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5. Divergent effects of genetic and pharmacological inhibition of Nox2 NADPH oxidase on insulin resistance related vascular damage

Author

Maqbool, A, Watt, N, Haywood, N, Viswambharan, H, Skromna, A, Makava, N, Visnagri, A, Shawer, HM, Bridge, K, Muminov, SK, Griffin, K, Beech, DJ, Wheatcroft, SB, Porter, KE, Simmons, KJ, Sukumar, P, Shah, AM, Cubbon, RM, Kearney, MT, and Yuldasheva, NY

Subjects
urogenital system, cardiovascular system, hormones, hormone substitutes, and hormone antagonists, circulatory and respiratory physiology
Abstract

Insulin resistance leads to excessive endothelial cell (EC) superoxide generation and accelerated atherosclerosis. The principal source of superoxide from the insulin-resistant endothelium is the Nox2 isoform of NADPH oxidase. Here we examine the therapeutic potential of Nox2 inhibition on: superoxide generation in saphenous vein EC (SVEC) from patients with advanced atherosclerosis and type 2 diabetes; and on vascular function, vascular damage and lipid deposition in Apolipoprotein E deficient (ApoE-/-) mice with EC specific insulin resistance (ESMIRO). To examine the effect of genetic inhibition of Nox2, ESMIRO mice deficient in ApoE-/- and Nox2 (ESMIRO/ApoE-/-/Nox2-/y) were generated and compared to ESMIRO/ApoE-/-/Nox2+/y littermates. To examine the effect of pharmacological inhibition of Nox2 we administered gp91dstat or scrambled peptide to ESMIRO/ApoE-/- mice. SVEC from diabetic patients had increased expression of Nox2 protein with concomitant increase in superoxide generation which could be reduced by the Nox2 inhibitor gp91dstat. After 12 weeks western diet, ESMIRO/ApoE-/-/Nox2-/y mice had reduced EC superoxide generation and greater aortic relaxation to acetylcholine. ESMIRO/ApoE-/-/Nox2-/y mice developed more lipid deposition in the thoraco-abdominal aorta with multiple foci of elastin fragmentation at the level of the aortic sinus and greater expression of intercellular adhesion molecule-1 (ICAM-1). Gp91dstat reduced EC superoxide and lipid deposition in the thoraco-abdominal aorta of ESMIRO/ApoE-/- mice without causing elastin fragmentation or increased ICAM-1 expression. These results demonstrate that insulin resistance is characterized by increased Nox2-derived vascular superoxide. Complete deletion of Nox2 in mice with EC insulin resistance exacerbates, whereas partial pharmacological Nox2 inhibition protects against, insulin resistance-induced vascular damage.

Published
2020

7. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

Author

Young, R. B and Bridge, K. Y

Subjects
Life Sciences (General)
Abstract

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

Published
2003

8. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

Author

Young, R. B, Bridge, K. Y, and Cureri, Peter A

Subjects
Life Sciences (General)
Abstract

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of cAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of cAMP by either epinephrine or isoproterenol.

Published
2002

9. Effect of Serum from Chickens Treated with Clenbuterol on Myosin Accumulation, Beta-Adrenergic Receptor Population, and Cyclic AM Synthesis in Embryonic Chicken Skeletal Muscle Cell Cultures

Author

Young, R. B, Bridge, K. Y, Wuethrich, A. J, Hancock, D. L, and Whitaker, Ann F

Subjects
Life Sciences (General)
Abstract

Broiler chickens at 35 days of age were fed 1 ppm clenbuterol for 14 days. This level of dietary clenbuterol led to 5-7% increases in weights of leg and breast muscle tissue. At the end of the 14-day period, serum was prepared from both control and clenbuterol-treated chickens and was then employed as a component of cell culture media at a final concentration of 20% (v/v). Muscle cell cultures were prepared from both the leg and breast muscle groups of twelve-day chick embryos. Treatment groups included control chicken serum to which 10 nM, 50 nM, and 1 micron clenbuterol had been added, as well as cells grown in media containing 10% horse serum. Cultures were subjected to each treatment for 3 days beginning on the seventh day in culture. Neither the percent fusion nor the number of nuclei in myotubes were significantly affected by any of the treatments. The quantity of MHC was not increased by serum from clenbuterol-treated chickens in either breast and leg muscle cultures; however, MHC quantity was 50- 100% higher in cultures grown in control chicken serum to which 10 nM and 50 nM clenbuterol had also been added. The Beta-AR population was 4,000-7,000 Beta-AR per cell in cultures grown in chicken serum, with leg muscle cultures having approximately 25-30% more receptors than breast muscle cultures. Receptor population was not significantly affected by the presence of clenbuterol or by the presence of serum from clenbuterol-treated chickens. In contrast, the Beta-AR population in leg and breast muscle cultures grown in the presence of 10% horse serum was 18,000-20,000 Beta-AR per cell. Basal concentration of cAMP was not significantly affected by any of the treatments. When cultures grown in chicken serum were stimulated for 10 min with 1 micron isoproterenol, limited increases of 12-20% in cAMP concentration above basal levels were observed. However, when cultures grown in the presence of horse serum were stimulated with 1 micron isoproterenol, increases of 600-800 % in cAMP concentration above basal levels were observed. Thus, not only did cells grown in horse serum have a higher Beta-AR population, each receptor had a higher capacity for cAMP synthesis following isoproterenol stimulation. Finally, the hypothesis was tested that clenbuterol exerts its action on muscle protein content by changes in cAMP concentration. No correlation was apparent between basal cAMP concentration and MHC content.

Published
2001

10. Effect of electrical stimulation on beta-adrenergic receptor population and cyclic amp production in chicken and rat skeletal muscle cell cultures

Author

Young, R. B, Bridge, K. Y, and Strietzel, C. J

Subjects
Life Sciences (General)
Abstract

Expression of the beta-adrenergic receptor (betaAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the betaAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for 7 d in culture were subjected to electrical stimulation for an additional 2 d at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the betaAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. In contrast, the betaAR population in rat muscle cells was increased slightly but not significantly by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was increased by almost twofold. The basal levels of intracellular cyclic AMP in neither rat muscle cells nor chicken muscle cells were affected by electrical stimulation.

Published
2000
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11. Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

Author

Young, R. B, Bridge, K. Y, and Rose, M. Franklin

Subjects
Fluid Mechanics And Thermodynamics
Abstract

Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

Published
2000

12. Developmental Changes is Expression of Beta-Adrenergic Receptors in Cultures of C2C12 Skeletal Muscle Cells

Author

Young, Ronald B, Bridge, K. Y, and Vaughn, J. R

Subjects
Life Sciences (General)
Abstract

beta-Adrenergic receptor (bAR) agonists have been reported to modulate growth in several mammalian and avian species, and bAR agonists presumably exert their physiological action on skeletal muscle cells through this receptor. Because of the importance of bAR regulation on muscle protein metabolism in muscle cells, the objectives of this study were to determine the developmental expression pattern of the bAR population in C2C12 skeletal muscle cells, and to analyze changes in both the quantity and isoform expression of the major muscle protein, myosin. The number of bAR in mononucleated C2C12 cells was approximately 8,000 bAR per cell, which is comparable with the population reported in several other nonmuscle cell types. However, the bar population increased after myoblast fusion to greater than 50,000 bAR per muscle cell equivalent. The reasons for this apparent over-expression of bAR in C2C12 cells is not known. The quantity of myosin also increased after C2C12 myoblast fusion, but the quantity of myosin was less than that reported in primary muscle cell cultures. Finally, at least five different isoforms of myosin heavy chain could be resolved in C2C12 cells, and three of these exhibited either increased or decreased developmental regulation relative to the others. Thus, C2C12 myoblasts undergo developmental regulation of bAR population and myosin heavy chain isoform expression.

