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https://www.readbyqxmd.com/read/28089783/characterization-of-rat-or-human-hepatocytes-cultured-in-microphysiological-systems-mps-to-identify-hepatotoxicity
#1
Shih-Yu Chang, Jenna L Voellinger, Kirk P Van Ness, Brian Chapron, Rachel M Shaffer, Thomas Neumann, Collin C White, Terrance J Kavanagh, Edward J Kelly, David L Eaton
The liver is the main site for drug and xenobiotics metabolism, including inactivation or bioactivation. In order to improve the predictability of drug safety and efficacy in clinical development, and to facilitate the evaluation of the potential human health effects from exposure to environmental contaminants, there is a critical need to accurately model human organ systems such as the liver in vitro. We are developing a microphysiological system (MPS) based on a new commercial microfluidic platform (Nortis, Inc...
January 12, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28065467/lung-adenocarcinoma-with-muc4-expression-is-associated-with-smoking-status-her2-protein-expression-and-poor-prognosis-clinicopathologic-analysis-of-338-cases
#2
Mariyo Rokutan-Kurata, Akihiko Yoshizawa, Shinji Sumiyoshi, Makoto Sonobe, Toshi Menju, Masanobu Momose, Mizuki Koyama, Shohei Shigeto, Masakazu Fujimoto, Meng Zhang, Satoshi Morita, Hiroshi Date, Hironori Haga
BACKGROUND: MUC4 is a transmembrane glycoprotein that plays a role in the cell growth signaling pathway and has been studied in various organ malignancies. This study aimed to analyze MUC4 expression in resected lung adenocarcinomas (ADCs) to define the clinicopathologic characteristics of MUC4-positive cancers. PATIENTS AND METHODS: Immunohistochemical MUC4 analysis was performed using tissue microarray slides containing 338 lung ADCs. Associations between MUC4 expression and the following clinicopathologic parameters were evaluated: sex; age; smoking status; tumor stage; tumor grade; lymphovascular invasion; pleural invasion; TTF-1 and HNF4α expression; EGFR, KRAS, BRAF, and HER2 mutation status; and ALK and ROS1 fusion status...
December 2, 2016: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28039934/prostaglandin-e2-promotes-hepatic-bile-acid-synthesis-by-an-e-prostanoid-receptor-3-mediated-hepatocyte-nuclear-receptor-4%C3%AE-cholesterol-7%C3%AE-hydroxylase-pathway-in-mice
#3
Shuai Yan, Juan Tang, Yuyao Zhang, Yuanyang Wang, Shengkai Zuo, Yujun Shen, Qianqian Zhang, Di Chen, Yu Yu, Kai Wang, Sheng-Zhong Duan, Ying Yu
: Prostaglandin E2 (PGE2 ) is an important lipid mediator of inflammation. However, whether and how PGE2 regulates hepatic cholesterol metabolism remains unknown. We found that expression of the PGE2 receptor, E prostanoid receptor 3 (EP3) expression is remarkably increased in hepatocytes in response to hyperlipidemic stress. Hepatocyte-specific deletion of EP3 receptor (EP3(hep-/-) ) results in hypercholesterolemia and augments diet-induced atherosclerosis in low-density lipoprotein receptor knockout (Ldlr(-/-) ) mice...
November 5, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28003637/differential-toxicity-between-perfluorooctane-sulfonate-pfos-and-perfluorooctanoic-acid-pfoa
#4
Shuji Tsuda
Perfluoroalkyl substances (PFASs) are persistent environmental contaminants. Perfluorooctane sulfonate (PFOS) and Perfluorooctanoic acid (PFOA) are representatives of PFASs. Recently, the U.S. Environmental Protection Agency (US EPA) set the health advisory level as 70 parts per trillion for lifetime exposure to PFOS and PFOA from drinking water, based on the EPA's 2016 Health Effects Support Documents. Then, a monograph on PFOA was made available online by the International Agency for Research on Cancer, where the agency classified PFOA as "possibly carcinogenic to humans" (Group 2B)...
2016: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28000155/hepatocyte-nuclear-factor-4-alpha-promotes-definitive-endoderm-differentiation-from-human-induced-pluripotent-stem-cells
#5
Morifumi Hanawa, Kazuo Takayama, Fuminori Sakurai, Masashi Tachibana, Hiroyuki Mizuguchi
Hepatocyte nuclear factor 4 alpha (HNF4α) is a key transcription factor for liver development. Although HNF4α is necessary for hepatoblast differentiation, the function of HNF4α before the hepatoblast differentiation, such as in definitive endoderm differentiation, is not well known. In addition, it is known that there are nine HNF4α isoforms, but the expression and function of each HNF4α isoform during the definitive endoderm differentiation is also not clear. In this study, we examined the expression pattern of HNF4α and its functions in the definitive endoderm differentiation from human induced pluripotent stem (iPS) cells...
