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)

The University of Wisconsin's (UW) solution has been used commonly for current liver transplantation. However, its effect on the vascular endothelium remains unclear. Experiments were designed to study the effects. Human hepatic arteries harvested from patients with hepatocellular carcinoma undergoing liver resection were preserved in 4 degree C physiological solution (group 1, the content showed on the text) and UW solution (group 2) for 1 hr. Segments of preserved and control (group 3) hepatic arteries were suspended in organ chamber to measure the isometric force. The relaxations to acetylcholine (ACH) and adenosine diphosphate in segments of hepatic artery with endothelium were significantly greater than those segments without endothelium. The maximal relaxation to ACH in arterial segments with endothelium of group 2 was significantly different from those of group 1 and 3 (group 1 to group 3, 82 +/- 2%, 57 +/- 6%, and 83 +/- 4% of the initial tension contracted by neoepinephrine (3 X 10-7 mole/l, P < 0.05). The maximal relaxation to adenosine diphosphate was similar to the response to ACH. Perfusate hypoxia (oxygen tension 30 +/- 5 mmHG) caused endothelium-dependent contraction of the arterial segments (group 1 to group 3, 233 +/- 32%, 276 +/- 35%, and 251 +/- 40% of the initial tension, P < 0.05). Endothelium-independent relaxation and contraction of human hepatic artery to sodium nitroprusside and norepinephrine were not altered by UW solution. In summary, the impaired endothelium-dependent relaxation by UW solution and prominent endothelium-dependent contraction to hypoxia of human hepatic artery would favor vasospasm and thrombus formation after liver transplantation.
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PMID:The endothelium-dependent response of human hepatic artery after preservation with the UW solution. 865 29

Activation of purinergic receptors by ATP stimulates Cl- efflux in biliary epithelial cells. To determine whether purinergic agonists are present under physiological conditions, we have assayed mammalian bile for nucleotides and assessed whether hepatoma and cholangiocarcinoma cell lines are capable of nucleotide release. Bile samples were collected from human, rat, and pig donors and assayed for nucleotide concentrations by luminometry. ATP, ADP, and AMP were present in bile from each species, and the average total nucleotide concentration in human bile was 5.21 +/- 0.91 microM (n = 16). In an in vitro model of HTC rat hepatoma cells or Mz-ChA-1 cholangiocarcinoma cells on a superfused column, nucleotides were present in the effluent from each cell type. Addition of alpha, beta-methyleneadenosine 5'-diphosphate (50 microM) to inhibit 5'-nucleotidase activity increased AMP concentrations two- to threefold. Exposure to forskolin (100 microM) or ionomycin (2 microM) stimulated nucleotide release from cholangiocarcinoma but not hepatoma cells. These studies indicate that adenosine nucleotides are present in bile in concentrations sufficient to activate purinergic receptors. Purinergic receptor activation by local nucleotide release might constitute an autocrine and/or paracrine mechanism for modulation of biliary secretion.
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PMID:Adenosine nucleotides in bile. 877 65

Treatment of hepatocyte-hepatoma hybrid cells with Clostridium botulinum C2 toxin led to a 167% increase in monomeric globular actin (G-actin) and to a 57% decrease in filamentous actin (F-actin) within 2 h. Simultaneously, the level of actin mRNA was specifically decreased to 49% and actin synthesis was significantly diminished. In contrast, treatment of hybrid cells with phalloidin led to a decrease in G-actin to 55% and to a reciprocal increase in actin mRNA to 244% and an increase in actin synthesis. These alterations of actin synthesis depending on the G-actin/F-actin ratio corresponded to the autoregulation of actin synthesis observed in primary cultures of rat hepatocytes. Microinjection of C2 toxin or of phalloidin into hepatocyte-hepatoma hybrid cells had the same effects on actin synthesis as incubation with either toxin in the culture medium. Microinjection of nonpolymerizable ADP-ribosylated G-actin into hepatocyte-hepatoma hybrid cells specifically decreased the incorporation of [35S]methionine into newly synthesized actin within 1 h. This decrease continued for at least 19 h. Microinjection of ADP-ribosylated actin led to rounding of cells and obvious disaggregation of actin filaments, which might be due to capping of actin filaments by the ADP-ribosylated actin. Because stabilization of actin filaments by phalloidin before microinjection of ADP-ribosylated actin also resulted in decreased actin synthesis, the concentration of monomeric G-actin seems to be responsible for the regulation of actin synthesis in hepatocyte-hepatoma hybrid cells, which can be regarded as immortalized hepatocytes.
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PMID:Microinjection of ADP-ribosylated actin inhibits actin synthesis in hepatocyte-hepatoma hybrid cells. 892 Sep 89

