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https://www.readbyqxmd.com/read/28317394/an-update-on-the-pathophysiology-and-management-of-polycystic-liver-disease
#1
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 18, 2017: Expert Review of Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28315314/nicotine-promotes-cholangiocarcinoma-growth-in-xenograft-mice
#2
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 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...
March 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28300663/1-2-dichloropropane-generates-phosphorylated-histone-h2ax-via-cytochrome-p450-2e1-mediated-metabolism
#3
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- (1-10 mM: 4 h) and time-dependent (1-24 h: 5 mM) γ-H2AX generation in cultured human hepatocytes (WRL-68) and cholangiocytes (MMNK-1)...
March 11, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28289714/bile-acids-initiate-cholestatic-liver-injury-by-triggering-a-hepatocyte-specific-inflammatory-response
#4
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
#5
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
#6
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
#7
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
https://www.readbyqxmd.com/read/28250026/foxo3-increases-mir-34a-to-cause-palmitate-induced-cholangiocyte-lipoapoptosis
#8
Sathish Kumar Natarajan, Bailey A Stringham, Ashley M Mohr, Cody J Wehrkamp, Sizhao Lu, Mary Anne Phillippi, Dee Harrison-Findik, Justin L Mott
Non-alcoholic steatohepatitis (NASH) patients have elevated plasma saturated free fatty acid levels. These toxic fatty acids can induce liver cell death and our recent results demonstrated that the biliary epithelium may be susceptible to lipotoxicity. Here, we explored the molecular mechanisms of cholangiocyte lipoapoptosis in cell culture and in an animal model of NASH. Treatment of cholangiocytes with palmitate showed increased caspase-3/7 activity, and increased levels of cleaved PARP and cleaved caspase 3 demonstrating cholangiocyte lipoapoptosis...
March 1, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28249268/bile-acids-in-polycystic-liver-diseases-triggers-of-disease-progression-and-potential-solution-for-treatment
#9
Maria J Perugorria, Ibone Labiano, Aitor Esparza-Baquer, Marco Marzioni, Jose J G Marin, Luis Bujanda, Jesús M Banales
Polycystic liver diseases (PLDs) are a group of genetic hereditary cholangiopathies characterized by the development and progressive growth of cysts in the liver, which are the main cause of morbidity. Current therapies are based on surgical procedures and pharmacological strategies, which show short-term and modest beneficial effects. Therefore, the determination of the molecular mechanisms of pathogenesis appears to be crucial in order to find new potential targets for pharmacological therapy. Ductal plate malformation during embryogenesis and abnormal cystic cholangiocyte growth and secretion are some of the key mechanisms involved in the pathogenesis of PLDs...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28249265/role-of-the-g-protein-coupled-bile-acid-receptor-tgr5-in-liver-damage
#10
Maria Reich, Caroline Klindt, Kathleen Deutschmann, Lina Spomer, Dieter Häussinger, Verena Keitel
BACKGROUND: TGR5 (G protein-coupled bile acid receptor 1, M-Bar) is a G protein-coupled cell surface receptor responsive to bile acids (BA) and different steroid hormones. TGR5 mRNA is detected almost ubiquitious in human and rodent tissues with a very high expression in gallbladder, liver and intestine. In liver, TGR5 is found in sinusoidal endothelial cells, Kupffer cells and cholangiocytes. Activation of TGR5 triggers an elevation of intracellular cyclic AMP and further downstream signalling...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28249264/bile-acids-and-deregulated-cholangiocyte-autophagy-in-primary-biliary-cholangitis
#11
Motoko Sasaki, Yasuni Nakanuma
BACKGROUND: Primary biliary cholangitis (PBC) is characterized by a high prevalence of serum anti-mitochondrial antibodies against the E2 subunit of the pyruvate dehydrogenase complex and bile duct lesions called chronic non-suppurative destructive cholangitis (CNSDC) in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. Macroautophagy (a major type of autophagy) is a process of cellular self-digestion that plays a critical role in energy homeostasis and in the cytoprotection to various stresses...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28249257/therapeutic-mechanisms-of-bile-acids-and-nor-ursodeoxycholic-acid-in-non-alcoholic-fatty-liver-disease
