Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A major cause of liver cirrhosis and hepatocarcinoma is chronic infection by hepatitis C virus. Ethanol consumption is the most significant environmental factor that exacerbates the progression of chronic hepatitis C to liver cirrhosis and hepatocarcinoma, perhaps due to increased cytokine secretion together with increased lipid peroxidation. In this study, we compare the intensity of lipid peroxidation (estimated as malondialdehyde (MDA) serum levels), the antioxidant status, (measured as glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities in red blood cells), and levels of cytokines derived from Th1 cells (such as interferon gamma (IFNG)), Th2 cells (such as interleukin (IL)-4), Th3 cells (such as transforming growth factor beta (TGF-beta)), and IL-6, IL-8, and tumor necrosis factor (TNF)-alpha in patients affected by chronic hepatitis C virus infection, 26 drinkers of alcohol and 40 nondrinkers of alcohol. Patients showed significantly higher TNF-alpha (Z = 4.92, P < 0.001), IL-8 (Z = 4.95, P < 0.001), IFNG (Z = 2.81, P = 0.005), TGF-beta (t = 2.12, P = 0.037), MDA (Z = 5, P < 0.001), but lower IL-6 (Z = 3.61, P < 0.001) and GPX (F = 4.30, P < 0.05) than controls, whereas no differences were observed regarding IL-4 (Z = 0.35, P = 0.72), GPX and SOD activities. Alcoholics showed significantly higher TNF-alpha, but lower IL-4, MDA, and GPX, than nonalcoholics. TNF-alpha was significantly related to albumin and prothrombin activity, whereas TGF-beta was significantly related to MDA levels. Thus, cytokine secretion is altered in HCV infection. This alteration mainly consists of a stimulation of Th1 cytokines and an inhibition--or at least, no stimulation--of Th2 cytokines; these changes are especially marked among alcoholics with HCV infection, and are accompanied by raised TGF-beta.
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PMID:Cytokines and lipid peroxidation in alcoholics with chronic hepatitis C virus infection. 1821 80

AMP-activated protein kinase (AMPK) responds to oxidative stress. Previous work has shown that ethanol treatment of cultured hepatoma cells and of mice inhibited the activity of AMPK and reduced the amount of AMPK protein. Ethanol generates oxidative stress in the liver. Since AMPK is activated by reactive oxygen species, it seems paradoxical that ethanol would inhibit AMPK in the hepatoma cells. In an attempt to understand the mechanism whereby ethanol inhibits AMPK, we studied the effect of ethanol on AMPK activation by exogenous hydrogen peroxide. The effects of ethanol, hydrogen peroxide, and inhibitors of protein phosphatase 2A (PP2A) [either okadaic acid or PP2A small interference RNA (siRNA)] on AMPK phosphorylation and activity were examined in rat hepatoma cells (H4IIEC3) and HeLa cells. In H4IIEC3 cells, hydrogen peroxide (H(2)O(2), 1 mM) transiently increased the level of phospho-AMPK to 1.5-fold over control (P < 0.05). Similar findings were observed in HeLa cells, which do not express the upstream AMPK kinase, LKB1. H(2)O(2) markedly increased the phosphorylation of LKB1 in H4IIEC3 cells. Ethanol significantly inhibited the phosphorylation of PKC-zeta, LKB1, and AMPK caused by exposure to H(2)O(2). This inhibitory effect of ethanol required its metabolism. More importantly, the inhibitory effects of ethanol on H(2)O(2)-induced AMPK phosphorylation were attenuated by the presence of the PP2A inhibitor, okadaic acid, or PP2A siRNA. The inhibitory effect of ethanol on AMPK phosphorylation is exerted through the inhibition of PKC-zeta and LKB1 phosphorylation and the activation of PP2A.
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PMID:Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation. 1883 48

