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)

We determined the plasma antigen levels of urokinase-type plasminogen activator(u-PA) and plasminogen activator inhibitor 2(PAI-2) in 41 patients with hepatocellular carcinoma and 28 patients with different stages of liver cirrhosis. No significant differences of u-PA and PAI-2 levels were calculated between the two groups of tumor patients (HCC) and liver cirrhosis without tumor (non-HCC). Within both study groups, no significant differences were found in u-PA and PAI-2 levels of the different Child categories. Discriminative functions of both u-PA and PAI-2 (total error count estimates of 43.1% and 43.6%, respectively), were low compared to that (29.0%) of alpha-fetoprotein (AFP). The combinations of AFP and u-PA lowered the total error rate (21.9%) more than that of each marker alone. However, whether plasma u-PA and PAI-2 may be considered as a risk factor further investigation was needed and our findings raise the question as to whether these markers could be considered as useful screening markers for earlier detection of HCC in liver cirrhosis because discriminant functions of u-PA and PAI-2 were not significant. Sensitivities and specificities of u-PA and PAI-2 were also not high enough, resulting in the ranges of total diagnostic efficiency from 43% to 50%, and, from 49% to 63%, respectively, at different cut-off values. No direct relationship was detected between AFP and u-PA, between AFP and PAI-2, and between u-PA and PAI-2.
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PMID:Diagnostic efficacy of plasma urokinase-type plasminogen activator and plasminogen activator inhibitor-2 in differentiation of hepatocellular carcinoma from cirrhosis. 857 13

It has become more and more clear in recent decades that the plasminogen activation system, which includes urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), plasminogen activator inhibitor (PAI)-1 and PAI-2, plays a very important role in the aggressiveness of cancer. Using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), the expression of these four components of the uPA system was analyzed in 19 cases of hepatocellular carcinoma (HCC) and 18 cases of the adjacent non-cancer tissues which all had chronic active hepatitis with liver fibrosis or liver cirrhosis. Four cases of normal liver tissues, as controls for immunohistochemical stains, were obtained from the hepatectomized liver of patients with metastatic cancer in the liver. The positive rates of uPA, uPAR, PAI-1 and PAI-2 for immunohistochemical stains in cancer tissues were 78.9, 68.4, 57.9 and 31.6%, respectively. Positive signals were mainly distributed in the cytoplasm of the cancer and in stromal cells. Moreover, the strong stains were chiefly located in the invasive front of the cancer cells. No specific stain was detected in four cases of normal liver tissues. In ELISA, there were significant differences between cancer and non-cancer tissues in concentration of uPA, uPAR and PAI-1 (P < 0.0003, 0.0024 and 0.01, respectively), but there was no significant difference in that of PAI-2 (P = 0.37). These results suggest that uPA, uPAR and PAI-1 are related to invasion of HCC.
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PMID:Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 and -2 in hepatocellular carcinoma. 1084 28

Hepatocyte growth factor/scatter factor (HGF/SF) is one of the most important humoral mediators of liver regeneration. It is potentially related to molecular mechanisms of hepatocarcinogenesis via a paracrine system involving its cellular receptor, c-met. In this study, the expression patterns of HGF and c-met were evidenced by multiplex RT-PCR in different specimens of human hepatic tissues (n = 71). A significant increase of c-met mRNA expression was detected in hepatitis (P = 0.001), cirrhosis (P = 0.006), and hepatocellular carcinoma (HCC) tissue (P = 0.003) compared with normal parenchyma and steatosis. HGF mRNA expression was significantly higher only in hepatitis (P = 0.01). Over-expression of c-met mRNA and under-expression of HGF mRNA were detected in the HCCs compared with the corresponding peri-tumoral tissues. Neither HGF nor c-met expression was related to age, sex, tumor size, grading, presence of pseudocapsula, and proliferative activity of the malignant hepatocytes. A significant inverse correlation was found between c-met mRNA expression level and survival (in months) of patients (P = 0.007), as previously shown for urokinase-type plasminogen activator (u-PA) mRNA (P = 0.027). In addition, c-met mRNA expression was strictly associated with u-PA mRNA level in HCC samples (P = 0.001). These data show that a loss of balance concerning HGF, c-met, and u-PA mRNA expression occurs during hepatocarcinogenesis. Particularly, up-regulation of c-met and u-PA mRNA transcription appears to be coordinately regulated, and their levels of expression are inversely correlated with survival; they must therefore play an important role in the development and progression of human HCC and may also be relevant prognostic markers.
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PMID:u-PA and c-MET mRNA expression is co-ordinately enhanced while hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma. 1092 56