#12
Daniel Steinacher, Thierry Claudel, Michael Trauner
Non-alcoholic fatty liver disease is one of the most rapidly rising clinical problems in the 21st century. So far no effective drug treatment has been established to cure this disease. Bile acids (BAs) have a variety of signaling properties, which can be used therapeutically for modulating hepatic metabolism and inflammation. A side-chain shorted derivative of ursodeoxycholic acid (UDCA) is 24 nor-ursodeoxycholic acid (NorUDCA) and it represents a new class of drugs for treatment of liver diseases. NorUDCA has unique biochemical and therapeutic properties, since it is relatively resistant to conjugation with glycine or taurine compared to UDCA...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28245426/histopathological-evidence-for-the-existence-of-primary-liver-progenitor-cell-cancer-insight-from-cancer-stem-cell-pathobiology
#13
Cheng-Maw Ho, Shu-Li Ho, Chia-Tung Shun, Po-Huang Lee, Ya-Hui Chen, Chin-Sung Chien, Hui-Ling Chen, Rey-Heng Hu
BACKGROUND: Primary liver progenitor cell cancer is a rare disease entity. Current nomenclature of primary liver cancer with prominent progenitor features is not comprehensive. This study was aimed to investigate the existence of this type of primary liver cancer and characterize it immunohistopathologically based on the emerging understanding of cancer stem cell pathobiology. METHODS: Surgical specimens from a primary liver cancer were stained with antibodies against well-defined markers of progenitor cells, stemness, and differentiation toward hepatocytes or cholangiocytes...
January 2017: Discovery Medicine
https://www.readbyqxmd.com/read/28237397/sox17-regulates-cholangiocyte-differentiation-and-acts-as-a-tumor-suppressor-in-cholangiocarcinoma
#14
M Merino-Azpitarte, E Lozano, M J Perugorria, A Esparza-Baquer, O Erice, A Santos-Laso, C J O'Rourke, J B Andersen, R Jiménez-Agüero, A Lacasta, M D'Amato, O Briz, N Jalan-Sakrikar, R C Huebert, K M Thelen, S A Gradilone, A M Aransay, J L Lavín, M G Fernández-Barrena, A Matheu, M Marzioni, G J Gores, L Bujanda, J J G Marin, J M Banales
BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a biliary malignancy linked to genetic and epigenetic abnormalities, such as hypermethylation of SOX17 promoter. Here, the role of SOX17 in cholangiocyte differentiation and cholangiocarcinogenesis was studied. METHODS: SOX17 expression/function was evaluated along the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation process of normal human cholangiocytes (NHC) in culture and in cholangiocarcinogenesis...
February 22, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28213465/epithelial-morphogenesis-during-liver-development
#15
Naoki Tanimizu, Toshihiro Mitaka
Tissue stem/progenitor cells supply multiple types of epithelial cells that eventually acquire specialized functions during organ development. In addition, three-dimensional (3D) tissue structures need to be established for organs to perform their physiological functions. The liver contains two types of epithelial cells, namely, hepatocytes and cholangiocytes, which are derived from hepatoblasts, fetal liver stem/progenitor cells (LPCs), in mid-gestation. Hepatocytes performing many metabolic reactions form cord-like structures, whereas cholangiocytes, biliary epithelial cells, form tubular structures called intrahepatic bile ducts...
February 17, 2017: Cold Spring Harbor Perspectives in Biology
https://www.readbyqxmd.com/read/28201845/regenerative-medicine-and-the-biliary-tree
#16
Thiago M De Assuncao, Nidhi Jalan-Sakrikar, Robert C Huebert
Despite decades of basic research, biliary diseases remain prevalent, highly morbid, and notoriously difficult to treat. We have, however, dramatically increased our understanding of biliary developmental biology, cholangiocyte pathophysiology, and the endogenous mechanisms of biliary regeneration and repair. All of this complex and rapidly evolving knowledge coincides with an explosion of new technological advances in the area of regenerative medicine. New breakthroughs such as induced pluripotent stem cells and organoid culture are increasingly being applied to the biliary system; it is only a matter of time until new regenerative therapeutics for the cholangiopathies are unveiled...
