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

Hepatocyte growth factor (HGF) plays a crucial role in the recovery of injured liver. Liver functions are mostly impaired in patients with liver diseases including cirrhosis. However, a significant amount of inactive HGF precursor (proHGF) is reported in the plasma of these patients. proHGF is proteolytically converted to an active form (mature HGF) by HGF-activator. Thus conversion of proHGF into mature HGF presumably contributes to the recovery of liver functions. In this study, rats with a partial hepatectomy were used, as proHGF is accumulated in the remnant liver. Recombinant human HGF-activator was administered via the portal vein to investigate the effect on molecular forms of HGF and its biological signaling. rhHGF-activator promptly converted proHGF into mature HGF, reaching maximal levels at 5-10 min after the injection, while the decreased proHGF was quickly recovered to the initial levels in the liver. The HGF receptor/c-Met was found to be autophosphorylated in the liver treated with rhHGF-activator. Further, the proliferating cell nuclear antigen labeling index and the liver regeneration rate were significantly higher in rhHGF-activator group than in control animals. These results indicate that exogenously administered HGF-activator produces a biologically active HGF from its precursor form and increases the potential for liver regeneration in vivo.
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PMID:Exogenously administered HGF activator augments liver regeneration through the production of biologically active HGF. 1177 95

AIM:To determine whether proliferating cell nuclear antigen (PCNA) is present in the peripheral circulation and whether PCNA levels correlate with cnhanced regenerative activity.METHODS:In animal studies, adult male Sprague-Dawley rats (n = 3-4/group) were sacrificed at 0, 12, 24, 36, 48, 72 and 96 hours following 70% partial hepatectomy.At each interval,sera were analyzed by Western blot for PCNA by two monoclonal antibodies (PC-10 and 19F-4).In human studies, sera from 4 patients with liver cirrhosis and 4 healthy controls were tested in a similar manner.RESULTS:The PC-10 monoclonal antibody identified a protein with a molecular mass of 120 KD which remained stable in rat sera for 24 hours following partial hepatectomy,then increased 1.5-fold at 48 hours prior to returning to baseline at 96 hours after partial hepatectomy.However,it was not detected in the sera of patients with or without liver disease. In the 19F-4 monoclonal antibody, a protein with a molecular mass of approximately 46 KD was found. Which was present in rat sera prior to partial hepatectomy and for 12 hours after surgery. Thereafter, levels fell by approximately 50% at 24 hours, 65% at 36 hours and 75% at 48 hours where they remained until 96 hours after partial hepatectomy. The decrease in levels correlated with the extent of partial hepatectomy. In human sera, the appearance of this inhibitory cell nuclear antigen (IC-NA) was higher in the sera of patients with cirrhosis than in healthy controls.CONCLUSION:The PC-10 monoclonal antibody can detect a protein in the circulation when active hepatic regenerative activity is taking place. The 19F-4 monoclonal antibody, however, identifies a protein in both rat and human sera that inversely correlates with hepatic regenerative activity. This protein which is tentatively referred to as inhibitory cell nuclear antigen (IC-NA) may be used in documenting the extent of suppression of hepatic regeneration.
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PMID:Appearance of an inhibitory cell nuclear antigen in rat and human serum during variable degrees of hepatic regenerative activity. 1181 3

We have previously shown that the administration of low doses of insulin-like growth factor-I (IGF-I) to CCl4-cirrhotic rats improves liver function and reduces fibrosis. To better understand the mechanisms behind the hepatoprotective effects of IGF-I, and to identify those genes whose expression is affected in cirrhosis and after IGF-1 treatment, we have performed differential display of mRNA analysis by means of polymerase chain reaction (PCR) in livers from control and CCl4-cirrhotic rats treated or not with IGF-I. We have identified 16 genes that were up- or down-regulated in the cirrhotic liver. IGF-I treatment partially normalized the expression of eight of these genes, including serine proteinase inhibitors such as serpin-2 and alpha-1-antichymotripsin, alpha-1-acid glycoprotein, and alpha-2u-globulin. Additionally, we show that IGF-I enhanced the regenerative activity in the cirrhotic liver, as determined by the increased expression of the proliferating cell nuclear antigen (PCNA). Finally, IGF-I treatment partially restored the expression of growth hormone receptor (GHR) and the levels of global genomic DNA methylation, which are reduced in human and experimental cirrhosis. Taken together, our observations confirm the hepatoprotective effects of IGF-I, and suggest that this action can be exerted in part through the normalization of liver gene expression, growth hormone (GH) responsiveness and global genomic DNA methylation.
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PMID:Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I. 1184 91