Alcohol use has become far too prevalent in our society. Alcohol kills 6.5 times more youth than all other illicit drugs combined. In combination with traumatic and hemorrhagic injuries, alcohol results in a much higher mortality rate. Alcohol, alone and in high dosages, also causes great damage to the body, often leading to death as well. Thus, it is of utmost importance that research is conducted to help explain the pathological mechanism of high fatalities and injuries associated with alcohol use. In order to simulate this complex situation in vitro, a rat hepatoma cell line (H-II-4-E) was exposed to various concentrations of ethanol as well as the condition of hypoxia. Hypoxia mimics the primary level of tissue damage caused by hemorrhage after impact in a car accident. In this way, we tested the hypothesis that the presence of ethanol in combination with hypoxia causes greater cellular damage compared to conditions of ethanol or hypoxia alone. Ethanol, alone and in high concentrations, was found to greatly affect cell function as shown by decreased cellular ATP levels, increased LDH release, and a downregulated expression of CYP2E1 gene. By adding the condition of hypoxia to low concentrations of ethanol, cellular damage increased dramatically as well. Decreased gene expression and protein levels of CYP2E1 correlated with increased hepatocyte injury and thus, this enzyme may significantly contribute to the severity of cellular damage. These results provide useful information for future research on the effects of ethanol in combination with hemorrhage on cells in vitro, simulating the condition of driving while intoxicated and binge drinking.
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PMID:The double danger of ethanol and hypoxia: their effects on a hepatoma cell line. 1907 54

Hepatocellular carcinoma is increasingly detected at small size, usually 5 cm or smaller in diameter. For small hepatocellular carcinoma, percutaneous ablation is a potentially curative treatment. Ethanol injection is able to achieve a complete response of 70-80% and a 5-year survival of 40-60% in the treatment of hepatocellular carcinoma of 3 cm or less. Radiofrequency ablation has emerged as the more powerful alternative method. Randomized controlled trials show that radiofrequency ablation offers a higher complete response at fewer treatment sessions and better survival compared with ethanol injection. Microwave ablation has been demonstrated to be equivalent to radiofrequency ablation in both local efficacy and long-term outcome. Laser ablation is mainly applied in clinical settings in Europe. Nowadays, percutaneous ablation is commonly accepted as the best option for patients with small hepatocellular carcinoma who are not candidates for surgical resection or liver transplantation. However, whether it can compete with surgery as the first-line treatment has long been debated. There are some retrospective studies and only a few randomized controlled trials to compare the two modalities. The currently available data are not robust enough to draw a solid conclusion. This review article provides an overview of the current status of percutaneous ablation in management of small hepatocellular carcinoma and also focuses on comparison with surgical resection.
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PMID:Percutaneous ablation for small hepatocellular carcinoma. 1935 Dec 83

Ethanol induces hepatic steatosis via a complex mechanism that is not well understood. Among the variety of molecules that have been proposed to participate in this mechanism, the sterol regulatory element (SRE)-binding proteins (SREBPs) have been identified as attractive targets for therapeutic intervention. In the present study, we evaluated the effects of honokiol on alcoholic steatosis and investigated its possible effect on the inhibition of SREBP-1c maturation. In in vitro studies, H4IIEC3 rat hepatoma cells developed increased lipid droplets when exposed to ethanol, but co-treatment with honokiol reversed this effect. Honokiol inhibited the maturation of SREBP-1c and its translocation to the nucleus, the binding of nSREBP-1c to SRE or SRE-related sequences of its lipogenic target genes, and the expression of genes for fatty acid synthesis. In contrast, magnolol, a structural isomer of honokiol, had no effect on nSREBP-1c levels. Male Wistar rats fed with a standard Lieber-DeCarli ethanol diet for 4 weeks exhibited increased hepatic triglyceride and decreased hepatic glutathione levels, with concomitantly increased serum alanine aminotransferase and TNF-alpha levels. Daily administration of honokiol (10 mg/kg body weight) by gavage during the final 2 weeks of ethanol treatment completely reversed these effects on hepatotoxicity markers, including hepatic triglyceride, hepatic glutathione, and serum TNF-alpha, with efficacious abrogation of fat accumulation in the liver. Inhibition of SREBP-1c protein maturation and of the expression of Srebf1c and its target genes for hepatic lipogenesis were also observed in vivo. A chromatin immunoprecipitation assay demonstrated inhibition of specific binding of SREBP-1c to the Fas promoter by honokiol in vivo. These results demonstrate that honokiol has the potential to ameliorate alcoholic steatosis by blocking fatty acid synthesis regulated by SREBP-1c.
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PMID:Honokiol reverses alcoholic fatty liver by inhibiting the maturation of sterol regulatory element binding protein-1c and the expression of its downstream lipogenesis genes. 1937 23

