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https://www.readbyqxmd.com/read/28543567/tgr5-contributes-to-hepatic-cystogenesis-in-rodents-with-polycystic-liver-diseases-via-camp-g%C3%AE-s-signaling
#1
Tatyana V Masyuk, Anatoliy I Masyuk, Maria Lorenzo Pisarello, Brynn N Howard, Bing Q Huang, Pui-Yuen Lee, Xavier Fung, Eduard Sergienko, Robert J Ardesky, Thomas Dy Chung, Anthony B Pinkerton, Nicholas F LaRusso
Hepatic cystogenesis in Polycystic Liver Disease (PLD) is associated with increased levels of cAMP in cholangiocytes lining liver cysts. TGR5, a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with PLD. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to: (i) TGR5 agonists [taurolithocholic acid (TLCA), oleanolic acid (OA) and two synthetic compounds]; (ii) a novel TGR5 antagonist (SBI-115); and (iii) a combination of SBI-115 and pasireotide, a somatostatin receptor (SSTR) analog...
May 23, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28526690/emerging-concepts-in-biliary-repair-and-fibrosis
#2
Luca Fabris, Carlo Spirli, Massimiliano Cadamuro, Romina Fiorotto, Mario Strazzabosco
Chronic diseases of the biliary tree (cholangiopathies) represent one of the major unmet needs in clinical hepatology and a significant knowledge gap in liver pathophysiology. The common theme in cholangiopathies is that the target of the disease is the biliary tree. After damage to the biliary epithelium, inflammatory changes stimulate a reparative response with proliferation of cholangiocytes and restoration of the biliary architecture, owing to the re-activation of a variety of morphogenetic signals. Chronic damage and inflammation, will ultimately result in pathologic repair, with generation of biliary fibrosis and clinical progression of the disease...
May 19, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28515290/a-point-mutation-in-the-rhesus-rotavirus-vp4-protein-generated-through-rotavirus-reverse-genetics-system-attenuates-the-murine-model-of-biliary-atresia
#3
Sujit K Mohanty, Bryan Donnelly, Phylicia Dupree, Inna Lobeck, Sarah Mowery, Jaroslaw Meller, Monica McNeal, Greg Tiao
Rotavirus infection is one of the most common causes of diarrheal illness in humans. In neonatal mice, rhesus rotavirus (RRV) can induce biliary atresia (BA), a disease resulting in inflammatory obstruction of the extra-hepatic biliary tract and intrahepatic bile ducts. We have previously shown that the amino acid, arginine (R) within the sequence "SRL" (amino acids 445-447) on the RRV VP4 protein is required for viral binding and entry into biliary epithelial cells. To determine if the single amino acid (R) influences the pathogenicity of the virus, we generated a recombinant virus with a single amino acid mutation at this site through a reverse genetics system...
May 17, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28506372/hepatic-progenitor-cells-an-update
#4
REVIEW
Matthias Van Haele, Tania Roskams
Liver regeneration is a fascinating and complex process with many medical implications. An important component of this regenerative process is the hepatic progenitor cell (HPC). These appealing cells are able to participate in the renewal of hepatocytes and cholangiocytes when the normal homeostatic regeneration is exhausted. Moreover, the HPC niche is of vital importance toward the activation, differentiation, and proliferation of the HPC. This niche provides a rich microenvironment for the regulation of the HPC, thanks to the intercellular secretion of molecules...
June 2017: Gastroenterology Clinics of North America
https://www.readbyqxmd.com/read/28502477/knockdown-of-hepatic-gonadotropin-releasing-hormone-by-vivo-morpholino-decreases-liver-fibrosis-in-multidrug-resistance-gene-2-knockout-mice-by-down-regulation-of-mir-200b
#5
Konstantina Kyritsi, Fanyin Meng, Tianhao Zhou, Nan Wu, Julie Venter, Heather Francis, Lindsey Kennedy, Paolo Onori, Antonio Franchitto, Francesca Bernuzzi, Pietro Invernizzi, Kelly McDaniel, Romina Mancinelli, Domenico Alvaro, Eugenio Gaudio, Gianfranco Alpini, Shannon Glaser
Hepatic fibrosis occurs during the progression of primary sclerosing cholangitis (PSC) and is characterized by accumulation of extracellular matrix proteins. Proliferating cholangiocytes and activated hepatic stellate cells (HSCs) participate in the promotion of liver fibrosis during cholestasis. Gonadotropin-releasing hormone (GnRH) is a trophic peptide hormone synthesized by hypothalamic neurons and the biliary epithelium and exerts its biological effects on cholangiocytes by interaction with the receptor subtype (GnRHR1) expressed by cholangiocytes and HSCs...