Published
2000

13. Electrical Stimulation Decreases Coupling Efficiency Between Beta-Adrenergic Receptors and Cyclic AMP Production in Cultured Muscle Cells

Author

Young, R. B and Bridge, K. Y

Subjects
Aerospace Medicine
Abstract

Electrical stimulation of skeletal muscle cells in culture is an effective way to simulate the effects of muscle contraction and its effects on gene expression in muscle cells. Expression of the beta-adrenergic receptor and its coupling to cyclic AMP synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this project was to determine if electrical stimulation altered the beta-adrenergic response in muscle cells. Chicken skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. At the end of this two-day stimulation period, beta-adrenergic receptor population was measured by the binding of tritium-labeled CGP-12177 to muscle cells, and coupling to cAMP synthesis was measured by Radioimmunoassay (RIA) after treating the cells for 10 min with the potent (beta)AR agonist, isoproterenol. The number of beta adrenergic receptors and the basal levels of intracellular cyclic AMP were not affected by electrical stimulation. However, the ability of these cells to synthesize cyclic AMP was reduced by approximately 50%. Thus, an enhanced level of contraction reduces the coupling efficiency of beta-adrenergic receptors for cyclic AMP production.

Published
1999

14. Beta-Adrenergic Receptor Expression in Muscle Cells

Author

Young, Ronald B, Bridge, K, and Vaughn, J. R

Subjects
Life Sciences (General)
Abstract

beta-adrenergic receptor (bAR) agonists presumably exert their physiological action on skeletal muscle cells through the bAR. Since the signal generated by the bAR is cyclic AMP (cAMP), experiments were initiated in primary chicken muscle cell cultures to determine if artificial elevation of intracellular cAMP by treatment with forskolin would alter the population of bAR expressed on the surface of muscle cells. Chicken skeletal muscle cells after 7 days in culture were employed for the experiments because muscle cells have attained a steady state with respect to muscle protein metabolism at this stage. Cells were treated with 0-10 uM forskolin for a total of three days. At the end of the 1, 2, and 3 day treatment intervals, the concentration of cAMP and the bAR population were measured. Receptor population was measured in intact muscle cell cultures as the difference between total binding of [H-3]CGP-12177 and non-specific binding of [H-3]CGP-12177 in the presence of 1 uM propranolol. Intracellular cAMP concentration was measured by radioimmunoassay. The concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. Increasing concentrations of forskolin also led to an increase in (beta)AR population, with a maximum increase of approximately 50% at 10 uM. This increase in (beta)AR population was apparent after only 1 day of treatment, and the pattern of increase was maintained for all 3 days of the treatment period. Thus, increasing the intracellular concentration of cAMP leads to up-regulation of (beta)AR population. Clenbuterol and isoproterenol gave similar effects on bAR population. The effect of forskolin on the quantity and apparent synthesis rate of the heavy chain of myosin (mhc) were also investigated. A maximum increase of 50% in the quantity of mhc was observed at 0.2 UM forskolin, but higher concentrations of forskolin reduced the quantity of mhc back to control levels.

Published
1999

15. Effect of Increased Cyclic AMP Concentration on Muscle Protein Synthesis and Beta-Adrenergic Receptor Expression in Chicken Skeletal Muscle Cells in Culture

Author

Young, R. B, Vaughn, J. R, Bridge, K. Y, and Smith, C. K

Subjects
Life Sciences (General)
Abstract

Analogies of epinephrine are known to cause hypertrophy of skeletal muscle when fed to animals. These compounds presumably exert their physiological action through interaction with the P-adrenergic receptor. Since the intracellular signal generated by the Beta-adrenergic receptor is cyclic AMP (cAMP), experiments were initiated in cell culture to determine if artificial elevation of cAMP by treatment with forskolin would alter muscle protein metabolism and P-adrenergic receptor expression. Chicken skeletal muscle cells after 7 days in culture were treated with 0.2-30 micrometers forskolin for a total of three days. At the end of the treatment period, both the concentration of cAMP and the quantity of myosin heavy chain (MHC) were measured. Concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. In contrast, the quantity of MHC was increased approximately 50% above control cells at 0.2 micrometers forskolin, but exhibited a gradual decline at higher levels of forskolin so that the quantity of MHC in cells treated with 30 micrometers forskolin was not significantly different from controls. Curiously, the intracellular concentration of cAMP which elicited the maximum increase in the quantity of MHC was only 40% higher than cAMP concentration in control cells.

Published
1998

16. Beta-Adrenergic Receptor Population is Up-Regulated in Chicken Skeletal Muscle Cells Treated with Forskolin

Author

Bridge, K. Y, Young, R. B, and Vaughn, J. R

Subjects
Life Sciences (General)
Abstract

Skeletal muscle hypertrophy is promoted by in vivo administration of beta-adrenergic receptor (betaAR) agonists. These compounds presumably exert their physiological action through the betaAR, and alterations in the population of betaAR could potentially change the ability of the cell to respond to the betaAR agonists. Since the intracellular chemical signal generated by the betaAR is cyclic AMP (cAMP), experiments were initiated in primary chicken muscle cell cultures to determine if artificial elevation of intracellular cAMP by treatment with forskolin would alter the population of functional betaAR expressed on the surface of muscle cells. Chicken skeletal muscle cells after 7 days in culture were employed for the experiments because muscle cells have attained a steady state with respect to muscle protein metabolism at this stage. Cells were treated with 0-10 microM forskolin for a total of three days. At the end of the 1, 2, and 3 day treatment intervals, the concentration of cAMP and the betaAR population were measured. Receptor population was measured in intact muscle cell cultures as the difference between total binding of [H-3]CGP-12177 and non-specific binding of [H-3]CGP-12177 in the presence of 1 microM propranolol. Intracellular cAMP concentration was measured by radioimmunoassay. The concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. Increasing concentrations of forskolin also led to an increase in betaAR population, with a maximum increase of approximately 50% at 10 microM. This increase in PAR population was apparent after only 1 day of treatment, and the pattern of increase was maintained for all 3 days of the treatment period. Thus, increasing the intracellular concentration of cAMP leads to up-regulation of betaAR population. The effect of forskolin on the quantity and apparent synthesis rate of the heavy chain of myosin (mhc) were also investigated. A maximum increase of 50% in the quantity of mhc was observed at 0.2 microM forskolin, but higher concentrations of forskolin reduced the quantity of mhc back to control levels.

Published
1998

17. Endothelial SHIP2 suppresses Nox2 NADPH oxidase-dependent vascular oxidative stress, endothelial dysfunction and systemic insulin resistance

Author

Watt, N T, Gage, M C, Patel, P A, Viswambharan, H, Sukumar, P, Galloway, S, Yuldasheva, N Y, Imrie, H, Walker, A M N, Griffin, K J, Makava, N, Skromna, A, Bridge, K, Beech, D J, Schurmans, S, Wheatcroft, S B, Kearney, M T, and Cubbon, R M

Abstract

Shc homology 2–containing inositol 5′ phosphatase-2 (SHIP2) is a lipid phosphatase that inhibits insulin signaling downstream of phosphatidylinositol 3-kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in ECs (ECSHIP2Δ/+). Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2Δ/+ was resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle compared with littermate controls. ECs from ECSHIP2Δ/+ mice had increased basal expression and activation of PI3K downstream targets, including Akt and endothelial nitric oxide synthase, although incremental activation by insulin and shear stress was impaired. Insulin-mediated vasodilation was blunted in ECSHIP2Δ/+ mice, as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2Δ/+ mice, which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2Δ/+ ECs and was suppressed by PI3K and NADPH oxidase 2 inhibitors. These findings were phenocopied in healthy human ECs after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction.