Viral dynamic studies in chronic hepatitis C virus (HCV) infection indicate a significantly shortened survival of virus-infected cells. Since at the steady state of chronic viral infection, the rate of infected cell elimination equals new cell regeneration, this would imply a high rate of hepatocyte turnover in chronic HCV liver disease. We estimated the fraction of regenerating hepatocytes in liver biopsy sections in chronic HCV liver disease, cirrhosis, and hepatocellular carcinoma (HCC). We used antibodies to proliferating cell nuclear antigen (PCNA) to detect proliferating cell nuclei in liver biopsy specimen from controls and patients with chronic hepatitis, cirrhosis, and HCC. We also used bis-benzimide to label fluorescently all hepatocyte nuclei simultaneously. Using digital image analysis, we calculated the area occupied by PCNA-stained hepatocyte nuclei, as a fraction of the total area occupied by fluorescently labeled hepatocyte nuclei (labeling index; LI). Antibody staining was negligible in the control specimen. The mean +/- SE PCNA LI increased from 0.21 +/- 0.1 in chronic hepatitis to 0.63 +/- 0.15 in HCC. There was no significant difference between chronic hepatitis and cirrhosis. The fraction of cells undergoing regeneration is increased in chronic HCV liver disease, HCV-related cirrhosis, and HCC. Increased hepatocyte turnover could provide the link between chronic HCV liver disease and HCC.
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PMID:Digital image analysis of the distribution of proliferating cell nuclear antigen in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. 1214 30

To investigate the significance of hepatocyte apoptosis, proliferation and oncogene c-fos expression in carbon tetrachloride (CCl4)-induced cirrhotic rat liver. Rat cirrhosis was induced by subcutaneous injection of 50% (v:v 1:1) CCl4. Hepatocyte apoptosis, proliferation and oncogene c-fos expression were examined with TUNEL, PCNA and c-fos immunohistochemical methods in control group and treatment group 72 h, 5, 7, 11 and 15 weeks after CCl4 induction. Hepatocyte apoptosis was rarely seen in control rat liver. The hepatocyte apoptosis was obviously increased 72 h after treatment. Fifteen weeks after treatment, the apoptosis was still more obvious in treatment group than that in controls. PCNA was constantly expressed in CCl4 group, with highest level at middle phase. C-fos was positive 7 and 11 weeks after CCl4 treatment. The results suggest that: 1) apoptosis is involved in rat liver damage at the early phase in CCl4-induced injury, and the process can alleviate nodule reconstruction or eradicate potentially mutational hepatocytes at the later phase; 2) hepatocytes constantly proliferate in CCl4-induced rat liver cirrhosis, especially at the middle phase; 3) c-fos might modulate hepatocyte proliferation in CCl4-induced rat liver cirrhosis.
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PMID:Studies on hepatocyte apoptosis, proliferation and oncogene c-fos expression in carbon tetrachloride-induced cirrhotic rat liver. 1284 Aug 77

Reactive oxygen species may be involved in the progression of chronic liver disease and the occurrence of hepatocellular carcinoma (HCC). To clarify whether clinicopathological findings in liver diseases are related to oxidative DNA damage, hepatic expression of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) was examined in 75 liver disease patients, which included 32 chronic hepatitis (CH), 13 liver cirrhosis (LC) and 30 HCC patients. The CH patients had higher 8-OHdG-positive hepatocytes than LC (P < 0.05). In CH and LC, the number of 8-OHdG-positive hepatocytes was correlated with alanine aminotransferase and asparate aminotransferase (P < 0.01 and P < 0.05, respectively). Of 30 HCC cases, 25 cases (83%) showed stronger immunoreactivity than non-cancerous counterparts. The patients with poorly differentiated HCC had a larger tumor size and higher levels of AFP, and exhibited higher labeling indices of PCNA-, TUNEL- and 8-OHdG-positive cells than those with well and moderately differentiated HCC. Our findings suggest that oxidative DNA damage is increased in association with necroinflammation in chronic liver disease and determination of 8-OHdG is useful in assessing high-grade malignancy in HCC.
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PMID:Expression of 8-hydroxy-2'-deoxyguanosine in chronic liver disease and hepatocellular carcinoma. 1470 94

A complementary way for the assessment of HCC prognosis is represented by the analysis of molecular markers. Thus, immunohistochemical assessment of proliferation can describe tumor aggressiveness, probability of local recurrence or metastasis potential, being very useful for the assessment of recurrence-free survival and survival until death. The aim of our study was to assess proliferating cell nuclear antigen activity in HCC and dysplastic nodules as compared with surrounding non-neoplasic areas. Immunohistochemical techniques were thus performed on the samples obtained by ultrasound-guided liver biopsies or intraoperative biopsies, in 32 patients with HCC, as well as in 3 patients with dysplastic nodules occurring in liver cirrhosis. Expression of PCNA within extranodular areas of the HCC patients in the absence or presence of cirrhosis, was increasing from 40% to 70%, respectively. PCNA expression further increased within intranodular areas of dysplastic nodules and HCC, to 100% and 96.88%, respectively. A progressive increase of the mean values of PCNA-LI was also observed from extranodular areas without or with cirrhosis, towards intranodular areas of dysplastic nodules and HCC (4.2%, 6.8%, 27.9%, 31.9%, respectively). Dysplastic nodules can thus be considered lesions with a high-proliferation rate, representing an early stage of hepatocarcinogenesis. This supported the current recommendations for borderline hepatocellular nodules identified by ultrasound, which indicate an aggressive treatment similar to malignant lesions. In summary, we demonstrated a progressively increasing rate of cellular proliferation, from extranodular non-neoplasic areas to intranodular areas (dysplastic nodules and HCC), as reflected by an increased expression of proliferating cell nuclear antigen labelling index.
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PMID:Immunohistochemical assessment of proliferating cell nuclear antigen in primary hepatocellular carcinoma and dysplastic nodules. 1475 12

