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Search Results: 1 - 10 of 481161 matches for " Paul A Kirkham "
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Cigarette Smoke Exposure Alters mSin3a and Mi-2α/β Expression; implications in the control of pro-inflammatory gene transcription and glucocorticoid function
John A Marwick, Christopher S Stevenson, Kian Chung, Ian M Adcock, Paul A Kirkham
Journal of Inflammation , 2010, DOI: 10.1186/1476-9255-7-33
Abstract: Wild type, PI3Kγ knock-out (PI3Kγ-/-) and PI3K kinase dead knock-in (PI3KδD910/A910) transgenic mice were exposed to cigarette smoke for 3 days and the expression levels of the co-repressor complex components HDAC-2, mSin3a, Mi-2α and Mi-2β and HDAC-2 activity in the lungs were assessed.Cigarette smoke exposure impaired glucocorticoid function and reduced HDAC-2 activity which was protected in the PI3KδD910/A910 mice. Both mSin3a and Mi-2α protein expression was reduced in smoke-exposed mice. Budesonide alone protected mSin3a protein expression with no additional effect seen with abrogation of PI3Kγ/δ activity, however Mi-2α, but not Mi-2β, expression was protected in both PI3KδD910/A910 and PI3Kγ-/- budesonide-treated smoke-exposed mice. The restoration of glucocorticoid function coincided with the protection of both HDAC activity and mSin3a and Mi-2α protein expression.Cigarette smoke exposure induced glucocorticoid insensitivity and alters co-repressor activity and expression which is prevented by blockade of PI3K signaling with glucocorticoid treatment. Inhibition of PI3Kδ signalling in combination with glucocorticoid treatment may therefore provide a therapeutic strategy for restoring oxidant-induced glucocortiocid unresponsiveness.Gene transcription is tightly regulated by a highly complex and dynamic set of processes central to which is the recruitment of co-repressors to promoter bound sequence specific transcription factors [1-3]. Two of the major co-repressor complexes in mammalian cells are the mammalian Sin3a (mSin3a) and Mi-2/nucleosome remodelling and deacetylase (NuRD) complex, both of which are ubiquitously expressed [2,4-6]. The mammalian genome encodes two Mi-2 proteins; Mi-2α (encoded by the Chd3 gene) and Mi-2β (encoded by the Chd4 gene). Although the latter is predominantly associated with the NuRD complex they are structurally similar and no functional or cell type specific differentiation between Mi-2α and Mi-2β has yet been made [6].Both the
LPS induced inflammatory responses in human peripheral blood mononuclear cells is mediated through NOX4 and Giα dependent PI-3kinase signalling
Anta Ngkelo, Koremu Meja, Mike Yeadon, Ian Adcock, Paul A Kirkham
Journal of Inflammation , 2012, DOI: 10.1186/1476-9255-9-1
Abstract: Bacterial infections are one of the dominant causes of acute exacerbations in chronic obstructive pulmonary disease (COPD). Lipopolysaccharide (LPS) is the most abundant component within the cell wall of Gram-negative bacteria. It can stimulate the release of interleukin 8 (IL-8, CXCL8, CXC ligand 8) and other inflammatory cytokines in various cell types, leading to an acute inflammatory response towards pathogens [1]. These responses are initiated by the activation of the TLR signalling through adaptor proteins, and include induction of gene expression via the activation of the NF-κB and AP-1 signal transduction pathways [2]. Bacterial LPS has been extensively used in models studying inflammation as it mimics many inflammatory effects of cytokines, such as TNF-α, IL-1β or IL-6. The cellular receptor transducing the LPS signal has been identified as Toll-like receptor 4 (TLR4) [3-5]. Binding of LPS to TLR4 leads to the activation of NF-κB through the recruitment and activation of MyD88, IL-1R kinase (IRAK), TNFR associated factor 6 (TRAF-6), as well as NADPH oxidase (Nox) [2,6,7]. NF-κB plays a crucial role in regulating the transcription of genes related to innate immunity and inflammation responses and several studies indicate its activation is controlled by reactive oxygen species (ROS) in immune modulation in the lungs and in monocytes [8-11].Several studies searching for novel anti-inflammatory agents have led to the identification of a key role for phosphatidylinositol 3-kinase (PI3K) in transducing receptor-mediated signalling during inflammation in chronic inflammatory diseases, such as COPD [12]. The PI3K family is divided into three classes (I, II and III) depending on their structure, substrate and function [13]. The class I PI3Ks are further subdivided into class IA (p110α, p110β and p110δ) and class IB (p110γ). All class I PI3Ks mediate fundamental signalling pathways and cellular processes that orchestrate cell growth, proliferation, migration and surv
