Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C Virus (HCV) is associated with a severe liver disease and increased frequency in the development of hepatocellular carcinoma. Overexpression of HCV core protein is known to transform fibroblast cells. Phospholipase D (PLD) activity is commonly elevated in response to mitogenic signals, and has also been overexpressed and hyperactivated in some human cancer cells. The aim of this study was to understand how PLD was regulated in the HCV core protein-transformed NIH3T3 mouse fibroblast cells. We observed that PLD activity was elevated in the NIH3T3 cells overexpressing HCV core protein over the vector alone-transfected control cells, however, expression levels of PLD protein and protein kinase C (PKC) in the HCV core protein-transformed cells was similar to the control cells. Phorbol 12-myristate 13-acetate (PMA), which is known to activate PKC, stimulated PLD activity significantly more in the core protein-transformed cells, in comparison with that of the control cells. PLD activity assay using PKC isozyme-specific inhibitor and PKC translocation experiment showed that PKC-delta was mainly involved in the PMA- induced PLD activation in the core-transformed cells. Moreover, in cells overexpressing HCV core protein, PMA also stimulated p38 kinase more potently than that of the control cells, and an inhibitor of p38 kinase abolished PMA-induced PLD activation in cells overexpressing HCV core protein. Taken together, these results suggest that PLD might be implicated in core protein-induced transformation.
Exp Mol Med 2004 Oct 31
PMID:Phospholipase D activity is elevated in hepatitis C virus core protein-transformed NIH3T3 mouse fibroblast cells. 1555 17

Lentiviral vectors can stably transduce dividing and nondividing cells in vivo and are best suited to long-term correction of inherited liver diseases. Intraportal administration of lentiviral vectors expressing green fluorescent protein (Lenti-GFP) in mice resulted in a higher transduction of nonparenchymal cells than hepatocytes (7.32 +/- 3.66% vs 0.22 +/- 0.08%, respectively). Therefore, various treatments were explored to increase lentiviral transduction of hepatocytes. Lenti-GFP was injected into the common bile duct, which led to transduction of biliary epithelium and hepatocytes at low efficiency. Transient removal of the sinusoidal endothelial cell layer by cyclophosphamide to increase accessibility to hepatocytes did not improve hepatocyte transduction (0.42 +/- 0.36%). Inhibition of Kupffer cell function by gadolinium chloride led to a significant decrease in GFP-positive nonparenchymal cells (2.15 +/- 3.14%) and a sevenfold increase in GFP-positive hepatocytes compared to nonpretreated mice (1.48 +/- 2.01%). These findings suggest that sinusoidal endothelial cells do not significantly limit lentiviral transduction of hepatocytes, while Kupffer cells sequester lentiviral particles thereby preventing hepatocyte transduction. Therefore, the use of agents that inhibit Kupffer cell function may be important for lentiviral vector treatment of liver disease.
Mol Ther 2005 Jan
PMID:Kupffer cells and not liver sinusoidal endothelial cells prevent lentiviral transduction of hepatocytes. 1558 3

Autosomal-dominant polycystic liver disease (PCLD) is a rare disorder that is characterized by the progressive development of fluid-filled biliary epithelial cysts in the liver. Positional cloning has identified two genes that are mutated in patients with polycystic liver disease, PRKCSH and SEC63, which encode the beta-subunit of glucosidase II and Sec63, respectively. Both proteins are components of the molecular machinery involved in the translocation, folding and quality control of newly synthesized glycoproteins in the endoplasmic reticulum. Most mutations are truncating and probably lead to a complete loss of the corresponding proteins and the defective processing of a key regulator of biliary cell growth. The finding that PCLD is caused by proteins involved in oligosaccharide processing was unexpected and implicates a new avenue for research into neocystogenesis, and might ultimately result in the identification of novel therapeutic drugs.
Trends Mol Med 2005 Jan
PMID:Polycystic liver disease is a disorder of cotranslational protein processing. 1564 21

Hepatitis C virus (HCV) is a major causative agent in liver disease. In order to investigate if Korean type HCV core protein and its related mutants, S99Q and S1161, are cytopathic to liver, three types of transgenic mice were established. The expression of transgenes was confirmed by HCV specific RT-PCR and Western immunoblotting. The livers of all wild type core and S1161 transgenic lineages remained largely histologically normal. However, the livers of the S99Q transgenic mice showed significant high level of cell dysplasia associated with the transgene expression in hepatocytes largely located around the central veins by in situ hybridization analysis. In conclusion, the mutant HCV core protein at S99Q may contribute to the progress of HCV induced liver disease.
Exp Mol Med 2004 Dec 31
PMID:Transgenic expression of Korean type hepatitis C virus core protein and related mutants in mice. 1567 43

