Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To study the effects of acute ethanol on regenerating rat liver, the mRNA transcript levels of growth suppressor genes (prohibitin, TGF beta-1 and p53) were measured by Northern blot analysis during the G0, G1, and early S phases of compensatory growth after 70% partial hepatectomy (PH) in adult male rats. Selected animals were gavaged with either ethanol (3 g/kg) or glucose and underwent PH 1 h later. Other animals were either sham operated or underwent PH without gavage. Prohibitin and p53 transcripts were increased in relative abundance (as measured by an increase in band intensity) near the G1/S boundary (8-12 h post-PH) following both glucose and ethanol gavage. A transient increase in prohibitin transcripts at 0.5-1 h post-PH was found to be characteristic of glucose and nongavaged rats. Ethanol gavage significantly increased the relative abundance of prohibitin transcripts at 0.5-2 h post-PH. An increase in the TGF beta-1 transcripts at 4 h post-PH was found in the glucose and nongavaged rats. Ethanol gavage resulted in variable TGF beta-1 transcript expression near hepatectomy (0 h); however, mean differences were not statistically significant. Sham operation had no effect on the mRNA transcripts of the selected genes during the time periods sampled. These results and previous work suggest that the mitoinhibitory effects of acute ethanol exposure may occur via modulation of growth suppressor and proto-oncogene expression.
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PMID:Acute ethanol and selected growth suppressor transcripts in regenerating rat liver. 754 33

Ethanol ingestion may interrupt the proregenerative signal transduction that is initiated by injury-related cytokines such as tumor necrosis factor (TNF)-alpha and TNF-alpha- inducible cytokines including interleukin (IL)-6. To test this theory, liver regeneration, TNF-alpha and IL-6 expression, and cytokine-regulated prereplicative events were compared in ethanol-fed rats and isocalorically fed controls after 70% partial hepatectomy (PH). Ethanol feeding inhibits hepatocyte replication and recovery of liver mass after PH but generally promotes induction of both cytokines in the liver and extrahepatic tissues (i.e., white adipose tissue). Cytokine-regulated events that occur early in the prereplicative period are influenced differentially. TNF-alpha-dependent increases in hepatic nuclear factor-kappaB (NF-kappaB) p50 and p65 expression and DNA binding activity are prevented, whereas IL-6-dependent inductions of hepatic Stat-3 phosphorylation and DNA binding activity occur normally. In contrast, events (e.g., induction of cyclin D1, cdk-1, cyclin D3, and p53 mRNA) that occur at the end of the prereplicative period are uniformly inhibited. These findings indicate that chronic ethanol ingestion arrests the regenerative process during the prereplicative period and demonstrate that increased TNF-alpha, IL-6 and Stat-3 are not sufficient to assure hepatocyte proliferation after PH.
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PMID:Effects of chronic ethanol consumption on cytokine regulation of liver regeneration. 975 99

The Long-Evans Cinnamon (LEC) rat is a mutant strain characterized by abnormal copper metabolism and a high incidence of hepatitis and hepatoma. Using a yeast-based assay which scores mutants in p53 gene transcripts as red colonies, we detected frequent mutations in the liver of LEC rats. The majority (50-60%) of these were frameshift mutations caused by the insertion of an extra adenine (A) in the regions containing six consecutive adenines. The rate of A insertion was calculated to be 6.9-9.0% of the total p53 cDNA. Insertions of an extra adenine were found almost exclusively in the mRNA (cDNA), especially in the (A)(6) tract located at the most 5'-side (exon 4) among the three (A)(6) tracts (exons 4, 7, and 8), but rarely in the corresponding sites of genomic DNA. Wild-type p53 cDNA was transcribed in vitro into mRNA with the use of SP6 RNA polymerase and tested by the yeast functional assay. Subsequent sequencing detected A insertions at an overall rate of 1.6% in exons 7 and 8 but none in exon 4. This indicates that the A insertion in the exon 4 (A)(6) tract was an in vivo phenomenon rather than an artifact in reverse transcription or polymerase chain reaction. The percentage of red colonies increased sharply to about 20% of the liver samples in the acute hepatitis stage, and returned to control level of those in the chronic hepatitis stage, and increased again slightly to those in the neoplastic stage. The percentage of red colonies correlated with the serum GOT level (r=0.96, p<0.001) but not with the contents of copper and 8-hydroxydeoxyguanosine in the liver of LEC rats. Ethanol treatment of hepatic cell lines also increased the rate of transcriptional slippage at the (A)(6) tract. These findings indicate that cellular damage is responsible for the increase in the rate of mutation at the transcriptional level, and suggest that cellular damage degrades transcriptional fidelity, thereby further impairing cellular functions.
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PMID:Transcriptional slippage of p53 gene enhanced by cellular damage in rat liver: monitoring the slippage by a yeast functional assay. 1075 4

