Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of opioids, dopamine and serotonin in ethanol (EtOH) reward and preference was investigated in non-deprived, Alcohol-Preferring (P), and genetically heterogenous Wistar rats. Operant responding for ethanol was initiated using sweet-solution substitution procedures. The rats were then trained in 30-min daily sessions to respond for ethanol (10% v/v) versus water under a two-lever, free-choice contingency. All testing was conducted in the absence of water and food deprivation or addition of sweeteners to the ethanol drinking solution. Rats of both strains developed stable preferences in responding for ethanol over water and consumed ethanol at quantities sufficient to produce pharmacologically relevant mean blood alcohol concentrations (P-Rats: 98 +/- 19.6 mg%; unselected Wistars: 41.7 +/- 8.5 mg%). In P-rats, systemic naloxone (NAL; 0.125, 0.25 and 0.5 mg/kg) pretreatments resulted in a dose-dependent suppression in responding for both ethanol and water, but did not alter ethanol preference (expressed as percent ethanol of total intake). In contrast, bromocriptine (BRO; 1.0, 2.0 and 4.0 mg/kg) produced a significant, dose-dependent shift in preference from ethanol toward water by inhibiting responding for ethanol while enhancing water consumption. In unselected Wistar rats, NAL and BRO treatments produced changes in ethanol preference patterns similar to those observed in P-rats. However, compared to P-rats, these changes were smaller and not consistently dose dependent. No changes in ethanol preference and water or ethanol intake were observed with methysergide (MET; 2.5, 5.0, 10.0 mg/kg) in either strain of rat. Together, the results suggest a possible involvement of dopaminergic mechanisms in the reinforcing properties of ethanol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Free-choice responding for ethanol versus water in alcohol preferring (P) and unselected Wistar rats is differentially modified by naloxone, bromocriptine, and methysergide. 234 59

Diethyldithiocarbamic-acid-methyl ester (DDTC-Me) is a major metabolite of disulfiram. When given to rats, DDTC-Me was found to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) without having any effect on the high Km isoenzyme. Inhibition of low Km ALDH by DDTC-Me in vivo exhibited a dose-response relationship, with inhibition of ALDH from 11% to 90% found when DDTC-Me was administered in a dose range from 1.8 to 158 mg/kg, IP. After a single dose of DDTC-Me (41.2 mg/kg, IP), the low Km ALDH was inhibited for 168 hours suggesting an irreversible enzyme inhibition. After an ethanol challenge to DDTC-Me-treated rats, a decrease in mean arterial pressure (MAP) and increase in heart rate was observed. Decreases in MAP occurred almost immediately after ethanol challenge and remained low throughout a four hour post-ethanol period. These results suggest that in vivo administration of DDTC-Me can cause an alcohol-sensitizing reaction, and that DDTC-Me actually may be the metabolite of disulfiram which produces the disulfiram-ethanol reaction. It is proposed the reaction be more correctly identified as the DDTC-Me-Ethanol Reaction or D-MER.
Alcohol
PMID:Diethyldithiocarbamic acid-methyl ester: a metabolite of disulfiram and its alcohol sensitizing properties in the disulfiram-ethanol reaction. 282 42

Four consecutive menstrual cycles were studied in six healthy parous women. A solvent mixture comprising propylene glycol:ethanol:water (3:3:4) was sprayed intranasally daily using a glass atomizer between days 5 and 24 of the first (control) menstrual cycle. NET was dissolved in the solvent and similarly administered at a daily dose of 100 mcg during the second and third menstrual cycles. Nasal sprays were not administered during the fourth post-treatment cycle. Blood samples were taken during four consecutive cycles between days 8 and 15 and again between days 20 and 24 of the cycle to estimate levels of estradiol (E2), FSH, LH and progesterone (P). These studies revealed that nasal sprays of NET were well accepted and that no adverse clinical effects or menstrual disturbances occurred. NET inhibited ovulation in one cycle. The E2-induced mid-cycle rise in FSH and LH was either suppressed or inhibited in nine out of the 12 treated cycles. P levels in three treated cycles were indicative of luteal inadequacy. These endocrine effects of NET persisted into the post-treatment cycle in two cases.
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PMID:Reproductive endocrine effects of intranasal administration of norethisterone (NET) to women. 393 71

Fractions produced during routine production of human plasma protein concentrates using cold ethanol precipitation have been tested for their ability to support animal cell growth in vitro. A mouse-mouse hybridoma cell line, ES-6, which secretes a monoclonal antibody (mab) to human group A red blood cell antigen, has been used as a model. Fraction 4-1 protein has been found to be effective at 0.5-1.0 g/l in RPMI 1640 and has supported growth of ES-6 for 18 months, both growth and mab. production being comparable with that achieved in 10% foetal calf serum. Fraction 4-1 protein has been shown to contain albumin, transferrin, alpha-1 antitrypsin and immunoglobulin. It is reported to be a source of somatomedin C. The immunoglobulin content can be reduced. Other mouse and rat hybridomas, human mab. producing lymphoblastoid cells, Namalva and HEP-2 cells have grown well in medium supplemented with Fraction 4-1 protein.
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PMID:Use of plasma protein fractions as serum substitutes for in vitro cell culture. 404 43

