A5030060152- Nitric Oxide and Endothelin Effects
- Pancreatic function and diabetes
- Parvovirus B19 Infection Studies
- Receptor Mechanisms and Signaling
- Diabetes and associated disorders
- Metabolism, Diabetes, and Cancer
- Synthesis and Biological Evaluation
- Growth Hormone and Insulin-like Growth Factors
- MicroRNA in disease regulation
- Dermatological and COVID-19 studies
- Thyroid Disorders and Treatments
- Electron Spin Resonance Studies
- Drug Transport and Resistance Mechanisms
- Estrogen and related hormone effects
- Chemical Synthesis and Analysis
- Protein Kinase Regulation and GTPase Signaling
- Diet, Metabolism, and Disease
- Virus-based gene therapy research
- Asymmetric Hydrogenation and Catalysis
- Adenosine and Purinergic Signaling
- Tryptophan and brain disorders
- Prenatal Screening and Diagnostics
- Pharmacogenetics and Drug Metabolism
- Extracellular vesicles in disease
- Erythrocyte Function and Pathophysiology
University of Nottingham
2021-2024
Loughborough University
2021
University of Warwick
2017
Pharmadrome (United Kingdom)
2015-2016
John Radcliffe Hospital
1992-2013
University of Oxford
2013
Eli Lilly (United States)
1991-2012
Colorado State University Pueblo
2011
University of Aberdeen
1984-2008
University of Cincinnati
1984-2004
Abstract Activation of protein kinase Cβ (PKCβ) has been repeatedly implicated in tumor-induced angiogenesis. The PKCβ-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. PKCβ now also tumor cell proliferation, apoptosis, invasiveness. Herein, we show that a direct effect on human cells, inducing apoptosis suppressing the proliferation cultured cells. treatment phosphorylation GSK3βser9,...
Human parvovirus is the causative agent of erythema infectiosum, a mild epidemic illness. In recent outbreak in northeast Scotland, six women had serologic evidence having contracted human infection during pregnancy. Two midtrimester abortions, and both abortuses were grossly hydropic with anemia. They similar microscopical histopathological features--a pronounced leukoerythroblastic reaction, hepatitis, excessive iron pigment liver, eosinophilic changes hematopoietic cell nuclei. Dot...
We have altered the fatty acid composition of Friend erythroleukemia cells and studied effect on binding parameters insulin receptor. Cells were grown for about five generations in media enriched with oleate (a monounsaturated acid) or linoleate polyunsaturated acid). The microsomal phospholipids normally contained 40% saturated, monounsaturated, 20% acids. In oleate, monounsaturates rose to 63% linoleate, component 52%. Fluidity determination by electron spin resonance similarly indicated...
Abstract Glucocorticoids (GCs) are the mainstay of asthma therapy; however, major side effects limit their therapeutic use. GCs influence expression genes either by transactivation or transrepression. The antiinflammatory steroids thought to be due transrepression and effects, transactivation. Recently, a compound, RU 24858, has been identified that demonstrated dissociation between in vitro. 24858 exerts strong AP-1 inhibition (transrepression), but little no We investigated whether this...
Apart from islet cell antibodies (ICAs), to glutamate decarboxylase (GAD), insulin autoantibodies (IAAs), and a novel antigen (37k antigen) are potential markers for insulin-dependent diabetes mellitus (IDDM). GAD is also an in stiff-man syndrome (SMS), both SMS IDDM associated with ICAs autoimmunity other endocrine organs. We investigated possible links between antibody responses antigens organs determined which specific can identify individuals who progress IDDM. Antibodies were detected >...
The application of a series (cyclopentadienone)iron tricarbonyl complexes to "borrowing hydrogen" reactions between amines and alcohols was completed in order assess their catalytic activity. electronic variation the aromatic groups flanking C═O cyclopentadienone influenced efficiency reactions; however, other cases, Knölker catalyst 1, containing trimethylsilyl ketone, gave best results. In some change ratio amine alcohol improves conversion significantly. iron catalysts synthesis range...