Radiofrequency (RF) ablation has gained great popularity in the treatment of Hepatocellular Carcinoma (HCC) on cirrhosis and is replacing Percutaneous Ethanol Injection (PEI) in treating 3 cm or less HCC nodules. Its necrotic effect is more predictable than that of PEI and therefore RF can achieve a longer local tumor progression control and survival. In the last four years many data on its efficacy have been added in the Literature and long-term results on 3-5-year survival are available. In this Review article data of the last 4 years on percutaneous RF ablation of HCC on cirrhosis are discussed in order to give an answer to questions put forward on this matter at 2000 EASL Barcelona Consensus Conference. Moreover, new perspectives in the percutaneous treatment of some form of advanced HCC (the so-called percutaneous thrombectomy) are presented together with some patents in the treatment of HCC.
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PMID:Percutaneous radiofrequency ablation of hepatocellular carcinoma on cirrhosis: state of the art and future perspectives. 1966 3

Ethanol treatment of cultured hepatoma cells and of mice inhibited the activity of AMP-activated protein kinase (AMPK). This study shows that the inhibitory effect of ethanol on AMPK phosphorylation is exerted through the inhibition of the phosphorylation of upstream kinases and the activation of protein phosphatase 2A (PP2A).Inhibition of AMPK phosphorylation by palmitate was attributed to ceramide-dependent PP2A activation. We hypothesized that the inhibitory effect of ethanol on AMPK phosphorylation was mediated partly through the generation of ceramide. The effect of ethanol and inhibitors of ceramide synthesis on AMPK phosphorylation, ceramide levels, and PP2A activity were assessed in rat hepatoma cells (H4IIEC3). The effect of ethanol on hepatic ceramide levels was also studied in C57BL/6J mice fed the Lieber-DeCarli diet. In H4IIEC3 cells, ceramide reduced AMPK phosphorylation when they were treated for between 4 and 12 h. The basal level of AMPK phosphorylation in hepatoma cells was increased with the treatment of ceramide synthase inhibitor, fumonisin B1. Ethanol treatment significantly increased cellular ceramide content and PP2A activity by approximately 18-23%, when the cells were treated with ethanol for between 4 and 12 h. These changes in intracellular ceramide concentrations and PP2A activity correlated with the time course over which ethanol inhibited AMPK phosphorylation. The activation of PP2A and inhibition of AMPK phosphorylation caused by ethanol was attenuated by fumonisin B1 and imipramine, an acid sphingomyelinase (SMase) inhibitor. There was a significant increase in the levels of ceramide and acid SMase mRNA in the livers of ethanol-fed mice compared with controls. We concluded that the effect of ethanol on AMPK appears to be mediated in part through increased cellular levels of ceramide and activation of PP2A.
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PMID:Inhibitory effect of ethanol on AMPK phosphorylation is mediated in part through elevated ceramide levels. 2022 5