Whether alcohol-induced heart failure is caused by a direct toxic effect of ethanol, metabolites, or whether it is a secondary result of neurohumoral, hormonal, or nutritional factors is not clear. To address this question a Langendorff retrograde coronary perfusion model of rat heart was used to study the effect of 0.5% (v/v) ethanol (n = 7) and 0.5 mM acetaldehyde (n = 9) on left ventricular expression of ANP, BNP, p53, p21, TNF-alpha,bax, bcl-2 as well as on DNA-fragmentation. Ethanol infusion of 150 min duration significantly induced both ANP and p21 mRNA expression of ventricular myocardium compared with hearts infused with vehicle (n = 8). Acetaldehyde did not exert any significant effects on any of the parameters studied, although the mean expression of TNF-alpha tended to be lower in the acetaldehyde-treated hearts than in control hearts. No evidence of increased DNA-fragmentation was found in ethanol or acetaldehyde treated groups. We conclude that ethanol per se is capable of inducing genes associated with hypertrophy and impaired function of the heart whereas a significant apoptosis is not involved in the initial phase of alcohol-induced cardiac injury.
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PMID:Ethanol infusion increases ANP and p21 gene expression in isolated perfused rat heart. 1118 Oct 50

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.
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PMID:Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons. 1176 90

Ethanol consumption represents a major risk factor for cancer development, and a significant fraction of hepatocarcinomas arises in alcoholic liver cirrhosis. Increasing evidence indicates that ethanol acts as a tumor promoter on genetically initiated cells, by increasing the intracellular concentration of reactive oxygen species and promoting tissue necrosis/regeneration and cell proliferation. The tumor suppressor p53 restrains the expansion of carcinogen-initiated cells by inducing cell cycle arrest and apoptosis; accordingly, p53-deficient mice develop spontaneous and chemically induced neoplasms at a much higher frequency than normal mice. In normal mice exposed to a subacute (3 weeks) ethanol intoxication, a significant increase in the number of apoptotic hepatocytes was observed in concomitance with the up-regulation of the mitochondrial superoxide scavenger MnSOD, a reliable indicator of oxidative stress. Cell death occurred in the absence of liver inflammation and necrosis. Ethanol-induced hepatocyte apoptosis was completely abrogated in the p53 null background, suggesting that the tumor suppressor is necessary for hepatocyte death by ethanol. Accordingly, p53 -/- MEF were, unlike wild type cells, completely insensitive up to 0.5M ethanol in the culture medium. Strikingly, marked and widespread signs of dysplasia, with nuclear pleomorphisms and initial loss of normal architecture, heralding malignant transformation, were scored in all the mutant mice exposed to ethanol, but not in the control-fed littermates nor in ethanol-fed normal mice. These observations suggest that p53-dependent apoptosis restrains the tumorigenic effect of ethanol on liver cells, in agreement with the frequent loss of p53 function in HCC, and reveal an unexpected carcinogenic potential of alcohol which appears to be independent from the induction of cirrhosis and hepatocyte regeneration.
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PMID:Abrogation of hepatocyte apoptosis and early appearance of liver dysplasia in ethanol-fed p53-deficient mice. 1552 6

Ethanol is a potent neurotoxin particularly for the developing nervous system. Intrauterine exposure to ethanol during the last trimester of human gestation can produce a broad spectrum of neuropathologic consequences. This period of human brain development is roughly equivalent to the first week of rodent postnatal life and acute exposure of neonatal mice to ethanol produces massive neuronal apoptosis throughout the brain. We have previously demonstrated that ethanol-induced neuron apoptosis is critically dependent on expression of Bax, a proapoptotic member of the Bcl-2 family. To further define the molecular pathway regulating ethanol-induced neuron apoptosis, we analyzed the effects of acute ethanol exposure on cerebellar internal granule cell neurons both in vivo and in vitro. Ethanol produced extensive Bax-dependent caspase-3 activation and neuron apoptosis in the cerebellar internal granule cell layer, which was maximal at approximately 6 hours postadministration. This effect was recapitulated in vitro and required new gene transcription, protein translation, Bax expression, and caspase activation. Ethanol-induced neuron death was independent of p53 expression and was unaffected by deficiency in the proapoptotic Bcl-2 family members Bid or Bad. These studies indicate that ethanol activates an intrinsic apoptotic death program in neurons that is likely to contribute to the neuropathologic effects of human fetal alcohol exposure.
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PMID:Molecular regulation of acute ethanol-induced neuron apoptosis. 1597 40