May 11, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28480071/targeted-therapy-in-biliary-tract-cancers-current-limitations-and-potentials-in-the-future
#6
REVIEW
Selley Sahu, Weijing Sun
Biliary tract cancers (BTC)/Cholangiocarcinoma (CCA) is an aggressive biliary tract epithelial malignancy from varying locations within the biliary tree with cholangiocyte depreciation., including intrahepatic cholangiocarcinoma (iCCA) (iCCA), extrahepatic cholangiocarcinoma (eCCA) and gallbladder carcinoma (GBC). The disease is largely heterogeneous in etiology, epidemiology, and molecular profile. There are limited treatment options and low survival rates for those patients with advanced or metastatic disease...
April 2017: Journal of Gastrointestinal Oncology
https://www.readbyqxmd.com/read/28462819/human-esc-ipsc-derived-hepatocyte-like-cells-achieve-zone-specific-hepatic-properties-by-modulation-of-wnt-signaling
#7
Seiji Mitani, Kazuo Takayama, Yasuhito Nagamoto, Kazuo Imagawa, Fuminori Sakurai, Masashi Tachibana, Ryo Sumazaki, Hiroyuki Mizuguchi
The function of hepatocytes largely depends on their position in the liver lobule. Although the method of differentiating hepatocytes from human pluripotent stem cells has been largely improved over the past decade, there remains no technique for generating hepatocyte-like cells (HLCs) with zone-specific hepatic properties. In this study, we searched for the factors that promote acquisition of zone-specific properties of HLCs. Here, we identified that WNT7B and WNT8B secreted from hepatocytes and cholangiocytes play important roles in achieving perivenous zone-specific characteristics, such as the enhancement of glutamine secretion, citric acid cycle, cytochrome P450 (CYP) 1A2 metabolism, and CYP1A2 induction capacities...
April 24, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28425707/development-of-a-potent-wound-healing-agent-based-on-the-liver-fluke-granulin-structural-fold
#8
Paramjit S Bansal, Michael J Smout, David Wilson, Claudia Cobos Caceres, Mohadeseh Dastpeyman, Javier Sotillo, Julia Seifert, Paul J Brindley, Alex Loukas, Norelle L Daly
Granulins are a family of protein growth factors that are involved in cell proliferation. An orthologue of granulin from the human parasitic liver fluke Opisthorchis viverrini, known as Ov-GRN-1, induces angiogenesis and accelerates wound repair. Recombinant Ov-GRN-1 production is complex and poses an obstacle for clinical development. To identify the bioactive region(s) of Ov-GRN-1, four truncated N-terminal analogues were synthesized and characterized structurally using NMR spectroscopy. Peptides that contained only two native disulfide bonds lack the characteristic granulin β-hairpin structure...
May 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28407375/h19-promotes-cholestatic-liver-fibrosis-by-preventing-zeb1-mediated-inhibition-of-epcam
#9
Yongfeng Song, Chune Liu, Xia Liu, Jocelyn Trottier, Michele Beaudoin, Li Zhang, Chad Pope, Guangyong Peng, Olivier Barbier, Xiaobo Zhong, Linheng Li, Li Wang
Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic lncRNA H19 expression, we sought to elucidate the role of H19 in cholestatic liver fibrosis. Hepatic overexpression of H19RNA augmented bile duct ligation (BDL)-induced liver fibrosis, which was accompanied by the elevation of serum ALT, AST, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19-BDL vs Null-BDL mice, whereas genes in BA synthesis were decreased...
April 13, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28397810/hepatocytic-parental-progenitor-cells-of-rat-small-hepatocytes-maintain-self-renewal-capability-after-long-term-culture
#10
Masayuki Ishii, Junichi Kino, Norihisa Ichinohe, Naoki Tanimizu, Takafumi Ninomiya, Hiromu Suzuki, Toru Mizuguchi, Koichi Hirata, Toshihiro Mitaka
The liver has a variety of functions for maintaining homeostasis, and hepatocytes play a major role. In contrast with the high regenerative capacity of mature hepatocytes (MHs) in vivo, they have not been successfully expanded ex vivo. Here we demonstrate that CD44-positive cells sorted from small hepatocyte (SH) colonies derived from a healthy adult rat liver can proliferate on a Matrigel-coated dish in serum-free chemically defined medium; in addition, a subpopulation of the cells can divide more than 50 times in a period of 17 weeks every 4-week-passage...
