Hepatic Cell News Volume 3.11 | Mar 29 2019

TOP STORY

SIRT1/MRPS5 Axis Enhances the Metabolic Flexibility of Liver Cancer Stem Cells

Researchers confirmed that mitochondrial ribosomal protein S5 (MRPS5) promoted the production of NAD⁺, which was necessary for enhanced mitochondrial function in liver cancer stem cells (CSCs). MRPS5 played a critical role for liver CSCs to maintain stemness properties and to participate in tumor progression. [Hepatology] Abstract

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Anti-CD24 Antibody-Nitric Oxide Conjugate (ANC) Selectively and Potently Suppresses Hepatic Carcinoma

Scientists conjugated HL-2 with an antibody that targeted CD24 through a thioether bond to generate an antibody-drug conjugate-like immunoconjugate, ANC, which they named HN-01. HN-01 showed efficient internalization and significantly increased the release of nitric oxide in hepatic carcinoma cells in vitro. [Cancer Res] Abstract | Full Article

Inhibitory Effect of Sestrin2 on Hepatic Stellate Cell Activation and Liver Fibrosis via Blocking Transforming Growth Factor-β Signaling

Sestrin2 (Sesn2) protein and mRNA levels were upregulated in activated primary hepatic stellate cells (HSCs), and by increasing transcription, transforming growth factor-β (TGF-β) also increased Sesn2 expression in HSCs. Furthermore, Smad activation was primarily initiated by TGF-β signaling, and Smad3 activation increased Sesn2 luciferase activity. [Antioxid Redox Signal] Abstract

MCUR1 Facilitates Epithelial-Mesenchymal Transition and Metastasis via the Mitochondrial Calcium Dependent ROS/Nrf2/Notch Pathway in Hepatocellular Carcinoma

The effect of mitochondrial calcium uniporter regulator 1 (MCUR1) expression on epithelial-mesenchymal transition in hepatocellular carcinoma (HCC) cells was first evaluated by immunofluorescent staining and Western blot. Then, in vitro invasion and in vivo metastasis assays were used to evaluate the function of MCUR1 in HCC metastasis. The underlying mechanism was also explored by investigating the effect of MCUR1 on ROS/Nrf2/Notch1 pathway. [J Exp Clin Cancer Res] Full Article

Integrated In Vitro Models for Hepatic Safety and Metabolism: Evaluation of a Human Liver-Chip and Liver Spheroid

Investigators present a comprehensive evaluation of two promising models to assess mechanistic hepatotoxicity, microengineered Organ-Chips and 3D hepatic spheroids, which have enhanced liver phenotype, metabolic activity and stability in culture not attainable with conventional 2D models. [Arch Toxicol] Full Article

Engagement with tNOX (ENOX2) to Inhibit SIRT1 and Activate p53-Dependent and -Independent Apoptotic Pathways by Novel 4,11-Diaminoanthra[2,3-b]furan-5,10-diones in Hepatocellular Carcinoma Cells

The authors investigated three selected 4,11-diaminoanthra[2,3-b]furan-5,10-dione derivatives for their cytotoxicity and the underlying molecular mechanisms in wild-type or p53-deficient hepatocellular carcinoma cells. Cytotoxicity was determined by WST-1 assays and cell impedance measurements and apoptosis was analyzed by flow cytometry. The interaction between compounds and tumor-associated NADH oxidase was studied by cellular thermal shift assay. [Cancers] Full Article

Human Relaxin-2 Attenuates Hepatic Steatosis and Fibrosis in Mice with Non-Alcoholic Fatty Liver Disease

Relaxin-2 had no direct anti-steatotic effect on primary mouse hepatocytes, but S-nitroso-N-acetylpenicillamine attenuated palmitic acid-induced steatosis and activated genes regulating fatty acid oxidation in hepatocytes. [Lab Invest] Abstract

PNPLA2 Influences Secretion of Triglyceride-Rich Lipoproteins by Human Hepatoma Cells

Researchers investigated the roles of patatin-like phospholipase domain containing protein (PNPLA)2, PNPLA3 and PNPLA4 in triglyceride metabolism of human Huh7 and HepG2 hepatoma cells using gene-specific inhibition methods. siRNA inhibition of PNPLA3 or PNPLA4 was not associated with changes in triglyceride hydrolysis, secretion of triglyceride-rich lipoproteins or triglyceride accumulation. [J Lipid Res] Abstract | Full Article

Regulation of Liver Receptor Homologue-1 by DDB2 E3 Ligase Activity Is Critical for Hepatic Glucose Metabolism

