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Significant Stimulation (significant + stimulation)
Selected AbstractsMechanism of the protective effect of hypothermia on ammonia toxicity in astrocytesJOURNAL OF NEUROCHEMISTRY, Issue 2002C. Zwingmann Ammonia is a key factor in the pathogenesis of hepatic encephalopathy (HE). Acute ammonia treatment causes energy failure of astrocytes, which are able to compensate partly by increased anaerobic metabolism as a means of making up for the energetic shortfall. As hypothermia offers protection from severe encephalopathy and lactate accumulation in liver failure, we investigated the mechanism by which hypothermia protects against ammonia toxicity by multinuclear NMR spectroscopy. 12 h exposure to 5 mm NH4CL decreased the phosphocreatine (PCr)/creatine (Cr) and ATP/ADP ratios to 65 and 76% of control, increased synthesis and release of glutamine to 200,250% and led to a significant stimulation of glycolytic activity reflected by increased uptake and consumption of glucose and accumulation of de novo synthesized intra- and extracellular lactate to 161 and 230% of control. The protective effect of mild hypothermia was evident from inhibiton of lactate accumulation and restoration of ammonia-induced depletion of PCr/Cr. Moderate hypothermia led to an increase of PCr/Cr ratio and inhibited lactate synthesis to 14% of normothermic control, but did not prevent the ATP decrease. While hypothermia inhibited glycolytic flux, intracellular glutamine remained elevated. The results suggest that hypothermia-induced protection against ammonia toxicity results from reduction of cellular energy demand leading to inhibition of anaerobic glucose metabolism and a compensatory stimulation of mitochondrial energy production. Acknowledgements:, Funded by CIHR Canada. [source] Coffee and Cigarette Consumption and Perceived Effects in Recovering Alcoholics Participating in Alcoholics Anonymous in Nashville, TennesseeALCOHOLISM, Issue 10 2008Michael S. Reich Background:, Alcoholics Anonymous (AA) members represent an important and relatively understudied population for improving our understanding of alcohol dependence recovery as over 1 million Americans participate in the program. Further insight into coffee and cigarette use by these individuals is necessary given AA members' apparent widespread consumption and the recognized health consequences and psychopharmacological actions of these substances. Methods:, Volunteers were sought from all open-AA meetings in Nashville, TN during the summer of 2007 to complete a questionnaire (n = 289, completion rate = 94.1%) including timeline followback for coffee, cigarette, and alcohol consumption; the Alcoholics Anonymous Affiliation Scale; coffee consumption and effects questions; the Fagerstrom Test for Nicotine Dependence (FTND); and the Smoking Effects Questionnaire. Results:, Mean (±SD) age of onset of alcohol consumption was 15.4 ± 4.2 years and mean lifetime alcohol consumption was 1026.0 ± 772.8 kg ethanol. Median declared alcohol abstinence was 2.1 years (range: 0 days to 41.1 years) and median lifetime AA attendance was 1000.0 meetings (range: 4 to 44,209 meetings); average AA affiliation score was 7.6 ± 1.5. Most (88.5%) individuals consumed coffee and approximately 33% of coffee consumers drank more than 4 cups per day (M = 3.9 ± 3.9). The most common self-reported reasons for coffee consumption and coffee-associated behavioral changes were related to stimulatory effects. More than half (56.9%) of individuals in AA smoked cigarettes. Of those who smoked, 78.7% consumed at least half a pack of cigarettes per day (M = 21.8 ± 12.3). Smokers' FTND scores were 5.8 ± 2.4; over 60% of smokers were highly or very highly dependent. Reduced negative affect was the most important subjective effect of smoking. Conclusions:, A greater proportion of AA participants drink coffee and smoke cigarettes in larger per capita amounts than observed in general U.S. populations. The effects of these products as described by AA participants suggest significant stimulation and negative affect reduction. Fundamental knowledge of the quantitative and qualitative aspects of coffee and cigarette consumption among AA members will enable future research to discern their impact on alcohol abstinence and recovery. [source] Molecular determinants of hyperosmotically activated NKCC1-mediated K+/K+ exchangeTHE JOURNAL OF PHYSIOLOGY, Issue 18 2010Kenneth B. Gagnon Na+,K+,2Cl, cotransport (NKCC) mediates the movement of two Cl, ions for one Na+ and one K+ ion. Under isosmotic conditions or with activation of the kinases SPAK/WNK4, the NKCC1-mediated Cl, uptake in Xenopus laevis oocytes, as measured using 36Cl, is twice the value of K+ uptake, as determined using 86Rb. Under hyperosmotic conditions, there is a significant activation of the bumetanide-sensitive K+ uptake with only a minimal increase in bumetanide-sensitive Cl, uptake. This suggests that when stimulated by hypertonicity, the cotransporter mediates K+/K+ and Cl,/Cl, exchange. Although significant stimulation of K+/K+ exchange was observed with NKCC1, a significantly smaller hyperosmotic stimulatory effect was observed with NKCC2. In order to identify the molecular determinant(s) of this NKCC1-specific activation, we created chimeras of the mouse NKCC1 and the rat NKCC2. Swapping the regulatory amino termini of the cotransporters neither conferred activation to NKCC2 nor prevented activation of NKCC1. Using unique restrictions sites, we created additional chimeric molecules and determined that the first intracellular loop between membrane-spanning domains one and two and the second extracellular loop between membrane-spanning domains three and four of NKCC1 are necessary components of the hyperosmotic stimulation of K+/K+ exchange. [source] Modulation of protein kinase C by curcumin; inhibition and activation switched by calcium ionsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2007Y A Mahmmoud Background and purpose: Previous studies have identified the natural polyphenol curcumin as a protein kinase C (PKC) inhibitor. In contrast, we found significant stimulation of PKC activity following curcumin treatment. Thus, the mechanism of curcumin interaction with PKC was investigated. Experimental approach: We employed phosphorylation assays in the presence of soluble or membrane-bound PKC substrates, followed by SDS,PAGE, autoradiography and phosphorylation intensity measurements. Key results: Curcumin inhibited PKC in the absence of membranes whereas stimulation was observed in the presence of membranes. Further analysis indicated that curcumin decreased PKC activity by competition with Ca2+ stimulation of the kinase, resulting in inhibition of activity at lower Ca2+ concentrations and stimulation at higher Ca2+ concentrations. The role of the membrane is likely to be facilitation of Ca2+ -binding to the kinase, thus relieving the curcumin inhibition observed at limited Ca2+ concentrations. Curcumin was found to mildly stimulate the catalytic subunit of PKC, which does not require Ca2+ for activation. In addition, studies on Ca2+ -independent PKC isoforms as well as another curcumin target (the sarcoplasmic reticulum Ca2+ -ATPase) confirmed a correlation between Ca2+ concentration and the curcumin effects. Conclusions and Implications: Curcumin competes with Ca2+ for the regulatory domain of PKC, resulting in a Ca2+ -dependent dual effect on the kinase. We propose that curcumin interacts with the Ca2+ -binding domains in target proteins. To our knowledge, this is the first study that defines an interaction domain for curcumin, and provides a rationale for the broad specificity of this polyphenol as a chemopreventive drug. British Journal of Pharmacology (2007) 150, 200,208. doi:10.1038/sj.bjp.0706970 [source] | |||||||||||||