Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molsidomine is effective in reducing portal hypertension in cirrhosis, but its effect on hepatitis is not known. In the present study, the effect of molsidomine on hepatitis was examined using mouse concanavalin A (Con A)-induced hepatitis and mouse anti-Fas antibody-induced hepatitis. Treatment of mice with Con A caused elevation of plasma alanine aminotransferase (ALT) at 8 and 24 h (n=4). Pretreatment of mice with molsidomine (3, 10, 30 and 100 mg/kg, i.p.) prevented Con A-induced hepatitis. Treatment of mice with anti-Fas antibody (150 microg/kg, i.v.) caused elevation of plasma ALT at 3.5 h. Pretreatment mice with molsidomine (10 mg/kg, i.p.) showed only 47% inhibition of anti-Fas antibody caused elevation of plasma ALT. The present results showed effectiveness of molsidomine in preventing Con A-induced mice hepatitis.
Int J Mol Med 2001 Mar
PMID:Prevention of concanavalin A-induced mice hepatitis by molsidomine. 1117 12

To clarify the sequential changes in pRB and p16 during different stages of hepatocarcinogenesis such as fibrosis, cirrhosis, hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC), male Fischer 344 rats were singly injected with diethylnitrosamine (DEN), immediately followed with phenobarbital for 1 wk and then thioacetamide (TAA) for 39 wk in drinking water. Rats were killed at 9, 20, 30, and 40 wk after DEN initiation and changes of pRB level, p16 gene hypermethylation, and in vivo gankyrin expression were examined. Histologic examination showed stepwise appearances of fibrosis, cirrhosis, HCA, and HCC at weeks 9, 20, 30, and 40, respectively. Hypermethylation of p16 exon 1 was not found until HCA but appeared in 50% of the rats with HCC accompanied by complete loss of its mRNA expression. The amount of glutathione S-transferase--gankyrin bound to pRB and pRB degradation in the liver depended on the concentration of gankyrin and incubation time. Gankyrin expression preceded pRB degradation in liver cirrhosis. In conclusion, gankyrin expression induced in liver fibrosis accelerated the degradation of pRB during liver cirrhosis, and inactivation of p16 exon 1 by DNA hypermethylation occurred during the progression of tumor cells to poorly differentiated HCC. Inactivation of pRB and/or p16 resulted in complete loss of regulation in the cell-division cycle during early and late stages, respectively, of hepatocarcinogenesis. Mol. Carcinog. 30:138--150, 2001.
Mol Carcinog 2001 Mar
PMID:Sequential changes in hepatocarcinogenesis induced by diethylnitrosamine plus thioacetamide in Fischer 344 rats: induction of gankyrin expression in liver fibrosis, pRB degradation in cirrhosis, and methylation of p16(INK4A) exon 1 in hepatocellular carcinoma. 1130 74

The cDNA clones, which were highly expressed in liver tissues of hepatocellular carcinoma (HCC) patients, were identified using dot hybridization and reconfirmed by Northern blot analysis. One of the clones, ninjurin (nerve injury induced protein), showed a much higher expression level in the liver tissue of HCC patients than in normal liver tissue. Interestingly, the presence of ninjurin mRNA transcripts was detected with high intensity in HCC tissues when combined with viral infection and cirrhosis, but not with a normal liver or HCC tissue unrelated with viral infection and cirrhosis. We produced a N-terminal part of recombinant ninjurin protein, as well as a monoclonal antibody specific to this polypeptide. The intensity of immunohistochemical staining of the liver tumor tissue, and regenerating tissue for the ninjurin protein, was stronger than that of normal liver tissue. These results suggest that ninjurin may play an important role in the development of HCC combined with cirrhosis and viral infection.
Mol Cells 2001 Apr 30
PMID:Up-Regulation of ninjurin expression in human hepatocellular carcinoma associated with cirrhosis and chronic viral hepatitis. 1135 94

alpha1-Antitrypsin (alpha1-AT) is the most abundant circulating proteinase inhibitor. The Z variant results in profound plasma deficiency as the mutant polymerizes within hepatocytes. The retained polymers are associated with cirrhosis, and the lack of circulating protein predisposes to early onset emphysema. We have investigated the role of the naturally occurring solute trimethylamine N-oxide (TMAO) in modulating the polymerization of normal M and disease-associated Z alpha1-AT. TMAO stabilized both M and Z alpha1-AT in an active conformation against heat-induced polymerization. Spectroscopic analysis demonstrated that this was due to inhibition of the conversion of the native state to a polymerogenic intermediate. However, TMAO did not aid the refolding of denatured alpha1-AT to a native conformation; instead, it enhanced polymerization. These data show that TMAO can be used to control the conformational transitions of folded alpha1-AT but that it is ineffective in promoting folding of the polypeptide chain within the secretory pathway.
Am J Respir Cell Mol Biol 2001 Jun
PMID:Prevention of polymerization of M and Z alpha1-Antitrypsin (alpha1-AT) with trimethylamine N-oxide. Implications for the treatment of alpha1-at deficiency. 1141 38