December 21, 2016: Stem Cell Reviews
https://www.readbyqxmd.com/read/27932985/pregnane-x-receptor-pxr-mediated-gene-repression-and-cross-talk-of-pxr-with-other-nuclear-receptors-via-coactivator-interactions
#6
REVIEW
Petr Pavek
Pregnane X receptor is a ligand-activated nuclear receptor (NR) that mainly controls inducible expression of xenobiotics handling genes including biotransformation enzymes and drug transporters. Nowadays it is clear that PXR is also involved in regulation of intermediate metabolism through trans-activation and trans-repression of genes controlling glucose, lipid, cholesterol, bile acid, and bilirubin homeostasis. In these processes PXR cross-talks with other NRs. Accumulating evidence suggests that the cross-talk is often mediated by competing for common coactivators or by disruption of coactivation and activity of other transcription factors by the ligand-activated PXR...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27909409/3-5-3-triiodo-l-thyronine-and-3-5-diiodo-l-thyronine-affected-metabolic-pathways-in-liver-of-ldl-receptor-deficient-mice
#7
Maria Moreno, Elena Silvestri, Maria Coppola, Ira J Goldberg, Li-Shin Huang, Anna M Salzano, Fulvio D'Angelo, Joel R Ehrenkranz, Fernando Goglia
3,5,3'-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2), when administered to a model of familial hypercholesterolemia, i.e., low density lipoprotein receptor (LDLr)-knockout (Ldlr(-/-)) mice fed with a Western type diet (WTD), dramatically reduce circulating total and very low-density lipoprotein/LDL cholesterol with decreased liver apolipoprotein B (ApoB) production. The aim of the study was to highlight putative molecular mechanisms to manage cholesterol levels in the absence of LDLr. A comprehensive comparative profiling of changes in expression of soluble proteins in livers from Ldlr(-/-) mice treated with either T3 or T2 was performed...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27903283/systematic-analysis-of-chromatin-interactions-at-disease-associated-loci-links-novel-candidate-genes-to-inflammatory-bowel-disease
#8
Claartje A Meddens, Magdalena Harakalova, Noortje A M van den Dungen, Hassan Foroughi Asl, Hemme J Hijma, Edwin P J G Cuppen, Johan L M Björkegren, Folkert W Asselbergs, Edward E S Nieuwenhuis, Michal Mokry
BACKGROUND: Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate genes is predominantly based on genes that localize close to or within identified loci. We have recently shown that 92 of the 163 inflammatory bowel disease (IBD)-loci co-localize with non-coding DNA regulatory elements (DREs). Mutations in DREs can contribute to IBD pathogenesis through dysregulation of gene expression...
November 30, 2016: Genome Biology
https://www.readbyqxmd.com/read/27878730/mesenchymal-epithelial-transition-in-culture-of-stromal-progenitor-cells-isolated-from-the-liver-of-a-patient-with-alcoholic-cirrhosis
#9
I V Kholodenko, R V Kholodenko, G V Manukyan, V V Burunova, K N Yarygin
The cells isolated from biopsy specimen of a patient with alcoholic liver cirrhosis and cultured under standard conditions for obtaining stromal cell culture clearly diverged during early passages into two morphologically and phenotypically different subtypes: epithelial and mesenchymal. Mesenchymal cells expressed CD90 and CD44 and epithelial cells expressed CD166, CD227, and hepatocyte growth factor receptor Met. Starting from passage 6, the culture underwent spontaneous morphological changes and by passages 8-10 contained only epithelium-like cells...
November 2016: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/27875772/hnf4%C3%AE-is-a-key-gene-that-can-generate-columnar-metaplasia-in-oesophageal-epithelium
#10
Benjamin J Colleypriest, Zoë D Burke, Leonard P Griffiths, Yu Chen, Wei-Yuan Yu, Ramiro Jover, Michael Bock, Leigh Biddlestone, Jonathan M Quinlan, Stephen G Ward, J Mark Farrant, Jonathan M W Slack, David Tosh
Barrett's metaplasia is the only known morphological precursor to oesophageal adenocarcinoma and is characterized by replacement of stratified squamous epithelium by columnar epithelium. The cell of origin is uncertain and the molecular mechanisms responsible for the change in cellular phenotype are poorly understood. We therefore explored the role of two transcription factors, Cdx2 and HNF4α in the conversion using primary organ cultures. Biopsy samples from cases of human Barrett's metaplasia were analysed for the presence of CDX2 and HNF4α...
