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https://www.readbyqxmd.com/read/28098760/autocrine-and-paracrine-mechanisms-promoting-chemoresistance-in-cholangiocarcinoma
#1
REVIEW
Massimiliano Cadamuro, Simone Brivio, Carlo Spirli, Ruth E Joplin, Mario Strazzabosco, Luca Fabris
Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in the tumor microenvironment. Here, recent evidence regarding molecular mechanisms of chemoresistance is reviewed, as well as associations between well-developed chemoresistance and activation of the cancer stem cell compartment...
January 13, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28088462/activation-of-the-hypoxia-inducible-factor-1-alpha-subunit-pathway-in-steatotic-liver-contributes-to-formation-of-cholesterol-gallstones
#2
Yoichiro Asai, Tetsuya Yamada, Sohei Tsukita, Kei Takahashi, Masamitsu Maekawa, Midori Honma, Masanori Ikeda, Keigo Murakami, Yuichiro Munakata, Yuta Shirai, Shinjiro Kodama, Takashi Sugisawa, Yumiko Chiba, Yasuteru Kondo, Keizo Kaneko, Kenji Uno, Shojiro Sawada, Junta Imai, Yasuhiro Nakamura, Hiroaki Yamaguchi, Kozo Tanaka, Hironobu Sasano, Nariyasu Mano, Yoshiyuki Ueno, Tooru Shimosegawa, Hideki Katagiri
BACKGROUND AND AIMS: Hypoxia inducible factor 1 alpha subunit (HIF1A) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with non-alcoholic fatty liver disease (NAFLD). NAFLD increases risk for cholesterol gallstone disease by unclear mechanisms. We studied the relationship between HIF1A and gallstone formation associated with liver steatosis. METHODS: We performed studies with mice with inducible disruption of Hif1a in hepatocytes, via a Cre adenoviral vector (iH-HIFKO mice), and mice without disruption of Hif1a (control mice)...
January 11, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28087162/mir-24-inhibition-increases-menin-expression-and-decreases-cholangiocarcinoma-proliferation
#3
Laurent Ehrlich, Chad Hall, Julie Venter, David Dostal, Francesca Bernuzzi, Pietro Invernizzi, Fanyin Meng, Jerome P Trzeciakowski, Tianhao Zhou, Holly Standeford, Gianfranco Alpini, Terry C Lairmore, Shannon Glaser
Menin (MEN1) is a tumor-suppressor protein in neuroendocrine tissue. Because cholangiocytes can take on a neuroendocrine phenotype, we tested the novel hypothesis that menin regulates cholangiocarcinoma proliferation. Menin and miR-24 expression levels were measured in the following intrahepatic and extrahepatic cholangiocarcinoma (CCA) cell lines, Mz-ChA-1, TFK-1, SG231, CCLP, HuCCT-1, and HuH-28, as well as the nonmalignant human intrahepatic biliary line, H69. miR-24 miRNA and menin protein levels were manipulated in vitro in Mz-ChA-1 cell lines...
January 10, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28074620/double-immunostaining-for-maspin-and-p53-on-cell-blocks-increases-the-diagnostic-value-of-biliary-brushing-cytology
#4
Maki Kanzawa, Tsuyoshi Sanuki, Manabu Onodera, Kohei Fujikura, Tomoo Itoh, Yoh Zen
Our objective is to elucidate the usefulness of maspin/p53 double immunostaining on biliary brushing cytology specimens. We first examined the expression of maspin in the biliary epithelium with variable degrees of dysplasia using surgically resected specimens (n = 56). Maspin appeared to be overexpressed in a stepwise manner from benign to malignant cholangiocytes: the reactive epithelium (20%), biliary intraepithelial neoplasia (~50%), and invasive cholangiocarcinomas (>90%). Next, an automated sequential double immunostaining protocol for maspin and p53 was applied to paraffin-embedded cell blocks of the biliary brushing cytology specimens obtained from 58 consecutive patients...
January 10, 2017: Pathology International
https://www.readbyqxmd.com/read/28055309/current-strategies-to-generate-mature-human-induced-pluripotent-stem-cells-derived-cholangiocytes-and-future-applications
#5
Eduardo Cervantes-Alvarez, Yang Wang, Alexandra Collin de l'Hortet, Jorge Guzman-Lepe, Jiye Zhu, Kazuki Takeishi
Stem cell research has significantly evolved over the last few years, allowing the differentiation of pluripotent cells into almost any kind of lineage possible. Studies that focus on the liver have considerably taken a leap into this novel technology, and hepatocyte-like cells are being generated that are close to resembling actual hepatocytes both genotypically and phenotypically. The potential of this extends from disease models to bioengineering, and even also innovative therapies for end-stage liver disease...
