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)

Expression and distribution of 17-1A, a human colon-carcinoma-associated antigen as defined by a monoclonal antibody (17-1A mAb), were evaluated in liver tissues from normal subjects and patients with inflammatory and noninflammatory liver diseases. The antigen recognized by 17-1A mAb is a 41-kD protein that does not belong to the proteins of the cytoskeleton. Using a streptavidin-biotin-peroxidase method on frozen sections of liver tissue, it was located in the cytoplasm of bile duct epithelial cells in normal livers, whereas the hepatocytes were completely unreactive. When diseased liver tissue was examined, a strong 17-1A Ag expression was demonstrable in the epithelium of typical and atypical bile ductules in portal areas. In addition, periportal or periseptal hepatocytes revealed variable staining for 17-1A Ag directly related to acute and chronic inflammatory changes. 17-1A Ag expression in hepatocytes reached the highest frequency in acute hepatitis (5/5) and chronic active hepatitis (17/19). These results indicate that periportal hepatocytes are capable of acquiring antigen expression common to bile ductular cells in inflammatory liver diseases, further supporting the view that these ductules represent transformed hepatocytes. Furthermore, two distinct pictures were found in primary liver malignancies. Neoplastic bile duct epithelium did not maintain 17-1A Ag expression in cholangiocarcinoma, whereas neoplastic liver cells acquired cytoplasmic 17-1A Ag expression in clustered areas in hepatocellular carcinoma and the intensity of staining and antigen distribution were inversely related to the grade of tumor differentiation.
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PMID:Expression and distribution of a human colon-carcinoma-associated antigen in normal and diseased liver tissue. 821 41

A one-step sandwich enzyme immunoassay system was developed with a pair of monoclonal antibodies against two individual oligopeptides prepared from the amino acid sequence of the human tissue inhibitor of metalloproteinases-2 (TIMP-2). The assay system consisting of two simultaneous immunoreactions used a solid phase monoclonal antibody and a horse-radish peroxidase-labeled monoclonal antibody. The system detected a free form of TIMP-2 and that complexed with active forms of matrix metalloproteinases (MMPs) giving a different sensitivity for each MMP but not TIMP-2 complexed with the precursor of 72 kDa gelatinase/type IV collagenase (MMP-2). The sensitivity of the system was 1.6 microgram/l (16 pg/assay) and linearity was obtained between 6.3 and 50 micrograms/l (63-500 pg/assay). TIMP-2 levels in the sera of 20 patients with rheumatoid arthritis (68 +/- 25 micrograms/l, mean +/- S.D.) and 13 patients with hepatocellular carcinoma (76 +/- 46 micrograms/l) were significantly higher (P < 0.05) than those of 18 normal subjects (5.6 +/- 7.4 micrograms/l). In contrast, the levels in the sera of 10 patients with gastric cancer (45 +/- 18 micrograms/l) and 7 patients with cancer of the uterus (36 +/- 13 micrograms/l) were significantly lower (P < 0.05 or P < 0.01) than those of normal subjects. Immunoreactivity analyses suggested that the precursor of MMP-2 in normal sera exists in a complexed form with TIMP-2 by interacting with the C-terminal domain of TIMP-2.
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PMID:A one-step sandwich enzyme immunoassay for tissue inhibitor of metalloproteinases-2 using monoclonal antibodies. 828 59

The uptake and distribution of phosphorothioate oligodeoxynucleotides by human cells were studied using 35S-labeled 28-mer phosphorothioate oligodeoxycytidine [S-(dC)28]. Accumulation of intracellular S-(dC)28 was found to be higher in the carcinoma cells (grown in monolayers) than in the leukemia cells (grown in suspension culture). A hepatoma cell line transfected with hepatitis B virus, 2215, was chosen for further studies. The uptake of S-(dC)28 was partially dependent on temperature and energy. The intracellular concentration was significantly higher than that in the medium and the amount accumulated was dependent on the extracellular concentration. It appears that the uptake of S-(dC)28 involves mechanisms of both fluid-phase pinocytosis and adsorptive endocytosis. Neither oligonucleotides nor 5'-phosphorylated nucleotides inhibited S-(dC)28 uptake. Unlike horseradish peroxidase, which was primarily associated with endosomes once it was taken into the cell, S-(dC)28 was found to be present in both nuclear and cytoplasmic fractions. Efflux of S-(dC)28 from the cell was multiphasic; a trapping mechanism that could be due to a potent interaction of S-(dC)28 with cellular proteins was implicated. This trapping mechanism could be responsible for the lack of biological activity such as cytotoxicity and antisense activity of phosphorothioate oligodeoxynucleotides in some human cells.
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PMID:Cellular pharmacology of phosphorothioate homooligodeoxynucleotides in human cells. 842 68

