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)

Recent progress in the field of infectious diseases involving carcinogenesis has been striking. Extensive studies of Helicobacter pylori, and hepatitis type B and C virus showed that they are the primary cause of gastric cancer and hepatoma, respectively. Also some parasites such as Opistorchis viverrini and Schistosoma haematobium are also putative causes of cholangiocarcinoma and urinary bladder cancer, respectively. All of them require a chronic infection of more than 15 years. More than 50% of Japanese cancers are thus considered to be caused by chronic infection. The classic theory of carcinogenesis is radiation, chemicals and viral infection. Recent studies in free radical and biochemical research in our infectious diseases show all carcinogenesis involves free radical generation such as superoxide (O2.-), nitric oxide (NO), and their adducts peroxynitrite (ONOO-), H2O2 hydrooxyl radical (.OH), HClO, and NO2Cl as well as alkylperoxy radicals. All these molecular species are capable of modifying nucleic acid and DNA or RNA; furthermore a strand break is frequently observed, and hence potent mutagenicity and a probable cause of cancer. Thus, the unifying theory of carcinogenesis may most likely involve the mechanism of free radicals. This means a paradigm shift is needed in the public health policy for the tactics of cancer prevention.
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PMID:[Carcinogenesis via microbial infection]. 972 37

The gene expression of heme oxygenase-1 (HO-1) was studied in mammalian cell lines exposed to hyperoxia. Northern blot analysis demonstrated that hyperoxic exposure increased the HO-1 mRNA levels in various types of cells, including human hepatoma (HepG2) cells. This increase was time- and dose-dependent, and reversible. The HO-1 mRNA levels in HepG2 cells were increased to 2.3- and 4.2-fold of the control by hyperoxic exposure of 6 and 23 h, respectively. Cycloheximide and actinomycin D inhibited the increases in the HO-1 mRNA level produced by hyperoxia, indicating that response to hyperoxia is dependent on de novo protein synthesis and mRNA transcription. Antioxidants, desferrioxamine (DES) and o-phenanthroline (OP) partially inhibited the HO-1 mRNA elevation by hyperoxia. In addition to hyperoxia, sodium arsenite (NaAsO2), cadmium chloride (CdCl(2)) and hydrogen peroxide (H2O2), which are reactive oxygen intermediates (ROI) generators, increased the HO-1 mRNA level by 11-, 22- and 2.5-fold, respectively. OP, an antioxidant and a bivalent metal chelator, blocked the HO-1 mRNA elevation induced either by hyperoxia or by the three ROI generators. In contrast to OP, N-acetylcysteine (NAC), an antioxidant and membrane-permeable reducing reagent, enhanced the HO-1 mRNA elevation induced by hyperoxia, although NAC inhibited the mRNA elevation induced by NaAsO2, CdCl2 and H2O2. These results indicate that oxygen tension regulates HO-1 gene expression and suggest that hyperoxia-specific and redox-sensitive regulators may be involved in hyperoxia-mediated HO-1 gene expression.
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PMID:Oxygen tension regulates heme oxygenase-1 gene expression in mammalian cell lines. 974 10

Oxidative stress interferes with several cellular functions, in particular transcriptional regulation. We show here that the human cytochrome P450 1A1 (CYP1A1) is down-regulated at the transcriptional level by oxidative stress. Basal as well as 2,3,7, 8-tetrachloro-p-dioxin-induced promoter activities are strongly impaired by H2O2 treatment or glutathione depletion with L-buthionine-(S,R)-sulfoximine. Tumor necrosis factor alpha inhibits CYP1A1 expression, and this inhibition is prevented by the antioxidant pyrrolidine dithiocarbamate. We show that these regulations depend on the integrity of the nuclear factor 1 (NFI) site located in the proximal promoter. We therefore examined the redox regulation of this transcription factor. Treatment of human HepG2 or rat H4 hepatoma cells with H2O2 or L-buthionine-(S, R)-sulfoximine inactivates the binding of the NFI transcription factor to its DNA consensus sequence. Furthermore, H2O2 treatment leads to a dose-dependent decrease of reporter gene expressions driven by promoters containing NFI binding sites. Glutathione depletion and catalase inhibition also repress a NFI-driven promoter. Under the same conditions, the CP-1 transcription factor activity is not affected by oxidative stress. Thus, NFI seems particularly sensitive to oxidative stress. This accounts, at least partially, for the regulation of cyp1A1 gene expression.
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PMID:Down-regulation of cytochrome P450 1A1 gene promoter by oxidative stress. Critical contribution of nuclear factor 1. 975 46