Published
2017

18. Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms

Author

Bridge, K, Revill, C, Marcrae, M, Yuldasheva, N, Wheatcroft, S, Butlin, R, Foster, R, Scott, D, Gils, Ann, Ariens, R, and Hagemeyer, Christoph E

Subjects
cardiovascular system, cardiovascular diseases
Abstract

OBJECTIVE: Thrombin-activatable fibrinolysis inhibitor (TAFI) reduces the breakdown of fibrin clots through its action as an indirect inhibitor of plasmin. Studies in TAFI-deficient mice have implicated a potential role for TAFI in Abdominal Aortic Aneurysm (AAA) disease. The role of TAFI inhibition on AAA formation in adult ApoE-/- mice is unknown. The aim of this paper was to investigate the effects of TAFI inhibition on AAA development and progression. METHODS: Using the Angiotensin II model of AAA, male ApoE-/- mice were infused with Angiotensin II 750ng/kg/min with or without a monoclonal antibody inhibitor of plasmin-mediated activation of TAFI, MA-TCK26D6, or a competitive small molecule inhibitor of TAFI, UK-396082. RESULTS: Inhibition of TAFI in the Angiotensin II model resulted in a decrease in the mortality associated with AAA rupture (from 40.0% to 16.6% with MA-TCK26D6 (log-rank Mantel Cox test p = 0.16), and 8.3% with UK-396082 (log-rank Mantel Cox test p = 0.05)). Inhibition of plasmin-mediated TAFI activation reduced the incidence of AAA from 52.4% to 30.0%. However, late treatment with MA-TCK26D6 once AAA were already established had no effect on the progression of AAA in this model. CONCLUSIONS: The formation of intra-mural thrombus is responsible for the dissection and early rupture in the angiotensin II model of AAA, and this process can be prevented through inhibition of TAFI. Late treatment with a TAFI inhibitor does not prevent AAA progression. These data may indicate a role for inhibition of plasmin-mediated TAFI activation in the early stages of AAA development, but not in its progression. ispartof: PLoS One vol:12 issue:5 ispartof: location:United States status: published

Published
2017

19. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Author

Jones, G.T., Tromp, G., Kuivaniemi, H., Gretarsdottir, S., Baas, A.F., Giusti, B., Strauss, E., Hof, F.N. van 't, Webb, T.R., Erdman, R., Ritchie, M.D., Elmore, J.R., Verma, A., Pendergrass, S., Kullo, I.J., Ye, Z., Peissig, P.L., Gottesman, O., Verma, S.S., Malinowski, J., Rasmussen-Torvik, L.J., Borthwick, K.M., Smelser, D.T., Crosslin, D.R., Andrade, M. de, Ryer, E.J., McCarty, C.A., Bottinger, E.P., Pacheco, J.A., Crawford, D.C., Carrell, D.S., Gerhard, G.S., Franklin, D.P., Carey, D.J., Phillips, V.L., Williams, M.J., Wei, W., Blair, R., Hill, A.A., Vasudevan, T.M., Lewis, D.R., Thomson, I.A., Krysa, J., Hill, G.B., Roake, J., Merriman, T.R., Oszkinis, G., Galora, S., Saracini, C., Abbate, R., Pulli, R., Pratesi, C., Saratzis, A., Verissimo, A.R., Bumpstead, S., Badger, S.A., Clough, R.E., Cockerill, G., Hafez, H., Scott, D.J., Futers, T.S., Romaine, S.P., Bridge, K., Griffin, K.J., Bailey, M.A., Smith, A., Thompson, M.M., Bockxmeer, F.M. van, Matthiasson, S.E., Thorleifsson, G., Thorsteinsdottir, U., Blankensteijn, J.D., Teijink, J.A., Wijmenga, C., Graaf, J. de, Kiemeney, L.A.L.M., Lindholt, J.S., Hughes, A., Bradley, D.T., Stirrups, K., Golledge, J., Norman, P.E., Powell, J.T., Humphries, S.E., Hamby, S.E., Goodall, A.H., Nelson, C.P., Sakalihasan, N., Courtois, A., Ferrell, R.E., Eriksson, P., Folkersen, L., Franco-Cereceda, A., Eicher, J.D., Johnson, A.D., Betsholtz, C., Ruusalepp, A., Franzen, O., Schadt, E.E., and Bjorkegren, J.L.

Subjects
Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], cardiovascular system, cardiovascular diseases
Abstract

Contains fulltext : 169744.pdf (Publisher’s version ) (Open Access) RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

Published
2017

20. Thrombin and fibrinogen gamma ' impact clot structure by marked effects on intrafibrillar structure and protofibril packing

Author

Domingues, M. M., Macrae, F. L., Duval, C., McPherson, H. R., Bridge, K. I., Ajjan, R. A., Ridger, V. C., Connell, S. D., Philippou, H., and Ariens, R. A. S.

Abstract

Previous studies have shown effects of thrombin and fibrinogen γ′ on clot structure. However, structural information was obtained using electron microscopy, which requires sample dehydration. Our aim was to investigate the role of thrombin and fibrinogen γ′ in modulating fibrin structure under fully hydrated conditions. Fibrin fibers were studied using turbidimetry, atomic force microscopy, electron microscopy, and magnetic tweezers in purified and plasma solutions. Increased thrombin induced a pronounced decrease in average protofibril content per fiber, with a relatively minor decrease in fiber size, leading to the formation of less compact fiber structures. Atomic force microscopy under fully hydrated conditions confirmed that fiber diameter was only marginally decreased. Decreased protofibril content of the fibers produced by high thrombin resulted in weakened clot architecture as analyzed by magnetic tweezers in purified systems and by thromboelastometry in plasma and whole blood. Fibers produced with fibrinogen γ′ showed reduced protofibril packing over a range of thrombin concentrations. High-magnification electron microscopy demonstrated reduced protofibril packing in γ′ fibers and unraveling of fibers into separate protofibrils. Decreased protofibril packing was confirmed in plasma for high thrombin concentrations and fibrinogen-deficient plasma reconstituted with γ′ fibrinogen. These findings demonstrate that, in fully hydrated conditions, thrombin and fibrinogen γ′ have dramatic effects on protofibril content and that protein density within fibers correlates with strength of the fibrin network. We conclude that regulation of protofibril content of fibers is an important mechanism by which thrombin and fibrinogen γ′ modulate fibrin clot structure and strength.

Published
2016

22. NAD+ and axon degeneration revisited: Nmnat1 cannot substitute for WldS to delay Wallerian degeneration.

Author

Conforti, L., Fang, G., Beirowski, B., Wang, M. S., Sorci, L., Asress, S., Adalbert, R., Silva, A., Bridge, K., Huang, X. P., Magni, G., Glass, J. D., and Coleman, M. P.

Subjects
NEURODEGENERATION, PROTEINS, FUSION (Phase transformation), NUCLEOTIDES, AXONS, GENETIC mutation
Abstract

The slow Wallerian degeneration protein (WldS), a fusion protein incorporating full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), delays axon degeneration caused by injury, toxins and genetic mutation. Nmnat1 overexpression is reported to protect axons in vitro, but its effect in vivo and its potency remain unclear. We generated Nmnat1-overexpressing transgenic mice whose Nmnat activities closely match that of WldS mice. Nmnat1 overexpression in five lines of transgenic mice failed to delay Wallerian degeneration in transected sciatic nerves in contrast to WldS mice where nearly all axons were protected. Transected neurites in Nmnat1 transgenic dorsal root ganglion explant cultures also degenerated rapidly. The delay in vincristine-induced neurite degeneration following lentiviral overexpression of Nmnat1 was significantly less potent than for WldS, and lentiviral overexpressed enzyme-dead WldS still displayed residual neurite protection. Thus, Nmnat1 is significantly weaker than WldS at protecting axons against traumatic or toxic injury in vitro, and has no detectable effect in vivo. The full protective effect of WldS requires more N-terminal sequences of the protein.Cell Death and Differentiation (2007) 14, 116–127. doi:10.1038/sj.cdd.4401944; published online 28 April 2006 [ABSTRACT FROM AUTHOR]

Published
2007
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25. Whole-body insulin resistance leads to accelerated atherosclerosis: role for Nox2 NADPH oxidase.