Cigarette smoke regulates VEGFR2-mediated survival signaling in rat lungs
John A Marwick, Indika Edirisinghe, Gnanapragasam Arunachalam, Christopher S Stevenson, William MacNee, Paul A Kirkham, Irfan Rahman
Journal of Inflammation , 2010, DOI: 10.1186/1476-9255-7-11
Abstract: Adult male Sprague-Dawley rats were exposed CS for 3 days, 8 weeks and 6 months to investigate the effect of CS on VEGFR2-mediated survival signaling by measuring the Akt/PI3-kinase/eNOS downstream signaling in rat lungs.We show that CS disrupts VEGFR2/PI3-kinase association leading to decreased Akt and eNOS phosphorylation. This may further alter the phosphorylation of the pro-apoptotic protein Bad and increase the Bad/Bcl-xl association. However, this was not associated with a significant lung cell death as evidenced by active caspase-3 levels. These data suggest that although CS altered the VEGFR2-mediated survival signaling in the rat lungs, but it was not sufficient to cause lung cell death.The rat lungs exposed to CS in acute, sub-chronic and chronic levels may be representative of smokers where survival signaling is altered but was not associated with lung cell death whereas emphysema is known to be associated with lung cell apoptosis.Maintenance of the microvasculature in the lung is critical for gas exchange, the integrity of the alveolar structure and tissue repair [1]. Cigarette smoke (CS)-induced emphysema is characterized by enlargement of the airspaces and a loss of alveolar structure [2,3]. Endothelial cell death and the regression of lung parenchyma, capillary density seen in emphysema may be linked to this loss of the alveolar structure [4,5].Vascular endothelial growth factor (VEGF) plays vital role in development and maintenance of vasculature and tissue regeneration [6]. VEGF signaling on endothelial cells is involved in several key processes during wound healing including degradation of the extracellular matrix of existing vessels, migration and proliferation of capillary endothelial cells, formation of new capillaries and restitution of the air-blood barrier in the alveoli [1,7]. Targeted disruption of VEGF gene in mice impairs blood vessel formation, growth retardation and premature death [8]. Furthermore, deletion or inhibition of VEGF in spe
Relaciones entre el sistema endocanabinoide y apetito: nuevos horizontes en el manejo de la obesidad
Tucci,Sonia A; Kirkham,Tim C;
Revista Venezolana de Endocrinología y Metabolismo , 2004,
Abstract: obesity has been described as a global epidemic. in most instances, obesity is a product of progressively less energetic lifestyles and the overconsumption of readily available, palatable, and highly caloric foods. past decades have seen massive investment in the search for effective anti-obesity therapies, so far with limited success. an important part of the process of developing new pharmacological treatments for obesity lies in bettering our understanding of the psychological and physiological processes that govern appetite and body weight regulation. recent discoveries concerning the endogenous cannabinoids are beginning to give greater insight into these processes. current research indicates that endocannabinoids may be key to the appetitive and consummatory aspects of eating motivation, possibly mediating the craving for and enjoyment of the most desired, most fattening foods. additionally, endocannabinoids appear to modulate central and peripheral processes associated with fat and glucose metabolism. selective cannabinoid receptor antagonist drugs have been shown to suppress motivation to eat, and preferentially reduce the consumption of palatable, energy- dense foods. here we review the background to these developments, and current theoretical accounts. we conclude that endocannabinoids represent an exciting target for new anti-obesity therapies.
