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  • Articles  (149)
  • Rats  (149)
  • American Association for the Advancement of Science (AAAS)  (149)
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  • 1
    Publication Date: 2003-07-19
    Description: Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grimsby, Joseph -- Sarabu, Ramakanth -- Corbett, Wendy L -- Haynes, Nancy-Ellen -- Bizzarro, Fred T -- Coffey, John W -- Guertin, Kevin R -- Hilliard, Darryl W -- Kester, Robert F -- Mahaney, Paige E -- Marcus, Linda -- Qi, Lida -- Spence, Cheryl L -- Tengi, John -- Magnuson, Mark A -- Chu, Chang An -- Dvorozniak, Mark T -- Matschinsky, Franz M -- Grippo, Joseph F -- New York, N.Y. -- Science. 2003 Jul 18;301(5631):370-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12869762" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Allosteric Regulation ; Animals ; Blood Glucose/metabolism ; *Carrier Proteins ; Diabetes Mellitus, Type 2/*drug therapy/metabolism ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Enzyme Activation ; Enzyme Activators/chemistry/pharmacology ; Glucokinase/*metabolism ; Glucose/*metabolism ; Glucose Tolerance Test ; Homeostasis ; Humans ; Hypoglycemic Agents/chemistry/pharmacology ; Insulin/blood/*secretion ; Islets of Langerhans/*drug effects/secretion ; Keto Acids/metabolism ; Liver/*drug effects/metabolism ; Liver Glycogen/biosynthesis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Proteins/metabolism/pharmacology ; Rats ; Rats, Wistar ; Recombinant Proteins/metabolism ; Stereoisomerism ; Thiazoles/chemistry/*pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 1998-10-23
    Description: Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wetterau, J R -- Gregg, R E -- Harrity, T W -- Arbeeny, C -- Cap, M -- Connolly, F -- Chu, C H -- George, R J -- Gordon, D A -- Jamil, H -- Jolibois, K G -- Kunselman, L K -- Lan, S J -- Maccagnan, T J -- Ricci, B -- Yan, M -- Young, D -- Chen, Y -- Fryszman, O M -- Logan, J V -- Musial, C L -- Poss, M A -- Robl, J A -- Simpkins, L M -- Slusarchyk, W A -- Sulsky, R -- Taunk, P -- Magnin, D R -- Tino, J A -- Lawrence, R M -- Dickson, J K Jr -- Biller, S A -- New York, N.Y. -- Science. 1998 Oct 23;282(5389):751-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. Wetterau_John_R@msmail.bms.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9784135" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine Transaminase/blood ; Animals ; Apolipoproteins B/*blood ; Aspartate Aminotransferases/blood ; Carrier Proteins/*antagonists & inhibitors ; Cholesterol/*blood ; Cricetinae ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Design ; Drug Evaluation, Preclinical ; Fluorenes/chemistry/pharmacokinetics/*pharmacology ; Humans ; Hyperlipidemias/blood/drug therapy ; Hyperlipoproteinemia Type II/*blood/drug therapy ; Lipids/blood ; Lipoproteins/blood ; Liver/metabolism ; Mice ; Piperidines/chemistry/pharmacokinetics/*pharmacology ; Rabbits ; Rats ; Triglycerides/*blood/metabolism ; Tumor Cells, Cultured
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2004-07-13
    Description: Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leist, Marcel -- Ghezzi, Pietro -- Grasso, Giovanni -- Bianchi, Roberto -- Villa, Pia -- Fratelli, Maddalena -- Savino, Costanza -- Bianchi, Marina -- Nielsen, Jacob -- Gerwien, Jens -- Kallunki, Pekka -- Larsen, Anna Kirstine -- Helboe, Lone -- Christensen, Soren -- Pedersen, Lars O -- Nielsen, Mette -- Torup, Lars -- Sager, Thomas -- Sfacteria, Alessandra -- Erbayraktar, Serhat -- Erbayraktar, Zubeyde -- Gokmen, Necati -- Yilmaz, Osman -- Cerami-Hand, Carla -- Xie, Qiao-Wen -- Coleman, Thomas -- Cerami, Anthony -- Brines, Michael -- New York, N.Y. -- Science. 2004 Jul 9;305(5681):239-42.