A novel bile acid-activated vitamin D receptor signaling in human hepatocytes.
Calcitriol/*metabolism; Calcitriol/pharmacology; Cell Membrane/drug effects/metabolism; Cell Nucleus/drug effects/metabolism; Cholesterol 7-alpha-Hydroxylase/antagonists & inhibitors/genetics; Enzyme Activation/drug effects; Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors; Genetic/genetics; Hep G2 Cells; Hepatocyte Nuclear Factor 4/metabolism; Hepatocytes/*drug effects/enzymology/*metabolism; Humans; Intracellular Space/drug effects/metabolism; Ligands; Lithocholic Acid/*pharmacology; Mitogen-Activated Protein Kinase Kinases/metabolism; Phosphorylation/drug effects; Phosphotyrosine/metabolism; Promoter Regions; Protein Kinase Inhibitors/pharmacology; Protein Transport/drug effects; Proto-Oncogene Proteins c-raf/metabolism; Receptors; Retinoid X Receptor alpha/metabolism; Signal Transduction/*drug effects; src-Family Kinases/metabolism; Steroid Hydroxylases/genetics/metabolism; Vitamin D3 24-Hydroxylase
Vitamin D receptor (VDR) is activated by natural ligands, 1alpha,
Han Shuxin; Li Tiangang; Ellis Ewa; Strom Stephen; Chiang John Y L
Molecular endocrinology (Baltimore, Md.)
2010
2010-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1210/me.2009-0482" target="_blank" rel="noreferrer noopener">10.1210/me.2009-0482</a>
Oxytocin-induced labor augments IL-1beta-stimulated lung fluid absorption in fetal guinea pig lungs.
*Labor; Absorption/drug effects; Amiloride/administration & dosage; Animals; Enzyme Activation/drug effects; Enzyme Inhibitors/administration & dosage; Epinephrine/metabolism; Extravascular Lung Water/*metabolism; Female; Fetal Organ Maturity/drug effects; Fetus/metabolism; Guinea Pigs; Hydrocortisone/metabolism; Induced; Interleukin-1/*administration & dosage/metabolism; Ion Transport/drug effects; Lung/*embryology; Maternal-Fetal Exchange/drug effects; Metyrapone/administration & dosage; Oxytocics/*administration & dosage; Oxytocin/*administration & dosage; Pregnancy; Propranolol/administration & dosage; Sodium Channel Blockers/administration & dosage; Sodium-Potassium-Chloride Symporters/metabolism; Vasodilator Agents/administration & dosage
We tested the hypothesis that oxytocin-induced labor augmented
Nair Prem K; Li Tianbo; Bhattacharjee Reshma; Ye Xin; Folkesson Hans G
American journal of physiology. Lung cellular and molecular physiology
2005
2005-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajplung.00256.2004" target="_blank" rel="noreferrer noopener">10.1152/ajplung.00256.2004</a>
High-content screen using zebrafish (Danio rerio) embryos identifies a novel kinase activator and inhibitor.
*Cancer; *Compound library; *Kinase; *Notochord; *Phenotypic screen; *Somites; *Zebrafish; Animals; Antineoplastic Agents/chemistry/pharmacology; Antitumor/methods; Benzoic Acid/chemistry/pharmacology; Death-Associated Protein Kinases/metabolism; Drug Discovery/*methods; Drug Screening Assays; Embryo; Enzyme Activation/drug effects; Enzyme Activators/*chemistry/*pharmacology; Neoplasms/drug therapy/enzymology; Nonmammalian/*drug effects/enzymology; Protein Kinase Inhibitors/*chemistry/*pharmacology; Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism; Zebrafish Proteins/antagonists & inhibitors/metabolism; Zebrafish/*embryology
In this report we utilized zebrafish (Danio rerio) embryos in a phenotypical high-content screen (HCS) to identify novel leads in a cancer drug discovery program. We initially validated our HCS model using the flavin adenosine dinucleotide (FAD) containing endoplasmic reticulum (ER) enzyme, endoplasmic reticulum oxidoreductase (ERO1) inhibitor EN460. EN460 showed a dose response effect on the embryos with a dose of 10muM being significantly lethal during early embryonic development. The HCS campaign which employed a small library identified a promising lead compound, a naphthyl-benzoic acid derivative coined compound 1 which had significant dosage and temporally dependent effects on notochord and muscle development in zebrafish embryos. Screening a 369 kinase member panel we show that compound 1 is a PIM3 kinase inhibitor (IC50=4.078muM) and surprisingly a DAPK1 kinase agonist/activator (EC50=39.525muM). To our knowledge this is the first example of a small molecule activating DAPK1 kinase. We provide a putative model for increased phosphate transfer in the ATP binding domain when compound 1 is virtually docked with DAPK1. Our data indicate that observable phenotypical changes can be used in future zebrafish screens to identify compounds acting via similar molecular signaling pathways.
Geldenhuys Werner J; Bergeron Sadie A; Mullins Jackie E; Aljammal Rowaa; Gaasch Briah L; Chen Wei-Chi; Yun June; Hazlehurst Lori A
Bioorganic & medicinal chemistry letters
2017
2017-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2017.02.068" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2017.02.068</a>
A scaffold hopping approach to identify novel monoamine oxidase B inhibitors.