November 19, 2016: Differentiation; Research in Biological Diversity
https://www.readbyqxmd.com/read/27809333/yes-associated-protein-tea-domain-family-member-and-hepatocyte-nuclear-factor-4-alpha-hnf4%C3%AE-repress-reciprocally-to-regulate-hepatocarcinogenesis-in-rats-and-mice
#11
Wang-Yu Cai, Ling-Yun Lin, Han Hao, Sai-Man Zhang, Fei Ma, Xin-Xin Hong, Hui Zhang, Qing-Feng Liu, Guo-Dong Ye, Guang-Bin Sun, Yun-Jia Liu, Sheng-Nan Li, Yuan-Yuan Xie, Jian-Chun Cai, Bo-An Li
: Great progress has been achieved in the study of Hippo signaling in regulating tumorigenesis; however, the downstream molecular events that mediate this process have not been completely defined. Moreover, regulation of Hippo signaling during tumorigenesis in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we systematically investigated the relationship between Yes-associated protein/TEA domain family member (YAP-TEAD) and hepatocyte nuclear factor 4-alpha (HNF4α) in the hepatocarcinogenesis of HCC cells...
November 3, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27752141/diabetes-linked-transcription-factor-hnf4%C3%AE-regulates-metabolism-of-endogenous-methylarginines-and-%C3%AE-aminoisobutyric-acid-by-controlling-expression-of-alanine-glyoxylate-aminotransferase-2
#12
Dmitry V Burdin, Alexey A Kolobov, Chad Brocker, Alexey A Soshnev, Nikolay Samusik, Anton V Demyanov, Silke Brilloff, Natalia Jarzebska, Jens Martens-Lobenhoffer, Maren Mieth, Renke Maas, Stefan R Bornstein, Stefanie M Bode-Böger, Frank Gonzalez, Norbert Weiss, Roman N Rodionov
Elevated levels of circulating asymmetric and symmetric dimethylarginines (ADMA and SDMA) predict and potentially contribute to end organ damage in cardiovascular diseases. Alanine-glyoxylate aminotransferase 2 (AGXT2) regulates systemic levels of ADMA and SDMA, and also of beta-aminoisobutyric acid (BAIB)-a modulator of lipid metabolism. We identified a putative binding site for hepatic nuclear factor 4 α (HNF4α) in AGXT2 promoter sequence. In a luciferase reporter assay we found a 75% decrease in activity of Agxt2 core promoter after disruption of the HNF4α binding site...
October 18, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27723751/nuclear-receptors-control-pro-viral-and-antiviral-metabolic-responses-to-hepatitis-c-virus-infection
#13
Gahl Levy, Naomi Habib, Maria Angela Guzzardi, Daniel Kitsberg, David Bomze, Elishai Ezra, Basak E Uygun, Korkut Uygun, Martin Trippler, Joerg F Schlaak, Oren Shibolet, Ella H Sklan, Merav Cohen, Joerg Timm, Nir Friedman, Yaakov Nahmias
Viruses lack the basic machinery needed to replicate and therefore must hijack the host's metabolism to propagate. Virus-induced metabolic changes have yet to be systematically studied in the context of host transcriptional regulation, and such studies shoul offer insight into host-pathogen metabolic interplay. In this work we identified hepatitis C virus (HCV)-responsive regulators by coupling system-wide metabolic-flux analysis with targeted perturbation of nuclear receptors in primary human hepatocytes. We found HCV-induced upregulation of glycolysis, ketogenesis and drug metabolism, with glycolysis controlled by activation of HNF4α, ketogenesis by PPARα and FXR, and drug metabolism by PXR...
October 10, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27709008/crosstalk-of-hnf4%C3%AE-with-extracellular-and-intracellular-signaling-pathways-in-the-regulation-of-hepatic-metabolism-of-drugs-and-lipids
#14
REVIEW
Hong Lu
The liver is essential for survival due to its critical role in the regulation of metabolic homeostasis. Metabolism of xenobiotics, such as environmental chemicals and drugs by the liver protects us from toxic effects of these xenobiotics, whereas metabolism of cholesterol, bile acids (BAs), lipids, and glucose provide key building blocks and nutrients to promote the growth or maintain the survival of the organism. As a well-established master regulator of liver development and function, hepatocyte nuclear factor 4 alpha (HNF4α) plays a critical role in regulating a large number of key genes essential for the metabolism of xenobiotics, metabolic wastes, and nutrients...