Rhodostomin (RHO) from Agkistrodon rhodostoma venom, consisting of 68 amino acids with an arginine-glycine-aspartic acid (RGD) sequence and 12 cysteine residues, is a potent inhibitor of platelet aggregation. We previously demonstrated that cell culture plates coated with the bacterially produced fusion protein of glutathione S-transferase-RHO [GST-RHO(RGD)] can facilitate human hepatoma cell attachment via intergrin interaction within 15 min. In this study, we further characterized the effect of RHO fusion protein on platelet cells by creating two other related fusion proteins, GST-RHO(RGE) and GST-(PS)RHO. The former was a single amino acid-substituted mutant, in which the aspartic acid residue of RGD was replaced by glutamic acid, and the latter was an insertion mutant, in which a pentapeptide of protein kinase A phosphorylation site was inserted between GST and RHO. These two mutant proteins together with a wild-type of GST-RHO(RGD) and native form of RHO were used to study effects on the inhibition of ADP-induced platelet aggregation. Results indicated that GST-RHO(RGD) inhibited platelet aggregation as potently as the native RHO, while the two other mutants were inactive. Furthermore, when unactivated platelet cells attached on the GST-RHO(RGD)-coated plate, they became a flattened pancake shape. From the results of facilitation of cell attachment on fusion protein-coated plates, we concluded that: (1) the GST-RHO(RGD) fusion protein is equally functional in inhibition of platelet aggregation and facilitation of cell attachment, which is through the interaction of RGD and integrins on the cell membrane; (2) the GST-RHO(RGE) mutant protein is unable to bind with integrins and results in loss of function; (3) the insertion mutant of GST-(PS)RHO may disrupt a proper conformation of RHO and also results in loss of function; (4) the bacterially produced fusion protein GST-RHO(RGD) can be properly used as an antithrombotic agent and an extracellular matrix.
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PMID:Glutathione S-transferase-rhodostomin fusion protein inhibits platelet aggregation and induces platelet shape change. 908 May 76

Gamma-glutamyltranspeptidase (GGT), a plasma membrane-bound enzyme, provides the only activity capable to effect the hydrolysis of extracellular glutathione (GSH), thus favoring the cellular utilization of its constituent amino acids. Recent studies have shown however that in the presence of chelated iron prooxidant species can be originated during GGT-mediated metabolism of GSH, and that a process of lipid peroxidation can be started eventually in suitable lipid substrates. The present study was undertaken to verify if a GGT-dependent lipid peroxidation process can be induced in the lipids of biological membranes, including living cells, and if this effect can be sustained by the GGT highly expressed at the surface of HepG2 human hepatoma cells. In rat liver microsomes (chosen as model membrane lipid substrate) exposed to GSH and ADP-chelated iron, the addition of GGT caused a marked stimulation of lipid peroxidation, which was further enhanced by the addition of the GGT co-substrate glycyl-glycine. The same was observed in primary cultures of isolated rat hepatocytes, where the lipid peroxidation process did not induce acute toxic effects. GGT-stimulation of lipid peroxidation was dependent both on the concentration of GSH and of ADP-chelated iron. In GGT-rich HepG2 human hepatoma cells, the exposure to GSH, glycyl-glycine, and ADP-chelated iron resulted in a nontoxic lipid peroxidation process, which could be prevented by means of GGT inhibitors such as acivicin and the serine-boric acid complex. In addition, by co-incubation of HepG2 cells with rat liver microsomes, it was observed that the GGT owned by HepG2 cells can act extracellularly, as a stimulant on the GSH- and iron-dependent lipid peroxidation of microsomes. The data reported indicate that the lipid peroxidation of liver microsomes and of living cells can be stimulated by the GGT-mediated metabolism of GSH. Due to the well established interactions of lipid peroxidation products with cell proliferation, the phenomenon may bear particular significance in the carcinogenic process, where a relationship between the expression of GGT and tumor progression has been envisaged.
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PMID:gamma-Glutamyl transpeptidase-dependent lipid peroxidation in isolated hepatocytes and HepG2 hepatoma cells. 911 54