Intrahepatic bile duct proliferation (ductular reaction) was examined histologically, immunohistochemically and ultrastructurally in four cases of canine liver disease, diagnosed as chronic hepatitis, liver fibrosis, cirrhosis and cholangiocellular carcinoma. Ductular reaction was a common finding in all cases. Most of the proliferated bile ducts were similar to normal bile ducts. In addition, duct-like structures occurred, consisting of hepatocytes and of intermediate cells that had phenotypic characteristics of both cholangiocytes and hepatocytes. The proliferated bile ducts were immunohistochemically negative for proliferating cell nuclear antigen (PCNA) and stem cell factor (SCF). The proliferated bile ducts in these four cases of canine liver disease thus showed both typical ductular reactions, such as elongation and tortuosity of the existing bile ducts, and atypical ductular reactions resulting from metaplasia of hepatocytes.
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PMID:Morphological characterization of ductular reactions in canine liver disease. 1500 64

Liver cirrhosis is the end stage of various chronic liver diseases and its prognosis is very poor. One of the most important causes of liver cirrhosis appears to be impaired proliferative capability of hepatocytes caused by continuous hepatic damage. Cell cycle-related molecules have been shown to play essential roles in cell proliferation. Specifically, G1-related cell cycle molecules are important, because they are requisite for the entry into the cell cycle from the quiescent state. However, the role of these cell cycle molecules during the development of liver cirrhosis remains to be examined. In the present study, liver cirrhosis was produced in rats by intraperitoneally administering dimethylnitrosamine (DMN). Proliferative capability of hepatocytes estimated immunohistochemically by proliferating cell nuclear antigen staining was markedly increased at an early stage of cirrhosis development. However, it was gradually decreased thereafter and suppressed substantially at the time of cirrhosis manifestation. Cyclin D1 expression estimated by a real-time reverse transcription-polymerase chain reaction (RT-PCR) method was also increased markedly at an early stage of cirrhosis development but decreased substantially thereafter. mRNA levels of catalytic subunits of cyclin D1, cyclin-dependent kinase 4 (Cdk4) and Cdk6, did not show significant changes during the development of liver cirrhosis. Among G1-specific Cdk inhibitors, expression of p15INK4b and p16INK4a estimated by an RT-PCR method was increased according to the progression of cirrhosis and reached a peak at the time of cirrhosis manifestation. Conversely, p18INK4c expression did not change significantly during the development of liver cirrhosis. These results suggest that cyclin D1 plays an essential role in hepatocyte proliferation in response to hepatic damage. However, with the decrease of cyclin D1 expression and increase of p15INK4b and p16INK4a expression, proliferative capability of hepatocytes is severely impaired and extracellular matrix components are deposited to retrieve space lost by the destruction of hepatic parenchyma, resulting in establishment of liver cirrhosis.
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PMID:Proliferative capability of hepatocytes and expression of G1-related cell cycle molecules in the development of liver cirrhosis in rats. 1513 12

Proliferation and differentiation of satellite cells are critical in the regeneration of atrophied muscle following immobilization and aging. We hypothesized that impaired satellite cell function is responsible for the atrophy of skeletal muscle also seen in cirrhosis. Myostatin and insulin-like growth factor 1 (IGF1) have been identified to be positive and negative regulators, respectively, of satellite cell function. Using a rat model of cirrhosis [portacaval anastamosis (PCA)] and sham-operated controls, we examined the expression of myostatin, its receptor activinR2b, and its downstream messenger cyclin-dependent kinase inhibitor p21 (CDKI p21) as well as IGF1 and its receptor in the gastrocnemius muscle. Expression of PCNA, a marker of proliferation, and myogenic regulatory factors (myoD, myf5, and myogenin), markers of differentiation of satellite cells, were also measured. Real- time PCR for mRNA and Western blot assay for protein quantification were performed. PCA rats had lower body weight and gastrocnemius weight compared with sham animals (P < 0.05). PCNA and myogenic regulatory factors were lower in PCA rats (P < 0.05). Myostatin, activinR2b, and CDKI p21 were higher in the PCA animals (P < 0.05). The expression of IGF1 and its receptor was lower in liver and skeletal muscle of PCA animals (P < 0.05). These data suggest that skeletal muscle atrophy seen in the portacaval shunted rats is a consequence of impaired satellite cell proliferation and differentiation mediated, in part, by higher myostatin and lower IGF1 expression.
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PMID:Skeletal muscle atrophy is associated with an increased expression of myostatin and impaired satellite cell function in the portacaval anastamosis rat. 1525 63


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