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉H. Lundbeck A/S, 2500 Valby, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15247477" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Binding Sites ; Cells, Cultured ; Diabetic Neuropathies/drug therapy ; Drug Design ; Encephalomyelitis, Autoimmune, Experimental/drug therapy ; Erythropoiesis ; Erythropoietin/*analogs & ; derivatives/chemistry/genetics/metabolism/pharmacology/*therapeutic use ; Female ; Hematocrit ; Humans ; Ligands ; Mice ; Mice, Inbred C3H ; Mutagenesis ; Nervous System Diseases/*drug therapy ; Neurons/metabolism ; Neuroprotective Agents/chemistry/metabolism/pharmacology/*therapeutic use ; Rats ; Rats, Sprague-Dawley ; Receptors, Erythropoietin/metabolism ; Recombinant Proteins ; Signal Transduction ; Spinal Cord Compression/drug therapy ; Stroke/drug therapy ; Structure-Activity Relationship
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    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2004-04-06
    Description: Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)-1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Steffan, Joan S -- Agrawal, Namita -- Pallos, Judit -- Rockabrand, Erica -- Trotman, Lloyd C -- Slepko, Natalia -- Illes, Katalin -- Lukacsovich, Tamas -- Zhu, Ya-Zhen -- Cattaneo, Elena -- Pandolfi, Pier Paolo -- Thompson, Leslie Michels -- Marsh, J Lawrence -- CA-62203/CA/NCI NIH HHS/ -- HD36049/HD/NICHD NIH HHS/ -- HD36081/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2004 Apr 2;304(5667):100-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA 92697, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15064418" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Cell Line ; Cell Nucleus/metabolism ; Corpus Striatum/cytology ; Cytoplasm/metabolism ; Drosophila ; Genes, MDR ; HeLa Cells ; Humans ; Huntington Disease/metabolism/*pathology ; Lysine/genetics/metabolism ; Mutation ; Nerve Degeneration ; Nerve Tissue Proteins/chemistry/genetics/*metabolism ; Neurons/metabolism ; Nuclear Proteins/chemistry/genetics/*metabolism ; Proline/genetics/metabolism ; Promoter Regions, Genetic ; Rats ; Recombinant Fusion Proteins/metabolism ; SUMO-1 Protein/genetics/*metabolism ; Transcription, Genetic ; Transfection ; Ubiquitin/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2003-02-08
    Description: We report the design and total chemical synthesis of "synthetic erythropoiesis protein" (SEP), a 51-kilodalton protein-polymer construct consisting of a 166-amino-acid polypeptide chain and two covalently attached, branched, and monodisperse polymer moieties that are negatively charged. The ability to control the chemistry allowed us to synthesize a macromolecule of precisely defined covalent structure. SEP was homogeneous as shown by high-resolution analytical techniques, with a mass of 50,825 +/-10 daltons by electrospray mass spectrometry, and with a pI of 5.0. In cell and animal assays for erythropoiesis, SEP displayed potent biological activity and had significantly prolonged duration of action in vivo. These chemical methods are a powerful tool in the rational design of protein constructs with potential therapeutic applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kochendoerfer, Gerd G -- Chen, Shiah-Yun -- Mao, Feng -- Cressman, Sonya -- Traviglia, Stacey -- Shao, Haiyan -- Hunter, Christie L -- Low, Donald W -- Cagle, E Neil -- Carnevali, Maia -- Gueriguian, Vincent -- Keogh, Peter J -- Porter, Heather -- Stratton, Stephen M -- Wiedeke, M Con -- Wilken, Jill -- Tang, Jie -- Levy, Jay J -- Miranda, Les P -- Crnogorac, Milan M -- Kalbag, Suresh -- Botti, Paolo -- Schindler-Horvat, Janice -- Savatski, Laura -- Adamson, John W -- Kung, Ada -- Kent, Stephen B H -- Bradburne, James A -- New York, N.Y. -- Science. 