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101.
Dzierba CD Sielecki TM Arvanitis AG Galka A Johnson TL Takvorian AG Rafalski M Kasireddy-Polam P Vig S Dasgupta B Zhang G Molski TF Wong H Zaczek RC Lodge NJ Combs AP Gilligan PJ Trainor GL Bronson JJ Macor JE 《Bioorganic & medicinal chemistry letters》2012,22(15):4986-4989
Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein. 相似文献
102.
103.
Background
Cytoplasmic polyadenylation element binding proteins (CPEBs) regulate translation by binding to regulatory motifs of defined mRNA targets. This translational mechanism has been shown to play a critical role in oocyte maturation, early development, and memory formation in the hippocampus. Little is known about the presence or functions of CPEBs in the retina. The purpose of the current study is to investigate the alternative splicing isoforms of a particular CPEB, CPEB3, based on current databases, and to characterize the expression of CPEB3 in the retina. 相似文献104.
Lewin TM de Jong H Schwerbrock NJ Hammond LE Watkins SM Combs TP Coleman RA 《Biochimica et biophysica acta》2008,1781(6-7):352-358
Glycerol-3-phosphate acyltransferase-1 (GPAT1), which is located on the outer mitochondrial membrane comprises up to 30% of total GPAT activity in the heart. It is one of at least four mammalian GPAT isoforms known to catalyze the initial, committed, and rate-limiting step of glycerolipid synthesis. Because excess triacylglycerol (TAG) accumulates in cardiomyocytes in obesity and type 2 diabetes, we determined whether lack of GPAT1 would alter the synthesis of heart TAG and phospholipids after a 2-week high-sucrose diet or a 3-month high-fat diet. Even in the absence of hypertriglyceridemia, TAG increased 2-fold with both diets in hearts from wildtype mice. In contrast, hearts from Gpat1(-/-) mice contained 20-80% less TAG than the wildtype controls. In addition, hearts from Gpat1(-/-) mice fed the high-sucrose diet incorporate 60% less [(14)C]palmitate into heart TAG as compared to wildtype mice. Because GPAT1 prefers 16:0-CoA to other long-chain acyl-CoA substrates, we determined the fatty acid composition of heart phospholipids. Compared to wildtype littermate controls, hearts from Gpat1(-/-)(-/-) mice contained a lower amount of 16:0 in phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine/phosphatidylinositol and significantly more C20:4n6. Phosphatidylcholine and phosphatidylethanolamine from Gpat1(-/-)(-/-) hearts also contained higher amounts of 18:0 and 18:1. Although at least three other GPAT isoforms are expressed in the heart, our data suggest that GPAT1 contributes significantly to cardiomyocyte TAG synthesis during lipogenic or high-fat diets and influences the incorporation of 20:4n6 into heart phospholipids. 相似文献
105.
Serotonin modulates agonistic and reproductive behavior across vertebrate species. 5HT1A and 5HT1B receptors mediate many serotonergic effects on social behavior, but other receptors, including 5HT2 receptors, may also contribute. We investigated serotonergic regulation of electrocommunication signals in the weakly electric fish Apteronotus leptorhynchus. During social interactions, these fish modulate their electric organ discharges (EODs) to produce signals known as chirps. Males chirp more than females and produce two chirp types. Males produce high-frequency chirps as courtship signals; whereas both sexes produce low-frequency chirps during same-sex interactions. Serotonergic innervation of the prepacemaker nucleus, which controls chirping, is more robust in females than males. Serotonin inhibits chirping and may contribute to sexual dimorphism and individual variation in chirping. We elicited chirps with EOD playbacks and pharmacologically manipulated serotonin receptors to determine which receptors regulated chirping. We also asked whether serotonin receptor activation generally modulated chirping or more specifically targeted particular chirp types. Agonists and antagonists of 5HT1B/1D receptors (CP-94253 and GR-125743) did not affect chirping. The 5HT1A receptor agonist 8OH-DPAT specifically increased production of high-frequency chirps. The 5HT2 receptor agonist DOI decreased chirping. Receptor antagonists (WAY-100635 and MDL-11939) opposed the effects of their corresponding agonists. These results suggest that serotonergic inhibition of chirping may be mediated by 5HT2 receptors, but that serotonergic activation of 5HT1A receptors specifically increases the production of high-frequency chirps. The enhancement of chirping by 5HT1A receptors may result from interactions with cortisol and/or arginine vasotocin, which similarly enhance chirping and are influenced by 5HT1A activity in other systems. 相似文献
106.
Erwin Datema Lukas A Mueller Robert Buels James J Giovannoni Richard GF Visser Willem J Stiekema Roeland CHJ van Ham 《BMC plant biology》2008,8(1):34
Background
Tomato (Solanum lycopersicon) and potato (S. tuberosum) are two economically important crop species, the genomes of which are currently being sequenced. This study presents a first genome-wide analysis of these two species, based on two large collections of BAC end sequences representing approximately 19% of the tomato genome and 10% of the potato genome. 相似文献107.
