Papers by Gianfranco D Alpini
AJP: Heart and Circulatory Physiology, 2004
Journal of Clinical Investigation, 2008
Hh pathway activity. Relief of ductal obstruction in BDL rats reduced Hh pathway activity, EMT, a... more Hh pathway activity. Relief of ductal obstruction in BDL rats reduced Hh pathway activity, EMT, and biliary fibrosis. In mouse cholangiocytes, coculture with myofibroblastic hepatic stellate cells, a source of soluble Hh ligands, promoted EMT and cell migration. Addition of Hh-neutralizing antibodies to cocultures blocked these effects. Finally, we found that EMT responses to BDL were enhanced in patched-deficient mice, which display excessive activation of the Hh pathway. Together, these data suggest that activation of Hh signaling promotes EMT and contributes to the evolution of biliary fibrosis during chronic cholestasis.
Hepatology, 2011
Background-Biliary Atresia (BA) is notable for marked ductular reaction and rapid development of ... more Background-Biliary Atresia (BA) is notable for marked ductular reaction and rapid development of fibrosis. Activation of the Hedgehog (Hh) pathway promotes the expansion of populations of immature epithelial cells that co-express mesenchymal markers and may be profibrogenic. We examined the hypothesis that in BA excessive Hh activation impedes ductular morphogenesis and enhances fibrogenesis by promoting accumulation of immature ductular cells with a mesenchymal phenotype.
Stem Cells, 2008
Liver injury activates quiescent (Q) hepatic stellate cells (HSC) to proliferative, myofibroblast... more Liver injury activates quiescent (Q) hepatic stellate cells (HSC) to proliferative, myofibroblasts (MF). Accumulation of MF-HSC sometimes causes cirrhosis and liver failure. However, MF-HSC also promote liver regeneration by producing growth factors for oval cells, bipotent progenitors of hepatocytes and cholangiocytes. Genes that are expressed by primary HSC isolates overlap with those expressed by oval cells, and hepatocytic and ductular cells emerge when HSC are cultured under certain conditions. We evaluated the hypothesis that HSC are a type of oval cell and, thus, capable of generating hepatocytes to regenerate injured livers. Because Q-HSC express glial fibrillary acidic protein (GFAP), we crossed mice in which GFAP promoter elements regulated Cre-recombinase with ROSA-loxP-stop-loxP-GFP mice to generate GFAP-Cre/GFP double transgenic mice. These mice were fed methionine choline deficient, ethionine supplemented (MCDE) diets to activate and expand HSC and oval cell populations. GFP(+) progeny of GFAPexpressing precursors were characterized by immunohistochemistry. Basal expression of mesenchymal markers was negligible in GFAP(+)Q-HSC. When activated by liver injury or culture, HSC down-regulated expression of GFAP but remained GFP(+); they became highly proliferative and began to co-express markers of mesenchyme and oval cells. These transitional cells disappeared as GFP-expressing hepatocytes emerged, began to express albumin, and eventually repopulated large areas of the hepatic parenchyma. Ductular cells also expressed GFAP and GFP, but their proliferative activity did not increase in this model. These findings suggest that HSC are a type of oval cell that transitions through a mesenchymal phase before differentiating into hepatocytes during liver regeneration.
The American Journal of Pathology, 2005
Gastroenterology, 2003
Gastroenterology, Volume 124, Issue 4, Pages A729, April 2003, Authors:Silvia Taffetani; Tushar P... more Gastroenterology, Volume 124, Issue 4, Pages A729, April 2003, Authors:Silvia Taffetani; Tushar Patel; Yoshiyuki Ueno; Julie Venter; Heather Francis; Brandy Baumann; Shannon Glaser; Carla Marienfeld; Jo Lynne Phinizy; Marco Marzioni; Antonio Benedetti; Gianfranco Alpini. ...
