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)

Growth arrest and DNA damage 45-alpha (GADD45-alpha) is a nuclear protein involved in maintenance of genomic stability, DNA repair, and suppression of cell growth through interaction with nuclear elements, including cyclin-dependent kinase inhibitor 1A (CDKN1A) and PCNA. In this study, GADD45-alpha expression was assessed in 28 cases of hepatocellular carcinoma (HCC) and matched cirrhosis tissues, and correlated with the presence of DNA-bound PCNA and CDKN1A as markers of DNA repair, as well as with clinicopathologic variables including histopathologic grade, tumor size, nodularity, viral status, alpha-fetoprotein serum levels, and p53 and Ki67 immunostaining. GADD45-alpha and CDKN1A messenger RNA (mRNA) were analyzed by reverse transcriptase-polymerase chain reaction. GADD45-alpha protein expression was evaluated by Western blot (WB) and enzyme-linked immunosorbent assays (ELISAs). PCNA and CDKN1A DNA-bound fractions were determined by WB. GADD45-alpha mRNA was down-regulated in 20 of 26 HCCs with respect to matched cirrhosis, but no correlation was found with the corresponding protein levels assessed by both WB and ELISA. GADD45-alpha and CDKN1A protein levels were related to each other both in cirrhotic and in neoplastic tissues, and a concordant up- or down-regulation was observed in HCCs with respect to cirrhosis. DNA-bound PCNA and CDKN1A were present in 5 HCCs and were associated with higher GADD45-alpha protein levels assessed by ELISA. No significant association was found in HCCs between GADD45-alpha protein expression and histopathologic grading, nodule size, focality, and proliferation, whereas a positive correlation was found with alpha-fetoprotein serum levels. In conclusion, GADD45-alpha mRNA was down-regulated with respect to matched cirrhosis in most HCCs; however, no correlation was found between mRNA and protein levels. GADD45-alpha protein levels were higher in HCCs with DNA-bound CDKN1A and PCNA, suggesting a possible role in DNA repair.
 ...
PMID:GADD45-alpha expression in cirrhosis and hepatocellular carcinoma: relationship with DNA repair and proliferation. 1626 Feb 67

This study compares the populations of liver mesenchymal cells (LMCs) and their proliferative activity in schistosomal periportal fibrosis and in hepatitis C virus-induced cirrhosis. LMCs were evaluated by immunohistochemical double staining for proliferating cell nuclear antigen (PCNA) and alpha-smooth muscle actin (alpha-SMA) or glial fibrillary acid protein (GFAP) in liver biopsies from humans with schistosomal fibrosis (n=40), hepatitis C virus-induced cirrhosis (n=20), and normal controls (n=20). The number of LMCs was found to be higher in schistosomal fibrosis than in the normal liver, but lower than in cirrhosis. alpha-SMA- and GFAP-positive cells were increased in both diseases, but more so in cirrhosis. In cirrhotic liver, alpha-SMA-positive cells were highly predominant in relation to GFAP-positive cells. However, there was an inverted ratio between these cells in schistosomiasis as compared to cirrhosis. The PCNA labeling index was higher in alpha-SMA-positive cells than in GFAP-positive cells, and did not differ between pipe-stem fibrosis and liver cirrhosis regarding alpha-SMA- or GFAP-positive cells. The predominance of GFAP-positive cells observed in schistosomiasis suggests that hepatic stellate cells (HSCs) have a major role in connective tissue deposition in the human schistosomal liver. On the other hand, the smaller number of LMCs in schistosomal fibrosis in comparison to liver cirrhosis may be related to mild and limited injury due to the schistosomal egg-induced inflammatory response. The granulomatous inflammation around Schistosoma mansoni eggs appears to mobilize and activate a reduced number of mesenchymal cells in comparison to the scattered necro-inflammatory reaction produced by the hepatitis C virus.
 ...
PMID:Hepatic stellate cells in human schistosomiasis mansoni: a comparative immunohistochemical study with liver cirrhosis. 1647 18