Author

Maqbool A, Viswambharan H, Skromna A, Makava N, Shawer H, Bridge K, Muminov SK, Imrie H, Griffin K, Wheatcroft SB, Sukumar P, Cubbon RM, Kearney MT, and Yuldasheva NY

Abstract

Insulin resistance underpins the progression of type 2 diabetes mellitus and leads to a collection of risk factors for the development of atherosclerosis. Whether or not insulin resistance at a whole-body level per se leads to accelerated atherosclerosis is unclear. To answer this question, we generated atherosclerosis-prone mice with whole-body insulin resistance secondary to haploinsufficiency of the insulin receptor (IR+/-) deficient in ApoE-/- (IR+/-/ApoE-/-). IR+/-/ApoE-/- and ApoE-/- littermates had similar weight, lipids, and glucose tolerance at baseline. After 12 weeks of Western high-cholesterol diet, IR+/-/ApoE-/- had significantly more atherosclerosis in the thoracoabdominal aorta and at the level of the aortic sinus than ApoE-/- littermates. Excess Nox2 NADPH oxidase (Nox2) derived superoxide has been suggested to underpin diabetes-related atherosclerosis. In IR+/-/ApoE-/- we examined the effect of inhibiting Nox2 using genetic or pharmacological approaches on the development of atherosclerosis. To genetically delete Nox2, we generated IR+/-/ApoE-/-/Nox2-/y and to inhibit Nox2 pharmacologically, we treated IR+/-/ApoE-/- with the peptide Nox2 inhibitor gp91dstat. IR+/-/ApoE-/-/Nox2-/y had significant disruption of the aortic wall with increased thoracoabdominal atherosclerosis when compared to IR+/-/ApoE-/-/Nox2+/y littermates. Inhibition of Nox2 using gp91dstat reduced atherosclerosis in the thoracoabdominal aorta of IR+/-/ApoE-/-. Whole-body insulin resistance accelerates the development of atherosclerosis. Genetic inhibition of Nox2 leads to disruption of the aortic wall in IR+/-/ApoE-/- mice with accelerated atherosclerosis, whereas pharmacological Nox2 inhibition reduces atherosclerosis in IR+/-/ApoE-/- without disruption of the arterial wall.

Published
2024
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26. Distinct, common and synergistic effects of insulin and IGF-1 receptors on healthy murine ageing.

Author

Walker AM, Watt NT, Yuldasheva NY, Dalmia S, Conning-Rowland M, Cheng CW, Warmke N, Bridge K, Brown OI, Luk C, Drozd M, Haywood NJ, Skromna A, Makava N, Wheatcroft SB, Kearney MT, and Cubbon RM

Abstract

Objective: Reduced IGF-1 signalling is an evolutionarily conserved mediator of longevity, yet the magnitude of this effect is substantially larger in organisms retaining a common insulin and IGF-1 receptor. Whether this reflects the failure to simultaneously reduce IGF-1 and insulin signalling in mammalian model systems remains unexplored, as is the associated impact on markers of healthy ageing. We set out to address these uncertainties., Methods: We compared the duration of healthy life (healthspan) in male mice with haploinsufficiency of the insulin receptor (IRKO), IGF-1 receptor (IGF-1RKO), or both (DKO), versus wildtype (WT) littermates. Cognitive performance was defined using nesting studies at 3- and 24-months of age. Brain transcriptome was characterised at 3- and 18-months of age using RNA-seq., Results: Healthspan was longer in DKO versus WT, with IRKO and IGF-1RKO being intermediate. At 2 years of age, DKO also exhibited preserved nesting behaviour in contrast with all other genotypes. Differential insulin sensitivity or weight gain during ageing did not explain the preserved healthspan of DKO, since these were comparable to IRKO littermates. Brain transcriptomics at 18 months of age revealed lower expression of canonical ageing-associated genes in DKO versus WT, although many of these findings were replicated in IRKO versus WT or IGF-1RKO vs WT., Conclusions: Reduced insulin and IGF-1 receptor expression have both common and synergistic effects upon elements of healthy mammalian ageing, suggesting future ageing studies should consider targeting both insulin and IGF-1 signalling., Competing Interests: None., (© 2024 The Authors. Published by Elsevier Ltd.)

Published
2024
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27. Flap Versus Flapless Implant Placement in Immediate Functional Loading: A Comparative Study.

Author

Javiya P, Anjan T, Duseja S, Matada Basavarajaiah J, Tate J, Puthenkandathil R, and Baig FAH

Abstract

Background: Dental implants are now the typical tooth replacement method. Because it speeds up therapy, quick functional loading-attaching prosthetic restorations to implants following surgery-has become popular. Flapless implant implantation reduces surgical stress and expedites recovery., Methods: A prospective comparative study of 100 flap and flapless dental implant patients was done. Patient-reported outcomes, implant survival, peri-implant parameters, and surgical complications were assessed. Statistical analysis compared the two groups' results., Results: Both flap and flapless methods exhibited good implant survival and similar peri-implant characteristics. Patients reported equal postoperative comfort and satisfaction in both groups. Surgical complications were similar for flap and flapless surgeries., Conclusion: In immediate functional loading, flap and flapless implant insertion are equally effective and safe. Both methods yield dependable implant survival, peri-implant health, patient comfort, and surgical safety. Dental professionals should evaluate patient variables and anatomical aspects while choosing an implant implantation surgery. Implant dentistry needs further study on long-term results and treatment regimens., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Pharmacy and Bioallied Sciences.)

Published
2024
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28. Single-Piece Implant Systems and its Longterm Stability: An Evaluative Research.

Author

Javiya P, Rajakumari K, Gorrepati S, Srilakshmi D, Mansoor MA, Abdul HN, and Baig FAH

Abstract

Objective: The objective of this research was to compare the longstanding stability of single-piece implant systems to typical two-piece systems by analyzing patient records retrospectively., Methods: A retrospective examination of patient records from January 2010 to December 2020 was undertaken at the Department of Oral Implantology, University Hospital. The research included dental rehabilitation patients who got single- or two-piece implant systems. Patient demographics, implant features, surgical procedures, and follow-up results were extracted. Implant success rates, stability defined by resonance frequency analysis (RFA) utilizing Osstell ISQ®, and peri-implant bone loss evaluated by standardized periapical radiographs at baseline and follow-up visits were the main outcomes., Results: The research involved 320 patients (160 per cohort). The average patient age was 52.7 years, with 55% men. The mandibular region received 65% of implants, and the maxillary region the rest. Single-piece cohort A had 94.6% implant success, and two-piece cohort B 96.2%. Implant success rates were similar between cohorts ( P = 0.412). The mean ISQ scores were 72.4 ± 4.8 in cohort A and 74.8 ± 5.1 in cohort B ( P = 0.086). Peri-implant bone loss was 1.8 ± 0.7 mm in cohort A and 1.4 ± 0.6 mm in cohort B ( P = 0.031)., Conclusion: Single-piece implant systems provide a stable and successful alternative to classic two-piece systems. However, patient selection, surgical technique, and monitoring are essential to reduce peri-implant problems and improve clinical results. To improve implant dentistry patient care and evidence-based clinical practice, single-piece and two-piece implant systems' design, biomechanical features, and longstanding performance should be studied., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Pharmacy and Bioallied Sciences.)

Published
2024
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29. Benefits and risks of complete denture therapy in fully edentulous Indian patients.

Author

Rami DS, Sutaria BS, Parmar VB, Detroja K, Sethuraman R, and Makwana T

Abstract

The perceptions of the patients regarding the benefits and risk of complete denture treatment in completely edentulous patients are of interest. The study composed of 79 participants who presented themselves for complete denture therapy. The perception of the participants towards the complete denture therapy was recorded using a validated questionnaire. The answers of the questionnaire were evaluated in three domains: (1) Benefits (positive perception) of the complete denture therapy' (2) Risks (Negative perception) of the complete denture therapy and (3) Consequences of no treatment. The data were tabulated for descriptive analysis. The average age of the total population was 62.22 ranging from 58 to 80 years. Total population included in the study shows positive perception regarding the complete denture therapy. The benefits of the complete denture therapy show highest score (1817) by all the participants while the risks of the complete denture therapy show lowest score (237). The gender, denture experience and the socioeconomic status had no influence on the perception towards the complete denture therapy. Participants showed positive perception towards the complete denture therapy with highest score in benefits and lowest score for the risks of the complete denture therapy. The perception of the complete denture therapy was not influenced by the gender, denture experience and the socioeconomic status., (© 2024 Biomedical Informatics.)

Published
2024
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30. Relationship Among Diabetes, Obesity, and Cardiovascular Disease Phenotypes: A UK Biobank Cohort Study.

