Noriatsu Kanno

Evaluation of differential gene expression by microarray analysis in small and large cholangiocytes isolated from normal mice

Aims: We have shown that large and small cholangiocytes, which reside primarily in large and small intrahepatic bile ducts, respectively, have different functions and responses to injuries. However, there are no systematic studies of the molecular differences between small and large cholangiocytes, which would explain cholangiocyte heterogeneity. To evaluate the differential gene expression between small and large cholangiocytes, microarray analysis was performed.

Gastrin inhibits cholangiocarcinoma growth through increased apoptosis by activation of Ca2+-dependent protein kinase C-α

BACKGROUND/AIMS We determined the role of gastrin in the regulation of cholangiocarcinoma growth. METHODS We evaluated for the functional presence of cholecystokinin (CCK)-B/gastrin receptors in the cholangiocarcinoma cell lines, Mz-ChA-1, HuH-28 and TFK-1. We determined the effect of gastrin on the growth of Mz-ChA-1, HuH-28 and TFK-1 cells. We evaluated the effect of gastrin on growth and apoptosis of Mz-ChA-1 in the absence or presence of inhibitors for CCK-A (L-364, 718) and CCK-B/gastrin (L-365, 260) receptors, the intracellular Ca2+ chelator (BAPTA/AM), and the protein kinase C (PKC)-alpha inhibitor, H7. We evaluated if gastrin effects on Mz-ChA-1 growth and apoptosis are associated with membrane translocation of PKC-alpha. RESULTS Gastrin inhibited DNA synthesis of Mz-ChA-1, HuH-28 and TFK-1 cells in a dose- and time-dependent fashion. The antiproliferative effect of gastrin on Mz-ChA-1 cells was inhibited by L-365, 260, H7 and BAPTA/AM but not L-364, 718. Gastrin induced membrane translocation of PKC-alpha. The inhibition of growth of Mz-ChA-1 cells by gastrin was associated with increased apoptosis through a PKC-dependent mechanism. CONCLUSIONS Gastrin inhibits the growth of Mz-ChA-1, HuH-28 and TFK-1 cells. Gastrin inhibits growth and induces apoptosis in Mz-ChA-1 cells through the Ca2+-dependent PKC-alpha. The data suggest a therapeutic role for gastrin in the modulation of cholangiocarcinoma growth.

Extracellular Branched-Chain Amino Acids, Especially Valine, Regulate Maturation and Function of Monocyte-Derived Dendritic Cells

The functions of dendritic cells (DCs) are impaired in patients with liver cirrhosis. It is well-known that cirrhotic patients show decreased levels of plasma branched-chain amino acids (BCAA). Although amino acids are associated with maintaining the cell structure and function in many organs, limited data are available regarding the role of amino acids including BCAA in the immune system. We aimed to investigate the roles of BCAA in the function of human monocyte-derived DCs (MoDC). CD14-positive monocytes (CD14 +) were isolated from PBMC from healthy volunteers and hepatitis C virus (HCV) cirrhotic patients. In medium deprived of BCAA or valine, monocytes were able to differentiate into immature, but not into mature, DCs and showed weak expression of CD83. The deprivation of leucine or isoleucine did not affect this process. The MoDC allostimulatory capacity was significantly decreased in medium deprived of BCAA or valine (p = 0.017, p = 0.012, Bonferroni’s analysis, respectively). Annexin VFITC/propidium iodide staining showed that the DC yield and viability were not significantly different under any medium. Immunoblotting demonstrated that depletion of valine or leucine decreased phospho-S6 kinase expression. Valine increased dose-dependently the allostimulatory capacity and IL-12 production of MoDC from both healthy volunteers and HCV cirrhotic patients. An elevated extracellular concentration of valine could improve the DC function in cirrhotic patients. These data provide a rationale for nutrition therapy that could be beneficial to patients with cirrhosis.