Plasma concentrations of endothelin-1 (ET-1) and nitrite/nitrate of patients with portal hypertension were measured. Sixteen patients with liver cirrhosis (the LC group) and 14 patients with idiopathic portal hypertension (the IPH group) and 12 healthy subjects (normal controls) were included in this study. The peripheral venous plasma concentration of ET-1 was significantly higher in the LC group (6.69+/-2.44 pg/ml) than in the IPH group (3.07+/-0.84 pg/ml) and normal controls (1.79+/-0.36 pg/ml), while the value in the IPH group was also significantly higher than that in normal controls. The peripheral venous plasma concentration of nitrite/nitrate was significantly higher in the LC group (67.7+/-38.9 &mgr;Mol/l) than in the IPH group (32.3+/-24.4 &mgr;Mol/l) and normal controls (26.1+/-9.8 &mgr;Mol/l). Hepatic venous plasma concentrations of ET-1 and nitrite/nitrate were measured in 8 patients from the LC group and 10 patients from the IPH group. The plasma concentration of ET-1 in the hepatic vein was significantly higher than that in the peripheral vein in both the LC and the IPH groups. The plasma concentration of nitrite/nitrate in the hepatic vein was significantly higher than that in the peripheral vein in the LC group. We also investigated the localization of ET-1, endothelin receptor (ET receptor) and nitric oxide synthase (NOS) in the liver tissue of LC patients (n=10), IPH patients (n=10) and normal controls (n=10). The expressions of ET-1, ET A receptors, ET B receptors, and inducive NOS (iNOS) were detected in patients with LC, and the labeling index (LI) was significantly higher than that in patients with IPH and normal controls. The expressions of ET-1, ET A receptors, and ET B receptors were found in patients with IPH, and the LI was significantly higher than that in normal controls. The expression of endothelial NOS (eNOS) was scarce in both LC and IPH patients. From these results, overproduction of ET-1 in the liver was regarded as one of the causes of the high plasma concentration of ET-1 in patients with LC and IPH. One of the causes of the high plasma concentration of nitrite/nitrate in LC was considered to be overproduction of nitric oxide (NO) in the liver. And we suggested that ET-1 is at a relatively higher density than NO in the hepatic sinusoid in LC and IPH.
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PMID:Clinical investigation of endothelin-1 and nitric oxide in patients with portal hypertension focusing on plasma levels and immunohistological staining of liver tissues. 1147 Jun 27

The possible role of iron in facilitating the development of liver cancer is still debated. The aims of this study were to define the prevalence of the mutations 845G --> A and 187C --> G (C282Y and H63D) in the HFE gene associated with hereditary hemochromatosis in Italian patients with hepatocellular carcinoma occurring in cirrhosis and to analyze the interaction between these mutations and other established risk factors for hepatocellular carcinoma. The HFE gene mutations, performed by polymerase chain reaction, were analyzed in 81 patients (63 males, 18 females) with hepatocellular carcinoma. None of the patients had a phenotype compatible with homozygous hereditary hemochromatosis. Interaction between HFE mutations and exogenous risk factors was analyzed by collecting information on alcohol consumption, hepatitis B and C virus infections, and iron status at the time of diagnosis of chronic liver disease. This analysis was performed only in males to rule out gender influence on patients' iron status by using the case-only approach specifically designed to estimate departure from multiplicative risk ratios under the assumption of independence between genotype and environmental exposure. The prevalence of the C282Y mutation was significantly higher in patients with hepatocellular carcinoma than in normal controls (8.6% vs 1.6%, P < 0.03). At univariate analysis, iron overload was significantly associated with both HFE mutations (P < 0.0001), whereas ongoing hepatitis B virus infection was associated with the C282Y mutation (P < 0.05). By multivariate analysis, a trend for an increased risk of being positive for hepatitis virus markers (OR 2.9, CI 95% 0.9-9.5) and of having been alcohol abusers (OR 3, CI 95% 0.7-14) was observed in patients heterozygous for the HFE mutations. These data indicate that the prevalence of the main mutation associated with hereditary hemochromatosis is significantly higher in cirrhotic Italian patients with hepatocellular carcinoma compared to a normal population and suggest that heterozygotes for HFE mutations exposed to hepatitis virus infections or who had been alcohol abusers could have an increased risk of developing cirrhosis and later liver cancer than people without the mutations exposed to the same risk factors.
Blood Cells Mol Dis
PMID:Mutations in the HFE gene and their interaction with exogenous risk factors in hepatocellular carcinoma. 1150 61