Author

Brown OI, Drozd M, McGowan H, Giannoudi M, Conning-Rowland M, Gierula J, Straw S, Wheatcroft SB, Bridge K, Roberts LD, Levelt E, Ajjan R, Griffin KJ, Bailey MA, Kearney MT, and Cubbon RM

Subjects
Humans, Overweight complications, Cohort Studies, Carotid Intima-Media Thickness, Biological Specimen Banks, Stroke Volume, Risk Factors, Body Mass Index, Ventricular Function, Left, Obesity epidemiology, Phenotype, Biomarkers, United Kingdom epidemiology, Cardiovascular Diseases etiology, Diabetes Mellitus, Myocardial Infarction complications, Ischemic Stroke complications
Abstract

Objective: Obesity and diabetes frequently coexist, yet their individual contributions to cardiovascular risk remain debated. We explored cardiovascular disease biomarkers, events, and mortality in the UK Biobank stratified by BMI and diabetes., Research Design and Methods: A total of 451,355 participants were stratified by ethnicity-specific BMI categories (normal, overweight, obese) and diabetes status. We examined cardiovascular biomarkers including carotid intima-media thickness (CIMT), arterial stiffness, left ventricular ejection fraction (LVEF), and cardiac contractility index (CCI). Poisson regression models estimated adjusted incidence rate ratios (IRRs) for myocardial infarction, ischemic stroke, and cardiovascular death, with normal-weight nondiabetes as comparator., Results: Five percent of participants had diabetes (10% normal weight, 34% overweight, and 55% obese vs. 34%, 43%, and 23%, respectively, without diabetes). In the nondiabetes group, overweight/obesity was associated with higher CIMT, arterial stiffness, and CCI and lower LVEF (P < 0.005); these relationships were diminished in the diabetes group. Within BMI classes, diabetes was associated with adverse cardiovascular biomarker phenotype (P < 0.005), particularly in the normal-weight group. After 5,323,190 person-years follow-up, incident myocardial infarction, ischemic stroke, and cardiovascular mortality rose across increasing BMI categories without diabetes (P < 0.005); this was comparable in the diabetes groups (P-interaction > 0.05). Normal-weight diabetes had comparable adjusted cardiovascular mortality to obese nondiabetes (IRR 1.22 [95% CI 0.96-1.56]; P = 0.1)., Conclusions: Obesity and diabetes are additively associated with adverse cardiovascular biomarkers and mortality risk. While adiposity metrics are more strongly correlated with cardiovascular biomarkers than diabetes-oriented metrics, both correlate weakly, suggesting that other factors underpin the high cardiovascular risk of normal-weight diabetes., (© 2023 by the American Diabetes Association.)

Published
2023
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31. Clinical evaluation of complete denture fabricated using two different final impression techniques on masticatory efficiency and oral health-related quality of life.

Author

Shah U, Mahajan N, and Bhatt N

Subjects
Humans, Aged, Oral Health, Geriatric Assessment, Quality of Life, Denture, Complete
Abstract

Aim: To compare the effect of complete denture fabricated using selective pressure impression and functional impression technique on masticatory efficiency and oral health-related quality of life (OHRQoL) in patients with resorbed ridges., Settings and Design: A randomized two arm, parallel group study., Materials and Methods: Forty-eight participants with set inclusion and exclusion criteria were randomly allocated into two groups. Complete denture was fabricated in Group A and Group B using selective pressure and functional impression technique, respectively. The follow-up was done at 3 months. Masticatory efficiency was measured by color-changing chewing gum, and OHRQoL was assessed using the Geriatric Oral Health Assessment Index (GOHAI) Hindi Version., Statistical Analysis Used: The Wilcoxon signed-rank test was applied to check the intergroup analysis for the GOHAI scores of both impression techniques. The Mann-Whitney U test was applied to compare intragroup analysis for masticatory efficiency and the GOHAI scores of both the techniques., Results: A total of 45 participants completed the follow-up. The mean age of the total participants was 62.7 ± 3.8. No statistically significant difference (P > 0.05) was observed between the masticatory efficiency and post-GOHAI scores of both the impression techniques., Conclusion: Selective pressure and functional impression techniques may be successfully used to fabricate complete dentures for patients with resorbed ridges., Competing Interests: None

Published
2022
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32. A comparative study to evaluate surface electromyographic correlations of mandibular implant-supported overdentures to conventional complete dentures in edentulous patients: An in vivo study.

Author

Garg Y, Nagrath R, and Lahori M

Subjects
Female, Humans, Male, Cross-Over Studies, Dental Prosthesis, Implant-Supported, Denture, Complete, Denture, Overlay, Dental Implants, Mouth, Edentulous
Abstract

Aim: The aim of this study was to compare the function and coordination of masticatory muscles for patients with two implant-supported mandibular overdenture (ISOD) with that of conventional complete dentures (CCD) using surface electromyography (sEMG). The objectives were to assess the muscle activity (efficiency) and clinical outcome after the transition of CCD patients to ISOD., Setting and Design: This was a crossover study., Materials and Methods: This clinical trial was conducted in the department of prosthodontics. A total of 15 patients (nine males and six females) were assessed using sEMG. In each patient, a total of four surfaces were examined above the following muscles - right and left masseter and right and left temporalis muscles. The electromyography readings were recorded to assess muscle activity during Clenching, cotton roll clenching, and chewing. The readings were recorded first for CCD and then for ISOD (after installing attachments)., Statistical Analysis Used: Data analysis was done using independent t-test and one-way ANOVA., Results: Mean muscular activity of masseter during clenching, cotton roll clenching, and chewing for patients with ISOD (44.3 ± 11.2 μV, 41.1 ± 13.4 μV, and 45.2 ± 17.5 μV) was higher than CCD (26.0 ± 11.3 μV, 22.6 ± 9.7 μV, and 24.2 ± 9.5 μV). The mean muscular activity of temporalis during clenching, cotton roll clenching, and chewing was also higher with ISOD (47.9 ± 11.2 μV, 45.6 ± 11.9 μV, and 51.0 ± 14.4 μV) than CCD (31.0 ± 12.2 μV, 29.7 ± 15.3 μV and 31.9 ± 14.2 μV). No statistically significant result was found between masseter and temporalis muscle activity on both sides (P < 0.05), indicating symmetrical activity on both the sides., Conclusion: Two-ISODs prove to be a better and efficient treatment modality in rehabilitating edentulous patients as it enhances retention and also increases masticatory muscle activity and chewing efficiency., Competing Interests: None

Published
2022
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33. Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat.

Author

Viswambharan H, Yuldasheva NY, Imrie H, Bridge K, Haywood NJ, Skromna A, Hemmings KE, Clark ER, Gatenby VK, Cordell P, Simmons KJ, Makava N, Abudushalamu Y, Endesh N, Brown J, Walker AMN, Futers ST, Porter KE, Cubbon RM, Naseem K, Shah AM, Beech DJ, Wheatcroft SB, Kearney MT, and Sukumar P

Subjects
Animals, Cells, Cultured, Humans, Hydrogen Peroxide metabolism, Insulin metabolism, Insulin-Like Growth Factor I metabolism, Mice, Mice, Inbred C57BL, MicroRNAs genetics, MicroRNAs metabolism, NADPH Oxidase 4 genetics, NADPH Oxidase 4 metabolism, Receptor, IGF Type 1 genetics, Receptor, IGF Type 1 metabolism, Adipose Tissue metabolism, Diabetes Mellitus, Type 2 metabolism, Endothelium, Vascular metabolism, Glucose metabolism, Muscle, Skeletal metabolism, Paracrine Communication
Abstract

[Figure: see text].

Published
2021
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34. Divergent effects of genetic and pharmacological inhibition of Nox2 NADPH oxidase on insulin resistance-related vascular damage.