Erythropoietin (Epo) synthesis is suppressed in normoxia and stimulated in hypoxia. To test the hypothesis that the cellular H2O2 level is important in the control of Epo synthesis, we have studied effects of modulators of H2O2 generation and degradation on Epo production in human hepatic cell cultures (hepatoma lines HepG2 and Hep3B). In addition, we measured the activities of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) in cultures following hypoxia exposure or H2O2 treatment. The results show that the formation of immunoreactive Epo was stimulated in normoxic cultures by treatment with exogenous catalase thus mimicking the effect of hypoxia (24 h incubation periods). Epo production was also stimulated when scavengers of reactive O2 species (tetramethylthiourea, dihydrorhodamine) were added to the cells. On the other hand, stimulators of H2O2 generation (xanthine oxidase, glucose oxidase, NADH, NADPH) lowered Epo production in hypoxic cultures. Hypoxia exposure decreased superoxide dismutase activity and H2O2 treatment reduced catalase activity thus influencing the endogenous antioxidant defense system. These findings support the concept that reactive O2 species, primarily H2O2, act as messengers in the O2-dependent control of the hepatic production of Epo. Changes in the cellular activities of antioxidant enzymes appear to play only a minor role in this process.
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PMID:Effects of modulators of the production and degradation of hydrogen peroxide on erythropoietin synthesis. 986 91

The protective effect of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a selenoorganic compound, against hydrogen peroxide (H2O2)-induced cytotoxicity and DNA damage was investigated in a human hepatoma cell line, HepG2. The inhibitory effect of H2O2 on cell growth was determined using the tetrazolium dye colorimetric test (MTT test), and the cytotoxicity and lipid peroxidation were estimated by lactate dehydrogenase (LDH) leakage and malondialdehyde (MDA) formation, respectively. DNA damage was detected using single cell gel electrophoresis (comet assay), and intracellular reactive oxygen species (ROS) formation was measured using a fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA). The results showed that H2O2 suppressed the growth of HepG2 cells and the addition of ebselen significantly reduced the suppression. Furthermore, ebselen also displayed a dose-dependent reduction of LDH leakage and MDA formation in H2O2-treated cells. The results also demonstrate that ebselen was able to reduce the ROS formation and DNA damaging effect caused by H2O2 in a dose-dependent manner. These findings suggest that ebselen has a strong protective ability against the cytotoxicity and DNA damaging effect caused by reactive oxygen species.
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PMID:Protective effect of ebselen against hydrogen peroxide-induced cytotoxicity and DNA damage in HepG2 cells. 989 May 54