The present study determined whether the reduction in serum progesterone (P4) concentrations which follows the administration of the antiestrogen ethamoxytriphetol [1-(rho-2-diethylaminoethoxyphenyl)1-phenyl-2-rho-methoxyphenyl ethanol (MER-25)] to pregnant baboons reflects a decline in placental and/or luteal function. Maternal saphenous venous blood was collected at 1- to 4-day intervals between day 70 of gestation and term in pregnant baboons. Four females received no other treatment, and eight females received MER-25 (15 mg/kg BW, orally) daily between day 130 of gestation and term. Four of the MER-25-treated baboons received no other treatment, and four had the corpus luteum of pregnancy surgically excised between days 104 and 118 of gestation. Serum P4 concentrations in the untreated baboons fluctuated, but no significant progressive rise or fall in P4 occurred. Administration of antiestrogen to intact pregnant baboons resulted in a 50% decline (P less than 0.001) in serum P4 concentrations from mean pretreatment values of 7.0-25.1 to 4.2-10.8 ng/ml thereafter. Although removal of the corpus luteum alone had no effect on serum P4, administration of MER-25 to luteectomized females resulted in an 80% decrease (P less than 0.001) in serum P4 concentrations from pretreatment means of 10.6-16.6 to 2.5-3.2 ng/ml thereafter. The results indicate that most or all of the P4 that remained in the peripheral circulation after MER-25 administration to intact pregnant baboons originated from the ovary, primarily the corpus luteum. Thus, the major site of action of antiestrogen in reducing P4 production during baboon pregnancy is on the placenta.
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PMID:Effect of the antiestrogen ethamoxytriphetol (MER-25) and luteectomy on serum progesterone concentrations in pregnant baboons. 648 60

To assess the relation between the physical order of a membrane and its sensitivity to ethanol, we enriched biomembranes with cholesterol, both in vivo and in vitro. Japanese quail of the SEA line (selectively bred for susceptibility to experimental atherosclerosis) were treated for 9 to 16 weeks with a diet that contained 2% cholesterol. This regimen increased the cholesterol content of serum and erythrocytes. The cholesterol content of brain synaptosomal plasma membranes (SPM) was unaffected by the high cholesterol diet. In other experiments, isolated mouse synaptosomal plasma membranes were incubated with cholesterol/phospholipid (C/P) vesicles; different amounts of cholesterol were transferred according to the sterol content of the donor vesicles. Membrane order was determined in both types of membranes by a sensitive electron paramagnetic resonance (EPR) technique. The order parameter with 5- and 12-doxylstearic acid increased along with the cholesterol content. As expected, ethanol disordered membranes (decreased the order parameter) in a concentration-related manner. The slope of the concentration response curve was less steep in high cholesterol than low cholesterol membranes, indicating that cholesterol enrichment partially blocks the membrane action of ethanol in both types of membranes.
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PMID:Cholesterol blocks the disordering effects of ethanol in biomembranes. 652 12

Daily injections of estradiol benzoate (EB) administered to ovariectomized rats given continuous access to a 10% ethanol solution, to water, and to laboratory chow led to decreases in ethanol consumption. The suppression was transient; ethanol consumption returned to the level of oil-treated control animals after 14 days despite continued hormone administration. This pattern of change in ethanol consumption closely resembled previously reported effects of EB on food intake. It is proposed that a common mechanism was responsible for EB-induced suppression of both food and ethanol intake. Ethamoxytriphetol, MER-25, which antagonizes many estrogen-dependent effects but which mimics the action of EB on food intake, also led to decreases in ethanol consumption that paralleled those reported for food intake. These behavioral effects of EB and MEr-25 were shown not to be due to altered ethanol metabolism or to result from malaise developing out of an interaction between EB and ethanol. It is thus suggested that voluntary consumption of ethanol by the rat is largely due to its caloric content. The relevance of these results for several recent reports of decreased ethanol intake during pregnancy is discussed.
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PMID:Effects of estradiol benzoate and MER-25 on ethanol consumption in the ovariectomized rat. 711 81