Author

Maqbool A, Watt NT, Haywood N, Viswambharan H, Skromna A, Makava N, Visnagri A, Shawer HM, Bridge K, Muminov SK, Griffin K, Beech DJ, Wheatcroft SB, Porter KE, Simmons KJ, Sukumar P, Shah AM, Cubbon RM, Kearney MT, and Yuldasheva NY

Subjects
Aged, Aged, 80 and over, Animals, Cells, Cultured, Diabetes Mellitus genetics, Diabetes Mellitus pathology, Endothelium, Vascular drug effects, Endothelium, Vascular pathology, Female, Humans, Male, Mice, Mice, Knockout, Mice, Transgenic, Middle Aged, NADPH Oxidase 2 deficiency, Organ Culture Techniques, Diabetes Mellitus metabolism, Endothelium, Vascular metabolism, Glycoproteins pharmacology, Insulin Resistance physiology, NADPH Oxidase 2 antagonists & inhibitors, NADPH Oxidase 2 genetics
Abstract

Insulin resistance leads to excessive endothelial cell (EC) superoxide generation and accelerated atherosclerosis. The principal source of superoxide from the insulin-resistant endothelium is the Nox2 isoform of NADPH oxidase. Here we examine the therapeutic potential of Nox2 inhibition on superoxide generation in saphenous vein ECs (SVECs) from patients with advanced atherosclerosis and type 2 diabetes and on vascular function, vascular damage, and lipid deposition in apolipoprotein E-deficient (ApoE -/- ) mice with EC-specific insulin resistance (ESMIRO). To examine the effect of genetic inhibition of Nox2, ESMIRO mice deficient in ApoE -/- and Nox2 (ESMIRO/ApoE -/- /Nox2 -/y ) were generated and compared with ESMIRO/ApoE -/- /Nox2 +/y littermates. To examine the effect of pharmacological inhibition of Nox2, we administered gp91dstat or scrambled peptide to ESMIRO/ApoE -/- mice. SVECs from diabetic patients had increased expression of Nox2 protein with concomitant increase in superoxide generation, which could be reduced by the Nox2 inhibitor gp91dstat. After 12 wk Western diet, ESMIRO/ApoE -/- /Nox2 -/y mice had reduced EC superoxide generation and greater aortic relaxation to acetylcholine. ESMIRO/ApoE -/- /Nox2 -/y mice developed more lipid deposition in the thoraco-abdominal aorta with multiple foci of elastin fragmentation at the level of the aortic sinus and greater expression of intercellular adhesion molecule-1 (ICAM-1). Gp91dstat reduced EC superoxide and lipid deposition in the thoraco-abdominal aorta of ESMIRO/ApoE -/- mice without causing elastin fragmentation or increased ICAM-1 expression. These results demonstrate that insulin resistance is characterized by increased Nox2-derived vascular superoxide. Complete deletion of Nox2 in mice with EC insulin resistance exacerbates, whereas partial pharmacological Nox2 inhibition protects against, insulin resistance-induced vascular damage.

Published
2020
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35. Evaluation of the effect of dentin surface treatment by air abrasion and Er:YAG laser on the retention of metal crowns luted with glass ionomer cement in teeth with reduced crown height: An in vitro study.

Author

Chauhan S, Mahajan N, Sethuraman R, and Naveen YG

Abstract

Aim and Objectives: The purpose of this study was to investigate the effect of dentin surface treatment with aluminum oxide air abrasion and Er:YAG laser on tensile bond strength of metal crowns. Metal crowns were luted with conventional glass ionomer cement (GIC) in the teeth with reduced crown height, where preparation geometry did not provide optimal retention form., Materials and Methods: Forty-eight human premolars were prepared to receive metal crowns and were randomly divided into four groups for tensile bond strength testing. Group A: Untreated dentin luted with self-adhesive composite resin cement as positive control; Group B: Untreated dentin luted with GIC as negative control; Group C: Surface treatment with 50 μm aluminum oxide air abrasion and luted with GIC; Group D: Surface treatment with Er:YAG laser (λ =2.94 mm) with a total energy 84.88 J/cm 2 of (60 mJ/pulse, 10 Hz, 60 pulses, and 100 μs pulse width) and luted with GIC. The cemented specimens were thermocycled and later subjected to axial load in a universal testing machine at 0.5 mm/min cross-head speed for tensile testing. Scanning electron microscopic evaluation of dentin surface treatment and cement-dentin interface was also done in representative specimens., Results: One-way analysis of variance showed statistically significant difference among/within the groups ( P < 0.001). Tukey's post hoc test presented significant increased tensile bond strength of Er:YAG laser group. Air abrasion group showed no significant increase in tensile bond strength values ( P = 0.033)., Conclusion: Dentin surface treatment with Er:YAG laser significantly improved the tensile bond strength of luting GIC compared to air-abraded and untreated dentin., Competing Interests: There are no conflicts of interest.

Published
2019
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36. Effects of obesity on insulin: insulin-like growth factor 1 hybrid receptor expression and Akt phosphorylation in conduit and resistance arteries.

Author

Mughal RS, Bridge K, Buza I, Slaaby R, Worm J, Klitgaard-Povlsen G, Hvid H, Schiødt M, Cubbon R, Yuldasheva N, Skromna A, Makava N, Skytte-Olsen G, and Kearney MT

Subjects
Animals, Antigens, CD metabolism, Aorta enzymology, Cells, Cultured, Diet, Fat-Restricted, Diet, High-Fat, Disease Models, Animal, Enzyme Activation, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells enzymology, Humans, Insulin-Like Growth Factor I pharmacology, Male, Mesenteric Arteries enzymology, Mesenteric Arteries physiopathology, Mice, Inbred C57BL, Obesity blood, Obesity physiopathology, Phosphorylation, Receptor, IGF Type 1 genetics, Receptor, Insulin metabolism, Receptors, Somatomedin metabolism, Signal Transduction drug effects, Vasodilation drug effects, Aorta drug effects, Insulin pharmacology, Mesenteric Arteries drug effects, Obesity enzymology, Proto-Oncogene Proteins c-akt metabolism, Receptor, IGF Type 1 metabolism, Vascular Resistance drug effects
Abstract

Insulin and insulin-like growth factor-1 stimulate specific responses in arteries, which may be disrupted by diet-induced obesity. We examined (1) temporal effects of high-fat diet compared to low-fat diet in mice on insulin receptor, insulin-like growth factor-1 receptor, insulin receptor/insulin-like growth factor-1 receptor hybrid receptor expression and insulin/insulin-like growth factor-1-mediated Akt phosphorylation in aorta; and (2) effects of high-fat diet on insulin and insulin-like growth factor-1-mediated Akt phosphorylation and vascular tone in resistance arteries. Medium-term high-fat diet (5 weeks) decreased insulin-like growth factor-1 receptor expression and increased hybrid expression (~30%) only. After long-term (16 weeks) high-fat diet, insulin receptor expression was reduced by ~30%, insulin-like growth factor-1 receptor expression decreased a further ~40% and hybrid expression increased a further ~60%. Independent correlates of hybrid receptor expression were high-fat diet, duration of high-fat diet and plasma insulin-like growth factor-1 (all p < 0.05). In aorta, insulin was a more potent activator of Akt than insulin-like growth factor-1, whereas in resistance arteries, insulin-like growth factor-1 was more potent than insulin. High-fat diet blunted insulin-mediated vasorelaxation ( p < 0.01) but had no effect on insulin-like growth factor-1-mediated vasorelaxation in resistance arteries. Our findings support the possibility that hybrid receptor level is influenced by nutritional and metabolic cues. Moreover, vessel-dependent effects of insulin and insulin-like growth factor-1 on vascular tone and Akt activation may have implications in treating obesity-related vascular disease.

Published
2019
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37. Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance.