Insulin-dependent diabetes mellitus (IDDM) is associated with antibodies to a 64,000-Mr islet cell protein, at least part of which identified as glutamic acid decarboxylase (GAD). These are detected two distinct antibody specificities 50,000-Mr and 37,000/40,000-Mr tryptic fragments the autoantigen (50K 37K antibodies, respectively). We determined frequencies intact GAD, antigen, (ICAs), insulin autoantibodies (IAAs) in sera from 58 nondiabetic identical twins patients IDDM, whom 12...
Patients with insulin-dependent diabetes (IDDM) possess antibodies to islet proteins of M(r)-64,000. Potential autoantigens this M(r) include glutamate decarboxylase (GAD) and 65 kD heat shock protein. We have detected two distinct antibody specificities in IDDM that bind 50,000 or 37,000/40,000 proteolytic fragments 64,000 proteins. In study, we investigated relationships these GAD Polyclonal bound antigen. Recombinant GAD65, but not GAD67, blocked binding antigen, suggesting are derived...
A series of vinylacetylene analogs Enviroxime (1) was synthesized. The new compounds are potent inhibitors poliovirus in tissue culture. Cross-sensitivity with Enviroxime-derived mutants shows that the have same mechanism action as Enviroxime, which involves viral 3A protein. In studies Rhesus monkeys, p-fluoro derivative 12 found to be unique providing oral bioavailability. Metabolism using hepatic microsomes suggest this procedure would a useful vitro method for selecting appropriate...
A series of propanones containing combinations aryloxy and alkoxy substituents at the 1- 3-positions were reduced to alcohols via asymmetric transfer hydrogenation using a tethered Ru(II)/TsDPEN catalyst. The enantioselectivities reductions reveal complex pattern electronic steric effects which, when used in matched combination, can lead formation products up 68% ee (84:16 er) from this highly challenging class substrate.
The fifth paper in this series describes the culmination of our investigations into development a potent and selective ET(A) receptor antagonist for treatment diseases mediated by ET-1. Receptor site mapping several antagonists prepared previously identified common cationic binding which prompted synthesis phenoxyphenylacetic acid derivative 13a, showed good vitro activity (IC(50) 59 nM, rat aortic ET(A)). Optimization 13a led to identification 27b, exhibited an IC(50) 4 nM. Although did not...
The synthesis and biological activity of trans-(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamid+ ++ e 1-oxide (8a, RP 49356) analogues is reported. These compounds constitute a new structural class K(+)-channel opener. effects changes in pyridyl group, thioamide, thiane ring on vitro opening reactivity are discussed. A 3-pyridyl or 3-quinolyl small N-alkyl thioamide function, oxide ring, which the sulfoxide trans relationship to preferred for activity. Selected were tested...
The Friend erythroleukemia cell has an insulin receptor with all the properties of mammalian receptors: rapid, reversible, and saturable binding insulin; specific for analogs; inversely proportional to temperatures; sharply pH dependent (optimum = 8.0); demonstrated ligand-induced accelerated dissociation consistent negative cooperativity. There were 17,200 sites per cell. After induction by dimethylsulfoxide, 80% cells became benzidine positive (i.e., contained hemoglobin). concentration...
Semagacestat is a functional γ-secretase inhibitor that has been shown to reduce the rate of formation amyloid-β in vitro and vivo. This study was conducted characterize disposition semagacestat humans. After single 140-mg dose [<sup>14</sup>C]semagacestat administered as an oral solution six healthy male subjects, rapidly absorbed (<i>T</i><sub>max</sub> ∼0.5 h) eliminated from systemic circulation (terminal <i>t</i><sub>1/2</sub> ∼2.4 h). The major circulating metabolites semagacestat, M2...
Abstract Nitrofen (2,4‐dichloro‐4′ ‐nitrodiphenyl ether) is an herbicide with potent teratogenic activity in rodent species. The present study was extension of previous efforts to characterize the distribution and metabolism nitrofen pregnant rats. Following a single p.o. exposure radiolabeled compound on day 10 pregnancy, maternal embryonic tissues were collected at intervals from 1.5 72 hours. Radioactivity accumulated retained fat for over Peak levels reached other organs 3–12 half‐life...