Hepatic Cell News Volume 3.12 | Apr 5 2019

TOP STORY

Golgi Apparatus-Targeted Chondroitin-Modified Nanomicelles Suppress Hepatic Stellate Cell Activation for the Management of Liver Fibrosis

Chondroitin sulfate nanomicelles (CSmicelles) were selectively taken up in activated hepatic stellate cells and hepatoma cells other than in normal hepatocytes, the internalization of which was proven to be mediated by CD44 receptors. Interestingly, doxorubicin+retinoic acid-CSmicelles preferentially accumulated in the Golgi apparatus, destroyed the Golgi structure, and ultimately downregulated collagen I production. [ACS Nano] Abstract | Graphical Abstract

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Mitotic Regulators and the SHP2-MAPK Pathway Promote IR Endocytosis and Feedback Regulation of Insulin Signaling

Investigators showed that insulin receptor (IR) substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote IR endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellular signal-regulated kinase 1 and 2 and Src homology phosphatase 2 (SHP2) ensured selective internalization of activated IR. [Nat Commun] Full Article

A Positive Feedback Loop between Cancer Stem-Like Cells and Tumor-Associated Neutrophils Controls Hepatocellular Carcinoma Progression

Scientists tested the effect of tumor-associated neutrophils (TANs) on hepatocellular carcinoma (HCC) cells in vitro and in vivo and investigated the mechanism of interaction between them. They showed that TANs secreted BMP2 and TGF-β2, and triggered miR-301b-3p expression in HCC cells, subsequently suppressed gene expression of limbic system-associated membrane protein and CYLD lysine 63 deubiquitinase and increased stem cell characteristics in HCC cells. [Hepatology] Abstract

YAP-Dependent Induction of UHMK1 Supports Nuclear Enrichment of the Oncogene MYBL2 and Proliferation in Liver Cancer Cells

The authors identified U2AF momology motif kinase 1 (UHMK1) as a direct transcriptional target of yes-associated protein (YAP) and the transcription factor forkhead box M1, which supported hepatocellular carcinoma cell proliferation but not migration. Indeed, UHMK1 stimulated the expression of genes that were specific for cell cycle regulation and which are known downstream effectors of YAP. [Oncogene] Abstract

Modulation of the IL-6 Signaling Pathway in Liver Cells by miRNAs Targeting gp130, JAK1 and/or STAT3

Scientists identified miR-3677-5p as a novel miRNA affecting protein expression of both, STAT3 and Janus kinase (JAK)1 whereas miR-16-1-3p, miR-4473 and miR-520f-3p reduced glycoprotein 130 (gp130) surface expression. Combination treatment with two or three miRNAs targeting either gp130 or different signaling molecules of the pathway did not increase the inhibitory effects on phospho-STAT3 levels and STAT3 target gene expression compared to treatment with single mimics. [Mol Ther Nucleic Acids] Abstract | Full Article

Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma

Researchers found that Withaferin A (WFA), a bioactive compound derived from Withania somnifera, was an effective agent for hepatocellular carcinoma (HCC) inhibition. Interestingly, they observed that in addition to inducing apoptotic cell death, WFA also induced autophagy in HCC cells. [Cancers] Full Article

Wolfberry-Derived Zeaxanthin Dipalmitate Attenuates Ethanol-Induced Hepatic Damage

The hepatoprotective effects of zeaxanthin dipalmitate (ZD) were evaluated in vitro and in vivo. Direct interacting receptors of ZD on cell membranes were identified by liver-specific knockdown and biophysical measurements. Downstream signaling pathways were delineated using molecular and cellular biological methods. [Mol Nutr Food Res] Abstract

Activation of the Oncogenic miR-21-5p Promotes HCV Replication and Steatosis Induced by the Viral Core 3a Protein

HCV replication and viral particle production were investigated in Jc1-infected Huh-7 cells after miR-21-5p inhibition. PTEN expression and steatosis were assessed in HCV-3a core protein-expressing Huh-7 cells and in mouse primary hepatocytes having miR-21-5p inhibited or genetically deleted, respectively. [Liver Int] Abstract

Simulated Microgravity Promotes the Formation of Tridimensional Cultures and Stimulates Pluripotency and a Glycolytic Metabolism in Human Hepatic and Biliary Tree Stem/Progenitor Cells

Scientists evaluated biological and functional effects, differentiation potential and exo-metabolome profile of simulated microgravity (SMG) on human hepatic cell line (HepG2) and human biliary tree stem/progenitor cells (hBTSCs). Both hBTSCs and HepG2 were cultured in a weightless and protected environment SMG produced by the Rotary Cell Culture System and control condition in normal gravity. [Sci Rep] Full Article

ZCCHC13-Mediated Induction of Human Liver Cancer Is Associated with the Modulation of DNA Methylation and the AKT/ERK Signaling Pathway

The overexpression of zinc-finger CCHC-type containing 13 (ZCCHC13) in hepatocellular carcinoma was attributed to DNA hypomethylation in the promoter region. Moreover, overexpression of ZCCHC13 in liver cancer cells promoted cell cycle progression by facilitating the G1-S transition, which was related to aberrant activation of the ATK/ERK/c-MYC/CDK pathway. [J Transl Med] Full Article

Antioxidant Effects of Sulforaphane in Human HepG2 Cells and Immortalized Hepatocytes

The effects of sulforaphane (SFN) were measured in both human hepatocyte and hepatoma cells. Results showed that SFN inhibited cell viability and induced DNA strand breaks at high doses. It also activated the nuclear factor (erythroid-derived 2)-like 2, and increased intracellular glutathione levels at 24 hours. [Food Chem Toxicol] Abstract

