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Epigenetics liver

Adil El Taghdouini, Leo A van Grunsven
Chronic liver injury to hepatocytes or cholangiocytes, when left unmanaged, leads to the development of liver fibrosis, a condition characterized by the excessive intrahepatic deposition of extracellular matrix proteins. Activated hepatic stellate cells constitute the predominant source of extracellular matrix in fibrotic livers and their transition from a quiescent state during fibrogenesis is associated with important alterations in their transcriptional and epigenetic landscape. Areas covered: We briefly describe the processes involved in hepatic stellate cell activation and discuss our current understanding of alterations in the epigenetic landscape, i...
October 20, 2016: Expert Review of Gastroenterology & Hepatology
Mariola Kurowska-Stolarska, Manhl K Hasoo, David J Welsh, Lynn Stewart, Donna McIntyre, Brian E Morton, Steven Johnstone, Ashley M Miller, Darren L Asquith, Neal L Millar, Ann B Millar, Carol A Feghali-Bostwick, Nikhil Hirani, Peter J Crick, Yuqin Wang, William J Griffiths, Iain B McInnes, Charles McSharry
BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF therefore microRNAs may reveal novel pathogenic pathways. OBJECTIVES: To determine the regulatory role of microRNA(miR)-155 in the pro-fibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts and its contribution to experimental pulmonary fibrosis...
October 13, 2016: Journal of Allergy and Clinical Immunology
Luca Tordella, Sadaf Khan, Anja Hohmeyer, Ana Banito, Sabrina Klotz, Selina Raguz, Nadine Martin, Gopuraja Dhamarlingam, Thomas Carroll, José Mario González Meljem, Sumit Deswal, Juan Pedro Martínez-Barbera, Ramón García-Escudero, Johannes Zuber, Lars Zender, Jesús Gil
Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16(INK4a) and p21(CIP1a) transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence...
October 13, 2016: Genes & Development
Xin Li, Yun Liu, Tal Salz, Kasper D Hansen, Andrew P Feinberg
DNA methylation at the 5-postion of cytosine (5mC) is an epigenetic modification that regulates gene expression and cellular plasticity in development and disease. The ten-eleven translocation (TET) gene family oxidizes 5mC to 5-hydroxymethylcytosine (5hmC), providing an active mechanism for DNA demethylation, and may also provide its own regulatory function. Here we applied oxidative bisulfite sequencing to generate whole-genome DNA methylation and hydroxymethylation maps at single-base resolution in paired human liver and lung normal and cancer...
October 13, 2016: Genome Research
Hang He, Ya-Li Nie, Jiang-Feng Li, Xiang-Guang Meng, Wei-Hong Yang, Yu-Long Chen, Shu-Jie Wang, Xiaochao Ma, Quan-Cheng Kan, Li-Rong Zhang
CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus...
September 9, 2016: Drug Metabolism and Pharmacokinetics
N A Wijetunga, M Pascual, J Tozour, F Delahaye, M Alani, M Adeyeye, A W Wolkoff, A Verma, J M Greally
The predisposition of patients with Hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) involves components of viral infection, inflammation and time. The development of multifocal, genetically distinct tumours is suggestive of a field defect affecting the entire liver. The molecular susceptibility mediating such a field defect is not understood. One potential mediator of long-term cellular reprogramming is heritable (epigenetic) regulation of transcription, exemplified by DNA methylation. We studied epigenetic and transcriptional changes in HCV-infected livers in comparison with control, uninfected livers and HCC, allowing us to identify pre-neoplastic epigenetic and transcriptional events...
October 10, 2016: Oncogene
Francesco M Serafini, David Radvinsky
Cholangiocarcinoma (CCA) is an aggressive malignancy that originates from the epithelial cells of the biliary duct system. Depending on the anatomical location, CCA can be considered extrahepatic (eCCA) or intrahepatic (iCCA) (1). Two thirds of CCAs involve the extrahepatic biliary system, whereas the rest are confined within the liver parenchyma, beyond the secondary biliary radicals (2). Due to its biological aggressiveness and difficulty in diagnosis, the majority of patients with CCA are unresectable at presentation and the overall 5-year survival is approximately five percent (4)...
August 16, 2016: Cancer Genetics
Haruhiko Takeda, Atsushi Takai, Tadashi Inuzuka, Hiroyuki Marusawa
Hepatitis virus infection is a leading cause of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Although anti-viral therapies against hepatitis B virus (HBV) and hepatitis C virus (HCV) have dramatically progressed during the past decade, the estimated number of people chronically infected with HBV and/or HCV is ~370 million, and hepatitis virus-associated hepatocarcinogenesis is a serious health concern worldwide. Understanding the mechanism of virus-associated carcinogenesis is crucial toward both treatment and prevention, and the recently developed whole genome/exome sequencing analysis using next-generation sequencing technologies has contributed to unveiling the landscape of genetic and epigenetic aberrations in not only tumor tissues but also the background liver tissues underlying chronic liver damage caused by hepatitis virus infection...
October 6, 2016: Journal of Gastroenterology
Hesbon Z Amenya, Chiharu Tohyama, Seiichiroh Ohsako
The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1)...
October 7, 2016: Scientific Reports
Jonathan Choiniere, Li Wang
Arsenic is a carcinogenic environmental factor found in food and drinking water around the world. The mechanisms in which arsenic alters homeostasis are not fully understood. Over the past few decades, light has been shed on varying mechanisms in which arsenic induces cancer. Such mechanisms include gut microbe perturbations, genotoxic effects, and epigenetic modification. Gut microbe perturbations have been shown to increase the level of pathogen-associated molecular patterns such as lipopolysaccharide (LPS) leading to uncontained inflammation...