We have characterized a new selenium-dependent glutathione peroxidase, GSHPx-GI, by expressing a GSHPx-GI cDNA isolated from human hepatoma HepG2 cells in human mammary carcinoma MCF-7 cells, which have virtually undetectable expression of either the classical cellular enzyme, GSHPx-1, or GSHPx-GI at the protein level. One of the G418-resistant clones, neo-D1, expresses the transfected GSHPx-GI cDNA. This is based on 1) the presence of an additional GSHPx-GI DNA restriction fragment detected by Southern analysis; 2) the presence of a 1.9-kilobase (kb) GSHPx-GI mRNA in addition to the 1.0-kb endogenous mRNA by Northern analysis; and 3) the appearance of a 22-kDa 75Se-labeled protein which is absent in parental MCF-7 cells revealed by SDS-polyacrylamide gel electrophoresis. GSHPx-GI expressed in neo-D1 is a tetrameric protein localized in cytosol. GSHPx-GI does not cross-react with antisera against human GSHPx-1 or human plasma glutathione peroxidase (GSHPx-P). Similar substrate specificities are found for GSHPx-1 and GSHPx-GI; they both catalyze the reduction of H2O2, tert-butyl hydroperoxide, cumene hydroperoxide, and linoleic acid hydroperoxide with glutathione, but not of phosphatidylcholine hydroperoxide. GSHPx-GI mRNA was readily detected in human liver and colon, and occasionally in human breast samples, but not other human tissues including kidney, heart, lung, placenta, or uterus. In rodent tissues, GSHPx-GI mRNA is only detected in the gastrointestinal tract, and not in other tissues including liver. In fact, GSHPx-GI appears to be the major glutathione-dependent peroxidase activity in rodent GI tract. This finding suggests that GSHPx-GI could play a major role in protecting mammals from the toxicity of ingested lipid hydroperoxides. In conclusion, we have demonstrated that GSHPx-GI is the fourth member in the selenium-dependent glutathione peroxidase family, in addition to GSHPx-1, GSHPx-P, and phospholipid hydroperoxide glutathione peroxidase (PHGPX).
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PMID:Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI. 842 33

An enzyme-linked immunosorbent assay (ELISA) was developed for measuring human hypocarboxyprothrombin, a protein induced by vitamin K antagonists (PIV KA-II). A specific monoclonal antibody (P1-2-B9) was prepared and used for coating a microELISA plate, and revelation proceeded with a rabbit polyclonal anti-human prothrombin antibody-peroxidase conjugate. This assay allowed the measurement of PIVKA-II at concentrations ranging from 2 to 200 ng/ml, with an intraassay coefficient of variation of less than 5.2% and an interassay coefficient of variation of less than 7.4%. This assay permits the direct evaluation of PIVKA-II in citrated plasma as well as in serum. The concentration of PIVKA-II is expressed in nanograms per milliliter. It offers specific measurement of PIVKA-II without any cross-reactivity from native prothrombin: the specificity for PIVKA-II respective to prothrombin is > 10(5). No reactivity was observed with other vitamin K-dependent proteins, whether fully active or decarboxylated. Complementary studies have demonstrated that the monoclonal antibody used was preferentially directed to 3 to 6 Gla hypocarboxylated prothrombin. PIVKA-II concentration was below 2.4 ng/ml in normal individuals (n = 59). In 61 patients given dicoumarol for more than 90 days (receiving a stable therapy), the measured concentrations of PIVKA-II ranged from 750 to 13,400 ng/ml. Combined with the assay of alpha-fetoprotein (AFP), measurement of PIVKA-II in patients with liver diseases introduces a complementary exploration for hepatocellular carcinoma (HCC). In a study in 59 patients with HCC, the assay sensitivity was 49.1% for PIVKA-II, 47.5% for AFP, and 71% for both markers combined.
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PMID:Specific measurement of hypocarboxylated prothrombin in plasma or serum and application to the diagnosis of hepatocellular carcinoma. 864 60