The American Journal of Pathology, 2008
We evaluated the morphological and functional features of hepatic cyst epithelium in adult autoso... more We evaluated the morphological and functional features of hepatic cyst epithelium in adult autosomal dominant polycystic kidney disease (ADPKD). In six ADPKD patients, we investigated the morphology of cyst epithelium apical surface by scanning electron microscopy and the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF1), IGF1 receptors (IGF1-R), growth hormone receptor, the proliferation marker proliferating cell nuclear antigen, and pAKT by immunohistochemistry and immunofluorescence. Proliferation of liver cyst-derived epithelial cells was evaluated by both MTS proliferation assay and [ 3 H]thymidine incorporation into DNA. The hepatic cyst epithelium displayed heterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortened cilia in 1-to 3-cm cysts, and exhibiting the absence of both primary cilia and microvilli in large cysts (>3 cm). Cyst epithelium showed marked immunohistochemical expression of ER, growth hormone receptor, IGF1, IGF1-R, proliferating cell nuclear antigen, and pAKT. IGF1 was 10-Supported by the Scott and White Hospital (grant award to G.A.), the Texas A&M University System (to G.A.), the Veterans Administration (merit award and research scholar award to G.A.), the National Institutes of Health (grants DK 58411 and DK062975 to G.A. and P30 DK-34928Y to D.M.J.), MIUR (Italian Ministry of Education, University and Research) (PRIN 2005 grants 2005069739_003 and 2005067975_002 to D.A. and A.F.A), Cofin 2003 (to E.G. and P.O.), Cofin 2005 (to E.G. and P.O.), Biomedicina (cluster C04, progetto n.ro 5, and ex 60% to E.G. and P.O.), the Fondazione San Martino (to M.S.), Bergamo (to M.S.), and Yale University (recruitment grant to M.S.).
Gastroenterology, 2000
Cholangiocarcinoma is an aggressive malignancy of the biliary tract for which effective treatment... more Cholangiocarcinoma is an aggressive malignancy of the biliary tract for which effective treatment is lacking. Tannic acid (TA) is a naturally occurring polyphenolic compound with antioxidant and radical scavenging properties as well as anticarcinogenic effects. TA inhibited proliferation of malignant human cholangiocytes in vitro. Furthermore, the growth rate of Mz-ChA-1 cholangiocarcinoma xenografts in balb/c athymic mice was reduced from 10.9 ŘŽ 1.8 mm 3 /d in mice fed with normal water to 5.5 ŘŽ 1.2 mm 3 /d in mice fed with water containing 0.05% TA. Pretreatment with 50 g/mL TA for 24 hours before xenograft implantation increased tumor latency by 2.5-fold compared with untreated controls, and decreased subsequent growth rates compared with controls in the absence of TA feeding. TA was not cytotoxic to Mz-ChA-1 cells in vitro, but enhanced sensitivity to camptothecin cytotoxicity. TA potently inhibited cell cycle progression, and increased expression of the cyclin-dependent kinase inhibitor p27 KIP1 . In addition, TA (0-50 g/mL) inhibited proteasomal activity in cholangiocyte cell extracts in a concentration-dependent manner. In conclusion, the growth inhibitory effects of TA may result from dysregulation of cell cycle progression due to altered proteasomal degradation of these cell cycle regulatory proteins. TA warrants evaluation as a candidate for the treatment of human cholangiocarcinoma either by itself or in combination with other chemotherapeutic agents.
American journal of physiology. Gastrointestinal and liver physiology, 2003
The aim of this study was to determine whether taurocholate prevents vagotomy-induced cholangiocy... more The aim of this study was to determine whether taurocholate prevents vagotomy-induced cholangiocyte apoptosis. After bile duct ligation (BDL) + vagotomy, rats were fed taurocholate for 1 wk in the absence or presence of wortmannin. Caspase involvement was evaluated by measurement of caspase 8, 9, and 3 activities. Proliferation was determined by morphometry and PCNA immunoblots. Changes in phosphatidylinositol 3-kinase (PI3-kinase) activity were estimated by the expression of the phosphorylated Akt protein. Apically located Na(+)-dependent bile acid transporter (ABAT) expression and activity were evaluated by immunoblots and [(3)H]taurocholate uptake, respectively. Cholangiocyte apoptosis increased, whereas proliferation decreased in BDL + vagotomy rats. Taurocholate feeding prevented vagotomy effects on cholangiocyte functions, which were abolished by wortmannin. ABAT expression and activity as well as phosphorylated Akt protein expression were reduced by vagotomy but restored by t...