April 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28390947/expression-patterns-of-nuclear-receptors-in-parenchymal-and-non-parenchymal-mouse-liver-cells-and-their-modulation-in-cholestasis
#11
Ester Gonzalez-Sanchez, Delphine Firrincieli, Chantal Housset, Nicolas Chignard
Nuclear receptors (NR), the largest family of transcription factors, control many physiological and pathological processes. To gain insight into hepatic NR and their potential as therapeutic targets in cholestatis, we determined their expression in individual cell types of the mouse liver in normal and cholestatic conditions. Hepatocytes, cholangiocytes, hepatic stellate cells (HSC), sinusoidal endothelial cells (SEC) and Kupffer cells (KC) were isolated from the liver of mice with acute or chronic cholestasis (i...
April 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28389139/emerging-molecular-therapeutic-targets-for-cholangiocarcinoma
#12
REVIEW
Sumera Rizvi, Gregory J Gores
Cholangiocarcinomas (CCAs) are diverse epithelial tumors arising from the liver or large bile ducts with features of cholangiocyte differentiation, and are classified anatomically into intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). Each subtype has distinct risk factors, molecular pathogenesis, therapeutic options, and prognosis. CCA is an aggressive malignancy with a poor overall prognosis and median survival of less than 2 years in patients with advanced disease. Potentially curative surgical treatment options are limited to the subset of patients with early stage disease...
April 4, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28333915/directed-differentiation-of-human-induced-pluripotent-stem-cells-into-functional-cholangiocyte-like-cells
#13
Fotios Sampaziotis, Miguel Cardoso de Brito, Imbisaat Geti, Alessandro Bertero, Nicholas Rf Hannan, Ludovic Vallier
The difficulty in isolating and propagating functional primary cholangiocytes is a major limitation in the study of biliary disorders and the testing of novel therapeutic agents. To overcome this problem, we have developed a platform for the differentiation of human pluripotent stem cells (hPSCs) into functional cholangiocyte-like cells (CLCs). We have previously reported that our 26-d protocol closely recapitulates key stages of biliary development, starting with the differentiation of hPSCs into endoderm and subsequently into foregut progenitor (FP) cells, followed by the generation of hepatoblasts (HBs), cholangiocyte progenitors (CPs) expressing early biliary markers and mature CLCs displaying cholangiocyte functionality...
April 2017: Nature Protocols
https://www.readbyqxmd.com/read/28317394/an-update-on-the-pathophysiology-and-management-of-polycystic-liver-disease
#14
May Yw Wong, Geoffrey W McCaughan, Simone I Strasser
Polycystic liver disease (PLD) is characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. They are classified as an inherited ciliopathy /cholangiopathy as pathology exists at the level of the primary cilia of cholangiocytes. Aberrant expression of the proteins in primary cilia can impair their structures and functions, thereby promoting cystogenesis. Areas covered: This review begins by looking at the epidemiology of PLD and its natural history...
March 28, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28315314/nicotine-promotes-cholangiocarcinoma-growth-in-xenograft-mice
#15
Allyson K Martínez, Kendal Jensen, Chad Hall, April O'Brien, Laurent Ehrlich, Tori White, Fanyin Meng, Tianhao Zhou, John Greene, Francesca Bernuzzi, Pietro Invernizzi, David E Dostal, Terry Lairmore, Gianfranco Alpini, Shannon S Glaser
Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes...
May 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28300663/1-2-dichloropropane-generates-phosphorylated-histone-h2ax-via-cytochrome-p450-2e1-mediated-metabolism
#16
Tatsushi Toyooka, Yukie Yanagiba, Megumi Suda, Yuko Ibuki, Rui-Sheng Wang
1,2-Dichloropropane (1,2-DCP), a synthetic chlorinated solvent, was recently classified as carcinogenic. Genotoxic events are known as a crucial step in the initiation of cancer. However, studies on the genotoxicity of 1,2-DCP are very limited, particularly studies investigating the mechanism behind DNA damage by 1,2-DCP. In this study, we examined the genotoxicity of 1,2-DCP using phosphorylated histone H2AX (γ-H2AX), a sensitive DNA damage marker. 1,2-DCP showed dose- (1-10mM: 4h) and time-dependent (1-24h: 5mM) γ-H2AX generation in cultured human hepatocytes (WRL-68) and cholangiocytes (MMNK-1)...
