ABSTRACT GPR40 (FFA1) is a fatty acid receptor whose activation results in potent glucose lowering and insulinotropic effects in vivo. Several reports illustrate that GPR40 agonists exert glucose lowering in diabetic humans. To assess the mechanisms by which GPR40 partial agonists improve glucose homeostasis, we evaluated the effects of MK-2305, a potent and selective partialRead More
In vitro and in vivo pharmacology of NXT629, a novel and selective PPARα antagonist
ABSTRACT Peroxisome-proliferator activated receptors (PPAR) are members of the nuclear hormone receptor superfamily which regulate gene transcription. PPARα is a key regulator of lipid homeostasis and a negative regulator of inflammation. Under conditions of metabolic stress such as fasting or glucose deprivation, PPARα is upregulated in order to control gene expression necessary for processing alternateRead More
Structure-activity relationship analysis of mitochondrial toxicity caused by antiviral ribonucleoside analogs
ABSTRACT Recent cases of severe toxicity during clinical trials have been associated with antiviral ribonucleoside analogs (e.g. INX-08189 and balapiravir). Some have hypothesized that the active metabolites of toxic ribonucleoside analogs, the triphosphate forms, inadvertently target human mitochondrial RNA polymerase (POLRMT), thus inhibiting mitochondrial RNA transcription and protein synthesis. Others have proposed that the prodrugRead More
JTP-117968, a novel selective glucocorticoid receptor modulator, exhibits improved transrepression/transactivation dissociation
ABSTRACT Classic glucocorticoids that have outstanding anti-inflammatory effects are still widely prescribed for the treatment of various inflammatory and autoimmune diseases. Conversely, glucocorticoids cause numerous unwanted side effects, particularly systemically dosed glucocorticoids. Therefore, selective glucocorticoid receptor modulator (SGRM), which maintains beneficial anti-inflammatory effects while reducing the occurrence of side effects, is one of the mostRead More
Detection of cytokeratin 18 in proliferating, primary-like upcyte® hepatocytes to predict drug-induced hepatotoxicity
View Full Size Research conducted by: Wiebe Schaefer (1), Astrid Noerenberg (1), Adrian Kling (2), Giannella Coghlan (2), Nils Runge (1), & Timo Johannssen (1) (1) upcyte technologies GmbH, Osterfeldstr. 12-14, 22529 Hamburg, Germany (2) VLVbio AB, Hästholmsvägen 32, 13130 Nacka, Sweden Date of Publication: 2017
Use of upcyte® hepatocytes as a steatosis model on a multi-organ chip
View Full Size Research conducted by: S. Bauer (2), C. Magauer (2), I. Maschmeyer (2), C. Drewell (1), A. Lorenz (2), N. Runge (3), T. Johannssen (3), U. Marx (2), & A. Noerenberg (3) (1) Technische Universität Berlin, Medizinische Biotechnologie (2) TissUse, Berlin, Germany (3) upcyte technologies GmbH, Osterfeldstr. 12-14, D-22529 Hamburg, Germany Date of Publication: 2017
Novel Small Molecule Guanidine Sigma1 Inhibitors for Advanced Prostate Cancer
ABSTRACT Prostate cancer is the most frequently diagnosed malignancy and the leading cause of cancer related death in men. First line therapy for disseminated disease relies on androgen deprivation, leveraging the addiction of these tumors on androgens for both growth and survival. Treatment typically involves antagonizing the androgen receptor (AR) or blocking the synthesis ofRead More
Profiling Drug Activity of Human and Ortholog Xenobiotic-Sensing Receptors: PXR, CAR, AhR, and FXR
View Full Size Research conducted by: Koji Toyokawa (1), Ewa Maddox (1), Jack Vanden Huevel (1,2), & Bruce Sherf (1) (1) INDIGO Biosciences, Inc., 1981 Pine Hall Rd, State College, PA, USA (2) Center for Molecular Toxicology and Carcinogenesis, 325 Life Sciences Building, Penn State University, University Park, PA 16802, USA Date of Publication: 2017
Validating the Gene Expression of Clinically Relevant CYP450 Enzymes and Transporters in Human upcyte® Hepatocytes to Develop an In Vitro Predictive Tool for DDI
View Full Size Research conducted by: Samaar Maalouf (1), Bruce Sherf(1), & Jack Vanden Huevel (1,2) (1) INDIGO Biosciences, Inc., 1981 Pine Hall Road, State College, PA, USA (2) Center for Molecular Toxicology and Carcinogenesis, 325 Life Sciences Building, Penn State University, University Park, PA 16802, USA Date of publication: 2017
Structural basis for differential activities of enantiomeric PPARγ agonists: Binding of S35 to the alternative site
ABSTRACT Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte differentiation, type 2 diabetes mellitus, and inflammation. Many PPARγ agonists bind to the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12)Read More