Hepatocellular carcinoma (HCC) remains one of the most important malignancies in Japan (1, 2). Lactic dehydrogenase (LDH), which is a glycolyticenzyme, and exists in various types of human tissue and neoplasms, has also been reported to demonstrate a high level (especially LDH 5) in the serum of patients with HCC (3-10). We herein report the findings of a 68-year-old male patient with hepatocellular carcinoma (HCC), whose serum lactic dehydrogenase (LDH) level more closely correlated with the clinical course than the alpha-feto-protein level (AFP). Both the AFP and LDH levels were high before the operation (AFP 1402 ng/ml; LDH 638 IU/L) (LDH1 11%; LDH2 24%; LDH3 34%; LDH4 19%; LDH5 12%). The levels of the serum LDH and AFP one week after the right hepatic lobectomy both decreased to 423 IU/L and 331 ng/ml, respectively. In addition, the LDH isozyme pattern returned to normal. Six weeks after the operation, the serum LDH increased to 3504 IU/L, however, the AFP levels remained low at 43.4 ng/ml, and the CT findings demonstrated multiple recurrent nodules in the whole remnant liver. At eighty-one days after the operation, the patient died due to a rupture of the recurrent HCC. Immunohistochemical observations were performed using the peroxidase labeled streptavidin-biotin technique with slight modifications and using two monoclonal antibodies for AFP and for Ki-67. Most portions of the primary tumor consisted of poorly to undifferentiated HCC. The portion of undifferentiated HCC did not stain for AFP antibody, but the portion of poorly differentiated HCC stained positively for it. It was thus speculated that LDH was mainly produced in the portion of undifferentiated HCC. In addition the undifferentiated HCC were strongly positive for Ki-67, while, in contrast, the poorly HCC was only weakly positive for Ki-67. Based on the above findings, HCC with a high serum level of LDH appears to show both a rapid growth and highly malignant tumors.
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PMID:The characteristics of hepatocellular carcinoma with a high level of serum lactic dehydrogenase: a case report. 922 98

Mice naturally infected by Helicobacter hepaticus develop a chronic active hepatitis leading to hepatocellular carcinoma. This mouse model of liver cancer was used to examine the impact of bacterial infection on the hepatic expression and activity of enzymes involved in carcinogen bioactivation (phase I enzymes) and detoxification (phase II enzymes). No major differences in total cytochrome P450 (CYP) content were found between control and infected mice during the course of the study. The most striking modulations of individual isoenzymes were the increases in immunohistochemical staining observed for CYP1A and CYP2A5 in relation to increasing age and liver lesions. The increase in CYP2A5 in mice aged over 12 months was confirmed by the observed increases in coumarin 7-hydroxylation (CYP2A5 substrate) in vitro and CYP2A5 mRNA levels by Northern blot analysis. Immunoblotting confirmed the specific induction of CYP1A2 in infected mice 12 and 18 months of age. Perfusion of liver with nitroblue tetrazolium, an indicator for superoxide formation, demonstrated that in livers of infected mice, hepatocytes often co-expressed CYP2A5 and formazan deposition. Concerning phase II enzymes, an enhancement of glutathione S-transferase (GST) activities, related to the disease process, was observed in infected mice. An age-specific increase of GSTpi and A4.4 (early stage of disease) and GST YaYa (>9 months) expression was also demonstrated by immunohistochemical staining. In contrast, catalase and glutathione-peroxidase activities, as well as reduced glutathione content were decreased in the early stages of disease (3-9 months) in infected mice compared to age-matched control mice. Overall, these results suggest that alterations in CYP and GST expression may contribute to the aetiology of tumour incidence due to H. hepaticus infection via production of reactive oxygen species.
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PMID:Distinct time courses of increase in cytochromes P450 1A2, 2A5 and glutathione S-transferases during the progressive hepatitis associated with Helicobacter hepaticus. 939 19