September 2016: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/27677335/epigenomic-profiling-of-primary-gastric-adenocarcinoma-reveals-super-enhancer-heterogeneity
#15
Wen Fong Ooi, Manjie Xing, Chang Xu, Xiaosai Yao, Muhammad Khairul Ramlee, Mei Chee Lim, Fan Cao, Kevin Lim, Deepak Babu, Lai-Fong Poon, Joyce Lin Suling, Aditi Qamra, Astrid Irwanto, James Qu Zhengzhong, Tannistha Nandi, Ai Ping Lee-Lim, Yang Sun Chan, Su Ting Tay, Ming Hui Lee, James O J Davies, Wai Keong Wong, Khee Chee Soo, Weng Hoong Chan, Hock Soo Ong, Pierce Chow, Chow Yin Wong, Sun Young Rha, Jianjun Liu, Axel M Hillmer, Jim R Hughes, Steve Rozen, Bin Tean Teh, Melissa Jane Fullwood, Shang Li, Patrick Tan
Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments...
September 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27660075/hnf-4alpha-negatively-regulates-hepcidin-expression-through-bmpr1a-in-hepg2-cells
#16
Wencai Shi, Heyang Wang, Xuan Zheng, Xin Jiang, Zheng Xu, Hui Shen, Min Li
Hepcidin synthesis is reported to be inadequate according to the body iron store in patients with non-alcoholic fatty liver disease (NAFLD) undergoing hepatic iron overload (HIO). However, the underlying mechanisms remain unclear. We hypothesize that hepatocyte nuclear factor-4α (HNF-4α) may negatively regulate hepcidin expression and contribute to hepcidin deficiency in NAFLD patients. The effect of HNF-4α on hepcidin expression was observed by transfecting specific HNF-4α small interfering RNA (siRNA) or plasmids into HepG2 cells...
September 23, 2016: Biological Trace Element Research
https://www.readbyqxmd.com/read/27659712/clinical-and-molecular-characterization-of-a-novel-ins-mutation-identified-in-patients-with-mody-phenotype
#17
Barbara Piccini, Rosangela Artuso, Lorenzo Lenzi, Monica Guasti, Giulia Braccesi, Federica Barni, Emilio Casalini, Sabrina Giglio, Sonia Toni
Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family...
November 2016: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/27610747/specific-oct1-and-abcg2-polymorphisms-are-associated-with-lamotrigine-concentrations-in-chinese-patients-with-epilepsy
#18
Chun-Hong Shen, Yin-Xi Zhang, Ru-Yi Lu, Bo Jin, Shan Wang, Zhi-Rong Liu, Ye-Lei Tang, Mei-Ping Ding
PURPOSE: The pharmacokinetics of Lamotrigine (LTG) varies widely among patients with epilepsy. In this study, we are aiming to investigate the effects of OCT1, ABCG2, ABCC2 and HNF4α genetic polymorphisms on plasma LTG concentrations and therapeutic efficacy in Chinese patients with epilepsy. METHODS: The study cohort comprised 112 Han Chinese patients with epilepsy who were receiving LTG monotherapy. Blood samples were taken and LTG levels were measured. The polymorphisms of OCT1 rs2282143, rs628031, ABCG2 rs2231142, rs2231137, ABCC2 rs2273697 and HNF4α rs2071197, rs3212183 were determined...
September 1, 2016: Epilepsy Research
https://www.readbyqxmd.com/read/27583872/dna-methylations-of-mc4r-and-hnf4%C3%AE-are-associated-with-increased-triglyceride-levels-in-cord-blood-of-preterm-infants
#19
Eun Jin Kwon, Hye Ah Lee, Young-Ah You, Hyesook Park, Su Jin Cho, Eun Hee Ha, Young Ju Kim
The association of preterm birth with obesity and metabolic syndrome later in life is well established. Although the biological mechanism for this association is poorly understood, epigenetic alterations of metabolic-related genes in early life may have important roles in metabolic dysfunction. Thus, we investigated the associations of DNA methylations of melanocortin 4 receptor (MC4R) and hepatocyte nuclear factor 4 alpha (HNF4α) with metabolic profiles in cord blood of term and preterm infants.We measured metabolic profiles in cord blood samples of 85 term and 85 preterm infants...
August 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27542413/hepatic-loss-of-borealin-impairs-postnatal-liver-development-regeneration-and-hepatocarcinogenesis
#20
Lu Li, Dan Li, Feng Tian, Jin Cen, Xiaotao Chen, Yuan Ji, Lijian Hui
Borealin, a member of the chromosomal passenger complex, plays a key regulatory role at centromeres and the central spindle during mitosis. Loss of Borealin leads to defective cell proliferation and early embryonic lethality. The in vivo functions of Borealin in mammalian postnatal development, tissue homeostasis, and tumorigenesis remain elusive. We specifically analyzed the role of Borealin in regulating postnatal liver development, damage-induced liver regeneration, and liver carcinogenesis using mice carrying conditional Borealin alleles...
September 30, 2016: Journal of Biological Chemistry
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