Liver cirrhosis is the fatal end stage of various chronic liver diseases. One of the most important causes of liver cirrhosis appears to be an impaired proliferative capability of hepatocytes caused by continuous hepatic damage. Hepatocyte growth factor (HGF) and its specific receptor, c-Met, play a pivotal role in hepatocyte proliferation. However, the relationship between the proliferative capability of hepatocytes and the intrahepatic expression of HGF and c-Met during the course of cirrhosis development has not been studied fully. In the present study, liver cirrhosis was produced in rats by intraperitoneally administering dimethylnitrosamine (DMN) and intrahepatic expression levels of HGF and c-Met were quantitatively estimated using a real-time reverse transcription-polymerase chain reaction (RT-PCR) method. Histological examination of liver sections and biochemical estimation of serum levels of transaminase revealed that the degree of hepatocyte destruction was elevated gradually during cirrhosis development in the DMN-induced rat cirrhosis model. The 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. Intrahepatic HGF expression was also increased significantly during the course of cirrhosis development but decreased significantly at the time of cirrhosis manifestation. Conversely, there was a tendency for the intrahepatic expression of c-Met to decrease from an early stage of cirrhosis development and intrahepatic c-Met expression was decreased significantly at the time of cirrhosis manifestation. These results suggest that the highly proliferative capability of hepatocytes at an early stage of cirrhosis development is induced by increased intrahepatic HGF expression. However, both HGF and c-Met expression levels in the liver are decreased significantly there-after. Accordingly, the 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 the establishment of liver cirrhosis.
 ...
PMID:Relationship between the proliferative capability of hepatocytes and the intrahepatic expression of hepatocyte growth factor and c-Met in the course of cirrhosis development in rats. 1659 71

We here report nine liver cirrhosis (LC) patients that underwent autologous bone marrow cell infusion (ABMI) from the peripheral vein. Subjects were patients with LC with total bilirubin of less than 3.0 mg/dl, platelet count of more than 5 (10(10)/l), and no viable hepatocellular carcinoma on diagnostic imaging. Autologous bone marrow (BM; 400 ml) was isolated from the ilium under general anesthesia. Mononuclear cells (MNCs) were separated by cell washing and were infused via the peripheral vein. MNC characteristics were confirmed by fluorescence-activated cell sorting analysis (CD34, CD45, and c-kit). After ABMI therapy, liver function was monitored by blood examination for 24 weeks. From 400 ml of BM, we obtained 7.81 +/- 0.98 x 10(9) MNCs. After washing, 5.20 +/- 0.63 x 10(9) MNCs were infused into patients with LC. Significant improvements in serum albumin levels and total protein were observed at 24 weeks after ABMI therapy (p < .05). Significantly improved Child-Pugh scores were seen at 4 and 24 weeks (p < .05). alpha-Fetoprotein and proliferating cell nuclear antigen (PCNA) expression in liver biopsy tissue was significantly elevated after ABMI therapy (p < .05). No major adverse effects were noted. In conclusion, ABMI therapy should be considered as a novel treatment for patients with decompensated LC.
 ...
PMID:Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. 1754 Aug 55

Increasing evidence suggests that liver regeneration is suppressed in patients with chronic HCV infection; however, the underlying mechanisms remain unclear. Previously, we demonstrated that injection of the synthetic double-stranded RNA (dsRNA) poly I:C to mimic viral infection suppresses liver regeneration in the partial hepatectomy (PHx) model, whereby IFN-gamma contributes to the inhibition. In this study, we examined the role of the IFN-gamma-activated downstream signal (STAT1) and genes (IRF-1, p21(cip1), and SOCS1) in liver regeneration and hepatocyte proliferation. Results show that disruption of the STAT1 gene abolished poly I:C suppression of liver regeneration and the inhibitory effect of poly I:C on liver regeneration was diminished in IRF-1(-/-) and p21(cip1-/-)mice. Treatment with IFN-gamma in vitro inhibited cell proliferation of wild-type mouse hepatocytes, but not STAT1(-/-) hepatocytes. The inhibitory effect of IFN-gamma on cell proliferation was also diminished in IRF-1(-/-) and p21(cip1-/-) hepatocytes, but enhanced in SOCS1(-/-) hepatocytes. Hepatocyte proliferation was unaffected by treatment with poly I:C alone, but when hepatocytes were co-cultured with liver lymphocytes, proliferation was inhibited by IFN-gamma/STAT1-dependent mechanisms. Moreover, in HCV-infected livers with cirrhosis, activation of STAT1 was detected and correlated positively with liver injury (elevated serum levels of AST) but negatively with hepatocyte proliferation (hepatocyte PCNA and Ki-67 positive immunostaining). In conclusion, STAT1 is involved in dsRNA suppression of liver regeneration; not only does STAT1 activation contribute to liver injury, it may also block liver repair through inhibition of hepatocyte proliferation in HCV-infected patients, playing an important role in the pathogenesis of disease.
 ...
PMID:STAT1 contributes to dsRNA inhibition of liver regeneration after partial hepatectomy in mice. 1700 30