Relaciones entre el sistema endocanabinoide y apetito: nuevos horizontes en el manejo de la obesidad
Sonia A Tucci,Tim C Kirkham
Revista Venezolana de Endocrinología y Metabolismo , 2004,
Abstract: La obesidad ha sido reconocida como una epidemia global. En la mayoría de los casos, la obesidad es el producto de un estilo de vida cada vez más sedentario aunado al consumo excesivo de alimentos asequibles, altamente apetitosos y calóricamente densos. Las décadas pasadas han sido testigo del gran esfuerzo dedicado a la búsqueda de tratamientos efectivos contra la obesidad, sin embargo los resultados obtenidos hasta el momento no han sido satisfactorios. Un aspecto importante del proceso de desarrollo de nuevos tratamientos farmacológicos para la obesidad se basa en el entendimiento de los procesos psicológicos y fisiológicos que gobiernan el apetito y la regulación del peso corporal. Los descubrimientos recientes referentes a los canabinoides endógenos han comenzado a esclarecer dichos procesos. Los conocimientos actuales indican que el sistema endocanabinoide parece ejercer un papel clave en las fases apetitiva y consumatoria de la motivación alimentaria, posiblemente mediando las ansias y el placer por las comidas más deseadas que son, generalmente, los alimentos calóricamente más densos. Además, los endocanabinoides parecen modular componentes centrales y periféricos asociados con el metabolismo de las grasas y de la glucosa. Los antagonistas selectivos de los receptores canabinoides han demostrado ser capaces de suprimir la motivación para la ingesta y reducir preferencialmente el consumo de alimentos apetitosos con alto valor energético. La siguiente revisión resume los avances recientes y las teorías actuales en este campo concluyendo que los endocanabinoides representan un blanco apasionante en la investigación sobre nuevas tratamientos anti-obesidad. Obesity has been described as a global epidemic. In most instances, obesity is a product of progressively less energetic lifestyles and the overconsumption of readily available, palatable, and highly caloric foods. Past decades have seen massive investment in the search for effective anti-obesity therapies, so far with limited success. An important part of the process of developing new pharmacological treatments for obesity lies in bettering our understanding of the psychological and physiological processes that govern appetite and body weight regulation. Recent discoveries concerning the endogenous cannabinoids are beginning to give greater insight into these processes. Current research indicates that endocannabinoids may be key to the appetitive and consummatory aspects of eating motivation, possibly mediating the craving for and enjoyment of the most desired, most fattening foods. Additionally,
Brd4 Is Essential for IL-1β-Induced Inflammation in Human Airway Epithelial Cells
Younis M. Khan, Paul Kirkham, Peter J. Barnes, Ian M. Adcock
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095051
Abstract: Background Chronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-κB). Histone acetylation plays a critical role in chronic inflammation and bromodomain and extra terminal (BET) proteins act as “readers” of acetylated histones. Therefore, we examined the role of BET proteins in particular Brd2 and Brd4 and their inhibitors (JQ1 and PFI-1) in oxidative stress- enhanced inflammation in human bronchial epithelial cells. Methods Human primary epithelial (NHBE) cells and BEAS-2B cell lines were stimulated with IL-1β (inflammatory stimulus) in the presence or absence of H2O2 (oxidative stress) and the effect of pre-treatment with bromodomain inhibitors (JQ1 and PFI-1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to the native IL-8 and IL-6 promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated. Result H2O2 enhanced IL1β-induced IL-6 and CXCL8 expression in NHBE and BEAS-2B cells whereas H2O2 alone did not have any affect. H3 acetylation at the IL-6 and IL-8 promoters was associated with recruitment of p65 and Brd4 proteins. Although p65 acetylation was increased this was not directly targeted by Brd4. The BET inhibitors JQ1 and PFI-1 significantly reduced IL-6 and CXCL8 expression whereas no effect was seen with the inactive enantiomer JQ1(-). Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ1 also inhibited p65 and Brd4 recruitment to the IL-6 and IL-8 promoters. Conclusion Oxidative stress enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by Brd4 inhibition. Brd4 plays an important role in the regulation of inflammatory genes and provides a potential novel anti-inflammatory target.