Author

Watt NT, Gage MC, Patel PA, Viswambharan H, Sukumar P, Galloway S, Yuldasheva NY, Imrie H, Walker AMN, Griffin KJ, Makava N, Skromna A, Bridge K, Beech DJ, Schurmans S, Wheatcroft SB, Kearney MT, and Cubbon RM

Subjects
Animals, Aorta, Cells, Cultured, Endothelial Cells, Gene Expression Regulation physiology, Glucose Clamp Technique, Glucose Intolerance, Mice, Mice, Knockout, NADPH Oxidase 2 genetics, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases genetics, Vasoconstriction physiology, Endothelium, Vascular metabolism, Insulin Resistance physiology, NADPH Oxidase 2 metabolism, Oxidative Stress physiology, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases metabolism
Abstract

Shc homology 2-containing inositol 5' phosphatase-2 (SHIP2) is a lipid phosphatase that inhibits insulin signaling downstream of phosphatidylinositol 3-kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in ECs (ECSHIP2 Δ/+ ). Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2 Δ/+ was resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle compared with littermate controls. ECs from ECSHIP2 Δ/+ mice had increased basal expression and activation of PI3K downstream targets, including Akt and endothelial nitric oxide synthase, although incremental activation by insulin and shear stress was impaired. Insulin-mediated vasodilation was blunted in ECSHIP2 Δ/+ mice, as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2 Δ/+ mice, which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2 Δ/+ ECs and was suppressed by PI3K and NADPH oxidase 2 inhibitors. These findings were phenocopied in healthy human ECs after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction., (© 2017 by the American Diabetes Association.)

Published
2017
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38. A comparative evaluation of chewing efficiency, masticatory bite force, and patient satisfaction between conventional denture and implant-supported mandibular overdenture: An in vivo study.

Author

Sharma AJ, Nagrath R, and Lahori M

Abstract

Purpose: The purpose of this within-subject crossover clinical trial was to compare and evaluate the chewing efficiency, masticatory bite force, and patient satisfaction with conventional dentures and two implant-retained mandible overdentures after 4 weeks of usage., Method: This within-subject crossover clinical trial was carried out in the Department of Prosthodontics in K.D Dental College and Hospital. A total 15 patients were selected for the study. To report the changes in chewing efficiency by chewing 6gms of peanuts with 40 chewing strokes and comparing the particle size of the chewed material between two implant retained mandibular overdenture with that of conventional denture using micro vu excel gantry type visual measurement machine. To report changes in masticatory bite force after transition of conventional complete denture patient to implant retained overdenture after using the prosthesis for four weeks each and recorded by digital transducer. To assess the patient satisfaction after transition of conventional complete denture patient to implant retained mandibular overdenture with help of OHIP edent patient satisfaction questionnaire., Results: The chewing efficiency for implant retained overdenture increased significantly than that of conventional denture. The particle size decreased to 76.34% for implant supported overdenture than that of conventional denture. The chewing strokes required by conventional denture was 69 strokes and that by implant supported overdenture which was 40 strokes to get the same mean particle size. The patients satisfaction after receiving the implant retained overdenture was significantly higher than that of complete denture., Conclusion: The provision of two mandibular implants significantly improves measures of oral function and better quality of life for edentulous patients., Competing Interests: There are no conflicts of interest.

Published
2017
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39. Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms.

Author

Bridge K, Revill C, Macrae F, Bailey M, Yuldasheva N, Wheatcroft S, Butlin R, Foster R, Scott DJ, Gils A, and Ariens R

Subjects
Animals, Aortic Aneurysm, Abdominal pathology, Apolipoproteins E genetics, Carboxypeptidase B2 metabolism, Disease Progression, Male, Mice, Mice, Knockout, Carboxypeptidase B2 antagonists & inhibitors, Disease Models, Animal, Fibrinolysin metabolism
Abstract

Objective: Thrombin-activatable fibrinolysis inhibitor (TAFI) reduces the breakdown of fibrin clots through its action as an indirect inhibitor of plasmin. Studies in TAFI-deficient mice have implicated a potential role for TAFI in Abdominal Aortic Aneurysm (AAA) disease. The role of TAFI inhibition on AAA formation in adult ApoE-/- mice is unknown. The aim of this paper was to investigate the effects of TAFI inhibition on AAA development and progression., Methods: Using the Angiotensin II model of AAA, male ApoE-/- mice were infused with Angiotensin II 750ng/kg/min with or without a monoclonal antibody inhibitor of plasmin-mediated activation of TAFI, MA-TCK26D6, or a competitive small molecule inhibitor of TAFI, UK-396082., Results: Inhibition of TAFI in the Angiotensin II model resulted in a decrease in the mortality associated with AAA rupture (from 40.0% to 16.6% with MA-TCK26D6 (log-rank Mantel Cox test p = 0.16), and 8.3% with UK-396082 (log-rank Mantel Cox test p = 0.05)). Inhibition of plasmin-mediated TAFI activation reduced the incidence of AAA from 52.4% to 30.0%. However, late treatment with MA-TCK26D6 once AAA were already established had no effect on the progression of AAA in this model., Conclusions: The formation of intra-mural thrombus is responsible for the dissection and early rupture in the angiotensin II model of AAA, and this process can be prevented through inhibition of TAFI. Late treatment with a TAFI inhibitor does not prevent AAA progression. These data may indicate a role for inhibition of plasmin-mediated TAFI activation in the early stages of AAA development, but not in its progression.

Published
2017
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40. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci.

Author

Jones GT, Tromp G, Kuivaniemi H, Gretarsdottir S, Baas AF, Giusti B, Strauss E, Van't Hof FN, Webb TR, Erdman R, Ritchie MD, Elmore JR, Verma A, Pendergrass S, Kullo IJ, Ye Z, Peissig PL, Gottesman O, Verma SS, Malinowski J, Rasmussen-Torvik LJ, Borthwick KM, Smelser DT, Crosslin DR, de Andrade M, Ryer EJ, McCarty CA, Böttinger EP, Pacheco JA, Crawford DC, Carrell DS, Gerhard GS, Franklin DP, Carey DJ, Phillips VL, Williams MJ, Wei W, Blair R, Hill AA, Vasudevan TM, Lewis DR, Thomson IA, Krysa J, Hill GB, Roake J, Merriman TR, Oszkinis G, Galora S, Saracini C, Abbate R, Pulli R, Pratesi C, Saratzis A, Verissimo AR, Bumpstead S, Badger SA, Clough RE, Cockerill G, Hafez H, Scott DJ, Futers TS, Romaine SP, Bridge K, Griffin KJ, Bailey MA, Smith A, Thompson MM, van Bockxmeer FM, Matthiasson SE, Thorleifsson G, Thorsteinsdottir U, Blankensteijn JD, Teijink JA, Wijmenga C, de Graaf J, Kiemeney LA, Lindholt JS, Hughes A, Bradley DT, Stirrups K, Golledge J, Norman PE, Powell JT, Humphries SE, Hamby SE, Goodall AH, Nelson CP, Sakalihasan N, Courtois A, Ferrell RE, Eriksson P, Folkersen L, Franco-Cereceda A, Eicher JD, Johnson AD, Betsholtz C, Ruusalepp A, Franzén O, Schadt EE, Björkegren JL, Lipovich L, Drolet AM, Verhoeven EL, Zeebregts CJ, Geelkerken RH, van Sambeek MR, van Sterkenburg SM, de Vries JP, Stefansson K, Thompson JR, de Bakker PI, Deloukas P, Sayers RD, Harrison SC, van Rij AM, Samani NJ, and Bown MJ

Subjects
Aortic Aneurysm, Abdominal epidemiology, Genetic Predisposition to Disease epidemiology, Genetic Variation genetics, Genome-Wide Association Study trends, Humans, Aortic Aneurysm, Abdominal diagnosis, Aortic Aneurysm, Abdominal genetics, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods
Abstract

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA., Objective: To identify additional AAA risk loci using data from all available genome-wide association studies., Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9., Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease., (© 2016 The Authors.)

Published
2017
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41. A comparative evaluation of the reliability of three methods of assessing gingival biotype in dentate subjects in different age groups: An in vivo study.