AJP: Gastrointestinal and Liver Physiology, 2006
Abbreviations used: BDI = bile duct incannulation; BDL = bile duct ligation; cAMP = adenosine 3',... more Abbreviations used: BDI = bile duct incannulation; BDL = bile duct ligation; cAMP = adenosine 3', 5'-monophosphate; PCNA = proliferating cellular nuclear antigen; r-VEGF-A = recombinant-VEGF-A; VEGF = vascular endothelial growth factor.
The incidence and mortality of cholangiocarcinoma are increasing worldwide. Cholangiocarcinogenes... more The incidence and mortality of cholangiocarcinoma are increasing worldwide. Cholangiocarcinogenesis is a multistep process evolving from a normal condition through chronic inflammation of the biliary tract to cholangiocarcinoma. The advances of molecular techniques reached in the last years were accompanied by a growing understanding of the molecular mechanisms involved in cholangiocarcinogenesis. However, many pathophysiologic aspects of this neoplasia are undefined.
The American Journal of Pathology, 2015
Cholangiocarcinomas (CCA) are comprised of a mucin-secreting form, intrahepatic (IH) or perihilar... more Cholangiocarcinomas (CCA) are comprised of a mucin-secreting form, intrahepatic (IH) or perihilar (pCCA), and, a mixed form located peripherally. We characterized cancer stem cells (CSCs) in CCA subtypes and evaluated their cancerogenic potential. CSC markers were investigated in 25 human CCAs, in primary cultures and established cell lines.
F1000 - Post-publication peer review of the biomedical literature, 2011
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2014
F1000 - Post-publication peer review of the biomedical literature, 2011
Vitamins and hormones, 2009
The endocannabinoid system comprises specific cannabinoid receptors such as Cb1 and Cb2, the endo... more The endocannabinoid system comprises specific cannabinoid receptors such as Cb1 and Cb2, the endogenous ligands (anandamide and 2-arachidonyl glycerol among others) and the proteins responsible for their synthesis and degradation. This system has become the focus of research in recent years because of its potential therapeutic value several disease states. The following review describes our current knowledge of the changes that occur in the endocannabinoid system during carcinogenesis and then focuses on the effects of anandamide on various aspects of the carcinogenic process such as growth, migration, and angiogenesis in tumors from various origins.
Hepatobiliary surgery and nutrition, 2014
Cholangiocyte proliferation is coordinately regulated by a number of gastrointestinal hormones/pe... more Cholangiocyte proliferation is coordinately regulated by a number of gastrointestinal hormones/peptides, some of which display stimulatory effects and some have inhibitory actions on cholangiocyte proliferation. Enhanced biliary proliferation [for example after bile duct ligation (BDL) and partial hepatectomy] is associated with increased expression of secretin receptor (SR), cystic fibrosis transmembrane conductance regulator (CFTR) and Cl(-)/HCO3 (-) anion exchanger 2 and secretin-stimulated ductal secretion, whereas loss/damage of bile ducts [for example after acute carbon tetrachloride (CCl4) administration] is associated with reduced secretin-stimulated ductal secretory activity. There is growing information regarding the role of gastrointestinal hormones the regulation of biliary growth. For example, while gastrin, somatostatin and serotonin inhibit bile duct hyperplasia of cholestatic rats by downregulation of cAMP signaling, secretin has been shown to stimulate the prolifera...
Hepatobiliary surgery and nutrition, 2014
The intrahepatic biliary epithelium is a three-dimensional tubular system lined by cholangiocytes... more The intrahepatic biliary epithelium is a three-dimensional tubular system lined by cholangiocytes, epithelial cells that in addition to modify ductal bile are also the targets of vanishing bile duct syndromes (i.e., cholangiopathies) such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) that are characterized by the damage/proliferation of cholangiocytes. Cholangiocyte proliferation is critical for the maintenance of the biliary mass and secretory function during the pathogenesis of cholangiopathies. Proliferating cholangiocytes serve as a neuroendocrine compartment during the progression of cholangiopathies, and as such secrete and respond to hormones, neurotransmitters and neuropeptides contributing to the autocrine and paracrine pathways that regulate biliary homeostasis. The focus of this review is to summarize the recent findings related to the role of melatonin in the modulation of biliary functions and liver damage in response to a number of insults...
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Papers by Gianfranco D Alpini