Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Experimentally induced liver tumors in mice harbor activating mutations in either Catnb (beta-catenin) or Ha-ras, according to the carcinogenic treatment. We have now investigated by microarray analysis the gene expression profiles in tumors of the two genotypes. In total, 364 genes or expressed sequences with aberrant expression relative to normal liver were identified, but only 30 of these demonstrated unidirectional changes in both tumor types. Several functional clusters were identified that involve changes in amino acid utilization and ammonia disposition in Catnb-mutated tumors as opposed to alterations in lipid and cholesterol metabolism in Ha-ras-mutated tumors. Moreover, several genes coding for inhibitory molecules within the Wnt-signaling pathway were upregulated in Catnb-mutated tumors, suggesting induction of a negative feedback loop, whereas Ha-ras-mutated tumors showed alterations in the expression of several genes functional in monomeric G-protein signaling. We conclude that mouse hepatoma cells adopt different evolutionary strategies that allow for their selective outgrowth under variable environmental conditions. Human hepatocellular cancers (HCC) lack RAS mutations but are frequently mutated in CTNNB1, the human Catnb ortholog. The set of genes aberrantly expressed in Catnb-mutated mouse tumors was used to screen, by expression profiling, for dysregulation of orthologous genes within a panel of 25 HCCs, of which 10 were CTNNB1-mutated. HCCs with activated beta-catenin displayed a gene expression profile that was similar to Catnb-mutated mouse tumors but distinct from the other human HCCs. In conclusion, expression fingerprints may be used for diagnostic purposes and potential new therapeutic intervention strategies. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index/html).
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PMID:Genotype-phenotype relationships in hepatocellular tumors from mice and man. 1596 25

(NH3)2Pt(triacid) and (PPh3)2Pt(dehydrocholate)2 are novel bile acid-conjugated platinum complexes administered by oral route. The aims of the present study were to evaluate their in vitro cytotoxic activities on rat hepatoma cell line N1-S1, the in vivo antitumour effects in a syngeneic and orthotopic rat hepatoma model and the drug-related toxicities. Cisplatin, carboplatin and mitoxantrone were used as control drugs. In vitro experiments showed a concentration- and time-dependent antiproliferative activity of bile-conjugated platinum complexes. (NH3)2Pt(triacid) had similar effects on cell growth of cisplatin and carboplatin (e.g. at 48 h, IC50 0.7+/-0.05 microM vs. 0.63+/-0.28 microM and 1.1+/-0.3 microM, respectively; mean+/-S.D.). (NH3)2Pt(triacid) was able to inhibit tumour growth in a dose-dependent extent, reaching the maximum inhibitory effect at the 80 mg/kg dose (1.95+/-0.5 g vs. 13.85+/-3.9 g of control tumour weight). By contrast, despite the promising in vitro antiproliferative activity, (PPh3)2Pt(dehydrocholate)2 showed no significant in vivo antitumour effect. The toxicity profile of (NH3)2Pt(triacid) resulted favourable with minimal loss of weight and no gastrointestinal or neurological symptoms. Instead, (PPh3)2Pt(dehydrocholate)2 showed dose-dependent signs of severe weight loss and neurological alterations. In conclusion (NH3)2Pt(triacid) is a tolerable and active platinum derivative endowed by a preclinical antitumour activity by oral route.
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PMID:In vitro and in vivo antitumour effects of novel, orally active bile acid-conjugated platinum complexes on rat hepatoma. 1697 99

