Medicine and Health Sciences Commons^™

Nicotinamide Riboside Kinase Structures Reveal New Pathways To Nad+, Wolfram Tempel, Wael M. Rabeh, Katrina L. Bogan, Peter Belenky, Marzena Wojcik, Heather F. Seidle, Lyudmila Nedyalkova, Tianle Yang, Anthony A. Sauve, Hee-Won Park, Charles Brenner

Dartmouth Scholarship

The eukaryotic nicotinamide riboside kinase (Nrk) pathway, which is induced in response to nerve damage and promotes replicative life span in yeast, converts nicotinamide riboside to nicotinamide adenine dinucleotide (NAD+) by phosphorylation and adenylylation. Crystal structures of human Nrk1 bound to nucleoside and nucleotide substrates and products revealed an enzyme structurally similar to Rossmann fold metabolite kinases and allowed the identification of active site residues, which were shown to be essential for human Nrk1 and Nrk2 activity in vivo. Although the structures account for the 500-fold discrimination between nicotinamide riboside and pyrimidine nucleosides, no enzyme feature was identified to recognize …

Diarrea Viral Bovina Y Animales Portadores Del Virus En Hatos Productores De Leche De La Irrigación De Majes, Arequipa, John C. Huaman G., Hermelinda G. Rivera, Mariluz Araínga, Cesar Gavidia Ch., Alberto Manchego S.

Journal Articles: Pharmacology & Experimental Neuroscience

The objective of this study was to determine the prevalence of bovine viral diarrhea virus (BVDV) and persistently infected (PI) animals in dairy herds located in Majes, Arequipa, Peru. In the first phase, 204 bulk tank milk samples from herds were collected and sent to the local commercial processing plant in Majes for detection of antibodies against BVDV by indirect ELISA test. In the second phase, 286 blood samples from 57 were collected strong positive (Optical Density [OD] ≥ 0.900) for the detection of herds antibodies against BVDV and in PI animals by the indirect and capture ELISAs respectively. In …

The Pharmacokinetics Of Taurolidine Metabolites In Healthy Volunteers., Li Gong, Howard E Greenberg, James L Perhach, Scott A Waldman, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Taurolidine is an experimental antibacterial and antiendotoxic compound whose clinical utility as an antitumor agent is being investigated in human clinical trials. Taurolidine in aqueous solution exists in equilibrium with taurultam. Taurultam is subsequently transformed to taurinamide. The pharmacokinetic profiles of these metabolites are not well established. In this study, 18 healthy volunteers were administered 5.0 g of taurolidine in 250 mL of 5% polyvinylpyrrolidone in water over 2, 1, or 0.5 hours by intravenous infusion in a parallel-group design. All subjects noted discomfort at the infusion site, although there were no serious adverse events. t(max) generally occurred at the …

Expansion Of The Calcium Hypothesis Of Brain Aging And Alzheimer's Disease: Minding The Store, Olivier Thibault, John C. Gant, Philip W. Landfield

Pharmacology and Nutritional Sciences Faculty Publications

Evidence accumulated over more than two decades has implicated Ca2+ dysregulation in brain aging and Alzheimer's disease (AD), giving rise to the Ca2+ hypothesis of brain aging and dementia. Electrophysiological, imaging, and behavioral studies in hippocampal or cortical neurons of rodents and rabbits have revealed aging-related increases in the slow afterhyperpolarization, Ca2+ spikes and currents, Ca2+transients, and L-type voltage-gated Ca2+ channel (L-VGCC) activity. Several of these changes have been associated with age-related deficits in learning or memory. Consequently, one version of the Ca2+ hypothesis has been that increased L-VGCC activity drives many of the other Ca2+-related biomarkers of hippocampal aging. …

Transgenic Avian-Derived Recombinant Human Interferon-Alpha2b (Avi-005) In Healthy Subjects: An Open-Label, Single-Dose, Controlled Study., T B Patel, E Pequignot, S H Parker, M C Leavitt, H E Greenberg, Walter K. Kraft

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND/AIMS: This study characterized the safety and pharmacological properties of AVI-005, a novel glycosylated recombinant human interferon-alpha2b produced from the egg whites of chickens transfected with human cDNA.

METHODS: 18 healthy volunteers received single subcutaneous rising doses (0.5, 1.66 or 5 million international units, MIU) of AVI-005. A randomized parallel comparator group of 10 subjects received 5 MIU of unglycosylated IFN-alpha2b (Intron A). The pharmacokinetic parameters t1/2, tmax, Cmax, AUC0-24h, Vd, and clearance were compared between AVI-005 and unglycosylated IFN-alpa2b.

RESULTS: At equipotent doses, AVI-005 had a larger AUC0-24h than the control interferon. Pharmacodynamic markers ofneopterin and beta2-microglobulin for the …

Beta Blocker Specificity: A Building Block Toward Personalized Medicine., Brent R Degeorge, Walter J Koch

Center for Translational Medicine Faculty Papers

Drugs known as beta blockers, which antagonize the beta-adrenergic receptor (beta-AR), are an important component of the treatment regimen for chronic heart failure (HF). However, a significant body of evidence indicates that genetic heterogeneity at the level of the beta(1)-AR may be a factor in explaining the variable responses of HF patients to beta blockade. In this issue of the JCI, Rochais et al. describe how a single amino acid change in beta(1)-AR alters its structural conformation and improves its functional response to carvedilol, a beta blocker currently used in the treatment of HF (see the related article beginning on …

Interaction Of Glycolysis And Mitochondrial Respiration In Metabolic Oscillations Of Pancreatic Islets, Richard Bertram, Leslie S. Satin, Morten Gram Pedersen, Dan S. Luciani, Arthur Sherman

Pharmacology and Toxicology Publications

Abstract

Insulin secretion from pancreatic β-cells is oscillatory, with a typical period of 2–7 min, reflecting oscillations in membrane potential and the cytosolic Ca²⁺ concentration. Our central hypothesis is that the slow 2–7 min oscillations are due to glycolytic oscillations, whereas faster oscillations that are superimposed are due to Ca²⁺ feedback onto metabolism or ion channels. We extend a previous mathematical model based on this hypothesis to include a more detailed description of mitochondrial metabolism. We demonstrate that this model can account for typical oscillatory patterns of membrane potential and Ca²⁺ concentration in islets. It also …