Alcohol drinking during pregnancy results in abnormal fetal development, including fetal alcohol syndrome (FAS) in humans and experimental animals. FAS is characterized by two major effects, including central nervous system (CNS) dysfunction and multiple anomalies recognizable mainly as a typical face. However, the mechanisms of alcohol-induced embryotoxicity have not been clearly demonstrated. The aim of the present study was to investigate the possible mechanisms underlying ethanol-induced FAS in the developing embryo. First, ethanol-induced developmental abnormalities were investigated in vitro. Postimplantation embryos at gestation day (GD) 9.5 were cultured for 48 h and observed for morphological changes. Ethanol-mediated changes in proteins regulated apoptosis (p53 and bcl-2), antioxidant (vitamin E and catalase) activities, generation of reactive oxygen species (ROS), and oxidative DNA damage shown as 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured in embryonic midbrain cells. Alcohol or acetaldehyde significantly induced cytotoxicity in cultured rat embryonic midbrain cells. The levels of p53, bcl-2, and 8-OHdG were concomitantly changed by alcohol and acetaldehyde treatment in midbrain cells. Injured cells induced by ROS were increased by alcohol or acetaldehyde treatment in midbrain cells. Cotreatment with alcohol or acetaldehyde and catalase decreased cytotoxicity in midbrain cells. In postimplantation embryo culture, alcohol or acetaldehyde-treated embryos showed retardation of embryonic growth and development in a concentration-dependent manner. These results indicate that alcohol and its metabolite acetaldehyde induce fetal developmental abnormalities by disrupting cellular differentiation and growth. Data demonstrate that some antioxidants can partially protect against the alcohol-induced embryonic developmental toxicity.
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PMID:Neurotoxic effects of alcohol and acetaldehyde during embryonic development. 1632 30

Cerebellar hypoplasia in experimental fetal alcohol syndrome (FAS) is associated with impaired insulin-stimulated survival signaling. In vitro studies demonstrated that ethanol inhibition of neuronal survival is mediated by apoptosis and mitochondrial dysfunction. Since insulin and insulin-like growth factors (IGFs) regulate energy metabolism, and ethanol can exert its toxic effects by causing oxidative damage to DNA and proteins, we further characterized the effects of chronic gestational exposure to ethanol on mitochondrial gene expression, and the degree to which ethanol inhibition of mitochondrial function is mediated by impaired insulin/IGF responsiveness. Pregnant Long-Evans rats were fed isocaloric liquid diets containing 0, 2, 4.5, 6.5, or 9.25% v/v ethanol from gestation day 6 through delivery. Cerebella harvested on postnatal day 1 were examined for indices of oxidative stress, and mRNA levels of mitochondrial, pro-oxidant, and pro-apoptosis gene expression. Rat primary cerebellar neuron cultures were used to characterize the effects of ethanol (50 mM for 96 h) on insulin and IGF stimulated mitochondrial function and ATP production. Ethanol-exposed cerebella had significantly reduced mRNA levels of mitochondrial genes encoding Complexes II-A, IV, and V, increased expression of p53 and NADPH oxidase (NOX) 1 and 3, and increased immunoreactivity for 4-hydroxy-2,3-nonenal (HNE) and 8-OHdG in cerebellar granule cells. The activations of p53 and NOX genes were highest in cerebella from pups exposed to the 6.5 or 9.25% ethanol containing diet, whereas the impairments in mitochondrial Complex IV and V expression were similar at low and high levels of ethanol exposure. In vitro experiments confirmed that ethanol treatment reduces neuronal expression of mitochondrial genes encoding Complexes IV and V, impairs mitochondrial function and ATP production, and increases HNE and 8-OHdG immunoreactivity, but they also showed that these effects were not insulin- or IGF-dependent. Together, the results suggest that mitochondrial dysfunction, oxidative stress, and DNA damage in FAS may be largely due to the toxic effects of ethanol rather than specific impairments in insulin or IGF signaling.
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PMID:Chronic ethanol exposure causes mitochondrial dysfunction and oxidative stress in immature central nervous system neurons. 1743 46

Although it has been well established that spermatogenic cells undergo apoptosis when treated with ethanol, the molecular mechanisms behind it remain to be investigated. Adult male mice were given intra-peritoneal injection (IP) of ethanol at a dose of 3 g (15%, v/v) per kg body weight per day during the period of 14 days. Testicular androgenesis and apoptotic germ cell death, along with different interrelated proteins expression, were evaluated. Ethanol treatment induced apoptotic spermatogenic cell death with a decrease in the plasma and intra-testicular testosterone concentration. Western blot analysis revealed that repeated ethanol treatment decreased the expression of steroidogenic acute regulatory protein (StAR), 3 beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17beta-HSD); increased the expression of active caspase-3, p53, Fas and Fas-L; and led to up-regulation of Bax/Bcl-2 ratio and translocation of cytochrome c from mitochondria to cytosol in testis. It has also been shown in our study that repeated ethanol treatment led to up-regulation of caspase-3, p53, Fas, Fas-L transcripts; increase in caspase-3 and caspase-8 activities; diminution of 3beta-HSD, 17beta-HSD, and GPx activities; decrease in the mitochondrial membrane potential along with ROS generation and depletion of glutathione pool in the testicular tissue. The present study has indicated that the ethanol treatment induced apoptosis in the mouse testis through the increased expression of Fas/Fas-L and p53, up-regulation of Bax/Bcl-2 ratio, cytosolic translocation of cytochrome c along with caspase-3 activation and glutathione depletion.
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PMID:Ethanol induces mouse spermatogenic cell apoptosis in vivo through over-expression of Fas/Fas-L, p53, and caspase-3 along with cytochrome c translocation and glutathione depletion. 2080 34


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