The most important stimulus for the enhanced synthesis of erythropoietin (Epo) is a lowered O2 tension in the tissue. However, the mechanism by which an impaired O2 supply is transduced into appropriate Epo production is still not fully understood. Recently, studies in human hepatoma cells (line HepG2) indicate that reactive O2 species are involved in the signal transduction from the cellular O2 sensor to the Epo gene. To clarify the role of reactive O2 species in the regulation of Epo synthesis in the kidney, the principal Epo-producing organ in vivo, we investigated the influence of potent pro- and antioxidants on Epo production in isolated perfused rat kidneys. Under normoxic conditions, the iron chelator desferrioxamine and the antioxidant vitamin A increased renal Epo production, mimicking hypoxic induction. In contrast, supplementation of the perfusion medium of hypoxically perfused kidneys with the prooxidant compounds H2O2 or pyrogallol caused a significant reduction of Epo synthesis. The inhibition of Epo formation by reactive O2 species could be completely antagonized by desferrioxamine and the hydroxyl radical-(OH*)-scavenger tetramethylthiourea. Vitamin A also antagonized the H2O2-dependent inhibition of hypoxically induced Epo synthesis. Interestingly, the addition of the antioxidant vitamin A to hypoxically perfused kidneys also induced Epo production significantly. Our data strongly support the idea that reactive O2 species, especially H2O2, are part of the signaling chain of the cellular O2-sensing mechanism regulating the renal synthesis of Epo.
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PMID:Effects of pro- and antioxidative compounds on renal production of erythropoietin. 992 88

We investigated whether the antitumor action of sodium 5,6-benzylidene-L-ascorbate (SBA) is mediated via oxidation-involved mechanism, in three different systems: 3'-methyl-4-dimethylaminoazobenzene (DAB)-induced rat hepatocellular carcinoma (in vivo), its homogenate (semi in vivo), and cultured cells (in vitro). Oral intake of DAB irreversibly produced hepatocellular carcinoma in rats, with a maximum incidence of carcinogenesis after 4 months. Intravenous administration of SBA induced vacuolar, eosinophilic degeneration and nuclear debris, producing greater amounts of ESR signal of ascorbate radical and hydrogen peroxide (H2O2)-derived chemiluminescence (CL) (H2O2-CL) in the cancerous tissue than in the normal tissue. When SBA was directly added to the homogenates, higher amounts of ascorbate radical and H2O2-CL were generated in cancerous tissues. When SBA was added to the RPMI1640 medium supplemented with 10% fetal bovine serum, methionine was oxidized to methionine sulfoxide and H2O2 was produced in amounts that sufficiently induce apoptotic cell death in human promyelocytic leukemic HL-60 cells. Cytotoxic activity of SBA was significantly reduced by catalase. These data suggest that antitumor activity of SBA in vivo might at least in part be due to H2O2, produced from SBA.
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PMID:Production of hydrogen peroxide in cancerous tissue by intravenous administration of sodium 5,6-benzylidene-L-ascorbate. 1022 47

1. Several ozonides, peroxides and aldehydes are formed during ozone therapy, recently introduced in medicine. tert-Butyl hydroperoxide (t-BHP), H2O2 and diamide were investigated as model substrate in rat hepatoma-derived Fa32 cells. 2. The cytotoxicity was measured by the neutral red uptake inhibition assay after 1 h or 24 h treatment. The relative toxicities were quantified by the determination of the NI50. This is the concentration of test compound required to induce an inhibition of 50% in neutral red uptake as compared to the control cells. All test chemicals were more toxic after 24 h than after 1 h. 3. The influence of the glutathione (GSH) alteration on the cytotoxicity was measured by treating the cells with 2-oxo-4-thiazolidine carboxylic acid (OTC) or L-buthionine sulfoximine (BSO). OTC increased the endogenous GSH content in the cells. BSO pretreatment strongly decreased the NI50 of the three chemicals. OTC pretreatment increased the NI50 of H2O2 but not of t-BHP and diamide. This can be explained by the strong GSH-depletion after 1 h by t-BHP and diamide, which contrasted with a weak GSH-depletion by H2O2 after the same time period. 4. The three test chemicals increased the endogenous GSH content after 24 h. t-BHP and H2O2, but not diamide, increased the total GSH transferase (GST) activity. Several alterations of the GST subunits were observed. Most striking was the increase of class alpha GST subunits, also for diamide. 5. Since H2O2 and t-BHP are ozone metabolites thought to be responsible for the therapeutic effects of well-dosed ozone, the results show that Fa32 cells can be used as a valuable alternative model system for studying the effects encountered in human ozone therapy.
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PMID:Glutathione protection against hydrogen peroxide, tert-butyl hydroperoxide and diamide cytotoxicity in rat hepatoma-derived Fa32 cells. 1055 15

