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)

Alpha-fetoprotein (AFP) is a 590 amino acid polypeptide that was initially defined as an embryonal serum globulin. The yolk sac endoderm, fetal liver and fetal gut were shown to be the main sites of AFP synthesis in the embryo (Gitlin and Boesman, J. Clin. Invest. 46: 1010-1016, 1967). AFP synthesis is still continued in human adults (Ruoslahti and Seppala, Int. J. Cancer 8: 374-383, 1971) although the physiological level of serum AFP is lower than 10 ng/ml. AFP was also demonstrated in certain tumors and in various diseases or conditions such as yolk sac tumor, hepatoma, hepatoblastoma, acute and chronic liver cirrhosis, pregnancy and so on (Abelev, Adv. Cancer Res. 14: 295-358, 1971; Ruoslahti and Seppala, Cancer Res. 29: 275-346, 1979). Salivary glands have not been implicated in AFP synthesis. We investigated the expression of AFP in normal human salivary glands by immunohistochemistry with a monoclonal antibody against AFP, and documented immunoreactivity in intercalated and striated ducts of adult human submandibular glands.
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PMID:Production of alpha-fetoprotein by human submandibular gland. 750 51

The mouse alpha-fetoprotein (AFP) gene is transcribed at high levels in the visceral endoderm of the yolk sac and fetal liver and at much lower rates in the endoderm of the fetal gut. Expression of the gene in vivo requires the presence of at least one of three enhancers which lie in its 5' flanking region. In this report, we establish that the most distal AFP enhancer directed consistent expression of a linked AFP minigene in all three endodermal tissues in transgenic mice. The enhancer is composed of three domains, each of which is essential for full enhancer function by transient transfection assays. DNase I footprinting identified three regions of the enhancer which are protected by human hepatoma nuclear extracts, one of which corresponded to a consensus site for HNF-3 binding. Site-directed mutations in this site caused a 10-fold reduction in enhancer function by transient transfection. In transgenic mice, however, the mutation resulted in sporadic expression of the transgene, dependent on the site of integration. A similar acquisition of position-dependent sporadic expression of the transgene was observed with a mutation in a second protein binding site, despite the fact that this mutation had very little effect on enhancer function as assessed by transient transfection. These studies underscore the value of examining the functions of specific protein binding sites in vivo.
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PMID:Molecular analysis of the distal enhancer of the mouse alpha-fetoprotein gene. 754 Jul 20

Supplemental glutamine prevents gut atrophy and enhances muscle protein synthesis in septic rats. This study investigated the effect of glutamine administration and mitomycin C treatment on protein turnover in tumor-bearing rats. AH109A rat ascites hepatoma cells (2 x 10(6)) were subcutaneously implanted in the back of male Donryu rats (n = 32, body weight 150-200 g) on Day 0. The animals were then fed rat chow ad libitum for 10 days. On Day 10, the rats were catheterized for TPN and randomized into four groups according to diet and treatment. The groups were: (i) standard total parenteral nutrition (STPN) + saline; (ii) glutamine-supplemented TPN (GTPN) + saline; (iii) STPN+mitomycin C (MMC); (iv) GTPN+MMC. GTPN was isocaloric (250 kcal/kg/day) and isonitrogenous (1.5 gN/kg/day) with STPN. The animals were maintained on TPN for 5 days and received mitomycin C (0.5 mg/kg) via the catheter every day. On the fifth day of TPN, [1-14C]leucine was given via a 5-hr continuous infusion (2.0 microCi/hr/rat) to determine the fractional synthesis rate of muscle, gut mucosa, liver, and tumor. Also, endogenous leucine production (not equal to whole body protein breakdown rate) was calculated. Body weight loss during TPN was reduced with GTPN. GTPN enhanced muscle FSR in untreated animals (STPN: 10.8 +/- 8.7%/day vs GTPN: 14.7 +/- 0.6%/day, P < 0.05) and in mitomycin C-treated animals (STPN+MMC: 9.6 +/- 0.9%/day, GTPN+MMC: 12.0 +/- 0.8%/day, P < 0.05). The whole body protein breakdown rate was reduced with GTPN. Mitomycin C reduced the mucosal fractional synthesis rate and GTPN did not prevent this reduction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of glutamine and chemotherapy on protein metabolism in tumor-bearing rats. 804 Nov 29

