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Hepatocyte polarity

Philippe Gual, Helene Gilgenkrantz, Sophie Lotersztajn
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the leading causes of cirrhosis and increase the risk of hepatocellular carcinoma and liver-related death. ALD and NAFLD share common pathogenic features extending from isolated steatosis to steatohepatitis, steatofibrosis, which can progress to cirrhosis and hepatocellular carcinoma. The pathophysiological mechanisms of the progression of NAFLD and ALD are complex and still unclear. Important links between the regulation of autophagy (Macroautophagy and Chaperome-mediated autophagy) and chronic liver diseases have been reported...
November 30, 2016: American Journal of Physiology. Cell Physiology
Aditya Ambade, Abhishek Satishchandran, Banishree Saha, Benedek Gyongyosi, Patrick Lowe, Karen Kodys, Donna Catalano, Gyongyi Szabo
Obesity-related inflammation promotes cancer development. Tissue resident macrophages affect tumor progression and the tumor micro-environment favors polarization into alternatively activated macrophages (M2) that facilitate tumor invasiveness. Here, we dissected the role of western diet-induced NASH in inducing macrophage polarization in a carcinogen initiated model of hepatocellular carcinoma (HCC). Adult C57BL/6 male mice received diethyl nitrosamine (DEN) followed by 24 weeks of high fat-high cholesterol-high sugar diet (HF-HC-HSD)...
2016: Oncoimmunology
Ki-Woong Kim, Yong Lim Won, Dong Jin Park, Young Sun Kim, Eun Sil Jin, Sung Kwang Lee
We determined the toxicity of mixtures of ethyl acetate (EA), isopropyl alcohol (IPA), methyl ethyl ketone (MEK), toluene (TOL) and xylene (XYL) with half-maximal effective concentration (EC50) values obtained using human hepatocytes cells. According to these data, quantitative property-activity relationships (QPAR) models were successfully proposed to predict the toxicity of mixtures by multiple linear regressions (MLR). The leave-one-out cross validation method was used to find the best subsets of descriptors in the learning methods...
October 2016: Toxicological Research
Sun Woo Sophie Kang, Ghada Haydar, Caitlin Taniane, Geoffrey Farrell, Irwin M Arias, Jennifer Lippincott-Schwartz, Dong Fu
Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria...
2016: PloS One
Liang Zhu, Huanming Xia, Zhenfeng Wang, Eliza Li Shan Fong, Junjun Fan, Wen Hao Tong, Yen Peng Daphne Seah, Weian Zhang, Qiushi Li, Hanry Yu
Although hepatocytes in vivo experience intra-abdominal pressure (IAP), pressure is typically not incorporated in hepatocyte culture systems. The cuboidal cell shape and extent of intercellular contact between cultured hepatocytes are critical parameters that influence the differentiated hepatic phenotype. Using a microfluidic device, the application of pressure to artificially compact cells and forge cell-cell interactions was previously demonstrated to be effective in accelerating hepatic repolarization. In seeking to implement this approach to higher throughput culture platforms for potential drug screening applications, we specifically designed a vertical-flow compaction bioreactor array (VCBA) that compacts hepatocytes within the range of IAP and portal pressure in vivo in a multi-well setup...
October 5, 2016: Lab on a Chip
Kenichi Arai, Toshiko Yoshida, Motonori Okabe, Mitsuaki Goto, Tanveer Ahmad Mir, Chika Soko, Yoshinari Tsukamoto, Toshihiro Akaike, Toshio Nikaido, Kaixuan Zhou, Makoto Nakamura
The development of new three-dimensional (3D) cell culture system that maintains the physiologically relevant signals of hepatocytes is essential in drug discovery and tissue engineering research. Conventional two-dimensional (2D) culture yields cell growth, proliferation and differentiation. However, gene expression and signaling profiles can be different from in vivo environment. Here, we report the fabrication of a 3D culture system using an artificial scaffold and our custom-made inkjet 3D-bioprinter as a new strategy for studying liver-specific functions of hepatocytes...
September 19, 2016: Journal of Biomedical Materials Research. Part A
Zhiqiang Li, Inamul Kabir, Hui Jiang, Hongwen Zhou, Jenny Libien, Jianying Zeng, Albert Stanek, Peiqi Ou, Kailyn R Li, Shane Zhang, Hai H Bui, Ming-Shang Kuo, Tae-Sik Park, Benjamin Kim, Tilla S Worgall, Chongmin Huan, Xian-Cheng Jiang
: Serine palmitoyltransferase is the key enzyme in sphingolipid biosynthesis. Mice lacking serine palmitoyltransferase are embryonic lethal. We prepared liver-specific mice deficient in the serine palmitoyltransferase long chain base subunit 2 gene using an albumin-cyclization recombination approach and found that the deficient mice have severe jaundice. Moreover, the deficiency impairs hepatocyte polarity, attenuates liver regeneration after hepatectomy, and promotes tumorigenesis. Importantly, we show that the deficiency significantly reduces sphingomyelin but not other sphingolipids in hepatocyte plasma membrane; greatly reduces cadherin, the major protein in adherens junctions, on the membrane; and greatly induces cadherin phosphorylation, an indication of its degradation...