2003 Feb 7;299(5608):884-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gryphon Therapeutics, 250 East Grand Avenue, Suite 90, South San Francisco, CA 94080, USA. Gkochendoerfer@gryphonRX.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12574628" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line ; Circular Dichroism ; *Drug Design ; Drug Stability ; Electrophoresis, Polyacrylamide Gel ; *Erythropoiesis ; Erythropoietin/chemistry/pharmacology ; Hematocrit ; Humans ; Isoelectric Point ; Mice ; Molecular Sequence Data ; Molecular Structure ; Molecular Weight ; *Polymers/*chemical synthesis/*chemistry/pharmacokinetics/pharmacology ; Protein Folding ; Proteins/*chemical synthesis/*chemistry/pharmacokinetics/pharmacology ; Rats ; Receptors, Erythropoietin/drug effects/metabolism ; Recombinant Proteins ; Spectrometry, Mass, Electrospray Ionization
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2004-02-21
    Description: Dietary cholesterol consumption and intestinal cholesterol absorption contribute to plasma cholesterol levels, a risk factor for coronary heart disease. The molecular mechanism of sterol uptake from the lumen of the small intestine is poorly defined. We show that Niemann-Pick C1 Like 1(NPC1L1) protein plays a critical role in the absorption of intestinal cholesterol. NPC1L1 expression is enriched in the small intestine and is in the brush border membrane of enterocytes. Although otherwise phenotypically normal, NPC1L1-deficient mice exhibit a substantial reduction in absorbed cholesterol, which is unaffected by dietary supplementation of bile acids. Ezetimibe, a drug that inhibits cholesterol absorption, had no effect in NPC1L1 knockout mice, suggesting that NPC1L1 resides in an ezetimibe-sensitive pathway responsible for intestinal cholesterol absorption.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Altmann, Scott W -- Davis, Harry R Jr -- Zhu, Li-Ji -- Yao, Xiaorui -- Hoos, Lizbeth M -- Tetzloff, Glen -- Iyer, Sai Prasad N -- Maguire, Maureen -- Golovko, Andrei -- Zeng, Ming -- Wang, Luquan -- Murgolo, Nicholas -- Graziano, Michael P -- New York, N.Y. -- Science. 2004 Feb 20;303(5661):1201-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cardiovascular/Endocrine Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ, 07033-0539, USA. scott.altmann@spcorp.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14976318" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Anticholesteremic Agents/pharmacology ; Azetidines/pharmacology ; Cholesterol/*metabolism ; Cholesterol, Dietary/*metabolism ; Cholic Acid/administration & dosage/pharmacology ; Computational Biology ; Enterocytes/*metabolism ; Ezetimibe ; Female ; Gene Expression Profiling ; Humans ; *Intestinal Absorption/drug effects ; Intestine, Small/metabolism ; Jejunum/metabolism ; Liver/metabolism ; Male ; Membrane Proteins/chemistry/genetics/*metabolism ; Membrane Transport Proteins/chemistry/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Sequence Data ; Oligonucleotide Array Sequence Analysis ; Proteins/chemistry/genetics/*metabolism ; Rats ; Rats, Sprague-Dawley
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 1998-10-23