To develop a model somatic gene therapy system for diabetes, a human hepatoma cell line (HEP G2) was transfected with a mammalian expression vector carrying the full-length human insulin cDNA. More proinsulin than insulin was released daily by the stably transformed cell line (HEP G2ins). However, on acute stimulation with 5mM 8-Br-cAMP and 10mM theophylline the HEP G2ins cells released predominantly insulin into the medium. The cells did not secrete insulin in response to glucose. Examination of acid-ethanol extracts confirmed insulin was preferentially being stored. Immunohistochemical analysis of the cells also showed (pro)insulin was being stored. Electron microscopy revealed large membrane-bound vacuoles, containing electron-dense material, which were not seen in control cells. Glucokinase activity and albumin secretion of the transfectants were unaltered from the controls. Five-minute pulse-chase labelling of the HEP G2ins cells with 3H-leucine confirmed insulin synthesis in the presence of 20mM glucose and 5mM 8-Br-cAMP. A dose-response curve for insulin synthesis was also generated to increasing concentrations of glucose with a half Vmax of 4.9mM. Our results show that the introduction of insulin cDNA into a human hepatoma cell line results in synthesis, storage and acute regulated insulin release and lend credence to the possibility of engineering a liver cell to secrete insulin acutely in response to physiological stimuli.
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PMID:Functional expression of the human insulin gene in a human hepatoma cell line (HEP G2). 761 54

In order to verify the role of activation of phosphatidylcholine (PC) hydrolysis by phospholipase D (PLD) in the initiation of mitogenic process of retinal capillary pericytes, platelet-derived growth factor (PDGF), a known PC hydrolysis stimulator, and exogenous PLD have been used to stimulate pericytes. Exogenous PLD (Streptomyces chromofuscus PLD) or PDGF BB homodimer (PDGF) was added to a medium of quiescent pericytes prelabeled with [32P]orthophosphate. In the presence of ethanol (300 mM), phosphatidic acid (PA) and its stable transphosphatidylated product, phosphatidylethanol (PEt), were determined. In parallel, [3H]thymidine incorporation was measured. Downregulation of PKC was achieved by long-term treatment with a phorbol ester. The addition of exogenous PLD or PDGF stimulated both [3H]thymidine incorporation and [32P]PEt formation in a similar kinetic fashion, suggesting that PC hydrolysis is involved in PDGF-mitogenic signaling pathway. PDGF-stimulated [3H]PA formation was significantly higher in the presence than in the absence of PA phosphohydrolase (PAP) inhibitor, indicating the activation of PLD/PAP pathway. In the presence of ethanol, a substantial level of PA at the steady state can be abolished by an inhibitor of diacylglycerol (DAG) kinase. This phenomenon indicates the existence of PC-phospholipase C (PLC)/DAG kinase pathway in PC hydrolysis. Insulin potentiated both PLD- and PDGF-induced DNA synthesis. Though similarities occur in the induction of DNA synthesis and PC hydrolysis by exogenous PLD and PDGF, the maximum extent of DNA synthesis of exogenous PLD was only approximately 43% of that induced by PDGF. Moreover, exogenous PLD-induced DNA synthesis was not blunted, while PDGF-elicited DNA synthesis was markedly reduced, by PKC downregulation. In addition, PDGF-induced PC hydrolysis was attenuated by a tyrosine kinase inhibitor, whereas exogenous PLD-induced PC hydrolysis was unchanged. Taken together, exogenous PLD may mimic PDGF action and partially account for the efficacy on DNA synthesis elicited by PDGF. The signal transduction initiated by exogenous PLD is able to bypass the PKC- and PTK-dependent activation of endogenous PLD. These findings provide evidence for the importance of PLD-mediated PC hydrolysis in pericyte DNA synthesis stimulated by PDGF.
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PMID:Phosphatidylcholine hydrolysis and DNA synthesis in cultured retinal capillary pericytes. 764 54

Alcohol use has been shown to decrease monocyte antigen presentation capacity and inflammatory cytokine production, thereby increasing susceptibility to infections. Here, we demonstrate that in vitro acute treatment of normal monocytes with pharmacological doses of ethanol can decrease superantigen [Staphylococcus enterotoxins B (SEB) and A (SEA)]-induced T cell proliferation. Furthermore, ethanol treatment (25-100 mM) significantly inhibited SEA- or SEB-induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6 in monocytes. Ethanol-induced down-regulation of monocyte TNF-alpha, IL-1 beta, and IL-6 occurred at both the protein and mRNA levels. Additional data suggest that ethanol can decrease IL-1 beta mRNA stability. Furthermore, experiments using cycloheximide indicate that de novo protein synthesis is required for the inhibitory effect of ethanol on SEB-induced IL-1 beta mRNA production. Finally, ethanol treatment decreased HLA-DR expression in monocytes, suggesting that ethanol treatment can compromise monocyte stimulation by down-regulating the SEB-binding capacity of monocytes. These results suggest that acute ethanol treatment can interfere with monocyte activation by SEB at multiple steps. Consequently, decreased superantigen-induced polyclonal T cell activation and inflammatory monokine production would contribute to an impaired immune response to bacterial challenge with superantigens after acute alcohol intake.
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PMID:Inhibition of superantigen-induced T cell proliferation and monocyte IL-1 beta, TNF-alpha, and IL-6 production by acute ethanol treatment. 766 90


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