Lack of evidence that bone marrow cells contribute to cholangiocyte repopulation during experimental cholestatic ductal hyperplasia

Abstract: Background: Ductopenia is observed in end‐stage human cholestatic diseases. The limited capability of cholangiocytes for proliferation is suggested to be the principal reason. Recently, bone marrow cells (BMCs) have been reported to behave as hepatic stem cells; however, their capability to differentiate into cholangiocytes in cholestasis remains unclear.

The model for end-stage liver disease score is useful for predicting economic outcomes in adult cases of living donor liver transplantation

BackgroundThe model for end-stage liver disease (MELD) is useful for assessing the recipients of liver transplants, namely, deceased-donor transplantation. The application of MELD for living donor liver transplantation (LDLT) is under investigation. Thus, the aim of this study was to analyze the impact of the MELD score in LDLT in Japan.MethodsSeventeen adult cases of LDLT during 2001 to 2005 were enrolled. Indications for LDLT were primary biliary cirrhosis, seven; liver cirrhosis, two; hepatocellular carcinoma (HCC), three; metabolic liver disease, one; primary sclerosing cholangitis, two; Carolis disease, one; and biliary atresia, one. Total medical charges during the operative periods were retrospectively evaluated. The united network of organ sharing (UNOS) modified was obtained using preoperative clinical data.ResultsThe average medical expense of the 17 cases was approximately

Amniotic epithelial cell-derived cholangiocytes in experimental cholestatic ductal hyperplasia

97 901. The UNOS-modified MELD score was 22.1. A statistically significant positive correlation was found between the MELD score and medical expense (P = 0.0086, ρ = 0.657), and between the MELD score and the length of stay in the intensive care unit (ICU) (P = 0.0396, ρ = 0.515). The cause of the liver disease leading to transplantation was not related to MELD score, medical expense, or length of ICU stay.ConclusionsAlthough not originally designed for the application to LDLT, the MELD score is useful for predicting medical expenses in LDLT. Similar to those of deceased-donor liver transplantation, the disadvantage of high medical expenses associated with a high MELD score allow consideration of an earlier elective operation in suitable cases.

Regulation of cholanglocyte apical bile acid transporter (ABAT) activity by biliary bile acids: Different potential compensatory changes for intrahepatic and extrahepatic cholestasis

Aim:  Bile duct paucity, ductopenia, is a feature of end‐stage chronic cholangiopathies such as primary biliary cirrhosis. The limited proliferative ability of cholangiocytes after specific injury is thought to be the principal cause of ductopenia, although the detailed mechanisms involved are unclear. It has been reported that human amniotic epithelial cells (AEC) express differentiation markers of hepatic parenchymal cells, suggesting a resemblance of AEC to hepatic progenitor cells. The aim of the present study was to develop a mouse model of experimental cholestasis to assess the capability of mouse AEC to trans‐differentiate into cholangiocytes.

The growth of two human cholangiocarcinoma cell lines is inhibited by alpha-2 adrenergic agonists by a cAMP-dependent mechanism through the inhibition of Raf-1 and MAPK systems

Regulation of Cholangiocyte Apical Bile Acid Transporter (ABAT) Activity by Biliary Bile Acids: Different Potential Compensatory Changes for Intrahepafic and Extrahepatic Cholestasis Gianfranco Alpini, The Texas AM Shannon Glaser, Jo Lynne Phinizy, Scott & White Memorial Hosp, Temple, TX; Noriatsu Kanno, The Texas AM Heather Francis, Scott & White Memorial Hosp, Temple, TX; Mikel Ludvik, The Texas AM Gene Lesage, Scott & White Memorial Hosp, Temple, TX

Regulation of cholangiocyte bicarbonate secretion

The Growth of Two Human Cholangiocaroinoma Cell Lines Is Inhibited by alpha-2 Adrenergic Agonists by a cAMP-Dependent Mechanism Through the Inhibition of Rat-1 and MAPK Systems. Noriatsu Kanno, The Texas AM Gene Lesage, Shannon Glaser, Jo Lynne Phinizy, Heather Francis, Scott & White Memorial Hosp, Temple, rx; Mikel Ludvik, Glanfranco Aipini, The Texas A&M Univ System Health Science Ctr, Temple, TX