cardiovascular-agents and Carcinoma--Hepatocellular

The early results of liver transplantations (OLT) in patients with advanced hepatocellular carcinoma (HCC) were poor because of frequent tumor recurrence. However, OLT has significant, theoretical advantage that it removes both the tumor and the organ that is at a risk of malignancy. The Japanese law on organ transplantation limited the availability of cadaveric liver donors until its revision on July 17, 2011. ABO-incompatible OLT was formerly contraindicated because performed anti-A/B antibodies on recipient endothelial cells raised the risk of antibody-mediated humoral graft rejection. We have herein described four successful cases of steroid withdrawal among adult patients who underwent living donor OLT from ABO-incompatible donors. In addition, we transplanted a liver from a living donor into an ABO-incompatible recipient on August 9, 2004. The 55-year-old man with HCC due to hepatitis B virus (HBV) a cirrhosis had a Child-Pugh score of C, and Model for End-stage Liver Disease score of 22. Two tumors greater than 5 cm, exceeded the Milan criteria. His des-gamma-carboxy prothrombin level was 6 mAu/mL, and alpha-fetoprotein, 18.78 ng/mL. Antirejection therapy included multiple perioperative plasmaphereses and splenectomy; with an immunosuppressive regimen consisting of tacrolimus, methylprednisolone, and mycophenolate mofetil. The maintenance dose of immunosuppression did not differ from that of ABO-identical cases. After transplantation, we used intrahepatic arterial infusion therapy with prostaglandin E1 (PG E1). The patient had complications of portal vein thrombosis, hepatic artery thrombosis, and acute myocardial infarction, which were treated by interventional radiology in the posttransplantation period. We controlled the HBsAb titer by administering hepatitis B immunoglobulin and lamivudine (200 IU/L doses) for 1 year after OLT and 100 IU/L doses thereafter. As a result, the patient achieved long-term, disease-free graft survival without steroids. He currently has good liver function and leads a normal lifestyle. Our results suggested the feasibility of controlling antibody-mediated humoral rejection and other complications in living donor liver transplantations into ABO-incompatible adults via intrahepatic arterial PG E1 infusion splenectomy, and plasmapheresis with regular immunosuppression. Withdrawal of steroids, HBV vaccination, and lamivudine, an nucleoside analog reverse transcriptase inhibitor, have achieved long-term (7 years) survival

Topics: ABO Blood-Group System; Alprostadil; Antiviral Agents; Blood Group Incompatibility; Carcinoma, Hepatocellular; Cardiovascular Agents; Disease-Free Survival; Drug Therapy, Combination; Graft Rejection; Graft Survival; Hepatitis B; Hepatitis B Vaccines; Histocompatibility; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Living Donors; Male; Middle Aged; Plasmapheresis; Severity of Illness Index; Splenectomy; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Insulin increases, through several molecular mechanisms, expression of plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of fibrinolysis. This phenomenon has been implicated as a cause of accelerated coronary artery disease and the increased incidence of acute coronary syndromes associated with type 2 diabetes. We have previously reported that physiologic and pharmacologic concentrations of insulin induce PAI-1 synthesis in human HepG2 cells and that simvastatin can attenuate its effects. This study was performed to further elucidate mechanisms responsible for the insulin-induced PAI-1 production.. Concentrations of PAI-1 mRNA were determined by real-time PCR, and PAI-1 protein was assayed by western blotting. PAI-1 promoter (-829 to +36 bp) activity was assayed with the use of luciferase reporter assays. The potential role of the 3'-untranslated region (UTR) in the PAI-1 gene was assayed with the use of luciferase constructs containing the 3'-UTR. Oxidative stress was measured by loading cells with carboxy-2,7 dichlorodihydrofluorescein.. Insulin increased PAI-1 promoter activity, PAI-1 mRNA, and accumulation of PAI-1 protein in the conditioned media. Insulin-inducible PAI-1 promoter activity was attenuated by simvastatin. Experiments performed with luciferase reporters containing the 3'-UTR showed that insulin increased luciferase activity through this region. Insulin also increased oxidative stress. Both insulin-inducible luciferase activity through the 3'-UTR and oxidative stress were attenuated by simvastatin.. Insulin can increase PAI-1 expression through multiple mechanisms including induction mediated by the 3'-UTR of the PAI-1 gene. Accordingly, beneficial pleiotropic effects of statins on coronary artery disease may be attributable, in part, to attenuation of overexpression of PAI-1 mediated by the 3'-UTR in syndromes of insulin resistance (such as the metabolic syndrome) and type 2 diabetes.