We describe a biphasic action of nitric oxide (NO) in its effects on oxidative killing of isolated cells: low concentrations protect against oxidative killing, while higher doses enhance killing, and these two effects occur by distinct mechanisms. While low doses of NO (from (Z)-1-[N-(3-ammonio propyl)-N-(n-propyl)-amino]-diazen-1-ium-1,2(2) diolate [PAPA/NO] or S-nitroso-N-acetyl-L-penicillamine [SNAP] prevent killing of rat hepatocytes by t-butylhydroperoxide (tBH), further increasing doses result in increased killing. Similar effects occur with rat hepatoma cells treated with PAPA/NO and tBH or H2O2. Increased killing with higher concentrations of NO donor is due to both NO and tBH, because NO donor alone is without effect. Glutathione (GSH) is not involved in either of these actions. Based on measurements of thiobarbituric acid-reactive substances (TBARS) and effects of lipid radical scavenger (DPPD) and deferoxamine, the protective effect, but not the enhancing effect, involves peroxidative chemistry. Fructose has no effect on tBH killing alone but provides substantial protection against killing by higher concentrations of NO plus tBH, suggesting that the enhancing effect involves mitochondrial dysfunction. Hepatocytes, when stimulated to produce NO endogenously, become resistant to tBH killing, indicative of the presence of an NO-triggered antioxidant defensive mechanism. The finding that the protective effects of low concentrations of NO and the harmful effects of high concentrations of NO are fundamentally different in nature suggest that therapeutic interventions could be designed, which selectively prevent its pro-oxidant activity at high concentrations, thus converting NO from a "Janus-faced" modulator of oxidant injury into a "pure" protectant.
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PMID:Cellular antioxidant and pro-oxidant actions of nitric oxide. 1064 30

Much research effort has focused on the identification of phytochemicals in fruit and vegetables which exert beneficial effects. Our research examines modulatory effects of phytochemicals on cytotoxicity, genotoxicity and oxidative reactions in cell systems. Two examples of our studies are discussed. First, the potential beneficial effects of flavonoids are demonstrated. Flavonoids are reported to exhibit a wide variety of biological effects, including antioxidant and free-radical-scavenging activities. The aim of the study was to determine if flavonoids could protect against H2O2-induced DNA damage, as measured by the comet assay, in Caco-2 and HepG2 cells. Both cell lines were supplemented with increasing concentrations of myricetin, quercetin and rutin for 24 h followed by exposure to H2O2 (50 microM) for 30 min. Exposure to H2O2 for 30 min at 37 degrees C resulted in significant DNA damage and pre-incubation with the flavonoids before H2O2 exposure significantly (P <0.05) protected Caco-2 and HepG2 cells against H2O2-induced DNA damage. Secondly, we illustrate the use of cellular models to study oxysterol-induced toxicity. Oxysterols are generated during the cooking and processing of foods and may be produced endogenously by the oxidation of membrane lipids. Recent findings suggest that oxysterols may modulate cytotoxicity by exerting effects on the induction of apoptosis. 7beta-Hydroxycholesterol (7beta-OHC) and 25-hydroxycholesterol, both of which are commonly found in foods, were investigated for their abilities to induce apoptosis in a human monocytic blood cell line, U937, and in the human hepatoma cell line, HepG2 cells. U937 and HepG2 cells were incubated for up to 48 h with 30 microM oxysterol. 7beta-OHC induced apoptosis in U937 cells as measured by non-random DNA fragmentation, condensed and fragmented nuclei, and the generation of hypodiploid cells. In contrast, oxysterols may induce cell death by a different mechanism in the hepatoma cells, possibly by necrosis.
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PMID:Cytotoxicity, genotoxicity and oxidative reactions in cell-culture models: modulatory effects of phytochemicals. 1081 93


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