Although essential for life, iron in excessive amounts may be toxic. The liver is particularly subject to the toxic effects of iron, since it is the major site of iron storage. Several inherited and acquired human disorders may result in hepatic iron overload, the most common of which are genetic hemochromatosis (GH) and transfusional iron overload. GH is an inherited disorder of iron metabolism, and in patients with GH excess iron absorbed from the gut is transported through the portal vein to the liver. The mechanisms by which excess iron exerts its cytotoxic effects include enhanced formation of free radicals and peroxidation of organelle membrane lipids. Lipid peroxidation can lead to structural and functional alterations in lysosomes, mitochondria and the endoplasmic reticulum. With massive iron overload, such iron-induced alterations may cause cell death, also known as sideronecrosis. At this stage, fibrogenesis is initiated and, if the excess iron is not removed, the increased deposition of collagen progresses to cirrhosis. However, the mechanisms underlying iron-induced fibrosis remain unclear. Transformation of fat-storing cells to collagen-producing myofibroblasts has been proposed to be induced either by iron; by lipid peroxides or other cellular factors released from iron-loaded, damaged hepatocytes; or by profibrogenic factors produced by activated Kupffer cells. In addition, iron may enhance the cytotoxic and, possibly, fibrogenic effects of other liver cell-damaging agents, such as alcohol or hepatotrophic viruses. Once cirrhosis is manifest, patients with GH demonstrate a 200-fold increase in the risk for development of hepatocellular carcinoma. In vitro, iron has been shown to possess mutagenic properties, but the results from in vivo models in which the genotoxic effects of iron overload have been studied are variable. Similarly, although iron has mitostimulatory effects on hepatocytes in vivo and preneoplastic cells in vitro, its role in tumor promotion and/or progression still remains unclear. Cirrhosis itself is of central importance in the carcinogenic process, but whether or not iron acts as an additional risk factor in this process, alone or by enhancing the tumorigenic properties of other hepatocarcinogens, has yet to be established.
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PMID:Iron as a hepatotoxin. 852 7

Since the amounts of hepatogenous enzymes discharged into the intestinal tract remain unknown, this study was initiated to evaluate the amounts of the enzymes in the intestinal tract. Whole gut lavage fluid (polyethyleneglycol electrolyte solution) was administered orally to 42 subjects, consisting of 5 patients with hepatoma, 10 with chronic hepatitis, 10 with colon polyps, and 17 control subjects without liver disease. Two hr after the large intestinal lavage, the digestive tract juice was aspirated by colonoscopy, and the bilirubin (Bil), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) in the aspirates were measured. A positive correlation between the AST and LDH values was found, and a significant difference in these values between the hepatic disorders and the normal controls was noticed. A significant positive correlation between the ALP and Bil values was found, and a statistical difference in these values between the group of colon polyps and the controls and other groups was observed. This lavage fluid technique enables to estimate the amounts of hepatic enzymes discharged into the intestinal tract, thereby opening a new avenue for future enzyme research.
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PMID:Enzymes in intestinal juice from patients with liver diseases and colon polyps: measurement of bilirubin, alkaline phosphatase, aspartate aminotransferase and lactate dehydrogenase. 872 97

The gut and liver share a common embryological origin. The gene encoding the gut hormone neurotensin/neuromedin N (NT/N) is expressed in the adult small bowel, and NT/N is transiently expressed in the fetal liver, suppressed in the adult liver, and reexpressed in certain liver cancers. In our present study, we found that the NT/N gene was expressed at high levels in the human hepatoma cell line Hep 3B but was not expressed in Hep G2 cells. To further determine the mechanisms regulating NT/N expression, we performed Southern blotting and gene cloning techniques. Neither alteration nor mutation of the NT/N gene was responsible for this differential NT/N expression pattern. Human NT/N promoter constructs were transfected into either Hep 3B or Hep G2. Both cell lines supported NT/N transcription, indicating that the absence of NT/N expression in Hep G2 cells was due to mechanisms other than the absence of positive transcription factors. The role of DNA methylation was next assessed. Methylation of NT/N promoter constructs in vitro resulted in a 67-fold reduction in promoter activity, whereas treatment with the demethylating agent 5-azacytidine induced NT/N expression in Hep G2 cells, thus suggesting that DNA methylation plays a role in the expression of the gut endocrine gene NT/N. Defining the mechanisms regulating NT/N expression in these hepatic-derived cell lines will provide not only a better understanding of cell-specific and developmental regulation of a gut endocrine gene but also possible insight into liver cell lineage patterns and the derivation of certain hepatocellular cancers.
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PMID:DNA methylation contributes to expression of the human neurotensin/neuromedin N gene. 953 Jan 55

Genetic hemochromatosis is an autosomal recessive disorder characterized by excessive iron absorption from the gut, resulting in increased total body iron stores, multisystem organ dysfunction, and an increased risk of hepatocellular carcinoma. The magnetic susceptibility effects of excess hepatocellular iron generally cause diffuse hepatic signal loss on T2- or T2*-weighted MR images. Although hepatic iron deposition is usually diffuse, focal areas of iron sparing can occur, and, when present, superimposed neoplasm is a consideration. We describe a patient with cirrhosis, hemochromatosis, and multiple small benign relatively hyperintense iron-poor foci consisting of piecemeal sideronecrosis.
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PMID:Ferumoxide-enhanced MRI of sideronecrosis superimposed on genetic hemochromatosis. 1005 Aug 15