Citrullinemia is a metabolic disorder characterized by elevated plasma concentrations of citrulline and ammonia. Adult-onset citrullinemia (type II, CTLN2) has been attributed to citrin deficiency caused by mutations in the SLC25A13 gene. CTLN2 is associated with a high incidence of hepatocellular carcinoma (HCC) in Japanese. We report a 48-year-old Taiwanese man with citrullinemia, who was in good health until the age of 34 when he had repeated episodes of consciousness disturbance. Hyperammonia (201 micromol/L) was found during an episode of coma. Liver function and electrolyte levels were normal at that time. Serologic markers of viral hepatitis B and C were negative. Analysis of genomic DNA extracted from peripheral blood leukocytes showed homozygous 851del4 mutation in exon 9 of the SLC25A13 gene on chromosome 7q21.3. Fourteen years after disease onset, at the age of 48, he was admitted due to an episode of coma. Abdominal sonography and computed tomography showed a 2.5 cm tumor in the left lobe of the liver, without evidence of liver cirrhosis. Wedge resection of the tumor was performed and grade 2 HCC was diagnosed. The nontumor part of the resected specimen showed chronic persistent hepatitis with moderate steatosis. The results in this case support that both citrin deficiency and steatohepatitis may contribute to hepatocarcinogenesis.
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PMID:Homozygous SLC25A13 mutation in a Taiwanese patient with adult-onset citrullinemia complicated with steatosis and hepatocellular carcinoma. 1700 Apr 60

Hepatic encephalopathy (HE) is a broad spectrum of neuropsychiatric manifestations usually affecting individuals with end-stage liver disease. The presence of HE is a poor prognostic sign, with 1-year mortality rates of almost 60%. There is much debate about the underlying mechanisms that result in this syndrome; however, elevated plasma and central nervous system ammonia levels are considered key factors in its pathogenesis. Initial evaluation of the patient presenting with overt HE should include a careful search for predisposing factors, including underlying infection, gastrointestinal (GI) bleeding, electrolyte disturbances, hepatocellular carcinoma, dehydration, hypotension, and excessive use of benzodiazepines, psychoactive drugs, or alcohol. The mainstay of treatment for many years has been nonabsorbable disaccharides, particularly lactulose. Alternative treatments, which usually are second line in patients who do not respond to lactulose, include zinc, antibiotics (neomycin, metronidazole, and rifaximin), ornithine aspartate, sodium benzoate, probiotics, and surgical intervention. Accepted treatments for HE are associated with significant unpleasant side effects, including diarrhea, renal failure, neuropathy, and other GI disturbance. Newer therapies are still in development, and most are awaiting human trials in order to confirm their benefit. These include manganese chelators, L-carnitine, N-methyl-d-aspartate receptor antagonists, blood purification dialysis system, and an intravenous combination of sodium benzoate and phenylacetate.
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PMID:Hepatic encephalopathy: a review of its pathophysiology and treatment. 1708 80

Glutamine is the most abundant amino acid in the human body and can be synthesized by almost all tissues by the glutamine synthetase (GS)-catalyzed amidation of glutamate. Hepatocytes have access to extracellular glutamine by the concentrative uptake via members of the sodium-dependent neutral amino acid transport systems N and A. Hepatic glutamine metabolism in connection with urea synthesis is importantly involved in systemic ammonia detoxication and pH regulation due to the unique regulatory properties of the liver-type glutaminase, the acinar compartimentation of urea and glutamine synthesis, and a cycling of glutamine between periportal and perivenous hepatocytes. Upregulation of GS expression in hepatocellular carcinoma is related to growth advantage and an enhanced metastatic potential. Glutamine is a potent activator of signal transduction. Recent progress concerns the understanding of glutamine-induced hepatocyte swelling and the downstream activation of integrins, Src, and MAP-kinases in the regulation of autophagic proteolysis, canalicular bile acid excretion, glycogen and fatty acid synthesis, insulin signaling, and protection from apoptosis. Most recently the first primary GS defect leading to inherited glutamine deficiency with fatal outcome was described in human. This review summarizes recent progress in the understanding of glutamine metabolism and signal transduction, which provides further rationale for the use of glutamine as a therapeutic tool.
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PMID:Glutamine metabolism and signaling in the liver. 1712 5