Structure of self-assembled Mn atom chains on Si(001)
R. Villarreal,M. Longobardi,S. A. K?ster,Ch. J. Kirkham,D. Bowler,Ch. Renner
Physics , 2015, DOI: 10.1103/PhysRevLett.115.256104
Abstract: Mn has been found to self-assemble into atomic chains running perpendicular to the surface dimer reconstruction on Si(001). They differ from other atomic chains by a striking asymmetric appearance in filled state scanning tunneling microscopy (STM) images. This has prompted complicated structural models involving up to three Mn atoms per chain unit. Combining STM, atomic force microscopy and density functional theory we find that a simple necklace-like chain of single Mn atoms reproduces all their prominent features, including their asymmetry not captured by current models. The upshot is a remarkably simpler structure for modelling the electronic and magnetic properties of Mn atom chains on Si(001).
Recognition and prevention of neurological complications in paediatric cardiac surgery
Fenella J Kirkham
Critical Care , 2000, DOI: 10.1186/cc672
Abstract: Some children are more at risk of neurodevelopmental problems, either because of their cardiac (egextensive aortopulmonary collaterals) or cerebrovascular (eg the propensity to large vessel dissection) anatomy or because of genetic predisposition (eg to prothrombotic disorders). The incidence may vary with the surgery (eg the Fontan operation) and the cardiopulmonary bypass technique neccessary to achieve an adequate technical repair (eg low or no flow at deep hypothermia). Recognition of the population at risk will lead to prevention of serious sequelae. Data collected in adults may be misleading, and many paediatric units have developed their own practice, but recent studies in animal models of infant surgery and in children have produced some evidence to guide management to ensure the optimal cerebral as well as cardiac outcome.Pump flow should be maintained at least 30 ml/kg per min where possible, with inotropic support to maintain blood pressure if necessary. If pump flow must go lower or circulatory arrest is essential, thorough cerebral cooling to deep hypothermic temperatures is mandatory; a pH-stat strategy may make this easier, but an α-stat strategy may be better in those operations that can be performed at moderate hypothermia. There is no evidence that the available pulsatile pumps offer an advantage. Tissue oxygenation may reach critical levels and a high haematocrit and oxygen tension may reduce the risk of significant hypoxia. There is a risk of embolization in children, which can be reduced with membrane oxygenators and careful monitoring; the role of arterial filtration remains controversial. The only protective agent that can be recommended at the present time is methylprednisolone to protect the spinal cord (eg in operations on the aortic arch). Further studies are needed in this important area.
Unique Physically Anchored Cryptographic Theoretical Calculation of the Fine-Structure Constant α Matching both the g/2 and Interferometric High-Precision Measurements
Charles Kirkham Rhodes
Physics , 2010,
Abstract: The fine-structure constant {\alpha}, the dimensionless number that represents the strength of electromagnetic coupling in the limit of sufficiently low energy interactions, is the crucial fundamental physical parameter that governs a nearly limitless range of phenomena involving the interaction of radiation with materials. Ideally, the apparatus of physical theory should be competent to provide a calculational procedure that yields a quantitatively correct value for {\alpha} and the physical basis for its computation. This study presents the first demonstration of an observationally anchored theoretical procedure that predicts a unique value for {\alpha} that stands in full agreement with the best (~370 ppt) high-precision experimental determinations. In a directly connected cryptographic computation, the method that gives these results also yields the magnitude of the cosmological constant {\Omega}{\Lambda} in conformance with the observational data and the condition of perfect flatness ({\Omega}{\Lambda} + {\Omega}m=1.0). Connecting quantitatively the colossal with the tiny by exact statements, these findings testify that the universe is a system of such astonishing perfection that an epistemological limit is unavoidably encountered.
Direct Cryptographic Computation of the Cosmological Constant $Ω_Λ$
Charles Kirkham Rhodes
Physics , 2012,
Abstract: A direct cryptographic computation of the Cosmological Constant {\Omega}{\Lambda} based solely on a physically anchored prime modulus that stands in full agreement with observational data on {\Omega}{\Lambda} and {\Omega}m and the conclusion of a flat universe ({\Omega}{\Lambda}+{\Omega}m=1.0) is demonstrated. The simplification derives from the fact that {\Omega}{\Lambda} defines the symmetry point of the cryptographic system.
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