January 5, 2017: Organogenesis
https://www.readbyqxmd.com/read/28055006/biliary-tract-instillation-of-a-smac-mimetic-induces-trail-dependent-acute-sclerosing-cholangitis-like-injury-in-mice
#6
Maria Eugenia Guicciardi, Anuradha Krishnan, Steven F Bronk, Petra Hirsova, Thomas S Griffith, Gregory J Gores
Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown etiopathogenesis characterized by fibrous cholangiopathy of large and small bile ducts. Systemic administration of a murine TNF-related apoptosis-inducing ligand (TRAIL) receptor agonist induces a sclerosing cholangitis injury in C57BL/6 mice, suggesting endogenous TRAIL may contribute to sclerosing cholangitis syndromes. Cellular inhibitor of apoptosis proteins (cIAP-1 and cIAP-2) are negative regulators of inflammation and TRAIL receptor signaling...
January 5, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28049946/ursodeoxycholic-acid-ameliorates-intrahepatic-cholestasis-independent-of-biliary-bicarbonate-secretion-in-vil2-kd-kd-mice
#7
Ryo Hatano, Kotoku Kawaguchi, Fumitaka Togashi, Masato Sugata, Shizuka Masuda, Shinji Asano
Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid that possesses many pharmacological effects, including increasing bile flow, changing the hydrophobicity of the bile acid pool, and modulation of the immune response. UDCA has been approved for treating cholestatic liver disease, such as primary biliary cholangitis. However, several unanticipated severe side effects of UDCA are observed in cholestatic patients, and its pharmacological benefits remain controversial. We reported that ezrin-knockdown (Vil2(kd/kd)) mice exhibited severe hepatic injury because of a functional disorder in bile duct fluidity and alkalinity regulation, resembling human intrahepatic cholestatic disease...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28029279/recellularization-via-the-bile-duct-supports-functional-allogenic-and-xenogenic-cell-growth-on-a-decellularized-rat-liver-scaffold
#8
Wessam Hassanein, Mehmet C Uluer, John Langford, Jhade D Woodall, Arielle Cimeno, Urmil Dhru, Avraham Werdesheim, Joshua Harrison, Carlos Rivera-Pratt, Stephen Klepfer, Ali Khalifeh, Bryan Buckingham, Philip S Brazio, Dawn Parsell, Charlie Klassen, Cinthia Drachenberg, Rolf N Barth, John C LaMattina
Recent years have seen a proliferation of methods leading to successful organ decellularization. In this experiment we examine the feasibility of a decellularized liver construct to support growth of functional multilineage cells. Bio-chamber systems were used to perfuse adult rat livers with 0.1% SDS for 24 hours yielding decellularized liver scaffolds. Initially, we recellularized liver scaffolds using a human tumor cell line (HepG2, introduced via the bile duct). Subsequent studies were performed using either human tumor cells co-cultured with human umbilical vein endothelial cells (HUVECs, introduced via the portal vein) or rat neonatal cell slurry (introduced via the bile duct)...
December 28, 2016: Organogenesis
https://www.readbyqxmd.com/read/28013213/environmental-xenoestrogens-super-activate-a-variant-murine-er-beta-in-cholangiocytes
#9
Stephanie K Meyer, Philip M E Probert, Anne K Lakey, Alastair C Leitch, Lynsay I Blake, Paul A Jowsey, Martin P Cooke, Peter G Blain, Matthew C Wright
High systemic levels of oestrogens are cholestatic and primary biliary cholangitis - which is characterised by hepatic ductular inflammation - is thought to be triggered by exposure to xenobiotics such as those around landfill sites. Xenoestrogens may be a component of this chemical trigger. We therefore hypothesised that xenoestrogens are present at higher levels in the proximity of landfill sites. To test this hypothesis, soil samples were collected, extracts prepared and biological oestrogenic activity examined using cell-based reporter gene assays...
December 24, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28009756/regeneration-and-cell-recruitment-in-an-improved-heterotopic-auxiliary-partial-liver-transplantation-model-in-the-rat
#10
Yoshihiro Ono, Angelica Pérez-Gutiérrez, Mladen I Yovchev, Kentaro Matsubara, Shinichiro Yokota, Jorge Guzman-Lepe, Kan Handa, Alexandra Collin de l'Hortet, Angus W Thomson, David A Geller, Hiroshi Yagi, Michael Oertel, Alejandro Soto-Gutierrez
BACKGROUND: Auxiliary partial liver transplantation (APLT) in humans is a therapeutic modality used especially to treat liver failure in children or congenital metabolic disease. Animal models of APLT have helped to explore therapeutic options. Though many groups have suggested improvements, standardizing the surgical procedure has been challenging. Additionally, the question of whether graft livers are reconstituted by recipient-derived cells after transplantation has been controversial...