Carbamoylphosphate synthetase-I is the flux-determining enzyme of the ornithine cycle, and neutralizes toxic ammonia by converting it to urea. An 80 bp glucocorticoid response unit located 6.3 kb upstream of the transcription start site mediates hormone responsiveness and liver-specific expression of carbamoylphosphate synthetase-I. The glucocorticoid response unit consists of response elements for the glucocorticoid receptor, forkhead box A, CCAAT/enhancer-binding protein, and an unidentified protein. With only four transcription factor response elements, the carbamoylphosphate synthetase-I glucocorticoid response unit is a relatively simple unit. The relationship between carbamoylphosphate synthetase-I expression and in vivo occupancy of the response elements was examined by comparing a carbamoylphosphate synthetase-I-expressing hepatoma cell line with a carbamoylphosphate synthetase-I-negative fibroblast cell line. DNaseI hypersensitivity assays revealed an open chromatin configuration of the carbamoylphosphate synthetase-I enhancer in hepatoma cells only. In vivo footprinting assays showed that the accessory transcription factors of the glucocorticoid response unit bound to their response elements in carbamoylphosphate synthetase-I-positive cells, irrespective of whether carbamoylphosphate synthetase-I expression was induced with hormones. In contrast, the binding of glucocorticoid receptor to the carbamoylphosphate synthetase-I glucocorticoid response unit was dependent on treatment of the cells with glucocorticoids. Only forkhead box A was exclusively present in hepatoma cells, and therefore appears to be an important determinant of the observed tissue specificity of carbamoylphosphate synthetase-I expression. As the glucocorticoid receptor is the only DNA-binding protein specifically recruited to the glucocorticoid response unit upon stimulation by glucocorticoids, it is likely to be directly responsible for the transcriptional activation mediated by the glucocorticoid response unit.
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PMID:Hepatocyte-specific interplay of transcription factors at the far-upstream enhancer of the carbamoylphosphate synthetase gene upon glucocorticoid induction. 1714 Apr 18

Adult-onset citrullinemia (CTLN2) is a rare hereditary metabolic disorder characterized by highly increased concentration of citrulline and ammonia in the plasma, which is ascribed to a deficiency of argininosuccinate synthetase (ASS), one of the urea cycle enzymes mainly located in the liver. Neurological manifestation in CTLN2 patients closely resemble those of hepatic encephalopathy and in the past, most patients usually followed rapidly deteriorating clinical courses and died of severe brain edema within a few years after onset. However, in 1995 the first CTLN2 patient who was successfully treated by living-related liver transplantation was reported and since then more than 30 patients had underwent this operation in our country, showing good outcomes. No primary defect had not been found within ASS gene locus, but the causative gene of this disorder is now identified as the "citrin gene", which might act as a aspartate/glutamate transporter in mitochondria. Different phenotypes are seen in the individuals with a citrin deficiency: neonatal intrahepatic cholestasis, juvenile-onset chronic pancreatitis and hepatocellular carcinoma without cirrhosis can precede the appearance of CTLN2. The precise pathogenesis of this disease that includes the relationship between the mutations of citrin gene and a deficiency of hepatic ASS activity remains unclear.
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PMID:[Adult-onset citrullinemia]. 1722 80

Adult-onset citrullinemia (CTLN2) is a rare hereditary metabolic disorder characterized by highly increased concentration of citrulline and ammonia in the plasma, which is ascribed to a deficiency of argininosuccinate synthetase (ASS), one of the urea cycle enzymes mainly located in the liver. Neurological manifestation in CTLN2 patients closely resemble those of hepatic encephalopathy and in the past, most patients usually followed rapidly deteriorating clinical courses and died of severe brain edema within a few years after onset. However, in 1995 the first CTLN2 patient who was successfully treated by living-related liver transplantation was reported and since then more than 30 patients had underwent this operation in our country, showing good outcomes. No primary defect had not been found within ASS gene locus, but the causative gene of this disorder is now identified as the "citrin gene", which might act as a aspartate/glutamate transporter in mitochondria. Different phenotypes are seen in the individuals with a citrin deficiency: neonatal intrahepatic cholestasis, juvenile-onset chronic pancreatitis and hepatocellular carcinoma without cirrhosis can precede the appearance of CTLN2. The precise pathogenesis of this disease that includes the relationship between the mutations of citrin gene and a deficiency of hepatic ASS activity remains unclear.
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PMID:[Adult-onset citrullinemia]. 1735 80