    Description: A map of 30,181 human gene-based markers was assembled and integrated with the current genetic map by radiation hybrid mapping. The new gene map contains nearly twice as many genes as the previous release, includes most genes that encode proteins of known function, and is twofold to threefold more accurate than the previous version. A redesigned, more informative and functional World Wide Web site (www.ncbi.nlm.nih.gov/genemap) provides the mapping information and associated data and annotations. This resource constitutes an important infrastructure and tool for the study of complex genetic traits, the positional cloning of disease genes, the cross-referencing of mammalian genomes, and validated human transcribed sequences for large-scale studies of gene expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deloukas, P -- Schuler, G D -- Gyapay, G -- Beasley, E M -- Soderlund, C -- Rodriguez-Tome, P -- Hui, L -- Matise, T C -- McKusick, K B -- Beckmann, J S -- Bentolila, S -- Bihoreau, M -- Birren, B B -- Browne, J -- Butler, A -- Castle, A B -- Chiannilkulchai, N -- Clee, C -- Day, P J -- Dehejia, A -- Dibling, T -- Drouot, N -- Duprat, S -- Fizames, C -- Fox, S -- Gelling, S -- Green, L -- Harrison, P -- Hocking, R -- Holloway, E -- Hunt, S -- Keil, S -- Lijnzaad, P -- Louis-Dit-Sully, C -- Ma, J -- Mendis, A -- Miller, J -- Morissette, J -- Muselet, D -- Nusbaum, H C -- Peck, A -- Rozen, S -- Simon, D -- Slonim, D K -- Staples, R -- Stein, L D -- Stewart, E A -- Suchard, M A -- Thangarajah, T -- Vega-Czarny, N -- Webber, C -- Wu, X -- Hudson, J -- Auffray, C -- Nomura, N -- Sikela, J M -- Polymeropoulos, M H -- James, M R -- Lander, E S -- Hudson, T J -- Myers, R M -- Cox, D R -- Weissenbach, J -- Boguski, M S -- Bentley, D R -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 1998 Oct 23;282(5389):744-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sanger Centre, Hinxton Hall, Hinxton, Cambridge CB10 1SA UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9784132" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromosomes, Human/*genetics ; Expressed Sequence Tags ; Gene Expression ; Genetic Markers ; *Genome, Human ; Human Genome Project ; Humans ; Internet ; *Physical Chromosome Mapping ; Rats ; Sequence Tagged Sites
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2002-07-27
    Description: D-fenfluramine (d-FEN) was once widely prescribed and was among the most effective weight loss drugs, but was withdrawn from clinical use because of reports of cardiac complications in a subset of patients. Discerning the neurobiology underlying the anorexic action of d-FEN may facilitate the development of new drugs to prevent and treat obesity. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we show that d-FEN-induced anorexia requires activation of central nervous system melanocortin pathways. These results provide a mechanistic explanation of d-FEN's anorexic actions and indicate that drugs targeting these downstream melanocortin pathways may prove to be effective and more selective anti-obesity treatments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heisler, Lora K -- Cowley, Michael A -- Tecott, Laurence H -- Fan, Wei -- Low, Malcolm J -- Smart, James L -- Rubinstein, Marcelo -- Tatro, Jeffrey B -- Marcus, Jacob N -- Holstege, Henne -- Lee, Charlotte E -- Cone, Roger D -- Elmquist, Joel K -- F31HG00201/HG/NHGRI NIH HHS/ -- P01DK056116/DK/NIDDK NIH HHS/ -- P01DK55819/DK/NIDDK NIH HHS/ -- R01MH061583/MH/NIMH NIH HHS/ -- R01MH44694/MH/NIMH NIH HHS/ -- R01MH61624/MH/NIMH NIH HHS/ -- R03TW01233/TW/FIC NIH HHS/ -- New York, N.Y. -- Science. 2002 Jul 26;297(5581):609-11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12142539" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Appetite Depressants/*pharmacology ; Arcuate Nucleus of Hypothalamus/*drug effects/metabolism ; Feeding Behavior/*drug effects ; Fenfluramine/*pharmacology ; Male ; Melanocyte-Stimulating Hormones/pharmacology ; Mice ; Mice, Obese ; Mice, Transgenic ; Neurons/drug effects/metabolism ; Paraventricular Hypothalamic Nucleus/drug effects/metabolism ; Patch-Clamp Techniques ; Pro-Opiomelanocortin/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Melanocortin, Type 3 ; Receptor, Melanocortin, Type 4 ; Receptor, Serotonin, 5-HT2C ; Receptors, Corticotropin/metabolism ; Receptors, Serotonin/metabolism ; Serotonin/metabolism ; Serotonin Agents/pharmacology ; alpha-MSH/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 1996-08-16