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Sex Differences in NAFLD: State of the Art and Identification of Research Gaps

In spite of tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), the understanding of sex-differences in NAFLD remains insufficient. The authors summarize current knowledge on sex differences in NAFLD, identify current gaps, and discuss important considerations for future research. [Hepatology] Abstract

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Intercept to Present Results from the First Successful Phase III Trial in Patients with Liver Fibrosis Due to NASH

Intercept Pharmaceuticals, Inc. announced that multiple obeticholic acid abstracts will be presented. [Press release from Intercept Pharmaceuticals, Inc. discussing research to be presented at the 54^th Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna] Press Release

Fractyl Announces New Clinical Data Showing Same-Day Procedure Can Benefit Both NAFLD/NASH and Type 2 Diabetes

Fractyl Laboratories Inc. announced the presentation of new clinical data showing its same-day therapeutic procedure can generate significant improvements in both non-alcoholic fatty liver disease (NAFLD/NASH) and type 2 diabetes in people with both conditions. [Press release from Fractyl Laboratories Inc. discussing research to be presented at the 54^th Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna] Press Release

Shionogi to Present Clinical Data on Lusutrombopag

Shionogi & Co., Ltd. and its European subsidiary, Shionogi B.V., announced it will present four posters on lusutrombopag, a once-daily, orally administered, small molecule thrombopoietin receptor agonist. [Press release from Shionogi & Co., Ltd. discussing research to be presented at the 54^th Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna] Press Release

MiNA Therapeutics Presents Pre-Clinical Data Supporting Combination of MTL-CEBPA with Sorafenib and Other Cancer Treatments

The first pre-clinical study highlights that the combination of MTL-CEBPA with sorafenib resulted in superior tumor growth inhibition and reduction of tumor biomarker alpha-fetoprotein compared to single agents as demonstrated in an immunocompetent rat model of hepatocellular carcinoma. [Press release from MiNA Therapeutics discussing research presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting, Atlanta] Press Release

Orgenesis Announces Collaboration with Digilab to Develop Industrial 3D Printing Capability for Cellular Structures and Tissues for Clinical Use

Orgenesis Inc. announced that it has entered into a collaboration agreement with Digilab Inc. to develop a live cell printing process and systems designed to automate the production of three-dimensional live cellular structures and tissues. [Orgenesis Inc.] Press Release

Salix Enters into License Agreement with the University of California to Develop and Commercialize Novel Compound for the Treatment of Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

Salix Pharmaceuticals and a wholly owned subsidiary of Bausch Health Companies Inc. announced its affiliate has entered into a license agreement with the University of California (UCLA) via UCLA’s Technology Development Group for certain intellectual property relating to an investigational compound targeting the pituitary adenylate cyclase receptor 1 in non-alcoholic fatty liver diseass, non-alcoholic steatohepatitis and various other gastrointestinal and liver diseases. [Salix Pharmaceuticals (PR Newswire Association LLC.)] Press Release

Study Confirms Tesamorelin Significantly Reduces Liver Fat in HIV Patients with NAFLD

Theratechnologies Inc. announced that top-line results, from a study funded by the National Institutes of Health led by Dr. Steve Grinspoon and conducted at the Massachusetts General Hospital and Harvard Medical School and the National Institutes of Health, conclude that tesamorelin significantly reduces liver fat in HIV patients with non alcoholic fatty liver disease (NAFLD) which was the primary endpoint of the study. [Theratechnologies Inc.] Press Release

Poxel Initiates Phase IIa Program for PXL770, a Direct AMPK Activator for the Treatment of NASH

POXEL SA announced initiation of the Phase IIa program for PXL770, a direct adenosine monophosphate-activated protein kinase activator (AMPK), for the treatment of non-alcoholic steatohepatitis (NASH). The Phase IIa twelve-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study, which will assess efficacy and safety, has been initiated. [POXEL SA] Press Release

Homology Medicines Announces FDA Clearance of Investigational New Drug Application for HMI-102 Gene Therapy Candidate for PKU

Homology Medicines, Inc. announced that the FDA has provided clearance for Homology to begin its Phase I/II pheNIX clinical trial with HMI-102, a one-time gene therapy candidate for adults with the rare genetic disease phenylketonuria (PKU), an inborn error of metabolism. [Homology Medicines, Inc.] Press Release

Algernon Pharmaceuticals Announces Reduction of Key Secondary Marker of Fibrosis in Pre-Clinical NASH Study

Algernon Pharmaceuticals Inc. announced that after additional biochemical analysis, NP-135, one of its lead compounds for non-alcoholic steatohepatitis (NASH), showed that in addition to being metabolically neutral in a number of important measurements, it further demonstrated a 34.6% reduction of a key secondary marker of fibrosis, liver hydroxyproline. [Algernon Pharmaceuticals Inc.] Press Release

Risky Stem-Cell Treatments Come Under FDA Scrutiny — Again

The FDA warned rogue stem-cell clinics to stop selling unproven treatments that could harm patients. The agency’s latest effort, like most of its previous ones, consisted only of letters to companies and clinics. [The New York Times] Editorial

FTC Hits Predatory Scientific Publisher with a $50 Million Fine

The Federal Trade Commission (FTC) has won a summary judgement that just might cause some predatory publishers to step back from their business model. An India-based predatory publisher has been hit with a $50 million dollar judgement for deceptive business practices, along with permanent injunctions against most of the activities that made it money. [Ars Technica] Editorial

NEW Keystone Symposia: Tumor Metabolism
March 8-12, 2020
Banff, Alberta, Canada

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NEW Doctoral Researcher – Lipid Droplets in Hepatitis C Virus (Helmholtz Centre for Infection Research)

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)

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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