Extrahepatic bioartificial liver devices should provide an intact urea cycle to detoxify ammonia. The C3A cell line, a subclone of the hepatoma-derived HepG2 cell line, is currently used in this context as it produces urea, and this has been assumed to be reflective of ammonia detoxification via a functional urea cycle. However, based on our previous findings of perturbed urea-cycle function in the non-urea producing HepG2 cell line, we hypothesized that the urea produced by C3A cells was via a urea cycle-independent mechanism, namely, due to arginase II activity, and therefore would not detoxify ammonia. Urea was quantified using (15)N-ammonium chloride metabolic labelling with gas chromatography-mass spectrometry. Gene expression was determined by real-time reverse transcriptase-PCR, protein expression by western blotting, and functional activities with radiolabelling enzyme assays. Arginase inhibition studies used N(omega)-hydroxy-nor-L-arginine. Urea was detected in C3A conditioned medium; however, (15)N-ammonium chloride-labelling indicated that (15)N-ammonia was not incorporated into (15)N-labelled urea. Further, gene expression of two urea cycle genes, ornithine transcarbamylase and arginase I, were completely absent. In contrast, arginase II mRNA and protein was expressed at high levels in C3A cells and was inhibited by N(omega)-hydroxy-nor-L-arginine, which prevented urea production, thereby indicating a urea cycle-independent pathway. The urea cycle is non-functional in C3A cells, and their urea production is solely due to the presence of arginase II, which therefore cannot provide ammonia detoxification in a bioartificial liver system. This emphasizes the continued requirement for developing a component capable of a full repertoire of liver function.
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PMID:Cells for bioartificial liver devices: the human hepatoma-derived cell line C3A produces urea but does not detoxify ammonia. 1768 Jun 61

It is well known that it would be important to cultivate human hepatocytes of about 10(10) cells at a high cell density, about 1 x 10(7) cells/cm(3), in the bioreactor for the development of bioartificial liver. However, since primary human hepatocytes lack an ability to proliferate in vitro, it is essential to establish a culture method for the proliferation of normal human hepatic stem cells as a cell source. In this study, it was found that human hepatoblasts, a kind of hepatic stem cells, were induced from human fetal hepatocytes while keeping the ability of proliferation by the treatment of 1mM sodium butyrate (SB) for 12 d of culture. The transformation of hepatoblasts was evaluated by abnormal prothrombin (PIVKA-II) assay, which is a clinical marker for hepatocellular carcinoma. The PIVKA-II production rate of the cells was suppressed to the normal level under 1 mM SB. The cells including hepatoblasts under 1 mM SB attached to the porous hydroxyapatite carriers and proliferated to a high cell density of about 1 x 10(7) cells/cm(3) in the carriers. The liver-specific function, cytochrome P450 3A4 activity (4.2 pmol/mg protein/min) of the cells in the carriers under 1 mM SB was comparable to that of primary human hepatocytes. Ammonia metabolizing activity (0.21 micromol/10(6) cells/h) of the cells was also comparable to that of porcine hepatocytes used in the bioartificial liver. The PIVKA-II production rate of the cells in the carrier was suppressed to the normal level. These results suggested that induction of human hepatoblasts from fetal hepatocytes by the treatment of 1mM SB and proliferation of the cells at a high cell density using hydroxyapatite carriers should be one of the more promising culture methods for bioartificial liver developments.
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PMID:Induction and high density culture of human hepatoblasts from fetal hepatocytes with suppressing transformation. 1805 17


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