January 2017: Transplantation
https://www.readbyqxmd.com/read/27981602/prohibitin-1-suppresses-liver-cancers-tumorigenesis-in-mice-and-human-hepatocellular-and-cholangiocarcinoma-cells
#11
Wei Fan, Heping Yang, Ting Liu, Jiaohong Wang, Tony W H Li, Nirmala Mavila, Yuanyuan Tang, JinWon Yang, Hui Peng, Jian Tu, Alagappan Annamalai, Mazen Noureddin, Anuradha Krishnan, Gregory J Gores, M L Martínez-Chantar, José M Mato, Shelly C Lu
: Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase α 1 (MATα1) have lower PHB1 expression and we reported c-MYC interacts directly with both proteins. Furthermore, c-MYC and MATα1 expert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MATα1 and c-MYC and PHB1's role in liver tumorigenesis. We found PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down-regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)...
December 16, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27979827/protective-roles-of-hepatic-gaba-signaling-in-acute-liver-injury-of-rats
#12
Shuanglian Wang, Yun-Yan Xiang, Jianchun Zhu, Fan Yi, Jingxin Li, Chuanyong Liu, Wei-Yang Lu
Gamma-aminobutyric acid (GABA) is produced by various cells through the catalytic activity of glutamic acid decarboxylase (GAD). Activation of type-A GABA receptor (GABAAR) inhibits stem cell proliferation but protects differentiated cells from injures. The present study investigated hepatic GABA signaling system and the role of this system in liver physiology and pathophysiology. RT-PCR and immunoblot assays identified GAD and GABAAR subunits in rat livers and in HepG2 and Clone 9 hepatocytes. Patch-clamp recording detected GABA-induced currents in Clone 9 hepatocytes and depolarization in WITT cholangiocytes...
December 15, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/27979774/gene-regulatory-networks-in-differentiation-and-direct-reprogramming-of-hepatic-cells
#13
REVIEW
Claude Gérard, Janne Tys, Frédéric P Lemaigre
Liver development proceeds by sequential steps during which gene regulatory networks (GRNs) determine differentiation and maturation of hepatic cells. Characterizing the architecture and dynamics of these networks is essential for understanding how cell fate decisions are made during development, and for recapitulating these processes during in vitro production of liver cells for toxicology studies, disease modelling and regenerative therapy. Here we review the GRNs that control key steps of liver development and lead to differentiation of hepatocytes and cholangiocytes in mammals...
December 12, 2016: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/27943623/challenges-on-the-road-to-a-multicellular-bioartificial-liver
#14
REVIEW
Viktoriia Starokozhko, Geny M M Groothuis
Over the past years the progress in the development of a bioartificial liver (BAL) as an extracorporeal device or as a tissue engineered transplantable organ has been immense. However, many important BAL characteristics that are necessary to meet clinical demands, have not been sufficiently addressed. This review describes the existing challenges in the development of a BAL for clinical applications, highlighting multicellularity and sinusoidal microarchitecture as crucial BAL characteristics to fulfill various liver functions...
December 12, 2016: Journal of Tissue Engineering and Regenerative Medicine
https://www.readbyqxmd.com/read/27936185/hedgehog-signaling-overcomes-an-ezh2-dependent-epigenetic-barrier-to-promote-cholangiocyte-expansion
#15
Nidhi Jalan-Sakrikar, Thiago M De Assuncao, Jie Lu, Luciana L Almada, Gwen Lomberk, Martin E Fernandez-Zapico, Raul Urrutia, Robert C Huebert
BACKGROUND & AIMS: Developmental morphogens play an important role in coordinating the ductular reaction and portal fibrosis occurring in the setting of cholangiopathies. However, little is known about how membrane signaling events in ductular reactive cells (DRCs) are transduced into nuclear transcriptional changes to drive cholangiocyte maturation and matrix deposition. Therefore, the aim of this study was to investigate potential mechanistic links between cell signaling events and epigenetic regulators in DRCs...