*Monoamine Oxidase/chemistry/metabolism; Benzofurans/chemistry/pharmacology; Enzyme Activation/drug effects; Flavonoids/chemistry/pharmacology; Humans; Inhibitory Concentration 50; Models; Molecular; Molecular Structure; Monoamine Oxidase Inhibitors/*chemistry/*pharmacology; Protein Binding/drug effects; Small Molecule Libraries; Structure-Activity Relationship
Monoamine oxidase B (MAO-B) inhibitors are used to treat Parkinson's disease. In this study, we searched for novel MAO-B inhibitors using a scaffold hopping approach based on our experience with the thiazolidinedione (TZD) class of compounds as MAO-B inhibitors. Several novel compounds were identified, with potencies in the low nanomolar and low micromolar range. We also found that derivatives of the natural product sulfuretin are potent MAO-A and MAO-B inhibitors.
Geldenhuys Werner J; Funk Max O; Van der Schyf Cornelis J; Carroll Richard T
Bioorganic & medicinal chemistry letters
2012
2012-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2011.12.056" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2011.12.056</a>
A plant lignan, 3'-O-methyl-nordihydroguaiaretic acid, suppresses papillomavirus E6 protein function, stabilizes p53 protein, and induces apoptosis in cervical tumor cells.
Apoptosis Regulatory Proteins/metabolism; Apoptosis/*drug effects; bcl-2-Associated X Protein/metabolism; Caspase 3/metabolism; Caspase 9/metabolism; Cultured/drug effects; Enzyme Activation/drug effects; Female; Genetic; Humans; Luciferases; Masoprocol/*analogs & derivatives/therapeutic use; Oncogene Proteins; Plants/chemistry; Proto-Oncogene Proteins/metabolism; Repressor Proteins/*metabolism; Transcription; Tumor Cells; Tumor Suppressor Protein p53/genetics/*metabolism; Uterine Cervical Neoplasms/*drug therapy/metabolism/pathology; Viral/*metabolism
Persistent infection with oncogenic human papillomaviruses (HPVs) is the most important factor in the induction of uterine cervical cancer, a leading cause of cancer mortality in women worldwide. Upon cell transformation, continual expression of the viral oncogenes is required to maintain the transformed phenotype. The viral E6 protein forms a ternary complex with the cellular E6-AP protein and p53 protein which promotes the rapid degradation of p53. Recent studies have revealed that lignans from the creosote bush (3'-O-methyl-nordihydroguaiaretic acid) can repress the viral promoter responsible for E6 gene expression. Work reported here shows that the lignan can subvert viral oncogene function resulting in stabilized p53 protein within treated HPV-containing tumor cells. The stabilized p53 is transcriptionally active as demonstrated by a luciferase reporter vector and induction of genes for Bax and PUMA proteins. Apoptosis is detected by annexin V binding to treated cells as analyzed by flow cytometry. Programmed cell death is confirmed by the induction of active caspases and TUNEL assay. Initiator caspase-9 is activated first, followed later by the effector caspase-3 enzyme. The stabilization and induced apoptosis are not observed within treated HPV-negative cervical tumor cells. Quantitative real time RT-PCR analysis of endogenous E6 gene transcription from the integrated HPV 16 promoter shows at least a fivefold repression of expression as compared to untreated cells. These results indicate that the loss of E6 protein in treated cells could be, in part, responsible for the stabilization of p53 within the lignan treated cells.
Allen Kristi L; Tschantz Deidra R; Awad Keytam S; Lynch William P; DeLucia Angelo L
Molecular carcinogenesis
2007
2007-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/mc.20305" target="_blank" rel="noreferrer noopener">10.1002/mc.20305</a>
Inhibition of dopamine and choline acetyltransferase concentrations in rat CNS neurons by rat alpha 1- and alpha 2-macroglobulins.
alpha-Macroglobulins/administration & dosage/*pharmacology; Animals; Cells; Choline O-Acetyltransferase/*antagonists & inhibitors; Corpus Striatum/drug effects/*enzymology/metabolism; Cultured; Dopamine Antagonists/*pharmacology; Dopamine/analysis/*metabolism; Enzyme Activation/drug effects; Injections; Intraventricular; Male; Neurons/drug effects/*enzymology/metabolism; Rats; Serotonin/pharmacology; Sprague-Dawley; Stereotaxic Techniques
Previous studies have implicated human alpha-2-macroglobulin (alpha2M) as a potential regulator of neuronal development and function. Rat alpha-1-macroglobulin (alpha1M) and acute-phase alpha-2-macroglobulin (alpha2M) are murine homologues of human alpha2M. In this report, we tested the effect of intracranially infused serotonin-activated rat alpha1M (5HT-alpha1M) on the concentration of dopamine (DA) in the corpus striatum in vivo and the effect of
Hu Y Q; Liebl D J; Dluzen D E; Koo P H
Journal of neuroscience research
1998
1998-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/(SICI)1097-4547(19980215)51:4%3C541::AID-JNR14%3E3.0.CO;2-6" target="_blank" rel="noreferrer noopener">10.1002/(SICI)1097-4547(19980215)51:4%3C541::AID-JNR14%3E3.0.CO;2-6</a>