Hepatitis C virus (HCV), a positive-sense, single-stranded RNA virus of the Flaviviridae family, is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Its RNA is difficult to study because biological materials are scarce and RNA replication is of low efficiency. This review focuses on the structure and functions of HCV RNA along with their biological and clinical significance. Despite the challenging characteristics of HCV, significant progress has been made in understanding the properties of HCV RNA and developing viral replication systems toward the improvement of antiviral therapies.
Cell Mol Life Sci 2001 Aug
PMID:Hepatitis C viral RNA: challenges and promises. 1157 84

Upon activation by liver injury, hepatic stellate cells produce excessive fibrous tissue leading to cirrhosis. The hepatotoxin CCl(4) induced activation of RSK, phosphorylation of C/EBPbeta on Thr(217), and proliferation of stellate cells in normal mice, but caused apoptosis of these cells in C/EBPbeta-/- or C/EBPbeta-Ala(217) (a dominant-negative nonphosphorylatable mutant) transgenic mice. Both C/EBPbeta-PThr(217) and the phosphorylation mimic C/EBPbeta-Glu(217), but not C/EBPbeta-Ala(217), were associated with procaspases 1 and 8 in vivo and in vitro and inhibited their activation. Our data suggest that C/EBPbeta phosphorylation on Thr(217) creates a functional XEXD caspase substrate/inhibitor box (K-Phospho-T(217)VD) that is mimicked by C/EBPbeta-Glu(217) (KE(217)VD). C/EBPbeta-/- and C/EBPbeta-Ala(217) stellate cells were rescued from apoptosis by the cell permeant KE(217)VD tetrapeptide or C/EBPbeta-Glu(217).
Mol Cell 2001 Oct
PMID:C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. 1168 16

An estimated 400 million people are chronically infected with the hepatitis B virus (HBV). Chronic viral hepatitis infection incurs serious sequelae such as liver cirrhosis and hepatocellular carcinoma. Prevention and treatment, thus, represent an important target for public health. Preventive vaccines using HBsAg alone or combined with other antigens allow for the generation of neutralizing antibodies which effectively prevent infection in immunocompetent individuals. Cell-mediated immunological mechanisms are thought to be crucial in determining viral persistence or viral elimination. Therapeutic approaches aiming to shift cellular immunity towards viral elimination have been on the research agenda for many years. This paper summarizes pre-clinical and clinical results obtained with the use of immunogenic peptides formulated as vaccines to selectively boost cellular immune responses. Such vaccines are capable of generating cellular immune responses in animal models as well as in humans and represent an important step towards the development of a therapeutic vaccine against chronic hepatitis.
Mol Immunol 2001 Dec
PMID:Peptide vaccines against hepatitis B virus: from animal model to human studies. 1174 95

Hepatitis C virus (HCV) is a widespread infectious disease in humans with the negative implication of becoming chronic in most persons. Patients infected with HCV are at risk of liver cirrhosis or hepatocellular carcinoma at later stages. In contrast to hepatitis A and hepatitis B, there is no immunization yet available, neither prophylactic nor therapeutic. Thus, there is an urgent need to develop a safe, protective vaccine against this fatal disease. Developing countries are even more at risk for HCV. There are currently a number of scientific approaches aimed towards solving this problem. Taking both risks and costs of immunization into consideration, a peptide-based vaccine may be a reasonable prophylactic protection. Also, it might be of therapeutic use in already infected patients by increasing a specific CTL response against HCV. In our lab, we are focusing on immunopotentiating reconstituted influenza virosomes (IRIVs) as carriers for immunogenic HLA-A2-restricted core epitopes to induce peptide-specific cytotoxic T lymphocytes (CTLs). The IRIVs are similar to liposomes, but in addition contain influenza-derived hemagglutinin and neuraminidase on their outer surface which makes them fusogenic, thus, permitting antigen delivery to host cells. So far, virosomes have been successfully used for vaccine development and as a result a virosomal vaccine against both influenza virus (Inflexal) BERNA) and hepatitis A virus (HAV) (Epaxal) BERNA) already exist on the market. This paper focuses on the importance of development of a successful vaccine against HCV and, more specifically, we discuss the use, advantages and disadvantages of a peptide-based vaccine. A brief report of our latest findings will be included.
Mol Immunol 2001 Dec
PMID:Perspectives: towards a peptide-based vaccine against hepatitis C virus. 1174 97


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