In present study we studied the cytotoxic effects of beta-lapachone, a potent anticancer drug, on the human hepatoma cell line (HepA2) under serum-free condition. Most cells died after 2 microM beta-lapachone addition at 48 hours. No apoptotic characteristics of DNA ladder was documented by agarose DNA electrophoresis. The blockage of cell cycle at S phase and unscheduled DNA synthesis were demonstrated by flow cytometric analysis and anti-bromodeoxyuridine immunocytochemistry. Ultrastructural observation showed that the swollen mitochondria, dilatation and vesiculation of rER and proliferation of peroxisome-like granules appeared within the cytoplasm of HepA2 cells following drug treatment. Using enzyme cytochemistry, both peroxidase and acid phosphatase activities but not catalase activity were localised in these peroxisome-like granules. Therefore, these results suggested that (a) beta-lapachone has a novel cytotoxic effect on human hepatoma cell; (2) beta-lapachone induces the interruption of the cell cycle and unscheduled DNA synthesis in HepA2 cells; and (3) beta-lapachone promotes the proliferation of peroxisome-like granules containing peroxidase and acid phosphatase activities without evidence of catalase activity in hepatoma cell line.
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PMID:beta-Lapachone induced cell death in human hepatoma (HepA2) cells. 947 38

2-Nitropropane (2-NP) is a well-known genotoxin and carcinogen in rat liver. Several metabolic pathways, particularly cytochrome P450-, peroxidase- and sulfotransferase-dependent ones, have been suggested to lead to the formation of DNA-reactive species from 2-NP. Because rat liver cells express most types of xenobiotic-metabolizing enzymes, the role of specific pathways in the metabolic activation of 2-NP is difficult to assess in these cells. We have therefore investigated the genotoxicity of 2-NP and its anionic form, propane 2-nitronate (P2N), in cultured ovine seminal vesicle (OSV) cells. OSV cells lack cytochrome P450-dependent monooxygenase activity, but express prostaglandin-H-synthase (PHS) and, as we found out, phenol sulfotransferase. The induction of DNA repair synthesis and specific DNA modifications served as indicators for the genotoxicity of 2-NP and P2N. Both forms strongly induced repair, P2N being more active than 2-NP. The secondary nitroalkanes nitrocyclopentane and nitrocyclohexane also induced repair, whereas 1-nitropropane and the reduction product of 2-NP, acetone oxime, did not. P2N also elicited the formation of the characteristic DNA modifications 'DX1' and 8-aminodeoxyguanosine and increased the level of 8-oxodeoxyguanosine residues in the DNA. Pretreatment of OSV cells with indomethacin, an inhibitor of PHS, affected neither the induction of repair nor the formation of the DNA modifications, and P2N was not a reducing substrate for the PHS-peroxidase activity. In contrast, the sulfotransferase inhibitor pentachlorophenol strongly reduced genotoxicity. The results show that cytochrome P450-dependent monooxygenases are not required for the metabolic conversion of secondary nitroalkanes or their nitronates into DNA-damaging products, nor is PHS involved in the metabolic activation. Instead, the data corroborate an essential role of sulfotransferase(s) in the genotoxicity and carcinogenicity of secondary nitroalkanes. Moreover, it is demonstrated for the first time that these compounds can be genotoxic in cells other than hepatocytes or hepatoma cells. This implies that in species other than the rat, organs other than the liver can be targets for the genotoxicity, and possibly carcinogenicity, of secondary nitroalkanes.
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PMID:Sulfotransferase-mediated genotoxicity of propane 2-nitronate in cultured ovine seminal vesicle cells. 960 60

The method of surface-enhanced Raman microspectroscopy was developed for direct detection of membrane-bound enzymes in cells. Cells were cultured, fixed, and incubated with specific primary antibodies and their corresponding labeled secondary antibodies, and surface-enhanced Raman scattering (SERS) was detected directly in the wells of a multiwell plate. First, specific primary antibodies were separately bound to enzymes in cells. Then, the peroxidase-labeled secondary antibodies were added to bind these primary antibodies. Peroxidase substrates, o-phenylenediamine and hydrogen peroxide, were added and reacted for 15 min at room temperature to form azoaniline, a compound with strong Raman scattering. Then, Raman scattering of this enzymatic product was enhanced by silver colloids. Samples were excited with a He/Ne laser at 632.8 nm and SERS was detected by a CCD camera. The SERS spectrum of this product showed an intense peak at 1370 cm-1 and its intensity was used for assessment of cellular enzymes. The observed amount of enzyme was normalized to protein content in each well. The method was successfully used to detect prostaglandin H synthase-1 and -2 (PGHS-1 and -2) in normal human hepatocytes and human hepatocellular carcinoma (HepG2) cells. The detection limit of these PGHS enzymes by this method was about 0.1 pg per well. An immunohistochemical staining was also used to detect the expression of both PGHS isozymes in these cells.
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PMID:Detection of membrane-bound enzymes in cells using immunoassay and Raman microspectroscopy. 961 99


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