Microwave coagulation therapy (MCT) is one of the treatment modalities for patients with hepatocellular carcinoma (HCC). A 67-year-old man with liver cirrhosis underwent MCT during a laparotomy for a deeply located HCC (2.5 cm in diameter) at the border of the anterior and posterior segments of the right hepatic lobe. Two weeks after MCT, he complained of abdominal fullness. Portal vein thrombosis (PVT) was diagnosed because he had massive ascites and an echogenic mass in the portal vein on abdominal ultrasonography. PVT was successfully treated by fibrinolytic therapy with a selective infusion of urokinase via the superior mesenteric artery (SMA). There have been few reports on PVT as a complication of MCT. Attention should be paid to the possible occurrence of PVT as a critical complication after MCT for liver tumors adjacent to the portal vein. Fibrinolytic therapy via the SMA is thus considered to be an effective approach for PVT after MCT.
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PMID:Portal vein thrombosis caused by microwave coagulation therapy for hepatocellular carcinoma: report of a case. 1103 17

Liver cirrhosis represents a worldwide health problem and is a major cause of mortality. Cirrhosis is the result of extensive hepatocyte death and fibrosis induced by chronic alcohol abuse and hepatitis B and C viruses. Successful gene therapy approaches to this disease may require both reversal of fibrosis and stimulation of hepatocyte growth. Urokinase-type plasminogen activator (uPA) may serve this function, as it is an initiator of the matrix proteolysis cascade and induces hepatocyte growth factor expression. In a rat cirrhosis model, a single iv administration of a replication-deficient adenoviral vector encoding a nonsecreted form of human uPA resulted in high production of functional uPA protein in the liver. This led to induction of collagenase expression and reversal of fibrosis with concomitant hepatocyte and improved liver function. Thus, uPA gene therapy may be an effective strategy for treating cirrhosis in humans.
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PMID:Liver cirrhosis is reverted by urokinase-type plasminogen activator gene therapy. 1112 55

Hepatocyte growth factor (HGF) was purified as a potent mitogen for rat hepatocytes in primary culture and is believed to be the most physiological hepatotrophic factor that triggers liver regeneration. HGF is one of the largest disulfide-linked cytokines, consisting of a 60-kDa heavy chain and a 35-kDa light chain. Human HGF is synthesized as a single polypeptide chain precursor of 728 amino acid residues that has an appreciable homology with plasminogen, and it is processed proteolytically to release an N-terminal signal peptide of 31 amino acids and to generate an active heterodimer after secretion. The novel serine protease HGF activator and urokinase-type plasminogen activator (u-PA) are responsible for the latter extracellular processing. HGF stimulates the proliferation of rat hepatocytes in primary culture at concentrations as low as 10 pM. It also stimulates the growth of various epithelial cells, endothelial cells, and some kinds of mesenchymal cells. HGF inhibits the proliferation of several tumor cell lines and induces apoptosis of some of them. It also has motogenic, morphogenic, anti-apoptotic, angiogenic, and immunoregulatory activities. The receptor of HGF is the product of c-met proto-oncogene with tyrosine kinase activity that mediates the transduction of multiple biological signals of HGF. During liver regeneration, HGF gene expression in the liver, spleen, and lung and HGF levels in the blood and liver increase prior to the induction of liver DNA synthesis. Liver regeneration is markedly inhibited by continuous administration of a neutralizing anti-HGF antibody. HGF production in cultured cells is induced by PKC-activating agents, cAMP-elevating agents, PKA-activating agents, growth factors, and inflammatory cytokines; and it is inhibited by TGF-beta, glucocorticoids, 1,25-dihydroxyvitamin D3, and retinoic acid. There are many reports on potential application of HGF as a therapeutic agent for organ diseases that are difficult to cure such as liver cirrhosis, chronic renal failure, pulmonary fibrosis, myocardial infarction, and arteriosclerosis obliterans utilizing its potent growth-stimulating activity for a wide variety of cells. ELISA kits for assays of serum and plasma HGF levels are clinically used to prognosticate the development of fulminant hepatic failure.
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PMID:[Function and regulation of production of hepatocyte growth factor (HGF)]. 1206 Nov 40