In cultured human hepatoma HepG2 cells, cytochrome (CYP) 1A-associated 7-ethoxyresorufin-O-deethylase (EROD), CYP 3A-associated benzyloxyresorufin O-debenzylase (BROD) and CYP 2E1-associated p-nitrophenol-hydroxylase (PNPH) decreased during time in culture. The enzyme activities in cells at confluence were 35-60% of the activities in cells 24 hours after seeding. Similarly, CYP 3A and CYP 2E1 proteins were present at higher concentrations in growing (G) than in confluent (C) HepG2 cells. CYP 1A1/1A2 protein was not detected, neither in G nor in C HepG2 cells but was strongly induced by 3-methylcholanthrene (3-MC) treatment. Ethanol (EtOH) was shown to increase CYP 2E1 and CYP 3A proteins and CYP 1A1/1A2-, CYP 2E1- and CYP 3A-associated mixed-function oxidase activities (MFOs) in HepG2 cells, as has been previously reported for primary cultures of human hepatocytes. These effects were observed only at the beginning of culture, in growing HepG2 cells, demonstrating the influence of the growth stage of HepG2 cells on their response to EtOH treatment. This is, to our knowledge, the first report on increases in CYP proteins and associated MFOs by EtOH in HepG2 cells. It suggests that growing HepG2 cells provide a useful in vitro model system in which to study the regulation of human CYPs by EtOH.
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PMID:Expression of Cytochromes P-450 2E1, 3A4 and 1A1/1A2 in Growing and Confluent Human HepG2 Hepatoma Cells-Effect of Ethanol. 2065

Chronic alcohol consumption is associated with steatohepatitis and cirrhosis, enhancing the risk for hepatocellular carcinoma. RNA polymerase (pol) III transcribes a variety of small, untranslated RNAs, including tRNAs and 5S rRNAs, which determine the biosynthetic capacity of cells. Increased RNA pol III-dependent transcription, observed in transformed cells and human tumors, is required for oncogenic transformation. Given that alcohol consumption increases risk for liver cancer, we examined whether alcohol regulates this class of genes. Ethanol induces RNA pol III-dependent transcription in both HepG2 cells and primary mouse hepatocytes in a manner that requires ethanol metabolism and the activation of JNK1. This regulatory event is mediated, at least in part, through the ability of ethanol to induce expression of the TFIIIB components, Brf1, and the TATA-binding protein (TBP). Induction of TBP, Brf1, and RNA pol III-dependent gene expression is driven by enhanced c-Jun expression. Ethanol promotes a marked increase in the direct recruitment of c-Jun to TBP, Brf1, and tRNA gene promoters. Chronic alcohol administration in mice leads to enhanced expression of TBP, Brf1, tRNA, and 5S rRNA gene transcription in the liver. These alcohol-dependent increases are more pronounced in transgenic animals that express the HCV NS5A protein that display increased incidence of liver tumors. Together, these results identify a new class of genes that are regulated by alcohol through the co-regulation of TFIIIB components and define a central role for c-Jun in this process.
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PMID:Alcohol induces RNA polymerase III-dependent transcription through c-Jun by co-regulating TATA-binding protein (TBP) and Brf1 expression. 2110 30

Nonalcoholic fatty liver disease (NAFLD), a manifestation of metabolic syndrome, includes a wide range of clinical entities from simple fatty liver, a benign condition, to nonalcoholic steatohepatitis (NASH), a condition which can progress to cirrhosis, hepatocellular carcinoma and hepatic failure. The diagnosis of NASH requires no history of previous or current significant alcohol consumption and no evidence of other chronic liver diseases. Ethanol intake levels of 20 g daily (or 140 g weekly) are endorsed as the acceptable threshold to define nonalcoholic patients. Liver biopsy is the current gold standard for the diagnosis of NASH and provides prognostic information. Histopathological diagnosis of NASH is based on the following 3 features: (1) hepatic macrovesicular steatosis; (2) lobular inflammation; and (3) ballooning degeneration of hepatocytes. It is impractical to biopsy every patient with suspected NAFLD. Although highly accurate and affordable noninvasive screening tools can differentiate NASH from NAFLD, no imaging studies or laboratory tests are able to precisely diagnose NASH. There is no universal agreement regarding the indications for liver biopsy in NAFLD patients. In Japan, liver biopsies are considered in patients with suspected NAFLD based on several criteria including low platelet counts, elevated fibrosis markers, increasing age and other deciding parameters. Further studies are needed to establish a suitable scoring system that can distinguish steatohepatitis from simple steatosis.
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PMID:Current status and agenda in the diagnosis of nonalcoholic steatohepatitis in Japan. 2116 Sep 46


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