December 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Alexandra M Hetherington, Cynthia G Sawyez, Emma Zilberman, Alexandra M Stoianov, Debra L Robson, Nica M Borradaile
BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) progression to fibrosis, cirrhosis and hepatocellular carcinoma, alters the cellular composition of this organ. During late-stage NAFLD, fibrotic and possibly cancerous cells can proliferate and, like normal hepatocytes, are exposed to high concentrations of fatty acids from both surrounding tissue and circulating lipid sources. We hypothesized that primary human activated hepatic stellate cells and epithelial hepatoma (HepG2) cells respond differently to lipotoxic conditions, and investigated the mechanisms involved...
2016: Cellular Physiology and Biochemistry
Changhwan Ahn, Da-Hye Shin, Dongoh Lee, Su-Myung Kang, Ju-Hyung Seok, Hee Young Kang, Eui-Bae Jeung
Tight junctions are the outermost structures of intercellular junctions and are classified as transmembrane proteins. These factors form selective permeability barriers between cells, act as paracellular transporters and regulate structural and functional polarity of cells. Although tight junctions have been previously studied, comparison of the transcriptional‑translational levels of these molecules in canine organs remains to be investigated. In the present study, organ‑specific expression of the tight junction proteins, claudin, occludin, junction adhesion molecule A and zona occludens 1 was examined in the canine duodenum, lung, liver and kidney...
October 2016: Molecular Medicine Reports
Ioannis D Kyriazis, Olga S Koutsoni, Nektarios Aligiannis, Kalliopi Karampetsou, Alexios-Leandros Skaltsounis, Eleni Dotsika
BACKGROUND: Much research effort has been focused on investigating new compounds derived from low-cost sources, such as natural products, for treating leishmaniasis. Oleuropein derived from numerous plants, particularly from the olive tree, Olea europaea L. (Oleaceae), is a biophenol with many biological activities. Our previous findings showed that oleuropein exhibits leishmanicidal effects against three Leishmania spp. in vitro, and minimizes the parasite burden in L. donovani-infected BALB/c mice...
2016: Parasites & Vectors
Jorge Alberto García-Díaz, Gabriel Navarrete-Vázquez, Sara García-Jiménez, Sergio Hidalgo-Figueroa, Julio C Almanza-Pérez, Francisco Javier Alarcón-Aguilar, Jaime Gómez-Zamudio, Miguel Cruz, Maximiliano Ibarra-Barajas, Samuel Estrada-Soto
Flavonoids from medicinal plants have been used in traditional medicine to treat a variety of prevalent diseases. Flavones activate the signaling pathways promoting fuel metabolism and insulin sensitizing in hepatocytes and adipocytes, which suggests that flavones may have the potential to exert in vivo antidiabetic and antihyperlipidemic effects. Thus, the aim of the current study was to determine the antidiabetic, antihyperlipidemic and anti-inflammatory effects of tilianin in diabetic rats. Also, to understand the mechanism involved using in vitro 3T3-L1 cells and tissues from experimental animals treated with test samples through molecular profile studies...
July 26, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Kavindra Kumara Wijesundera, Takeshi Izawa, Anusha Hemamali Tennakoon, Hossain Md Golbar, Miyuu Tanaka, Mitsuru Kuwamura, Jyoji Yamate
INTRODUCTION: Liver steatosis is the most frequent liver disease and may further develop into non-alcoholic steatohepatitis (NASH), liver cirrhosis, and finally hepatocellular carcinoma. Adipophilin (Adp) is localized on lipid droplet membrane in cytoplasm, and its increased expression is related to development of steatosis and NASH. The relationship between M1-/M2-macrophage polarization and Adp-rich hepatocyte-consisting pseudolobules (PLs) was investigated in thioacetamide (TAA)-induced rat cirrhosis...
August 2016: Experimental and Molecular Pathology
Bo Wang, Adam E Jakus, Pedro M Baptista, Shay Soker, Alejandro Soto-Gutierrez, Michael M Abecassis, Ramille N Shah, Jason A Wertheim
UNLABELLED: : Induced pluripotent stem cells (iPSCs) are new diagnostic and potentially therapeutic tools to model disease and assess the toxicity of pharmaceutical medications. A common limitation of cell lineages derived from iPSCs is a blunted phenotype compared with fully developed, endogenous cells. We examined the influence of novel three-dimensional bioartificial microenvironments on function and maturation of hepatocyte-like cells differentiated from iPSCs and grown within an acellular, liver-derived extracellular matrix (ECM) scaffold...