Gene therapy may represent a new avenue for the development of multimodal treatment for diverse forms of cirrhosis. This study explores the potential benefits of combining adenovirus-mediated human urokinase-plasminogen activator (AdHuPA) gene delivery and biliodigestive anastomosis to enhance the therapeutic efficacy of each treatment alone for cholestatic disorders resulting in secondary biliary cirrhosis. In an experimental model of secondary biliary cirrhosis, application of 6 x 10(11) vp/kg AdHuPA adenovirus vector resulted in 25.8% liver fibrosis reduction and some improvement in liver histology. The relief of bile cholestasis by a surgical procedure (biliodigestive anastomosis) combined with AdHuPA hepatic gene delivery rendered a synergistic effect, with a substantial 56.9 to 42.9% fibrosis decrease. AdHuPA transduction resulted in clear-cut expression of human uPA protein detected by immunohistochemistry and induction of up-regulation in the expression of metalloproteinases MMP-3, MMP-9, and MMP-2. Importantly, functional hepatic tests, specifically direct bilirubin, were improved. Also, hepatic cell regeneration, rearrangement of hepatic architecture, ascites, and gastric varices improved in cirrhotic rats treated with AdHuPA but not in counterpart AdGFP cirrhotic animals. We believe this might represent a novel therapeutic strategy for human cholestatic diseases.
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PMID:Improved effects of viral gene delivery of human uPA plus biliodigestive anastomosis induce recovery from experimental biliary cirrhosis. 1474 75

Human urokinase-type plasminogen activator (uPA) gene administration via an adenoviral (Ad)-vector induced cirrhosis regression and ameliorated hepatic dysfunction in a model of experimental liver cirrhosis. The administration of a single dose of 6 x 10(11) viral particles per kilogram of a clinical-grade Ad-vector was evaluated after the onset of rat liver cirrhosis via degradation of deposited collagen and a substantial decrease of alpha-sma-positive cells. Also, gene expression for pro-fibrogenic molecules (Col I, III, IV, TIMP-1 and PAI-1) was clearly down-regulated. In contrast, gene expression for collagen-degrading enzymes such as MMP-13 and MMP-2 was up-regulated. These events correlated with increased amounts of proteic free-TIMP-1, i.e. non-complexed with metalloproteinases (MMPs), indicating the presence of higher amounts of active MMPs inside the liver of cirrhotic animals treated with Ad-huPA. The harmonized and concerted expression of HGF and c-met resulted in exacerbated hepatocyte proliferation, although these events did not induce an abnormal liver growth. Angiogenesis, i.e. formation of new blood vessels, was evaluated by vascular endothelial growth factor (VEGF) expression which was notably detected to be 10 times higher during the first 6 days after Ad-huPA-treatment in cirrhotic animals as compared with controls. These events provide a clearer rationale as to how Ad-huPA-induced liver regeneration on CCl(4)-induced liver fibrosis takes place.
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PMID:Urokinase-type plasminogen activator gene therapy in liver cirrhosis is mediated by collagens gene expression down-regulation and up-regulation of MMPs, HGF and VEGF. 1695 60

The fibrinolytic characteristics and clinical pathological significance of pleural and ascitic fluid were studied in patients with malignant tumour, tuberculosis or liver cirrhosis. Urokinase plasminogen activator (uPA) and urokinase plaminogen activator receptor (uPAR) levels were measured by enzyme-linked immunoadsorbent assay and tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), plasminogen (Plg), plasmin (Pl) and alpha(2) plasmin inhibitor (alpha(2)PI) by colorimetric assay. uPA and uPAR levels were higher in malignant tumour and tuberculosis compared with liver cirrhosis, whereas tPA levels were significantly higher in liver cirrhosis and malignant tumour than in tuberculosis patients. Tuberculosis patients showed statistically higher PAI-1, Plg and Pl concentrations than malignant tumour patients, which, in turn, were higher than those in liver cirrhosis patients. alpha(2)PI levels were markedly higher in malignant tumour and liver cirrhosis than in tuberculosis. In the malignant tumour group, only uPA level was significantly different between the samples that contained cancer cells and those that did not. We found significant differences between the fibrinolytic characteristics in pleural and ascitic fluid in patients with malignant tumour, tuberculosis and liver cirrhosis. The analysis of several fibrinolytic parameters could help to determine the quality of pleural and ascitic fluid, and also to further understand the pathological processes of these diseases.
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PMID:Fibrinolytic characteristics and their significance in malignant, tuberculous and cirrhotic pleural and ascitic fluids. 1747 86

Hepatitis C virus (HCV) causes persistent infection and induces chronic hepatitis, liver cirrhosis and finally hepatocellular carcinoma. Current therapies for HCV infection have not been satisfactory, and more effective anti-viral treatments are needed. In this regard, detailed analysis of HCV has been hampered by a lack of appropriate viral culture systems and small animal models of infection. However, rapid progress in HCV research has recently been achieved, such as a subgenomic replicon system, a viral culture system using JFH-1 clone and the Alb-uPA/SCID mouse transplanted with human liver cells. Such progress will propel HCV research and anti-HCV drug discovery toward the next generation.
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PMID:HCV research and anti-HCV drug discovery: toward the next generation. 1786 75


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