In human hepatoma cells, scientists observed that protein levels of endogenous liver receptor homologue-1 (LRH-1) were increased by insulin without a change in mRNA levels of LRH-1. However, overexpression of DNA damage-binding protein 2 (DDB2) impaired the insulin-stimulated increase in LRH-1 levels. [Sci Rep] Full Article

Epithelial-Mesenchymal Transition Induced Cancer-Stem-Cell-Like Characteristics in Hepatocellular Carcinoma

Bioinformatics analysis was performed to evaluate the relationship between epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). The EMT and CSC regulatory mechanism was investigated through Transwell, wound-healing, sphere formation, colony-forming, and western blotting assays. Immunofluorescence and immunoprecipitation were used to study the interaction of hypoxia inducible factor 1α/Notch1. [J Cell Physiol] Abstract

Chlorogenic Acid and Caffeic Acid from Sonchus oleraceus Linn Synergistically Attenuate Insulin Resistance and Modulate Glucose Uptake in HepG2 Cells

Pre-treatment of HepG2 cells with crude extract (CE) or phenolic acids (PA) enhanced levels of glucose production and avoided the decrease total levels of IRS-1 triggered by high insulin concentration. CE or PA pre-treatment also could prevent the inactivation of the PI3K/AKT pathway, as well as the diminution of GLUT4 levels induced by high glucose. [Food Chem Toxicol] Abstract

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The Liver-Alpha Cell Axis and Type 2 Diabetes

Emerging data now indicate that the elevated plasma concentrations of glucagon may be associated with hepatic steatosis and not necessarily with the presence or absence of type 2 diabetes. Thus, fatty liver disease, most often secondary to overeating, may result in impaired amino acid turnover, leading to increased plasma concentrations of certain glucagonotropic amino acids. [Endocr Rev] Abstract

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Spring Bank Announces Inarigivir Abstracts Accepted for Oral and Poster Presentations

Spring Bank Pharmaceuticals, Inc. announced the acceptance of a late breaker oral presentation and a poster presentation. [Press release from Spring Bank Pharmaceuticals, Inc. discussing research to be presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna] Press Release

CymaBay Therapeutics Announces Multiple Presentations

CymaBay Therapeutics, Inc. announced that multiple seladelpar presentations will be delivered. Seladelpar is a potent and selective peroxisome proliferator-activated receptor delta agonist currently in development for primary biliary cholangitis and nonalcoholic steatohepatitis. [Press release from CymaBay Therapeutics, Inc. discussing research to be presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna] Press Release

Assembly Biosciences Announces Multiple Abstracts Highlighting HBV Core Inhibitor Portfolio Accepted for Oral and Poster Presentations

Assembly Biosciences, Inc. had four abstracts accepted highlighting its hepatitis B virus (HBV) core protein inhibitor pipeline, including late breaker presentations on the interim results from the Phase IIa studies of ABI-H0731 and final results of the recently completed ABI-H2158 Phase Ia study. [Press release from Assembly Biosciences, Inc. discussing research to be presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna] Press Release

Promethera Biosciences Announces Late-Breaking Data Presentation

Promethera Biosciences SA announced that clinical data from the ongoing Phase IIa study of its lead product candidate HepaStem^® in patients with Acute-on-Chronic Liver Failure (ACLF) or acute decompensation at risk of developing ACLF has been selected for an oral presentation by the principal investigator. [Press release from Promethera Biosciences SA discussing research to be presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna] Press Release

Gilead to Present New Data From Multiple Liver Disease Research and Development Programs

Gilead Sciences, Inc. announced that data from the company’s research and development programs in nonalcoholic steatohepatitis, primary sclerosing cholangitis and viral hepatitis will be presented. [Press release from Gilead Sciences, Inc. discussing research to be presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna] Press Release

Enanta Pharmaceuticals Announces Data Presentations

Enanta Pharmaceuticals, Inc. announced that new preclinical data from Enanta’s wholly-owned development programs for hepatitis B virus and non-alcoholic steatohepatitis have been accepted for presentations. [Press release from Enanta Pharmaceuticals, Inc. discussing research to be presented at the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna] Press Release

Barc Lab and OWL Metabolomics Announce Strategic Partnership on Deploying Metabolomic Technology in Clinical Trials

This strategic partnership between Barc Lab and OWL Metabolomics will provide a broad range of clinical support solutions for the expanding number of biopharmaceutical companies active in non-alcoholic steatohepatitis research leveraging cutting-edge, metabolomic technology and expertise. [BARC LAB] Press Release

Allena Pharmaceuticals Announces Agreement with Duke Clinical Research Institute for Urirox-2 Pivotal Phase III Trial

Allena Pharmaceuticals, Inc. announced an agreement with the Duke Clinical Research Institute to support the URIROX-2 Phase III clinical trial of reloxaliase in enteric hyperoxaluria. [Allena Pharmaceuticals, Inc.] Press Release