March 12, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28289714/bile-acids-initiate-cholestatic-liver-injury-by-triggering-a-hepatocyte-specific-inflammatory-response
#17
Shi-Ying Cai, Xinshou Ouyang, Yonglin Chen, Carol J Soroka, Juxian Wang, Albert Mennone, Yucheng Wang, Wajahat Z Mehal, Dhanpat Jain, James L Boyer
Mechanisms of bile acid-induced (BA-induced) liver injury in cholestasis are controversial, limiting development of new therapies. We examined how BAs initiate liver injury using isolated liver cells from humans and mice and in-vivo mouse models. At pathophysiologic concentrations, BAs induced proinflammatory cytokine expression in mouse and human hepatocytes, but not in nonparenchymal cells or cholangiocytes. These hepatocyte-specific cytokines stimulated neutrophil chemotaxis. Inflammatory injury was mitigated in Ccl2(-/-) mice treated with BA or after bile duct ligation, where less hepatic infiltration of neutrophils was detected...
March 9, 2017: JCI Insight
https://www.readbyqxmd.com/read/28271527/the-role-of-lncrna-h19-in-gender-disparity-of-cholestatic-liver-injury-in-mdr2-mice
#18
Xiaojiaoyang Li, Runping Liu, Jing Yang, Lixin Sun, Luyong Zhang, Zhenzhou Jiang, Puneet Puri, Emily C Gurley, Guanhua Lai, Yuping Tang, Zhiming Huang, William M Pandak, Phillip B Hylemon, Huiping Zhou
The multi-drug resistance 2 knockout (Mdr2(-/-) ) mouse is a well-established model of cholestatic cholangiopathies. Female Mdr2(-/-) mice develop more severe hepatobiliary damage than male Mdr2(-/-) mice, which is correlated with a higher proportion of taurocholate (TCA) in bile. Although estrogen has been identified as an important player in intrahepatic cholestasis, the underlying molecular mechanisms of gender-based disparity of cholestatic injury remain unclear. The long non-coding RNA H19 is an imprinted, maternally expressed and estrogen-targeted gene, which is significantly induced in human fibrotic/cirrhotic liver and bile duct ligated mouse liver...
March 8, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28261592/pathology-of-intrahepatic-cholangiocarcinoma
#19
REVIEW
Sandrine Vijgen, Benoit Terris, Laura Rubbia-Brandt
Intrahepatic cholangiocarcinoma (iCC) is a primary carcinoma of the liver with increasing significance and major pathogenic, clinical and therapeutic challenges. Classically, it arises from malignant transformation of cholangiocytes bordering small portal bile duct (BD) to second-order segmental large BDs. It has three major macroscopic growth pattern [mass-forming (MF), periductal infiltrative (PI), and intraductal growth (IG)] and histologically is a desmoplastic stroma-rich adenocarcinoma with cholangiocyte differentiation...
February 2017: Hepatobiliary Surgery and Nutrition
https://www.readbyqxmd.com/read/28256736/substance-p-increases-liver-fibrosis-by-differential-changes-in-senescence-of-cholangiocytes-and-hepatic-stellate-cells
#20
Ying Wan, Fanyin Meng, Nan Wu, Tianhao Zhou, Julie Venter, Heather Francis, Lindsey Kennedy, Trenton Glaser, Francesca Bernuzzi, Pietro Invernizzi, Shannon Glaser, Qiaobing Huang, Gianfranco Alpini
Substance P (SP) is involved in the proliferation of cholangiocytes in bile duct ligated (BDL) mice and human cholangiocarcinoma growth by interacting with the neurokinin-1 receptor (NK-1R). To identify whether SP regulates liver fibrosis during cholestasis, wild type (WT) or NK-1R knockout (NK-1R(-/-) ) mice that received BDL or sham surgery and Mdr2(-/-) mice treated with either an NK-1R antagonist (L-733,060) or saline were used. Additionally, WT mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of TAC1 (coding SP) and NK-1R in both BDL and Mdr2(-/-) mice compared to WT mice...
March 3, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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