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Quelling an innate response to dsRNA.
Ogden KM, Prasad BV
(2015) Oncotarget 6: 28535-6
MeSH Terms: 2',5'-Oligoadenylate Synthetase, Animals, Antiviral Agents, Endoribonucleases, Evolution, Molecular, Exoribonucleases, Gene Expression Regulation, Viral, Host-Pathogen Interactions, Humans, Immunity, Innate, Molecular Targeted Therapy, Nucleic Acid Conformation, Phosphodiesterase Inhibitors, RNA, Double-Stranded, RNA, Viral, Signal Transduction, Viral Proteins, Viruses
Added April 26, 2017
0 Communities
1 Members
0 Resources
18 MeSH Terms
Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets.
Dai C, Brissova M, Hang Y, Thompson C, Poffenberger G, Shostak A, Chen Z, Stein R, Powers AC
(2012) Diabetologia 55: 707-18
MeSH Terms: Adolescent, Adult, Animals, Female, Gene Expression Profiling, Gene Expression Regulation, Homeodomain Proteins, Humans, Hyperglycemia, Insulin, Insulin Secretion, Islets of Langerhans, MafB Transcription Factor, Male, Mice, Mice, Inbred Strains, Middle Aged, Phosphodiesterase Inhibitors, Protein Transport, RNA, Messenger, Secretory Pathway, Species Specificity, Tissue Culture Techniques, Trans-Activators, Young Adult
Show Abstract · Added December 5, 2013
AIMS/HYPOTHESIS - Our understanding of the transcription factors that control the development and function of rodent islet beta cells is advancing rapidly, yet less is known of the role they play in similar processes in human islets.
METHODS - To characterise the abundance and regulation of key proteins involved in glucose-regulated insulin secretion in human islets, we examined the expression of MAFA, MAFB, GLUT2 (also known as SLC2A2), βGK (also known as GCK) and PDX1 in isolated, highly purified human islets with an intact insulin secretory pattern. We also assessed these features in islets from two different mouse strains (C57BL/6J and FVB).
RESULTS - Compared with mouse islets, human islets secreted more insulin at baseline glucose (5.6 mmol/l), but less upon stimulation with high glucose (16.7 mmol/l) or high glucose plus 3-isobutyl-1-methyl-xanthine. Human islets had relatively more MAFB than PDX1 mRNA, while mouse islets had relatively more Pdx1 than Mafb mRNA. However, v-maf musculoaponeurotic fibrosarcoma oncogene homologue (MAF) B protein was found in human islet alpha and beta cells. This is unusual as this regulator is only produced in islet alpha cells in adult mice. The expression of insulin, MAFA, βGK and PDX1 was not glucose-regulated in human islets with an intact insulin secretory pattern.
CONCLUSIONS/INTERPRETATION - Our results suggest that human islets have a distinctive distribution and function of key regulators of the glucose-stimulated insulin secretion pathway, emphasising the urgent need to understand the processes that regulate human islet beta cell function.
3 Communities
2 Members
0 Resources
25 MeSH Terms
Effect of a phosphodiesterase 5 inhibitor on pulmonary and cerebral arteries of newborn piglets with chronic hypoxia-induced pulmonary hypertension.
Fike CD, Kaplowitz M, Zhang Y, Dantuma M, Madden JA
(2012) Neonatology 101: 28-39
MeSH Terms: 3',5'-Cyclic-AMP Phosphodiesterases, Animals, Animals, Newborn, Chronic Disease, Disease Models, Animal, Hypertension, Pulmonary, Hypoxia, Middle Cerebral Artery, Phosphodiesterase Inhibitors, Pulmonary Artery, Purinones, Swine, Vasodilation
Show Abstract · Added May 20, 2014
BACKGROUND - The use of phosphodiesterase 5 (PDE5) inhibitors to treat newborns with pulmonary hypertension is increasing. The effect of PDE5 inhibitors on the neonatal cerebral circulation remains unknown. The neonatal piglet model of chronic hypoxia-induced pulmonary hypertension allows the study of the effects of PDE5 inhibitors on both the pulmonary and cerebral circulations.
OBJECTIVES - To determine whether the PDE5 inhibitor, zaprinast, causes dilation in pulmonary and middle cerebral arteries (MCA) of normoxic newborn piglets and those with chronic hypoxia-induced pulmonary hypertension, and to evaluate whether zaprinast alters responses to increased pressure (autoregulatory ability) of the MCA.
