Hepatic Cell News Volume 3.41 | Nov 1 2019

TOP STORY

Human Liver Stem Cell-Derived Extracellular Vesicles Attenuate Liver Fibrosis and Inflammation in a Murine Model of Non-Alcoholic Steatohepatitis

Bio-distribution evaluated by optical imaging showed a preferential accumulation in normal and in particular in fibrotic liver. Extracellular vesicles treatment significantly improved liver function and reduced signs of liver fibrosis and inflammation, at both morphological and molecular levels. [Mol Ther] Abstract

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A Novel AKR1C3 Specific Prodrug TH3424 With Potent Anti-Tumor Activity in Liver Cancer

AKR1C3 inhibitors failed to suppress liver cancer cell growth. The pro-drug TH3424, which released a DNA alkylating reagent upon reduction by AKR1C3, was developed to target tumors with overexpression of AKR1C3. [Clin Pharmacol Ther] Abstract

iRhom2 Inhibits Bile Duct Obstruction-Induced Liver Fibrosis

Using the murine bile duct ligation (BDL) model, investigators showed that the abundance of iRhom2 and activation of ADAM17 increased during liver fibrosis. Consistent with this, concentrations of ADAM17 substrates were increased in plasma samples from mice after BDL and in patients suffering from liver cirrhosis. [Sci Signal] Full Article

DDX17 Promotes Hepatocellular Carcinoma Progression via Inhibiting Klf4 Transcriptional Activity

In vitro, DDX17 was ascertained to alter HCC migratory and invasive capacities after overexpression and knockdown in HCC cell lines. Moreover, by performing co-immunoprecipitation and GST-pull down assay, the physical association between DDX17 and Klf4 was discovered and validated. [Cell Death Dis] Full Article

NPAS2 Contributes to Liver Fibrosis by Directly Transcriptional Activation of Hes1 in Hepatic Stellate Cells

Scientists showed that NPAS2, one of the core circadian molecules which has been shown to promote hepatocarcinoma cells proliferation, significantly contributed to the liver fibrogenesis. NPAS2 was upregulated in the HSCs after fibrogenic injury, which subsequently contributed to the activation of HSC. [Mol Ther Nucleic Acids] Abstract

Pig Liver Esterases PLE1 and PLE6: Heterologous Expression, Hydrolysis of Common Antibiotics and Pharmacological Consequences

Researchers showed that pig liver esterase 1 (PLE1) and PLE6 were highly active toward amoxicillin and ampicillin, two major antibiotics that are widely used in food-supplements. Mass-spectrometric analysis established that the hydrolysis occurred at the β-lactam amide bond and the hydrolysis drastically decreased or completely eliminated the antibacterial activity. [Sci Rep] Full Article

Uncarboxylated Osteocalcin Ameliorates Hepatic Glucose and Lipid Metabolism in KKAy Mice via Activating Insulin Signaling Pathway

Uncarboxylated osteocalcin (GluOC) administration alleviated hyperglycemia through suppressing gluconeogenesis and promoting glycogen synthesis in KKAy mice and in cultured hepatocytes in vitro. Moreover, GluOC administration dose-dependently ameliorated dyslipidemia and attenuated hepatic steatosis in KKAy mice by inhibiting hepatic de novo lipogenesis and promoting fatty-acid β-oxidation. [Acta Pharmacol Sin] Abstract

High-Throughput Screening Identified Mitoxantrone to Induce Death of Hepatocellular Carcinoma Cells with Autophagy Involvement

To identify cytotoxic compounds for potential hepatocellular carcinoma (HCC) treatments, 3271 compounds from three well established small molecule libraries were screened against HCC cell lines. Thirty-two small molecules were identified from the primary screen to induce cell death. Particularly, mitoxantrone (MTX), which is an established antineoplastic drug, significantly and specifically inhibited the growth and proliferation of HCC cells in vitro. [Biochem Biophys Res Commun] Abstract

Potent Repression of C-Reactive Protein (CRP) Expression by the JAK1/2 Inhibitor Ruxolitinib in Inflammatory Human Hepatocytes

Ruxolitinib was found to fully inhibit lipopolysaccharide (LPS)-induced CRP secretion and mRNA expression, at concentrations achievable in human blood. It similarly repressed CRP up-regulation due to several Toll-like receptor agonists or pro-inflammatory cytokines interleukin (IL) 1β, IL6 and tumor necrosis factor α and counteracted LPS-mediated induction of serum amyloid A, fibrinogen, haptoglobin and serpin. [Inflamm Res] Abstract

3-Amidinophenylalanine-Derived Matriptase Inhibitors Can Modulate Hepcidin Production In Vitro