2016: PloS One
https://www.readbyqxmd.com/read/27916538/myofibroblasts-derived-from-hepatic-progenitor-cells-create-the-tumor-microenvironment
#16
Sayaka Sekiya, Shizuka Miura, Kanae Matsuda-Ito, Atsushi Suzuki
Hepatic progenitor cells (HPCs) appear in response to several types of chronic injury in the human and rodent liver that often develop into liver fibrosis, cirrhosis, and primary liver cancers. However, the contribution of HPCs to the pathogenesis and progression of such liver diseases remains controversial. HPCs are generally defined as cells that can differentiate into hepatocytes and cholangiocytes. In this study, however, we found that HPCs isolated from the chronically injured liver can also give rise to myofibroblasts as a third type of descendant...
December 13, 2016: Stem Cell Reports
https://www.readbyqxmd.com/read/27912077/nlrp3-activation-induces-il-18-synthesis-and-affects-the-epithelial-barrier-function-in-reactive-cholangiocytes
#17
Luca Maroni, Laura Agostinelli, Stefania Saccomanno, Claudio Pinto, Debora Giordano, Chiara Rychlicki, Samuele De Minicis, Luciano Trozzi, Jesus M Banales, Espen Melum, Tom H Karlsen, Antonio Benedetti, Gianluca Svegliati Baroni, Marco Marzioni
Microbial products are thought to influence the progression of cholangiopathies, in particular primary sclerosing cholangitis (PSC). Inflammasomes are molecular platforms that respond to microbial products through the synthesis of proinflammatory cytokines. We investigated the role of inflammasome activation in cholangiocyte response to injury. Nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing protein 3 (Nlrp3) expression was tested in cholangiocytes of normal and cholestatic livers...
November 29, 2016: American Journal of Pathology
https://www.readbyqxmd.com/read/27895309/hepatocyte-specific-expression-of-an-oncogenic-variant-of-%C3%AE-catenin-results-in-cholestatic-liver-disease
#18
Ursula J Lemberger, Claudia Fuchs, Matthias Karer, Stefanie Haas, Tatjana Stojakovic, Christian Schöfer, Hanns-Ulrich Marschall, Fritz Wrba, Makoto M Taketo, Gerda Egger, Michael Trauner, Christoph H Österreicher
BACKGROUND: The Wnt/β-catenin signaling pathway plays a crucial role in embryonic development, tissue homeostasis, wound healing and malignant transformation in different organs including the liver. The consequences of continuous β-catenin signaling in hepatocytes remain elusive. RESULTS: Livers of Ctnnb1CA hep mice were characterized by disturbed liver architecture, proliferating cholangiocytes and biliary type of fibrosis. Serum ALT and bile acid levels were significantly increased in Ctnnb1CA hep mice...
November 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27881141/analysis-of-epithelial-mesenchymal-transition-markers-in-the-histogenesis-of-hepatic-progenitor-cell-in-hbv-related-liver-diseases
#19
Wei Xu, Nong-Rong Wang, Hua-Feng Wang, Qiong Feng, Jun Deng, Zhi-Qiang Gong, Jian Sun, Xiao-Liang Lou, Xue-Feng Yu, Lv Zhou, Jin-Ping Hu, Xiao-Feng Huang, Xiao-Qing Qi, Yan-Juan Deng, Rui Gong, Yan Guo, Meng-Meng Wang, Jia-Cheng Xiao, Huan Deng
BACKGROUND: The origin and heterogeneity of hepatic progenitor cells (HPCs) remain unclear. This study aimed to investigate the involvement of epithelial-mesenchymal transition (EMT) in the histogenesis of HPCs. METHODS: Surgical liver specimens from patients with HBV-related hepatitis and cirrhosis were investigated with double immunofluorescence labeling to detect antigens associated with HPCs and EMT. Ductular reactions were subjected to quantitative reverse transcription PCR following isolation by laser capture microdissection...
November 24, 2016: Diagnostic Pathology
https://www.readbyqxmd.com/read/27859498/the-srl-peptide-of-rhesus-rotavirus-vp4-protein-governs-cholangiocyte-infection-and-the-murine-model-of-biliary-atresia
#20
Sujit K Mohanty, Bryan Donnelly, Inna Lobeck, Ashley Walther, Phylicia Dupree, Abigail Coots, Jaroslaw Meller, Monica McNeal, Karol Sestak, Greg Tiao
: Biliary atresia (BA) is a neonatal obstructive cholangiopathy which progresses to end stage liver disease, often requiring transplantation. The murine model of BA, employing rhesus rotavirus (RRV), parallels human disease and has been used to elucidate mechanistic aspects of a virus induced biliary cholangiopathy. We previously reported that RRV VP4 gene plays an integral role in activating the immune system and induction of BA. Utilizing rotavirus binding and blocking assays, this study elucidated how RRV VP4 protein governs cholangiocyte susceptibility to infection both in vitro and in vivo in the murine model of BA...
November 17, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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