Topics: 3' Untranslated Regions; Binding Sites; Blotting, Western; Carcinoma, Hepatocellular; Cardiovascular Agents; Cyclic AMP; Genes, Reporter; Hep G2 Cells; Humans; Insulin; Liver Neoplasms; Oxidative Stress; Plasminogen Activator Inhibitor 1; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Simvastatin; Up-Regulation

Reports elsewhere demonstrated that Epimedin C, a constituent isolated from the leaves of Epimedium sagittatum, possessed anti-tumor activity. However, its mechanism of action remains unresolved. Using SK-Hep-1 cells, a poorly-differentiated hepatoma subline, as an experimental model, we present evidence here that the anti-tumor activity of Epimedin C may involve cell cycle blockage. Immunoblotting analyses demonstrated that Epimedin C caused a decreased expression of hyperphosphorylated retinoblastoma (Rb) protein, cyclin D1, c-Myc, and c-Fos. In parallel, we measured the kinase activities and found that CDK2 and CDK4 were suppressed with commensurate increased levels of CDK inhibitors, p21(Cip1) and p27(Kip1). These data suggested that Epimedin C arrested the proliferation of these cells at G0/G1 phase through inhibition of CDK2 and CDK4 activities via an increased induction of p21(Cip1) and p27(Kip1). Alternatively, we investigated whether the anti-proliferative effect of Epimedin C on these cells might involve MAP kinase cascade. Using western blotting technique, we demonstrated that Epimedin C also selectively decreased ERK1/2 phosphorylation. Among the downstream effectors of ERK examined, we found that Epimedin C selectively decreased the expression of c-Fos, but not c-Jun. By EMSA assay, we further demonstrated that decreased c-Fos resulted in the downregulation of AP-1/DNA binding activity. Taken together, the molecular mechanisms of anti-tumor activity of Epimedin C may be proceeded by the combined effects of the cell cycle blockage via either the inhibition of CDK2 and CDK4 activities, with commensurate increase in their inhibitors, p21(Cip1) and p27(Kip1) or negatively modulates the ERK/c-Fos/AP-1 signaling pathway.

Topics: Blotting, Western; Carcinoma, Hepatocellular; Cardiovascular Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; DNA, Neoplasm; Electrophoretic Mobility Shift Assay; Flavonoids; Gene Expression; Genes, fos; Genes, jun; Humans; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Mitogen-Activated Protein Kinases; Transcription Factor AP-1

The binding of prostaglandin (PG) E1 and Iloprost, a chemically stable PGI2-analogue, to purified plasma cell membranes (LPZM) from liver tissue samples obtained at surgery revealed heterogeneity of the binding sites identifying high and low affinity subpopulations. In contrast to these findings only high affinity binding sites were characterized for PGE2. Displacement studies exhibited the highest competition for the PGE1-sites by PGE1 and subsequently by PGE2, Iloprost, PGD2 and PGF2 alpha. The binding of PGE2 to the hepatic receptor could be best displaced by PGE2 and subsequently by PGE1 and Iloprost, PGD2 and PGF2 alpha. In addition, PGE1, PGE2 and Iloprost enhanced cAMP-production dose-dependently over baseline. Clinical studies revealed a remarkably lower binding capacity for PGE1 in hepatocellular cancer tissue than in normal liver parenchyma. The different binding behaviour of PGE1 (Iloprost) and PGE2 for the first time provides evidence that PGE1 and PGI2 like at platelet membranes occupate the same receptor also at human LPZM. Since a reasonable number of binding sites for these substances and an enhanced cAMP-production were shown in the liver, the study indicates a regulatory role of PGs in hepatic function.

Topics: Alprostadil; Binding, Competitive; Carcinoma, Hepatocellular; Cardiovascular Agents; Cyclic AMP; Dinoprostone; Epoprostenol; Humans; Iloprost; Liver; Liver Neoplasms; Prostaglandins; Radioligand Assay; Receptors, Prostaglandin