    Description: Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Howard, A D -- Feighner, S D -- Cully, D F -- Arena, J P -- Liberator, P A -- Rosenblum, C I -- Hamelin, M -- Hreniuk, D L -- Palyha, O C -- Anderson, J -- Paress, P S -- Diaz, C -- Chou, M -- Liu, K K -- McKee, K K -- Pong, S S -- Chaung, L Y -- Elbrecht, A -- Dashkevicz, M -- Heavens, R -- Rigby, M -- Sirinathsinghji, D J -- Dean, D C -- Melillo, D G -- Patchett, A A -- Nargund, R -- Griffin, P R -- DeMartino, J A -- Gupta, S K -- Schaeffer, J M -- Smith, R G -- Van der Ploeg, L H -- New York, N.Y. -- Science. 1996 Aug 16;273(5277):974-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Merck Research Laboratories, Rahway, NJ 07065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8688086" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Base Sequence ; Cell Line ; Codon ; DNA, Complementary/genetics ; GTP-Binding Proteins/metabolism ; Growth Hormone/*secretion ; Hormones/*metabolism ; Humans ; Hypothalamus, Middle/chemistry ; Indoles/*metabolism/pharmacology ; Macaca mulatta ; Molecular Sequence Data ; Oligopeptides/*metabolism ; Pituitary Gland/chemistry ; RNA, Complementary/genetics ; Rats ; Receptors, Cell Surface/analysis/chemistry/genetics/*metabolism ; *Receptors, G-Protein-Coupled ; Receptors, Ghrelin ; Spiro Compounds/*metabolism/pharmacology ; Swine
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 1996-05-03
    Description: The vascular complications of diabetes mellitus have been correlated with enhanced activation of protein kinase C (PKC). LY333531, a specific inhibitor of the beta isoform of PKC, was synthesized and was shown to be a competitive reversible inhibitor of PKC beta 1 and beta 2, with a half-maximal inhibitory constant of approximately 5 nM; this value was one-fiftieth of that for other PKC isoenzymes and one-thousandth of that for non-PKC kinases. When administered orally, LY333531 ameliorated the glomerular filtration rate, albumin excretion rate, and retinal circulation in diabetic rats in a dose-responsive manner, in parallel with its inhibition of PKC activities.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ishii, H -- Jirousek, M R -- Koya, D -- Takagi, C -- Xia, P -- Clermont, A -- Bursell, S E -- Kern, T S -- Ballas, L M -- Heath, W F -- Stramm, L E -- Feener, E P -- King, G L -- DK36836/DK/NIDDK NIH HHS/ -- EY05110-11/EY/NEI NIH HHS/ -- New York, N.Y. -- Science. 1996 May 3;272(5262):728-31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8614835" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Oral ; Albuminuria/prevention & control ; Animals ; Diabetes Mellitus, Experimental/*complications/enzymology/physiopathology ; Diabetic Angiopathies/enzymology/etiology/*prevention & control ; Diglycerides/metabolism ; Dose-Response Relationship, Drug ; Enzyme Activation ; Enzyme Inhibitors/chemistry/*pharmacology ; Glomerular Filtration Rate/drug effects ; Humans ; Indoles/administration & dosage/chemistry/*pharmacology ; Isoenzymes/*antagonists & inhibitors/metabolism ; Kidney Glomerulus/metabolism ; Male ; Maleimides/administration & dosage/chemistry/*pharmacology ; Muscle, Smooth, Vascular/enzymology ; Phosphorylation/drug effects ; Protein Kinase C/*antagonists & inhibitors/metabolism ; Protein Kinase C beta ; Rats ; Rats, Sprague-Dawley ; Regional Blood Flow/drug effects ; Renal Plasma Flow/drug effects ; Retina/metabolism ; Retinal Vessels/physiopathology ; Substrate Specificity
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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