February 2017: Seminars in Liver Disease
https://www.readbyqxmd.com/read/28196718/the-neuropeptide-galanin-is-up-regulated-during-cholestasis-and-contributes-to-cholangiocyte-proliferation
#17
Matthew McMillin, Gabriel Frampton, Stephanie Grant, Sharon DeMorrow
During the course of cholestatic liver diseases, mitotically dormant cholangiocytes proliferate and subsequently acquire a neuroendocrine phenotype. Galanin is a neuroendocrine factor responsible for regulation of physiological responses, such as feeding behavior and mood, and has been implicated in the development of fatty liver disease, although its role in biliary hyperplasia is unknown. Biliary hyperplasia was induced in rats via bile duct ligation (BDL) surgery, and galanin was increased in serum and liver homogenates from BDL rats...
February 11, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28184004/ets-proto-oncogene-1-transcriptionally-up-regulates-the-cholangiocyte-senescence-associated-protein-cyclin-dependent-kinase-inhibitor-2a
#18
Steven P O'Hara, Patrick L Splinter, Christy E Trussoni, Maria J Lorenzo Pisarello, Lorena Loarca, Noah S Splinter, Bryce F Schutte, Nicholas F LaRusso
Primary sclerosing cholangitis (PSC) is a chronic, fibro-inflammatory cholangiopathy (disease of the bile ducts) of unknown pathogenesis. We reported that cholangiocyte senescence features prominently in PSC and neuroblastoma RAS viral oncogene homolog (NRAS) is activated in PSC cholangiocytes. Additionally, persistent microbial insult (e.g., lipopolysaccharides [LPS]) induces Cyclin Dependent Kinase Inhibitor 2A (CDKN2A/p16INK4a) expression and senescence in cultured cholangiocytes in an NRAS-dependent manner...
February 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28135758/the-diversity-and-plasticity-of-adult-hepatic-progenitor-cells-and-their-niche
#19
REVIEW
Jiamei Chen, Long Chen, Mark A Zern, Neil D Theise, Ann Mae Diehl, Ping Liu, Yuyou Duan
The liver is a unique organ for homoeostasis with regenerative capacities. Hepatocytes possess a remarkable capacity to proliferate upon injury; however, in more severe scenarios liver regeneration is believed to arise from at least one, if not several facultative hepatic progenitor cell compartments. Newly identified pericentral stem/progenitor cells residing around the central vein is responsible for maintaining hepatocyte homoeostasis in the uninjured liver. In addition, hepatic progenitor cells have been reported to contribute to liver fibrosis and cancers...
January 30, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28120434/the-role-of-s1pr2-in-bile-acid-induced-cholangiocyte-proliferation-and-cholestasis-induced-liver-injury-in-mice
#20
Yongqing Wang, Hiroaki Aoki, Jing Yang, Kesong Peng, Runping Liu, Xiaojiaoyang Li, Xiaoyan Qiang, Lixin Sun, Emily C Gurley, Guanhua Lai, Luyong Zhang, Guang Liang, Masayuki Nagahashi, Kazuaki Takabe, William M Pandak, Phillip B Hylemon, Huiping Zhou
Bile duct obstruction is a potent stimulus for cholangiocyte proliferation, especially for large cholangiocytes. Our previous studies reported that conjugated bile acids (CBAs) activate the AKT and ERK1/2 signaling pathways via the sphingosine 1-phosphate receptor 2 (S1PR2) in hepatocytes and cholangiocarcinoma cells. It also has been reported that taurocholate (TCA) promotes large cholangiocyte proliferation and protects cholangiocytes from bile duct ligation (BDL)-induced apoptosis. However, the role of S1PR2 in bile acid-mediated cholangiocyte proliferation and cholestatic liver injury has not been elucidated...
January 24, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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