Basic fibroblast growth factor (FGF-2) appeared to be ADP-ribosylated on the surface of adult bovine aortic arch endothelial and human hepatoma cells. Further characterization of this reaction with cells expressing an arginine-specific, glycosylphosphatidylinositol-anchored, mono-ADP-ribosyltransferase demonstrated that FGF-2 is ADP-ribosylated on arginine. Incubation of transformed cells with FGF-2 and [adenylate-32P]nicotinamide-adenine dinucleotide (NAD) resulted in the rapid incorporation of [32P]ADP-ribose into FGF-2 in a time- and concentration-dependent manner, with labelling averaging 3 mol of ADP-ribose/mol of FGF-2. Excess ADP-ribose had no effect on these reactions, whereas excess NAD inhibited the ADP-ribosylation of FGF-2, consistent with an enzymic rather than a non-enzymic ADP-ribosylation reaction. Heparin also inhibited the ADP-ribosylation reaction, whereas a neutralizing polyclonal anti-peptide antibody had no effect. Furthermore, the addition of putative receptor binding domain peptide analogues of FGF-2 reduced the maximal ADP-ribosylation of FGF-2. These results identify the cell-surface ADP-ribosylation of FGF-2 as a potentially ubiquitous event.
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PMID:Cell-surface ADP-ribosylation of fibroblast growth factor-2 by an arginine-specific ADP-ribosyltransferase. 917 79

Alterations in the expression and activity of guanine nucleotide regulatory proteins (G proteins) have been linked to the growth of several human tumors. We hypothesized that the expression and activity of G proteins are altered in human hepatocellular carcinoma (HCC). The expression of Gi and Gs proteins was determined in six human tumors and six normal controls (adjacent nonneoplastic liver) by Western blotting using specific antisera raised against the alpha subunit of G proteins Gi1, Gi1-2, Gi3, and Gs. Differences in G-protein expression were quantified by densitometry and expressed as percentage change from normal controls. The expression of Gi alpha1 was significantly increased in 80% of tumors (Gi alpha1, 284% +/- 77%; P < .05 percent of normal tissue), whereas Gi alpha1-2 and Gi alpha3 expression was increased in 67% of tumors (Gi alpha1-2, 218% +/- 21%; Gi alpha3, 154% +/- 6%; P < .05 percent of normal tissue). The functional activity of Gi alpha proteins as determined by pertussis toxin-catalyzed adenosine diphosphate (ADP)-ribosylation was also significantly increased in these tumors. In contrast, Gs alpha-protein expression was significantly reduced in all tumors examined (74% +/- 8% of normal tissue, P < .05). The functional activity of Gs alpha, as determined by adenylyl cyclase (AC) activity, was significantly decreased in tumor as compared to normal liver under both basal and agonist stimulated (guanosine triphosphate gamma S and forskolin) conditions. In summary, these data show for the first time a significant alteration in G-protein expression and functional activity in human HCC tissue. These alterations indicate a down-regulation of the AC-linked enzyme effector system in HCC that may be of critical importance to the formation and progression of human hepatocellular carcinoma.
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PMID:Alterations in guanine nucleotide regulatory protein expression and activity in human hepatocellular carcinoma. 936 61

Guanine nucleotide regulatory proteins (G-proteins) play an important role in the onset and progression of malignancy. We hypothesized that alterations in inhibitory G-protein (Gi) expression and/or function may contribute to cellular invasion and formation of hepatocellular carcinoma (HCC). H4IIE hepatoma cells were inoculated directly into the liver parenchyma of ACI strain rats, and membranes were prepared from HCC livers and adjacent nonneoplastic livers 12 days following the initial inoculation. Expression of inhibitory Gialpha proteins was determined by Western blot analysis and changes in the functional activity of these proteins confirmed by pertussis toxin catalyzed ADP ribosylation and adenylyl cyclase activity. Inhibitory Gialpha1, Gialpha1/2, and Gialpha3 protein expression was significantly elevated in HCC when compared to adjacent nonneoplastic liver and sham-operated hepatic tissue. Pertussis toxin catalyzed ADP ribosylation of Gialpha substrates was significantly enhanced in HCC concomitant with increased basal and stimulated adenylyl cyclase activity following uncoupling of Gi-proteins with manganese ions. The role of Gi-proteins in cellular proliferation was confirmed using cultured H4IIE cells and normal hepatocytes. In quiescent H4IIE cells, mastoparan (Gialpha activator) increased [3H] thymidine incorporation and cell growth in a dose-dependent manner, whereas both pertussis toxin (a Gi-protein inhibitor) and 8-bromo-cAMP inhibited mitogenesis. In contrast, in isolated cultured hepatocytes, mastoparan inhibited [3H] thymidine incorporation, while pertussis toxin and 8-bromo-cAMP were mitogenic. We conclude that HCC is associated with marked changes in Gialpha-protein expression in vivo and in vitro, direct activation of which leads to increased mitogenesis in H4IIE cells in vitro.
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PMID:Altered expression of inhibitory guanine nucleotide regulatory proteins (Gi-proteins) in experimental hepatocellular carcinoma. 957 74

Expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene is induced by 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase. Synthesis of PEPCK mRNA is repressed by insulin, but remains detectable in H4IIE hepatoma cells exposed simultaneously to both 3-aminobenzamide and insulin. This capability of 3-aminobenzamide to block the inhibitory actions of insulin suggests that ADP-ribosylation is required for the regulation of PEPCK gene expression by insulin. Furthermore, neither changes in chromatin condensation nor cell growth status were linked to these events. The inability of 3,4-dihydro-5-methylisoquinolinone (PD128763), a selective inhibitor of poly(ADP-ribose) polymerase, to impede insulin-dependent repression of PEPCK gene expression, however, indicated that 3-aminobenzamide does not operate by inhibiting poly(ADP-ribosyl)ation. The potential involvement of mono(ADP-ribosyl)ation, a process that is also inhibited by 3-aminobenzamide, in the regulation of PEPCK gene activity was then evaluated. Analysis of poly(ADP-ribose) polymerase activity and poly(ADP-ribosyl)ation confirmed that there were no significant changes in response to insulin, while microsomal mono(ADP-ribosyl)transferase activity was elevated approximately fourfold. An increase in protein hydroxylamine-sensitive mono(ADP-ribosyl)ation was observed following insulin treatment. The sensitivity of the mono(ADP-ribosyl)transferase activity to 3-aminobenzamide but not PD128763 makes it plausible that mono(ADP-ribosyl)ation rather than poly(ADP-ribosyl)ation contributes to the regulation of PEPCK gene expression.
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PMID:Repression of phosphoenolpyruvate carboxykinase gene activity by insulin is blocked by 3-aminobenzamide but not by PD128763, a selective inhibitor of poly(ADP-ribose) polymerase. 957 65

The effects of extracellular ATP and other nucleotides on the cytosolic free Ca2+ concentration ([Ca2+]i) have been studied in single primary human hepatocytes and in human Hep G2 and HuH-7 hepatoma cells. ATP, adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS), and UTP caused a concentration-dependent biphasic increase in [Ca2+]i with an initial peak followed by a small sustained plateau in most cells. In some cells, however, repetitive Ca2+ transients were observed. The rank order of potency was ATP >/= UTP > ATPgammaS, and complete cross-desensitization of the Ca2+ responses occurred between ATP and UTP. The initial transient peak in [Ca2+]i was resistant to extracellular Ca2+ depletion, which demonstrates mobilization of internal Ca2+ by inositol 1,4,5-trisphosphate whose formation was enhanced by ATP and UTP. In contrast, the sustained plateau phase required influx of external Ca2+. Ca2+ influx occurs most likely through a capacitative Ca2+ entry mechanism, which was shown to exist in these cells by experiments performed with thapsigargin. On the molecular level, specific mRNA coding for the human P2Y1, P2Y2, P2Y4, and P2Y6 receptors could be detected by RT-PCR in Hep G2 and HuH-7 cells. However, ADP and UDP, which are agonists for P2Y1 and P2Y6 receptors, respectively, caused no changes in [Ca2+]i, demonstrating that these receptors are not expressed at a functional level. Likewise, alpha,beta-methylene-ATP, beta,gamma-methylene-ATP, AMP, and adenosine were inactive in elevating [Ca2+]i, suggesting that the ATP-induced increase in [Ca2+]i was not caused by activation of P2X or P1 receptors. Thus, on the basis of the pharmacological profile of the nucleotide-induced Ca2+-responses, extracellular ATP and UTP increase [Ca2+]i by activating P2Y2 and possibly P2Y4 receptors coupled to the Ca2+-phosphatidylinositol signaling cascade in human hepatocytes. This suggests that extracellular nucleotides from various sources may contribute to the regulation of human liver cell functions.
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PMID:Regulation of cytosolic free calcium concentration by extracellular nucleotides in human hepatocytes. 988 92


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