METHODS - Two-day-old piglets were raised in normoxia or hypoxia for 3 or 10 days. Pulmonary arteries and MCA were isolated and pressurized, after which changes in diameter to zaprinast were measured. MCA pressure-diameter relationships were determined.
RESULTS - Dilation to zaprinast was similar in pulmonary arteries from normoxic and hypoxic piglets. Zaprinast dilated MCA from all groups but the response was diminished in MCA from piglets raised in hypoxia for 10 days. MCA pressure-diameter relationships (autoregulation) did not differ between the groups.
CONCLUSIONS - Pulmonary artery dilation to zaprinast supports the use of PDE5 inhibitors to treat pulmonary hypertension in neonates. PDE5 inhibitors function as MCA dilators but do not impair the pressure-diameter behavior of the cerebral circulation of either normoxic newborn piglets or those with chronic hypoxia-induced pulmonary hypertension. These findings suggest that cerebral autoregulation is likely to be intact with acute PDE5 inhibitor treatment in infants with pulmonary hypertension in conditions associated with chronic hypoxia.
Copyright © 2011 S. Karger AG, Basel.
0 Communities
1 Members
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13 MeSH Terms
Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay.
Pantel J, Williams SY, Mi D, Sebag J, Corbin JD, Weaver CD, Cone RD
(2011) Eur J Pharmacol 660: 139-47
MeSH Terms: Allosteric Regulation, Cyclic AMP, Drug Evaluation, Preclinical, Furocoumarins, HEK293 Cells, High-Throughput Screening Assays, Humans, Luminescent Measurements, Phosphodiesterase Inhibitors, Pilot Projects, Receptor, Melanocortin, Type 4, Reproducibility of Results, Signal Transduction, Structure-Activity Relationship, Sulfonamides, Time Factors
Show Abstract · Added December 10, 2013
The melanocortin MC(4) receptor is a potential target for the development of drugs for both obesity and cachexia. Melanocortin MC(4) receptor ligands known thus far are orthosteric agonists or antagonists, however the agonists, in particular, have generally exhibited unwanted side effects. For some receptors, allosteric modulators are expected to reduce side-effect profiles. To identify allosteric modulators of the melanocortin MC(4) receptor, we created HEK293 cell lines coexpressing the human melanocortin MC(4) receptor and a modified luciferase-based cAMP sensor. Monitoring luminescence as a readout of real-time intracellular cAMP concentration, we demonstrate that this cell line is able to report melanocortin agonist responses, as well as inverse agonist response to the physiological AgRP peptide. Based on the MC4R-GLO cell line, we developed an assay that was shown to meet HTS standards (Z'=0.50). A pilot screen run on the Microsource Spectrum compound library (n=2000) successfully identified 62 positive modulators. This screen identified predicted families of compounds: β(2)AR agonists - the β(2)AR being endogenously expressed in HEK293 cells, an adenylyl cyclase activator and finally a distribution of phosphodiesterase (PDE) inhibitors well characterized or recently identified. In this last category, we identified a structural family of coumarin-derived compounds (imperatorin, osthol and prenyletin), along with deracoxib, a drug in veterinary use for its COX2 inhibitory properties. This latter finding unveiled a new off-target mechanism of action for deracoxib as a PDE inhibitor. Overall, these data are the first report of a HTS for allosteric modulators for a Gs protein coupled receptor.
Copyright © 2011 Elsevier B.V. All rights reserved.
0 Communities
3 Members
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16 MeSH Terms
Acute dysphonia secondary to vocal fold hemorrhage after vardenafil use.
Singh V, Cohen SM, Rousseau B, Noordzij JP, Garrett CG, Ossoff RH
(2010) Ear Nose Throat J 89: E21-2
MeSH Terms: Acute Disease, Adrenal Cortex Hormones, Adult, Dysphonia, Hemorrhage, Humans, Imidazoles, Male, Phosphodiesterase Inhibitors, Piperazines, Sulfones, Triazines, Vardenafil Dihydrochloride, Vasodilator Agents, Vocal Cords
Show Abstract · Added February 12, 2015
Owing to their vasodilatory effects, the phosphodiesterase-5 inhibitors have become widely used for the treatment of erectile dysfunction. Among the reported adverse events of these agents are epistaxis, variceal bleeding, intracranial hemorrhage, and hemorrhoidal bleeding. We report a case of vocal fold hemorrhage that occurred after vardenafil use in a 31-year-old man who was a professional singer.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Phosphodiesterase 5 inhibition improves beta-cell function in metabolic syndrome.