Responses of the liver to chronic injury include inflammation, regeneration and fibrosis, which finally lead to cirrhosis. The cause of liver cirrhosis appears to be impaired proliferative capability of hepatocytes caused by continuous hepatic damage, and subsequent accumulation of extracellular matrix produced by hepatic stellate cells (HSCs). Epidermal growth factor (EGF) and transforming growth factor-beta1 (TGF-beta1) play a crucial role in hepatocyte proliferation and hepatofibrogenesis, respectively. However, sequential analyses of the intrahepatic expression of EGF and TGF-beta1 in the course of cirrhosis development have not been examined fully. In the present study, liver cirrhosis was produced in rats by intraperitoneal administration of dimethylnitrosamine (DMN), and intrahepatic mRNA expression levels of proliferating cell nuclear antigen (PCNA), EGF and TGF-beta1 were quantitatively estimated by a real-time reverse transcription-polymerase chain reaction method. Histological and semiquantitative densitometric examination of liver sections revealed that the accumulation of extracellular matrix components was increased according to the period of DMN treatment. Histological examination of liver sections of rats treated with DMN for 4 and 6 weeks revealed pre-cirrhosis and cirrhosis, respectively. Intrahepatic mRNA expression levels of PCNA and EGF correlated well. Expression levels of both molecules were increased significantly during the course of cirrhosis development, but decreased significantly at the time of complete cirrhosis manifestation. In contrast, intrahepatic TGF-beta1 expression was increased significantly according to the period of DMN treatment, and reached a peak at the time of cirrhosis manifestation. These results suggest that proliferative capability of hepatocytes was impaired by continuous liver damage due, in part, to the decrease of a hepatocyte mitogen EGF, and that increased intrahepatic TGF-beta1 activated HSCs to retrieve space lost by hepatocyte destruction, resulting in complete cirrhosis manifestation.
 ...
PMID:Sequential assessment of the intrahepatic expression of epidermal growth factor and transforming growth factor-beta1 in hepatofibrogenesis of a rat cirrhosis model. 1720 7

Nucleophosmin (NPM, B23, numatrin, NO38) is an abundant nucleolar phosphoprotein involved in multiple cellular functions. Previous evidence indicates that high-level expression of NPM causes uncontrolled cell growth and suggests that NPM may have oncogenic potential. In this study, we examined NPM expression in 103 paired cases of hepatocellular carcinoma (HCC), 12 cases of hepatic focal nodular hyperplasia, 17 cases of liver tissue adjacent to a hepatic haemangioma, and series of array tissues from normal human organs and malignancies using a monoclonal antibody against NPM and reverse transcription-PCR techniques, Western blot analysis, immunohistochemistry, and immunocytofluorescence. Our data indicated that NPM expression was significantly higher in HCC than in the non-malignant hepatocytes (P<0.001). Nucleophosmin was weakly expressed in hepatocytes from a 5-month-old embryo and in stationary hepatocytes of healthy adults. Moreover, enhanced expression of NPM in HCC correlated with the level of PCNA (R(2)=0.5639) and with the clinical prognostic parameters such as serum alpha fetal protein level, tumour pathological grading, and liver cirrhosis (P<0.05). Our results suggest that NPM may play an important role in the progression of tumorigenesis and that NPM may serve as a potential marker for HCC.
 ...
PMID:Increased expression of nucleophosmin/B23 in hepatocellular carcinoma and correlation with clinicopathological parameters. 1724 42

In vitro and animal data suggest that hepatitis C virus (HCV) proteins might interfere with signal transducer and activator of transcription 3 (Stat3) signaling. It remains unknown whether Stat3 influences the apoptotic-proliferation balance and how this may relate to liver fibrosis progression in HCV-infected patients. We assessed Stat3 expression and DNA-binding as well as expression of its regulators protein inhibitor of activated Stat 3 (Pias3) and suppressor of cytokine signaling 3 (Socs3) in 65 HCV-infected livers at various stages of fibrosis progression. We then determined the level of expression of the proliferation markers cyclin D1 and proliferating cell nuclear antigen (PCNA) in conjunction with pro- and antiapoptotic markers Bax and Bcl-2 in the same liver samples. With the onset of fibrosis, Stat3 DNA-binding decreased and became almost undetectable in livers with bridging fibrosis or cirrhosis. Stat3 DNA-binding inversely correlated with Pias3 expression and Stat3-Pias3 interaction increased with the progression of fibrosis. Cyclin D1 and PCNA in hepatocytes decreased dramatically during fibrosis progression and levels highly correlated with Stat3 expression. In addition, an antiapoptotic profile due to upregulation of Bcl-2 principally in infiltrating inflammatory cells was observed with progressing fibrosis. In conclusion, fibrosis progression is characterized by a continuous decline in Stat3 DNA-binding activity related to overexpression and progressive interaction of Pias3-Stat3. The decrease in Stat3 activity correlated with reduced hepatocytes proliferation and a positive antiapoptotic balance in infiltrating inflammatory cells that are known mediators of cell damage in HCV.
 ...
PMID:Role of signal transducer and activator of transcription 3 in liver fibrosis progression in chronic hepatitis C-infected patients. 1731 96