Author

Memon S, Patel JR, Sethuraman R, Patel R, and Arora H

Abstract

Introduction: In the modern competitive society, a pleasing appearance often dictates the difference between success and failure in both our personal and professional lives. Evaluation of gingival biotype is very important from the start of treatment plan to the final restorative placement to provide excellent esthetics., Materials and Methodology: For the study, subjects were divided into 4 groups of different ages, from 20-30, 31-40, 41-50 and 51-60 years. 30 subjects (15 men and 15 women) were selected in each group for the study. Examination of the thickness of Gingival Biotype was done in 3 different ways; - Direct visual, William's Graduated Probe and Using modified wax caliper., Results: The McNemar test showed statistically significant differences in the way gingival biotype was identified when comparing visual assessment with assessment using direct measurement (P < 0.001). And there was no statistically significant difference when assessment using a periodontal probe was compared to direct measurement (P < 0.676). There is no correlation for the Biotype among the different age groups., Conclusion: Gingival biotype identification by visual assessment is statistically significantly different from assessment with direct measurement. Gingival biotype identification by assessment with a periodontal probe is not statistically significantly different from direct measurement.

Published
2015
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42. Comparative evaluation of the amount of gingival displacement produced by three different gingival retraction systems: An in vivo study.

Author

Chaudhari J, Prajapati P, Patel J, Sethuraman R, and Naveen YG

Abstract

Statement of Problem: Tetrahydrozoline has been introduced as new gingival retraction agent but its clinical efficacy with widely used conventional retraction agents has not been tested., Purpose: The study was designed to clinically evaluate efficacy of newer retraction agent tetrahydrozoline with two widely used retraction systems i.e., Expasyl retraction system and medicated retraction cords on basis of amount of gingival retraction., Materials and Methods: 30 subjects were selected according to inclusion and exclusion criteria. Maxillary Impressions were made with irreversible hydrocolloid for all subjects. Tray material was used for making the special tray. Latin Block Design was Used in the Study to avoid tissue fatigue. Retraction was done with aluminium chloride; Tetrahydrozoline and Expasyl according to Latin block design. Impressions were poured with die stone. Casts were retrieved and sections were made with die cutter. 3 mm thin slices were obtained. Each slice was used to measure the amount of retraction under stereomicroscope under 20x and images were transferred to image analyser., Results: The amount of gingival retraction obtained by using aluminium chloride as gingival retraction agent was maximum (148238.33 μm(2)) compared to tetrahydrozoline (140737.87 μm(2)) and Expasyl (67784.90 μm(2)).

Published
2015
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43. Member wellness--a comment.

Author

Bridge K

Subjects
Humans, Workforce, Burnout, Professional, Suicide, Veterinary Medicine
Published
2013

44. Comparative evaluation of bond strengths of different core materials with various luting agents used for cast crown restorations.

Author

Nayakar RP, Patil NP, and Lekha K

Abstract

The coronal cast restoration continues to be used commonly to restore mutilated, endodontically treated teeth. The tensile bond strength of luting cements is of critical importance as many of failures are at the core and the crown interface. An invitro study with aim to evaluate and compare bond strengths of luting cements between different core materials and cast crowns. A total of 45 extracted identical mandibular second premolars were endodontically treated and divided into 3 groups of 15 each. Specimens in first group were restored with cast post and core (Group C), and specimens in second group were restored with stainless steel parapost and composite core material (Group B) and specimens in third group were restored with stainless steel parapost and glass ionomer core build (Group G). Standardized crown preparation was done for all the specimens to receive cast crowns. Each group was further divided into 3 subgroups and were cemented using 3 different luting cements namely, resin cement, polycarboxylate cement, glass ionomer cement (Type I). The samples of each subgroup (n = 5) were subjected to tensile testing using Universal Testing Machine at a crosshead speed of 2 mm/min till the dislodgement of crown from the core surface was observed. The bond strengths were significantly different according one way ANOVA (F-150.76 and p < 0.0000). The results of the study showed that the specimens cemented with resin cement in cast core, composite core and glass ionomer core exhibited significantly higher bond strengths as compared to specimens cemented with glass ionomer and polycarboxylate cement. Composite resin core and resin cement combinations were superior to all other cement and core combinations tested.

Published
2012
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46. Effects of 1,3-butadiene, isoprene, and their photochemical degradation products on human lung cells.

Author

Doyle M, Sexton KG, Jeffries H, Bridge K, and Jaspers I

Subjects
Butadienes metabolism, Carcinogens metabolism, Cell Culture Techniques, Gene Expression Regulation drug effects, Hemiterpenes metabolism, Humans, Inflammation, Interleukin-8 biosynthesis, Pentanes metabolism, Photochemistry, Plants, Butadienes toxicity, Carcinogens toxicity, Hemiterpenes toxicity, Lung cytology, Lung pathology, Pentanes toxicity
Abstract

Because of potential exposure both in the workplace and from ambient air, the known carcinogen 1,3-butadiene (BD) is considered a priority hazardous air pollutant. BD and its 2-methyl analog, isoprene (ISO), are chemically similar but have very different toxicities, with ISO showing no significant carcinogenesis. Once released into the atmosphere, reactions with species induced by sunlight and nitrogen oxides convert BD and ISO into several photochemical reaction products. In this study, we determined the relative toxicity and inflammatory gene expression induced by exposure of A549 cells to BD, ISO, and their photochemical degradation products in the presence of nitric oxide. Gas chromatography and mass spectrometry analyses indicate the initial and major photochemical products produced during these experiments for BD are acrolein, acetaldehyde, and formaldehyde, and products for ISO are methacrolein, methyl vinyl ketone, and formaldehyde; both formed < 200 ppb of ozone. After exposure the cells were examined for cytotoxicity and interleukin-8 (IL-8) gene expression, as a marker for inflammation. These results indicate that although BD and ISO alone caused similar cytotoxicity and IL-8 responses compared with the air control, their photochemical products significantly enhanced cytotoxicity and IL-8 gene expression. This suggests that once ISO and BD are released into the environment, reactions occurring in the atmosphere transform these hydrocarbons into products that induce potentially greater adverse health effects than the emitted hydrocarbons by themselves. In addition, the data suggest that based on the carbon concentration or per carbon basis, biogenic ISO transforms into products with proinflammatory potential similar to that of BD products.

Published
2004
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47. beta-adrenergic receptor population is up-regulated by increased cyclic adenosine monophosphate concentration in chicken skeletal muscle cells in culture.

Author

Young RB, Bridge KY, and Vaughn JR

Subjects
Adrenergic beta-Agonists metabolism, Adrenergic beta-Agonists pharmacology, Animals, Cells, Cultured, Chick Embryo, Chickens, Colforsin pharmacology, Isoproterenol pharmacology, Muscle Proteins metabolism, Muscle, Skeletal cytology, Myosin Heavy Chains metabolism, Propanolamines metabolism, Time Factors, Tritium, Cyclic AMP metabolism, Muscle, Skeletal metabolism, Receptors, Adrenergic, beta metabolism, Up-Regulation
Abstract

Skeletal muscle hypertrophy is promoted in vivo by administration of beta-adrenergic receptor (betaAR) agonists. Chicken skeletal muscle cells were treated with 1 microM isoproterenol, a strong betaAR agonist, between days 7 and 10 in culture. betaAR population increased by approximately 40% during this treatment; however, the ability of the cells to synthesize cyclic adenosine monophosphate (cAMP) was diminished by twofold. Neither the basal concentration of cAMP nor the quantity of myosin heavy chain (MHC) was affected by the 3-d exposure to isoproterenol. To understand further the relationship between intracellular cAMP levels, betaAR population, and muscle protein accumulation, intracellular cAMP levels were artificially elevated by treatment with 0-10 betaM forskolin for 3 d. The basal concentration of cAMP in forskolin-treated cells increased up to sevenfold in a dose-dependent manner. Increasing concentrations of forskolin also led to an increase in betaAR population, with a maximum increase of approximately 40-60% at 10 microM forskolin. A maximum increase of 40-50% in the quantity of MHC was observed at 0.2 microM forskolin, but higher concentrations of forskolin reduced the quantity of MHC back to control levels. At 0.2 microM forskolin, intracellular levels of cAMP were higher by approximately 35%, and the betaAR population was higher by approximately 30%. Neither the number of muscle nuclei fused into myotubes nor the percentage of nuclei in myotubes was affected by forskolin at any of the concentrations studied.

Published
2000
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49. Richard Maunsell Martin.

Author

Bridge KB

Subjects
Family Practice history, History, 20th Century, New Zealand
Published
1977

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