September 2016: Acta Pharmaceutica Sinica. B
Otto K-W Cheung, Alfred S-L Cheng
Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD) and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose, and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation...
2016: Frontiers in Genetics
Hussein M Atta, Ayman A Al-Hendy, Salama R Abdel Raheim, Hend Abdel-Ghany, Khalid A Nasif, Ahlam M Abdellah, Nagwa M Zenhom, Heba S Kamel
AIM OF THE STUDY: Adenovector encoding tissue plasminogen activator (tPA) was shown to reduce experimental peritoneal adhesion. We investigated the targeting potential of our modified adenovector, its ability to reduce adhesions and the epigenetic role of histone methyltransferase EZH2 in adhesion formation. MATERIALS AND METHODS: Control lacZ, nonmodified tPA or modified tPA vectors were instilled in the peritoneal cavity after injury in de novo adhesions or after lysis of adhesions in recurrent adhesions...
October 3, 2016: Journal of Investigative Surgery: the Official Journal of the Academy of Surgical Research
Maria Grazia Clemente, Claudia Mandato, Marco Poeta, Pietro Vajro
Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A "multiple-hit" pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]...
September 28, 2016: World Journal of Gastroenterology: WJG
Hugh Thomas
No abstract text is available yet for this article.
September 28, 2016: Nature Reviews. Gastroenterology & Hepatology
Giovanni Musso, Maurizio Cassader, Solomon Cohney, Franco De Michieli, Silvia Pinach, Francesca Saba, Roberto Gambino
Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets...
October 2016: Diabetes Care
Kang Li, Xi Zhang, Li Yang, Xin-Xing Wang, De-Hua Yang, Guo-Qing Cao, Shuai Li, Yong-Zhong Mao, Shao-Tao Tang
Biliary atresia (BA) is a pediatric inflammatory disease of the biliary system which leads to cirrhosis and the need for liver transplantation. Various cells types have been reported to participate in the pro-inflammatory response, including Th1, Th2, Th17, CD8(+) T cells, or NK cells. The suppressive Treg cells, on the contrary, were not functioning properly. The underlying mechanism is largely unknown. Focusing on why the suppressive function of Treg was impaired, we found out methylation status of CpG islands within the Foxp3 promotor of Tregs in BA patients and murine models were both increased...
September 22, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Simone Jueliger, John Lyons, Sara Cannito, Illar Pata, Pille Pata, Marianna Shkolnaya, Oriana Lo Re, Marion Peyrou, Francesc Villarroya, Valerio Pazienza, Francesca Rappa, Francesco Cappello, Mohammad Azab, Pietro Taverna, Manlio Vinciguerra
Hepatocellular carcinoma (HCC) is a deadly malignancy characterized at the epigenetic level by global DNA hypomethylation and focal hypermethylation on the promoter of tumor suppressor genes. In most cases it develops on a background of liver steatohepatitis, fibrosis, and cirrhosis. Guadecitabine (SGI-110) is a second-generation hypomethylating agent, which inhibits DNA methyltransferases. Guadecitabine is formulated as a dinucleotide of decitabine and deoxyguanosine that is resistant to cytidine deaminase (CDA) degradation and results in prolonged in vivo exposure to decitabine following small volume subcutaneous administration of guadecitabine...
August 11, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Kelly McDaniel, Fanyin Meng, Nan Wu, Keisaku Sato, Julie Venter, Francesca Bernuzzi, Pietro Invernizzi, Tianhao Zhou, Konstantina Kyritsi, Ying Wan, Qiaobing Huang, Paolo Onori, Heather Francis, Eugenio Gaudio, Shannon Glaser, Gianfranco Alpini
BACKGROUND & AIMS: Biliary-committed progenitor cells (small cholangiocytes, SMCCs) from small bile ducts are more resistant to hepatobiliary injury than large mouse cholangiocytes (LGCCs) from large bile ducts. The definitive endoderm marker, FoxA2 is the key transcriptional factor that regulates cell differentiation and tissue regeneration. Our aim was to characterize the translational role of FoxA2 during cholestatic liver injury. METHODS: mRNA expression in SMCCs and LGCCs was assessed by PCR array analysis...
September 17, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Alexander Beck, Corinna Eberherr, Michaela Hagemann, Stefano Cairo, Beate Häberle, Christian Vokuhl, Dietrich von Schweinitz, Roland Kappler
Hepatoblastoma (HB) is the most common liver tumor of childhood, usually occurring in children under the age of 3 y. The prognosis of patients presenting with distant metastasis, vascular invasion and advanced tumor stages remains poor and children that do survive often face severe late effects from the aggressive chemotherapy regimen. To identify potential new therapeutics for high risk HB we used a 1,000-gene expression signature as input for a Connectivity Map (CMap) analysis, which predicted histone deacetylase (HDAC) inhibitors as a promising therapy option...
September 16, 2016: Cancer Biology & Therapy
Coralie Allain, Gaëlle Angenard, Bruno Clément, Cédric Coulouarn
Integrative genomics helped characterize molecular heterogeneity in HCC, leading to targeted drug candidates for specific HCC subtypes. However, no consensus was achieved for genes and pathways commonly altered in HCC. Here we performed a meta-analysis of 15 independent datasets (n=784 human HCC) and identified a comprehensive signature consisting of 935 genes commonly deregulated in HCC as compared to the surrounding non-tumor tissue. In the HCC signature, up-regulated genes were linked to early genomic alterations in hepatocarcinogenesis, particularly gains of 1q and 8q...
September 12, 2016: Cancer Research
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