Hill KD, Eckhauser AW, Marney A, Brown NJ
(2009) Diabetes Care 32: 857-9
MeSH Terms: Adult, Angiotensin-Converting Enzyme Inhibitors, Blood Pressure, Carbolines, Cross-Over Studies, Double-Blind Method, Female, Humans, Insulin-Secreting Cells, Male, Metabolic Syndrome, Phosphodiesterase 5 Inhibitors, Phosphodiesterase Inhibitors, Ramipril, Renin, Tadalafil
Show Abstract · Added December 10, 2013
OBJECTIVE - This study tested the hypothesis that phosphodiesterase 5 inhibition alone or in combination with ACE inhibition improves glucose homeostasis and fibrinolysis in individuals with metabolic syndrome.
RESEARCH DESIGN AND METHODS - Insulin sensitivity, beta-cell function, and fibrinolytic parameters were measured in 18 adults with metabolic syndrome on 4 separate days after a randomized, crossover, double-blind, 3-week treatment with placebo, ramipril (10 mg/day), tadalafil (10 mg o.d.), and ramipril plus tadalafil.
RESULTS - Ramipril decreased systolic and diastolic blood pressure, ACE activity, and angiotensin II and increased plasma renin activity. Ramipril did not affect insulin sensitivity or beta-cell function. In contrast, tadalafil improved beta-cell function (P = 0.01). This effect was observed in women (331.9 +/- 209.3 vs. 154.4 +/- 48.0 32 micro x mmol(-1) x l(-1), respectively, for tadalafil treatment vs. placebo; P = 0.01) but not in men. There was no effect of any treatment on fibrinolysis. CONCLUSIONS Phosphodiesterase 5 inhibition may represent a novel strategy for improving beta-cell function in metabolic syndrome.
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16 MeSH Terms
Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control.
Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW, Hiebert SW
(2008) Mol Cell 30: 61-72
MeSH Terms: Animals, Apoptosis, Caffeine, Cells, Cultured, DNA Damage, DNA Repair, Fibroblasts, Gene Expression Profiling, Gene Expression Regulation, Histone Deacetylases, Humans, Mice, Mice, Knockout, Mitosis, NIH 3T3 Cells, Neoplasms, Oligonucleotide Array Sequence Analysis, Phenotype, Phosphodiesterase Inhibitors, Radiation, Ionizing, S Phase
Show Abstract · Added August 13, 2010
Histone deacetylases (HDACs) are enzymes that modify key residues in histones to regulate chromatin architecture, and they play a vital role in cell survival, cell-cycle progression, and tumorigenesis. To understand the function of Hdac3, a critical component of the N-CoR/SMRT repression complex, a conditional allele of Hdac3 was engineered. Cre-recombinase-mediated inactivation of Hdac3 led to a delay in cell-cycle progression, cell-cycle-dependent DNA damage, and apoptosis in mouse embryonic fibroblasts (MEFs). While no overt defects in mitosis were observed in Hdac3-/- MEFs, including normal H3Ser10 phosphorylation, DNA damage was observed in Hdac3-/- interphase cells, which appears to be associated with defective DNA double-strand break repair. Moreover, we noted that Hdac3-/- MEFs were protected from DNA damage when quiescent, which may provide a mechanistic basis for the action of HDAC inhibitors on cycling tumor cells.
2 Communities
2 Members
0 Resources
21 MeSH Terms
Phosphodiesterase type-5 inhibitors and the reemerging HIV epidemic.
Hulgan T, Klausner JD
(2008) JAMA 299: 1426
MeSH Terms: HIV Infections, Homosexuality, Male, Humans, Male, Phosphodiesterase Inhibitors, Risk-Taking, Substance-Related Disorders, United States, Vasodilator Agents
Added December 10, 2013
0 Communities
1 Members
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9 MeSH Terms
The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud's phenomenon.