Bacterial constituents and products of the bacterial metabolism pass from the gut lumen to the portal vein and may influence the homeostasis of the liver. Our aim is to examine whether DNA synthesis of human hepatocyte cell lines is affected by constituents of Escherichia coli species as well as by intracolonic products of bacterial fermentation that reach the liver via the portal vein. Supernatant solutions and bacterial cell fractions (containing either whole dead bacteria, cell walls, cytosol or non-soluble intracellular components) of E. coli K12 and of E. coli species from rat fecal flora were separated by multi-step centrifugation, French press, and microfiltration. The supernatant solution and the cell fractions were incubated with a human hepatoma cell line (Hep-G2) and with a cell line derived from non-malignant human liver cells (Chang cells) for 24 h. The cells were labeled with tritiated thymidine before processing to autoradiography. DNA synthesis was estimated by the labeling index (LI%). DNA synthesis was also estimated following incubation of Hep-G2 cells with short chain fatty acids (acetic, propionic, butyric and succinic acid), acetaldehyde, and ammonium chloride. Epidermal growth factor and a water extract of Helicobacter pylori were used as references. The fractions of E. coli from rat fecal flora containing cytosol and non-soluble intracellular components significantly increased the labeling index in both Hep-G2 and Chang cells (p < 0.05). In addition, the supernatant solution significantly increased the LI in Chang cells (p < 0.05). Epidermal growth factor increased the LI of Hep-G2 cells dose-dependently (p < 0.05). Butyric acid reduced DNA synthesis at 10(-4) M (p < 0.05). The highest doses of acetaldehyde were cytotoxic and reduced the LI. Escherichia coli species contain mitogenic factors to human hepatocytes. The mitogen(s) are present in the supernatant solution, in the cytosol and in non-soluble intracellular components. Butyrate, which is a product of bacterial fermentation of colonic substrates inhibit DNA synthesis in the hepatocyte cell lines. Our findings suggest that soluble mitogen(s) that diffuse from the microorganism to the outer environment, intracellular bacterial constituents, and products of the bacterial metabolism that reach the liver via the portal vein may influence the cell kinetic steady-state of hepatic cells.
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PMID:Butyrate inhibits and Escherichia coli-derived mitogen(s) stimulate DNA synthesis in human hepatocytes in vitro. 1023 92

Watercress is an exceptionally rich dietary source of beta-phenylethyl isothiocyanate (PEITC). This compound inhibits phase I enzymes, which are responsible for the activation of many carcinogens in animals, and induces phase II enzymes, which are associated with enhanced excretion of carcinogens. In this study, we show that watercress extracts are potent inducers of quinone reductase (QR) in murine hepatoma Hepa 1c1c7 cells, a widely adopted assay for measuring phase II enzyme induction. However, contrary to expectations, this induction was not associated with PEITC (which is rapidly lost to the atmosphere upon tissue disruption due to its volatility) or a naturally occurring PEITC-glutathione conjugate, but with 7-methylsulfinyheptyl and 8-methylsulfinyloctyl isothiocyanates (ITCs). While it was confirmed that PEITC does induce QR (5 microM required for a two-fold induction in QR), 7-methylsulfinyheptyl and 8-methylsulfinyloctyl ITCs were more potent inducers (0.2 microM and 0.5 microM, respectively, required for a two-fold induction in QR). Thus, while watercress contains three times more phenylethyl glucosinolate than methylsulfinylalkyl glucosinolates, ITCs derived from methylsulfinylalkyl glucosinolates may be more important phase II enzyme inducers than PEITC, having 10 - to 25-fold greater potency. Analysis of urine by liquid chromatography-mass spectroscopy (LC-MS) following consumption of watercress demonstrated the presence of N:-acetylcysteine conjugates of 7-methylsulfinylheptyl, 8-methylsulfinyloctyl ITCs and PEITC, indicating that these ITCs are taken up by the gut and metabolized in the body. Watercress may have exceptionally good anticarcinogenic potential, as it combines a potent inhibitor of phase I enzymes (PEITC) with at least three inducers of phase II enzymes (PEITC, 7-methylsulfinylheptyl ITC and 8-methylsulfinyloctyl ITC). The study also demonstrates the application of LC-MS for the detection of complex glucosinolate-derived metabolites in plant extracts and urine.
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PMID:7-Methylsulfinylheptyl and 8-methylsulfinyloctyl isothiocyanates from watercress are potent inducers of phase II enzymes. 1106 58

Hepatoma derived growth factor (HDGF) was identified as a developmentally regulated cardiac gene by mRNA differential display using 12-day rat fetal conotruncus vs. newborn aorta. The full-length rat HDGF cDNA was cloned from a rat fetal heart cDNA library and found to be 94 and 88% homologous to the mouse and human sequence, respectively. The rat sequence, like the human and mouse, contains a highly conserved amino portion and putative bipartite nuclear localization sequence. By Northern analysis, HDGF is highly expressed in the fetal conotruncus, heart, kidney, brain, and gut. By immunocytochemistry, HDGF was first detected only in atrial myocytes, hind gut epithelia, and notochord of the E10 rat with a nuclear expression pattern. By E12, expression had broadened to include the ventricular myocytes, endocardial cells, and cells of the ventricular outflow tract. HDGF is unique in that it is the first described nuclear targeted growth factor in the developing heart. The early expression of HDGF in embryonic heart and fetal gut suggests that HDGF may play a role in cardiovascular growth and differentiation.
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PMID:Identification, cloning, and developmental expression of hepatoma-derived growth factor in the developing rat heart. 1174 79


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