September 2016: Stem Cells Translational Medicine
Natalie Porat-Shliom, Amber J Tietgens, Christina M Van Itallie, Lynn Vitale-Cross, Michal Jarnik, Olivia J Harding, James M Anderson, J Silvio Gutkind, Roberto Weigert, Irwin M Arias
UNLABELLED: Liver kinase B1 (LKB1) and its downstream effector AMP-activated protein kinase (AMPK) play critical roles in polarity establishment by regulating membrane trafficking and energy metabolism. In collagen sandwich-cultured hepatocytes, loss of LKB1 or AMPK impaired apical ABCB11 (Bsep) trafficking and bile canalicular formation. In the present study, we used liver-specific (albumin-Cre) LKB1 knockout mice (LKB1(-/-) ) to investigate the role of LKB1 in the maintenance of functional tight junction (TJ) in vivo...
October 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Mitesh Patel, Kunal S Taskar, Maciej J Zamek-Gliszczynski
This review provides a practical clinical perspective on the relevance of hepatic transporters in pharmacokinetics and drug-drug interactions (DDIs). Special emphasis is placed on transporters with clear relevance to clinical DDIs, efficacy, and safety. Basolateral OATP1B1 and 1B3 emerged as important hepatic drug uptake pathways, sites for systemic DDIs, and sources of pharmacogenetic variability. As the first step in hepatic drug removal from the circulation, OATPs are an important determinant of systemic pharmacokinetics, specifically influencing systemic absorption, clearance, and hepatic distribution for subsequent metabolism and/or excretion...
July 2016: Journal of Clinical Pharmacology
Vincent Andersson, Fredrik Bergström, Jonas Brånalt, Gunnar Grönberg, David Gustafsson, Staffan Karlsson, Magnus Polla, Joakim Bergman, Jan Kihlberg
The only oral direct thrombin inhibitors that have reached the market, ximelagatran and dabigatran etexilat, are double prodrugs with low bioavailability in humans. We have evaluated an alternative strategy: the preparation of a nonpeptidic, polar direct thrombin inhibitor as a single, macrocyclic esterase-cleavable (acyloxy)alkoxy prodrug. Two homologous prodrugs were synthesized and displayed high solubilities and Caco-2 cell permeabilities, suggesting high absorption from the intestine. In addition, they were rapidly and completely converted to the active zwitterionic thrombin inhibitor in human hepatocytes...
July 28, 2016: Journal of Medicinal Chemistry
Anitha Ravikrishnan, Tugba Ozdemir, Mohamed Bah, Karen A Baskerville, S Ismat Shah, Ayyappan K Rajasekaran, Xinqiao Jia
Epithelial-to-mesenchymal transition (EMT) is a well-studied biological process that takes place during embryogenesis, carcinogenesis, and tissue fibrosis. During EMT, the polarized epithelial cells with a cuboidal architecture adopt an elongated fibroblast-like morphology. This process is accompanied by the expression of many EMT-specific molecular markers. Although the molecular mechanism leading to EMT has been well-established, the effects of matrix topography and microstructure have not been clearly elucidated...
July 20, 2016: ACS Applied Materials & Interfaces
Guido Carpino, Valerio Nobili, Anastasia Renzi, Cristiano De Stefanis, Laura Stronati, Antonio Franchitto, Anna Alisi, Paolo Onori, Rita De Vito, Gianfranco Alpini, Eugenio Gaudio
Non-alcoholic fatty liver disease is one of the most important causes of liver-related morbidity in children. In non-alcoholic fatty liver disease, the activation of liver resident macrophage pool is a central event in the progression of liver injury. The aims of the present study were to evaluate the polarization of liver macrophages and the possible role of Wnt3a production by macrophages in hepatic progenitor cell response in the progression of pediatric non-alcoholic fatty liver disease. 32 children with biopsy-proven non-alcoholic fatty liver disease were included...
2016: PloS One
Jana C Mossanen, Oliver Krenkel, Can Ergen, Olivier Govaere, Anke Liepelt, Tobias Puengel, Felix Heymann, Sandra Kalthoff, Eric Lefebvre, Dirk Eulberg, Tom Luedde, Gernot Marx, Christian P Strassburg, Tania Roskams, Christian Trautwein, Frank Tacke
: Acetaminophen (APAP, paracetamol) poisoning is a leading cause of acute liver failure (ALF) in humans and induces hepatocyte necrosis, followed by activation of the innate immune system, further aggravating liver injury. The role of infiltrating monocytes during the early phase of ALF is still ambiguous. Upon experimental APAP overdose in mice, monocyte-derived macrophages (MoMFs) massively accumulated in injured liver within 12-24 hours, whereas the number of tissue-resident macrophages (Kupffer cells) decreased...
November 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Leonard J Nelson, Katie Morgan, Philipp Treskes, Kay Samuel, Catherine J Henderson, Claire LeBled, Natalie Homer, M Helen Grant, Peter C Hayes, John N Plevris
Conventional in vitro human hepatic models for drug testing are based on the use of standard cell lines derived from hepatomas or primary human hepatocytes (PHHs). Limited availability, inter-donor functional variability and early phenotypic alterations of PHHs restrict their use; whilst standard cell lines such as HepG2 lack a substantial and variable set of liver-specific functions such as CYP450 activity. Alternatives include the HepG2-derivative C3A cells selected as a more differentiated and metabolically active hepatic phenotype...
June 10, 2016: Basic & Clinical Pharmacology & Toxicology
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