Madrigal Pharmaceuticals Initiates Phase III, Multinational, Double-Blind, Randomized, Placebo-Controlled Study of Mgl-3196 (Resmetirom) in Patients with Non-Alcoholic Steatohepatitis (NASH) and Fibrosis to Resolve NASH and Reduce Progression to Cirrhosis and/or Hepatic Decompensation

Madrigal Pharmaceuticals, Inc. announced that it has initiated its Phase III trial in NASH with its once daily, oral thyroid hormone receptor beta selective agonist, MGL-3196. This double-blind, placebo-controlled study will be conducted at more than 150 sites in the United States and the rest of the world. [Madrigal Pharmaceuticals, Inc.] Press Release

Diasome Announces First Patient Enrolled in Phase II Study of Hepatocyte Directed Vesicle Nanotechnology for People with Type 1 Diabetes

Diasome Pharmaceuticals, Inc. announced that the first subject has been enrolled in its Phase II OPTI-1 study of injectable hepatocyte directed vesicle (HDV) plus insulin for the treatment of type 1 diabetes. This study is designed to optimize the ratio of long-acting to short-acting insulin therapies when using HDV. [Diasome Pharmaceuticals, Inc.] Press Release

Can-Fite Announces Phase II Advanced Liver Cancer Top-Line Results for Its Orphan/Fast Track Drug Namodenoson

Can-Fite BioPharma Ltd. announced that the Phase II advanced liver cancer study did not achieve its primary end point of overall survival in the whole population. At the same time, superiority in overall survival was found in the largest study subpopulation of CPB7 and in secondary end points in the whole population, including objective response measured by CT or MRI. These data strongly support the progression into Phase III. [Can-Fite BioPharma Ltd.] Press Release

DURECT Announces Patient Enrollment in Phase Ib Clinical Trial of Oral DUR-928 in Patients with Non-Alcoholic Steatohepatitis (NASH)

DURECT Corporation announced it has commenced patient enrollment in a Phase Ib trial with oral DUR-928 in patients with NASH. This is an open-label, Phase Ib study, evaluating three doses of oral DUR-928 administered daily for 28 consecutive days to evaluate safety, pharmacokinetics and signals of biological activity in patients with NASH. [DURECT Corporation] Press Release

Dynavax Announces European Medicines Agency Accepts Marketing Authorization Application for HEPLISAV-B^® for Prevention of Hepatitis B in Adults

Dynavax Technologies Corporation announced that the European Medicines Agency has accepted the company’s Marketing Authorization Application for review of HEPLISAV-B for prevention of infection caused by all known subtypes of hepatitis B virus in adults age 18 years and older. [Dynavax Technologies Corporation] Press Release

SteroTherapeutics Receives New US Patent for Treatment of Non-Alcoholic Steatohepatitis (NASH)

SteroTherapeutics announced that they have received patent approval from the United States Patent and Trademark Office on methods and composition for treatment of NASH. [SteroTherapeutics] Press Release

NIH May Bar Peer Reviewers Accused of Sexual Harassment

The National Institutes of Health (NIH) in Bethesda, Maryland, reminded the research community this week that the agency can—and sometimes does—bar scientists accused of sexual harassment from serving as peer reviewers. [ScienceInsider] Editorial

Top US Institutes Still Aren’t Reporting Clinical-Trial Results on Time

Many leading US universities are breaking the law by failing to make public the results of clinical trials. A report found that 25 of the 40 universities that sponsor the most trials in the United States did not post study results on a public, government register within 12 months of completion, as is required by US law. [Nature News] Editorial

NEW European Society for Medical Oncology (ESMO) 2019 Congress
September 27-October 1, 2019
Barcelona, Spain

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NEW Postdoctoral Research Scholarship – Liver Function & Disease (Karolinska Institutet)

Postdoctoral Research Fellow – Biology of Liver Cancer (Boston Children’s Hospital)

Postdoctoral Fellow – Alcoholic Liver Disease Research (Northeast Ohio Medical University)

Professor/Associate Professor – Cancer Biology (Norwegian University of Science and Technology)

Postdoctoral Position – Stem Cell Biology (University of Zurich)

Postdoctoral Position – Hepatitis C Virus Vaccine Research (TWINCORE – Centre for Experimental and Clinical Infection Research)

Postdoctoral Position – Non-Alcoholic Fatty Liver Disease (University of California, San Diego)

Assistant Professor – Computational Biology/Stem Cell Biology (University of Illinois at Chicago)

Postdoctoral Research Associate – Liver DIseases (University of Illinois at Chicago)

Senior Research Scientist – Nonalcoholic Steatohepatitis (Gilead Sciences, Inc)

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