The effects of four 3-amidinophenylalanine-derived combined matriptase-1/matriptase-2 inhibitors on hepcidin production were investigated in hepatocyte mono- and hepatocyte-Kupffer cell co-cultures. In MI-461-treated cell cultures, the extracellular hydrogen peroxide contents and the interleukin-6 and -8 levels were determined and compared to controls. [Naunyn Schmiedebergs Arch Pharmacol] Full Article

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Metabolic Rearrangements in Primary Liver Cancers: Cause and Consequences

The authors discuss the role of metabolic liver disruptions and the implications of processes in primary liver cancer, emphasizing their clinical relevance and value in early diagnosis and prognosis and as putative therapeutic targets. They also describe system biology approaches able to reconstruct the metabolic complexity of liver diseases. [Nat Rev Gastroenterol Hepatol] Abstract

Emerging Agents and Regimens for Hepatocellular Carcinoma

Sorafenib was the first agent shown to improve the survival of patients with advanced hepatocellular carcinoma. A decade after the approval of sorafenib, most agents failed to improve patient survival more than sorafenib. In recent years, treatment practices have changed, with lenvatinib as another first-line treatment choice and regorafenib, ramucirumab, and cabozantinib as second-line treatment options. [J Hematol Oncol] Full Article

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Intensity Therapeutics Treats First Patient with Combination of INT230-6 and Merck’s Keytruda^®

Intensity Therapeutics, Inc. announced that the first patient has been dosed with a combination of INT23006, the company’s lead investigational product, and Keytruda^®, Merck’s anti-PD-1 (programmed death receptor-1) therapy. [Intensity Therapeutics, Inc.] Press Release

Mirum Pharmaceuticals Announces Breakthrough Therapy Designation for Maralixibat for the Treatment of Pruritus Associated with Alagille Syndrome

Mirum Pharmaceuticals, Inc. announced that the FDA has granted Breakthrough Therapy Designation for maralixibat for the treatment of pruritus associated with Alagille syndrome in patients one year of age and older. [Mirum Pharmaceuticals, Inc.] Press Release

US FDA Agreed with Can-Fite’s Proposed Pivotal Phase III Trial Design to Support a New Drug Application Submission and Approval of Namodenoson in the Treatment of Liver Cancer

Can-Fite BioPharma Ltd. announced it has concluded an End-of-Phase II Meeting with the FDA regarding its recently completed Phase II study of Namodenoson in the treatment of hepatocellular cancer, the most common form of liver cancer. [Can-Fite BioPharma Ltd.] Press Release

Trump Nominates MD Anderson’s Stephen Hahn to Lead FDA

President Trump announced his intent to nominate Dr Stephen Hahn to lead the FDA. Dr Stephen Hahn is the chief medical executive at MD Anderson Cancer Center in Houston. While he is an accomplished physician and researcher, he has never worked in government, leaving his potential FDA agenda a mystery. [STAT News] Editorial

Swiss Authorities Probe Boehringer Ingelheim and Other Companies for Antitrust Practices

A Swiss government agency that last month opened an antitrust investigation into several drug makers and distributors has now disclosed the names of nearly a dozen companies that may have fixed the market for an ingredient used to make a treatment for stomach pain. [STAT News] Editorial

Increase in Academics Leaving the UK Since Brexit Vote

After the 2016 Brexit referendum, in which voters decided to have the UK leave the European Union (EU), the number of academics from EU countries leaving the United Kingdom for other university jobs increased by almost half, according to Times Higher Education. [The Scientist] Editorial

NEW FGF Signaling: Understanding Function and Devising Therapeutic Tools
May 10-15, 2020
Tuscany, Italy

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NEW Postdoctoral Researcher – Liver Disease Treatment (University of Southern Denmark)

NEW Postdoctoral Researcher – Personalized Medicine (Mayo Clinic Center for Individualized Medicine)

Postdoctoral Researcher – Liver Plasticity (University of Southern Denmark)

Postdoctoral Scientist – RAS Cancer Biology (Genetech, Inc.)

Postdoctoral Associates – Organogenesis of Liver, Heart and Pancreas (The University of Manchester)

Assistant Professor – Liver Research (The University of Hong Kong)

Research Associate – Pluripotent Stem Cells in Liver Development (The Wellcome Institute)

Research Scientist – Fibrosis (Gilead Sciences, Inc.)

Postdoctoral Researcher – Liver Cell-Cell Interactions (Flanders Institute for Biotechnology)

Principal Researcher – Systems Disease Biology (Boehringer Ingelheim)

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