Colin K. Combs Patricia Bates J. Colleen Karlo Gary E. Landreth 《Neurochemistry international》2001,39(5-6)
Amyloid deposition within the brains of Alzheimer's Disease patients results in the activation of microglial cells and the induction of a local inflammatory response. The interaction of microglia or monocytes with β-amyloid (Aβ) fibrils elicits the activation a complex tyrosine kinase-based signal transduction cascade leading to stimulation of multiple independent signaling pathways and ultimately to changes in proinflammatory gene expression. The Aβ-stimulated expression of proinflammatory genes in myeloid lineage cells is antagonized by the action of a family of ligand-activated nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs). We report that THP-1 monocytes express predominantly PPARγ isoform and lower levels of PPARα and PPARδ isoforms. PPAR mRNA levels are not affected by differentiation of the cells into a macrophage phenotype, nor are they altered following exposure to the classical immune stimulus, lipopolysaccharide. Previous studies have found that PPARγ agonists act broadly to inhibit inflammatory responses. The present study explored the action of the PPARα isoform and found that PPARα agonists inhibited the Aβ-stimulated expression of TNFα and IL-6 reporter genes in a dose-dependent manner. Moreover, the PPARα agonist WY14643 inhibited macrophage differentiation and COX-2 gene expression. However, the PPARα agonists failed to inhibit Aβ-stimulated elaboration of neurotoxic factors by THP-1 cells. These findings demonstrate that PPARα acts to suppress a diverse array of inflammatory responses in monocytes. 相似文献
108.
Marcinkeviciene J Luo Y Graciani NR Combs AP Copeland RA 《The Journal of biological chemistry》2001,276(26):23790-23794
Inhibition of beta-site amyloid precursor protein-cleaving enzyme by a statine-based inhibitor has been studied using steady state and stopped-flow methods. A slow onset rate of inhibition has been observed under steady state conditions, and a K(i) of 22 nm has been derived using progress curves analysis. Simulation of stopped-flow protein fluorescence transients provided an estimate of the K(d) for initial inhibitor binding of 660 nm. A two-step inhibition mechanism is proposed, wherein slower "tightening up" of the initial encounter complex occurs. Two hypotheses have been proposed in the literature to address the nature of the slow step in the inhibition of aspartic proteases by peptidomimetic inhibitors: a conformational change related to the "flap" movement and displacement of a catalytic water. We compared substrate and inhibitor binding rates under pre-steady-state conditions. Both ligands are likely to cause flap movement, whereas no catalytic water replacement occurs during substrate binding. Our results suggest that both ligands bind to the enzyme at a rate significantly lower than the diffusion limit, but there are additional rate limitations involved in inhibitor binding, resulting in a k(on) of 3.5 x 10(4) m(-)1 s(-)1 for the inhibitor compared with 3.5 x 10(5) m(-)1 s(-)1 for the substrate. Even though specific intermediate formation steps might be different in the productive inhibitor and substrate binding to beta-site amyloid precursor protein-cleaving enzyme, a similar final optimized conformation is achieved in both cases, as judged by the comparable free energy changes (DeltaDeltaG of 2.01 versus 1.97 kcal/mol) going from the initial to the final enzyme-inhibitor or enzyme-substrate complexes. 相似文献
109.
Xiang MA Chen RH Demarest KT Gunnet J Look R Hageman W Murray WV Combs DW Patel M 《Bioorganic & medicinal chemistry letters》2004,14(11):2987-2989
A novel series of spirobenzazepines was synthesized and evaluated for V1a and V2 receptor antagonist activity. Compounds 8b, 8i, and 8k have shown selective V1a receptor antagonist activity. Compounds 8p and 8q were shown to be dual V1a/V2 receptor antagonists. 相似文献
110.
The adipocyte-secreted protein Acrp30 enhances hepatic insulin action 总被引:116,自引:0,他引:116
Acrp30 is a circulating protein synthesized in adipose tissue. A single injection in mice of purified recombinant Acrp30 leads to a 2-3-fold elevation in circulating Acrp30 levels, which triggers a transient decrease in basal glucose levels. Similar treatment in ob/ob, NOD (non-obese diabetic) or streptozotocin-treated mice transiently abolishes hyperglycemia. This effect on glucose is not associated with an increase in insulin levels. Moreover, in isolated hepatocytes, Acrp30 increases the ability of sub-physiological levels of insulin to suppress glucose production. We thus propose that Acrp30 is a potent insulin enhancer linking adipose tissue and whole-body glucose metabolism. 相似文献