pharmacological treatment trials with dopaminergic and serotonergic substances: Myths or facts? by Gerhard A. Wiesbeck; and (6) Methodology and behavioral therapy of the U.S. acamprosate study, by Barbara J. Mason.
 ...
PMID:Pharmacological relapse prevention in alcohol dependence: from animal models to clinical trials. 1139 Oct 61

Etiological factors influencing the development of alcoholism are complex and, at a minimum, include an interaction between polygenic factors and personality and biological traits. Human and animal studies suggest that some genes may regulate both the traits associated with alcohol abuse, such as decreased sensitivity or anxiety, and vulnerability to alcoholism. The identification of these genes could elucidate neurochemical pathways that are important in the development of alcohol abuse. Results from the present study indicate that the gene encoding the neuronal-specific gamma subtype of protein kinase C (PKCgamma) influences both ethanol consumption and behavioral impulsivity, a personality characteristic associated with Type II alcoholics, in a pleiotropic manner. Mice lacking PKCgamma consume more ethanol in a two-bottle choice paradigm and also demonstrate increased behavioral impulsivity in an appetitive-signaled nosepoke task when compared with wild-type littermate control mice. Therefore, PKCgamma may be an important mechanism within the cell that mediates one or more neurochemical pathways relevant to an increased predisposition to alcoholism.
 ...
PMID:Ethanol consumption and behavioral impulsivity are increased in protein kinase Cgamma null mutant mice. 1160 60


1 2 3 Next >>