Alcohol ingestion causes alteration in several cellular mechanisms, and leads to inflammation, apoptosis, immunological response defects, and fibrosis. These phenomena are associated with significant changes in the epigenetic mechanisms, and subsequently, to liver cell memory. The ubiquitin-proteasome pathway is one of the vital pathways in the cell that becomes dysfunctional as a result of chronic ethanol consumption. Inhibition of the proteasome activity in the nucleus causes changes in the turnover of transcriptional factors, histone modifying enzymes, and therefore, affects epigenetic mechanisms. Alcohol consumption has been associated with an increase in histone acetylation and a decrease in histone methylation, which leads to gene expression changes. DNA and histone modifications that result from ethanol-induced proteasome inhibition are key players in regulating gene expression, especially genes involved in the cell cycle, immunological responses, and metabolism of ethanol. The present review highlights the consequences of ethanol-induced proteasome inhibition in the nucleus of liver cells that are chronically exposed to ethanol.
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"Further, the modest decreases in proteasome activity ensure that the viability of treated cells is maintained and that the results are not due to cell death since a profound inhibition of proteasome would likely cause apoptosis/necrosis. Thus, our data indicate that in addition to previously reported methylation-mediated regulation of proteasome activity in cells at the epigenetic level [19,20], proteasome function is also regulated at the level of SAM:SAH-dependent methylation reactions. Further, we observed greater inhibition of activity of IPr-enriched proteasome preparation with decreased SAM:SAH compared with 20S constitutive proteasome. "
[Show abstract][Hide abstract]ABSTRACT: The proteasome is a multi-catalytic protein degradation enzyme that is regulated by ethanol-induced oxidative stress; such suppression is attributed to CYP2E1-generated metabolites. However, under certain conditions, it appears that in addition to oxidative stress, other mechanisms are also involved in proteasome regulation. This study investigated whether impaired protein methylation that occurs during exposure of liver cells to ethanol, may contribute to suppression of proteasome activity. We measured the chymotrypsin-like proteasome activity in Huh7CYP cells, hepatocytes, liver cytosols and nuclear extracts or purified 20S proteasome under conditions that maintain or prevent protein methylation. Reduction of proteasome activity of hepatoma cell and hepatocytes by ethanol or tubercidin was prevented by simultaneous treatment with S-adenosylmethionine (SAM). Moreover, the tubercidin-induced decline in proteasome activity occurred in both nuclear and cytosolic fractions. In vitro exposure of cell cytosolic fractions or highly purified 20S proteasome to low SAM:S-adenosylhomocysteine (SAH) ratios in the buffer also suppressed proteasome function, indicating that one or more methyltransferase(s) may be associated with proteasomal subunits. Immunoblotting a purified 20S rabbit red cell proteasome preparation using methyl lysine-specific antibodies revealed a 25 kDa proteasome subunit that showed positive reactivity with anti-methyl lysine. This reactivity was modified when 20S proteasome was exposed to differential SAM:SAH ratios. We conclude that impaired methylation of proteasome subunits suppressed proteasome activity in liver cells indicating an additional, yet novel mechanism of proteasome activity regulation by ethanol.
Full-text · Article · Jan 2010 · Biochemical and Biophysical Research Communications
[Show abstract][Hide abstract]ABSTRACT: A novel configuration for two-step analog-to-digital (A/D) flash
conversion is described. The coarse and fine conversions are performed
with a four-bit multiplexed flash converter, so only 15 comparators are
necessary for an eight-bit converter. The D/A conversion and the
subtraction required for the circuit operation are performed using the
charge redistribution technique. A test chip, integrated with a 3-μm
CMOS technology (area=3 mm<sup>2</sup>), has demonstrated the
effectiveness of the proposed configuration