The aim of this study was to examine the effect of the antithrombotic drugs aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of liver cirrhosis and to determine if these two drugs are beneficial in animals with advanced fibrosis or with established cirrhosis undergoing partial hepatectomy. Thioacetamide-induced cirrhotic rats received saline (N=10), aspirin (N=7), or enoxaparin (N=11) for a 5-week treatment period. Hepatic fibrosis was assessed according to METAVIR score. Liver regeneration was monitored using PCNA immunostaining. Compared to untreated cirrhotic controls, a significant improvement in fibrosis grade was observed in the aspirin (43%; chi(2)=54, P<0.001) and enoxaparin (36%; chi(2)=43, P<0.001) treated groups. Postoperatively, total serum bilirubin levels were lower in the aspirin (1.4+/-0.18 mg/dl; P<0.01) and enoxaparin (1.8+/-0.35 mg/dl; P<0.05)-treated groups compared to untreated cirrhotic controls (3.2+/-0.6 mg/dl). Hepatic regenerative activity was significantly improved in the aspirin group (57.3%+/-6.8%, versus 34.2%+/-7.2% in untreated cirrhotic controls; P<0.01) but unchanged in the enoxaparin group. We conclude that aspirin and enoxaparin hold promise as a useful therapy for patients with extensive fibrosis.
 ...
PMID:The beneficial effect of aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of cirrhosis. 1737 20

Hepatocellular carcinoma (HCC) is among the ten most common cancers in Malaysian males. As cellular proliferation is an important feature of malignant transformation, we studied the proliferation pattern of normal and benign perineoplastic liver versus hepatocellular carcinoma in an attempt to further understand the tumour transformation process. 39 HCC (21 with accompanying and 18 without cirrhosis) histologically diagnosed at the Department of Pathology, University of Malaya Medical Centre between January 1992 and December 2003 were immunohistochemically studied using a monoclonal antibody to PCNA (Clone PC10: Dako). 20 livers from cases who had succumbed to traumatic injuries served as normal liver controls (NL). PCNA labeling index (PCNA-LI) was determined by counting the number of immunopositive cells in 1000 contiguous HCC, benign cirrhotic perineoplastic liver (BLC), benign perineoplastic non-cirrhotic (BLNC) and NL cells and conversion to a percentage. The PCNA-LI was also expressed as Ojanguren et al's grades. PCNA was expressed in 10% NL, 38.9% BLNC, 76.2% BLC and 71.8% HCC with BLNC, BLC and HCC showing significantly increased (p < 0.05) number of cases which expressed PCNA compared with NL. The number of BLC which expressed PCNA was also significantly increased compared with BLNC. PCNA-LI ranged from 0-2.0% (mean = 0.2%) in NL, 0-2.0% (mean = 0.3%) in BLNC, 0-3.6% (mean = 0.7%) in BLC and 0-53.8% (mean = 7.6%) in HCC with PCNA-LI significantly increased (p < 0.05) only in HCC compared with BLC, BLNC and NL. Accordingly, all NL, BLC and BLNC showed minimal (<5% cells being immunopositive) immunoreactivity on Ojanguren et al's grading system and only HCC demonstrated immunoreactivity which ranged up to grade 3 (75% of cells). From this study, there appears to be a generally increasing trend of proliferative activity from NL to BLNC to BLC and HCC. Nonetheless, BLNC and BLC, like NL, retained low PCNA-LI and only HCC had a significantly increased PCNA-LI compared with the benign categories. This is probably related to the malignant nature of HCC and may reflect the uncontrolled proliferation of the neoplastic hepatocytes.
 ...
PMID:Proliferating cell nuclear antigen (PCNA) activity in hepatocellular carcinoma, benign peri-neoplastic and normal liver. 1837 94


<< Previous 1 2 3 4 5 6 7 8 Next >>