Friedman EA, Harris PA, Wood AJ, Stein CM, Kurnik D
(2007) Clin Pharmacol Ther 81: 503-9
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Adult, Carbolines, Cold Temperature, Cross-Over Studies, Cyclic Nucleotide Phosphodiesterases, Type 5, Double-Blind Method, Female, Humans, Male, Phosphodiesterase Inhibitors, Raynaud Disease, Regional Blood Flow, Skin, Skin Temperature, Tadalafil, Vasoconstriction
Show Abstract · Added December 10, 2013
Raynaud's phenomenon (RP) is a disorder characterized by episodic periods of vasoconstriction typically provoked by exposure to cold. Phosphodiesterase 5 (PDE5) inhibitors may improve digital blood flow and clinical symptoms in patients with RP, but the mechanisms are unknown. We examined the hypothesis that a PDE5 inhibitor, tadalafil, attenuates cold-induced vasoconstriction. Additionally, we examined whether tadalafil reduced vascular dysfunction following ischemia, thus altering the response to repeated cooling. We conducted a double-blind, placebo-controlled crossover study in 20 subjects with RP on two separate study days, when subjects received either placebo or tadalafil (10 mg). Digital blood flow (flux) was measured by laser Doppler flowmetry at rest and during two graduated local heat and cold exposure cycles. Temperature-response curves were evaluated by E(max) (maximal flux during heating), E(min) (minimal flux during cooling), and ET(50) and ET(90) (the local temperature at which flux decreased by 50% and 90% of E(max)-E(min), respectively). Tadalafil did not increase baseline flux (81.0+/-73.0 vs 91.3+/-114.0 arbitrary unit (AU), P=0.57), E(max) (280.0+/-107.6 vs 279.5+/-119.8 AU, P=0.94), ET(50) (25.4+/-4.4 vs 26.6+/-5.7 degrees C, P=0.62), or ET(90) (21.2+/-3.9 vs 21.8+/-5.0 degrees C, P=0.78), (cycle 1 values presented). There were no differences between cycles on either study day. In conclusion, in patients with RP, single-dose tadalafil does not increase digital blood flow at baseline or in response to heating, nor does it attenuate cold-induced vasoconstriction. Furthermore, it does not precondition the endothelium to resist a second cooling challenge. The clinical benefit in patients with RP treated with PDE5 inhibitors probably involves mechanisms other than acute inhibition of cold-induced vasoconstriction.
0 Communities
1 Members
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17 MeSH Terms
Chronic ethanol feeding suppresses beta-adrenergic receptor-stimulated lipolysis in adipocytes isolated from epididymal fat.
Kang L, Nagy LE
(2006) Endocrinology 147: 4330-8
MeSH Terms: 3',5'-Cyclic-AMP Phosphodiesterases, 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone, Adipocytes, Adrenergic beta-Agonists, Animals, Carrier Proteins, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 4, Diet, Epididymis, Ethanol, Glycerol, Isoproterenol, Lipolysis, Male, Perilipin-1, Phosphodiesterase Inhibitors, Phosphoproteins, Phosphorylation, Rats, Rats, Wistar, Receptors, Adrenergic, beta, Sterol Esterase
Show Abstract · Added March 5, 2013
Chronic ethanol consumption disrupts G protein-dependent signaling pathways in rat adipocytes. Because lipolysis in adipocytes is regulated by G protein-mediated cAMP signal transduction, we hypothesized that cAMP-regulated lipolysis may be vulnerable to long-term ethanol exposure. Male Wistar rats were fed a liquid diet containing ethanol as 35% of total calories or pair-fed a control diet that isocalorically substituted maltose dextrins for ethanol for 4 wk. Lipolysis was measured by glycerol release over 1 h with or without agonists in adipocytes isolated from epididymal fat. Chronic ethanol feeding decreased beta-adrenergic receptor-stimulated lipolysis, but had no effect on basal lipolysis. In response to beta-adrenergic activation, the early peak of cAMP accumulation was suppressed after ethanol feeding, although the basal cAMP concentration in adipocytes did not differ between pair- and ethanol-fed rats. The suppression in cAMP accumulation caused by ethanol feeding was associated with increased activity of phosphodiesterase 4. Chronic ethanol feeding also decreased beta-adrenergic receptor-stimulated protein kinase A activation and phosphorylation of its downstream proteins, perilipin A and hormone-sensitive lipase, the primary lipase-mediating lipolysis. In conclusion, these data suggest that chronic ethanol feeding increased phosphodiesterase 4 activity in adipocytes, resulting in decreased accumulation of cAMP in response to beta-adrenergic activation and a suppression of beta-adrenergic stimulation of lipolysis.
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24 MeSH Terms