We analyzed lipids in liver diseases by agarose gel electrophoresis, and differential staining and simultaneous analysis of the cholesterol (Chol) and triglyceride (TG) fractions. Liver diseases were classified into chronic hepatitis (CH), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and metastatic liver cancer, and each fraction was compared among these diseases. Atypical patterns that were unclassifiable according to the WHO classification of hyperlipidemia phenotypes were classified, and their clinical importance was evaluated. With progression of the pathologic conditions of CH, LC, and HCC, the T-Chol level, each Chol fraction, and the TG fraction decreased while the LDL-TG fraction increased. Metastatic liver cancer showed a lower HDL-fraction level but higher levels of the other parameters than HCC. When the subjects were classified into survivors and patients who died, the HDL fraction level in HCC and metastatic liver cancer, and the LDL level in LC and metastatic liver cancer differed between survivors and patients who died. Phenotypes of hyperlipidemia also differed among diseases, and atypical patterns were frequently observed in patients who died. There were 6 atypical patterns, of which 4 (slow alpha HDL, abnormal LDL, Lp-X, and Lp-Y) were associated with liver diseases. Slow alpha HDL appeared during slight bile stagnation and was accompanied by increases in the apo E level and the HDL particle size. Abnormal LDL appeared with severe liver dysfunction; a TG peak appeared at the position of LDL, and the HDL and VLDL fractions were negligible. Lp-X was a Chol-rich band, occurring on the cathode side of LDL in the presence of marked bile stagnation such as that in obstructive jaundice, and was accompanied by appearance of abnormal LDL. Lp-Y was similar to Lp-X in terms of mobility and associated diseases but contained Chol and TG. Abnormal LDL, Lp-X, and Lp-Y were often observed in patients with poor outcomes. Lipid analysis in liver diseases by this method showed results reflecting the pathologic conditions and may be clinically useful.
Int J Mol Med 2005 Apr
PMID:Clinical significance of abnormal lipoprotein patterns in liver diseases. 1575 28

It becomes feasible to perform genome-wide differential gene or protein expression in the post genome era. However, little has been addressed on the effects of external stresses and microenvironment alterations on the outcomes of gene and protein expression. To identify downregulated genes during hepatoma development, we combined the cDNA representational difference analysis (RDA) and reverse Northern blot analysis identifying eight genes. Of interest, the expression of the clusterin gene was either down or upregulated in 8 and 7 out of the 20 hepatoma tissues, respectively. Further analysis revealed that its expression was independent of patients' age, gender, causes of liver disease, tumor size, tumor histological stage, or clinical outcome, but was strongly associated with the methods of hepatectomy procedures. In vitro studies disclosed that the clusterin mRNA was increased twofold in early exponential phase of cell proliferation followed by downregulation in the subsequent quiescence phase, whereas it was rapidly increased up to twelvefold upon UV-induced apoptosis. These results suggest that dys-regulation of the clusterin gene in human hepatoma was most likely due to cellular responses to external stresses especially during the procedures for sample collection rather than any correlation to hepatoma development or progression. Our findings that external stresses or microenvironmental changes could greatly affect gene or protein expression offer a general caution to all the studies conducted via genomic and proteomic approaches.
Mol Carcinog 2005 Jun
PMID:Dys-regulation of clusterin in human hepatoma is not associated with tumorigenesis but is secondary to cell response to external tresses. 1579 50

Expression of hepatocyte growth factor (HGF) and its receptor, c-met is up-regulated in various forms of liver injury. This study evaluated the relationship between HGF and c-met expression and pathological changes in experimental alcoholic liver disease. Rats (5 per group) were fed ethanol and a diet containing saturated fat corn oil or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in controls. In a second set of experiments, Kupffer cells, endothelial cells and hepatocytes were isolated from rats in each group. Pathological evaluation and analysis of HGF and c-met expression were performed in liver and the different cell types. Increased expression of HGF and c-met expression was detected in the liver of rats showing necroinflammatory changes. The Kupffer and endothelial cells were primarily responsible for the increase in HGF, c-met expression was seen only in hepatocytes. Thus, up-regulation of HGF and c-met occurred in the presence of the necrosis and inflammation suggesting that HGF may be acting to protect against liver injury or accelerate the regenerative process.
Int J Mol Med 2005 May
PMID:Expression of hepatocyte growth factor and its receptor c-met, correlates with severity of pathological injury in experimental alcoholic liver disease. 1580 3

Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumor. It is usually asymptomatic in the early stages and tends to be intravascularly and intrabiliary invasive. Therefore, most patients present with incurable disease at the time of detection and early diagnosis of HCC is critical for a good prognosis. The imaging-based diagnosis of small tumors is relatively inaccurate, as cirrhotic and dysplastic nodules mimic HCC radiologically. The availability of a suitable serological marker to distinguish between HCC and benign liver lesions would, therefore, be very useful for early diagnosis. The only serological marker currently widely used for the diagnosis of HCC is alphafetoprotein (AFP). However, the sensitivity of this marker is limited (41-65%). Given the high heterogeneity of HCC, it is currently thought that an optimal serological test for HCC will be based on the simultaneous measurement of two or three highly specific serological markers.Several laboratories have recently reported that glypican-3 (GPC3), a membrane-bound proteoglycan, is expressed by a large proportion of HCCs, but is undetectable in normal hepatocytes and non-malignant liver disease. Furthermore, various studies demonstrated that GPC3 could be used as a serological test for the diagnosis of patients with HCC. Although the specificity of the test was very high in the context of a population with chronic liver disease, the sensitivity was limited (within the same range as AFP). Interestingly, in most cases, elevated GPC3 values did not correlate with elevated AFP values. As a consequence, the serological level of at least one of the two markers was elevated in a large majority of HCC patients. These results suggest that the sensitivity of the diagnostic test can be significantly improved without compromising specificity with the simultaneous measurement of both GPC3 and AFP.
Mol Diagn 2004
PMID:Glypican-3 and alphafetoprotein as diagnostic tests for hepatocellular carcinoma. 1588 76

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are strong and independent risk factors for hepatocellular carcinoma (HCC) development. Patients with hereditary hemochromatosis (HH) are considered at risk of developing cancer. However, the interaction between HFE gene mutations and hepatitis viruses for HCC development has not been systematically searched for. To assess the interaction between HFE gene mutations and exogenous risk factors in the risk of HCC occurrence, a case-only approach, in which just a series of patients is enrolled, was used. Three hundred three cirrhotic patients (231 males, 72 females) from five liver units in different geographic areas of Italy, who developed HCC during regular follow-up between January 1999 and March 2003, and whose blood DNA was available, were analyzed. In all subjects, hepatitis B surface antigen (HBsAg), anti-HCV and HFE gene mutations were assayed; alcohol intake was recorded by history. The interaction between HFE genotypes and hepatitis viruses for HCC was estimated by multivariate analysis adjusting for the confounding effect of alcohol intake, area of residence and months of follow-up. Of the 303 HCC cases, 12 (4.0%) were heterozygous for the C282Y mutation, 93 (30.7%) for the H63D, and 198 (65.3%) homozygous for the wild allele. Multivariate analysis showed that C282Y heterozygous males were 3.8-fold (95% CI=1.0-15.2) more likely to be HBV positive and that H63D heterozygous females were 6.0-fold (95% CI=1.2-113.8) more likely to be HCV positive than wild type subjects. In conclusion, given the association between C282Y mutation and HBV infection in male patients with HCC, a careful evaluation and follow-up should be considered in the C282Y-positive subjects with hepatitis B virus related liver disease. The interaction between the H63D mutation and HCV, observed only in women, may reflect a higher sensitivity to H63D-induced iron metabolism abnormalities and a reduced antioxidant capability in the presence of an even minor increase of iron which may occur as a consequence of the coexistence of hepatitis C infection and heterozygosity for HH.
Blood Cells Mol Dis
PMID:Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma. 1589 95

The mechanism of the UAL cycle in the intragastric feeding model of alcoholic liver disease in the rat was investigated by administering dinitrophenol (DNP) with ethanol in the diet. The question was: is the rate of oxidative phosphorylation fluxuation essential for the cycle to occur? The question has been partially answered by showing that rotenone, which inhibits complex I, blocks the cycle by preventing the generation of NAD from NADH. This would inhibit ATP generation from complex I but would not affect oxidative phosphorylation by complex 2 and 3. Since the rate of O2 consumption is normal at the troughs of the cycle and decreases at the peaks of the cycle and the levels of ATP are reduced at the peaks of the cycle, it is likely that the rate of oxidative phosphorylation also cycles. Since 2-4 dinitrophenol (DNP) uncouples oxidative phosphorylation, it was anticipated that feeding it with ethanol would prevent the cycle from occurring. This proved to be the case. In addition, DNP caused energy wasting and prevented the increase in serum alanine aminotranspeptidase caused by ethanol feeding, probably by preventing the hypoxia which occurs at the peaks of the cycle.
Exp Mol Pathol 2005 Jun
PMID:Uncoupling of oxidative phosphorylation prevents the urinary alcohol level cycling caused by feeding ethanol continuously at a constant rate. 1592 76


<< Previous 1 2 3 4 5 6 7 8 9 10