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Molecular mechanisms of insulin-stimulated translocation of GLUT4 in 3T3-L1 adipocytesFletcher, Laura January 2000 (has links)
No description available.
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Protein phoshorylation and the regulation of translationFoulstone, Emily J. January 1996 (has links)
No description available.
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Insulin signalling to glycogen synthesis in cultured human muscle cellsArmstrong, Jane Louise January 2001 (has links)
No description available.
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Design and synthesis of chemical probes for the protein kinase B PH domainNemeth, Joseph January 2008 (has links)
Phosphatidyl D-myo-inositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] contributes to the activation of protein kinase B (PKB) by interacting with the PKB PH domain. PKB is known to be up-regulated in several cancer cell types. Compounds that can display selective inhibition of this kinase have promising chemotherapeutic potential, and inhibition of the PH domain of PKB represents a realistic means by which to achieve this. Analysis of the X-ray crystal structures of apo PKBαPH and PKBαPH bound to D-myo-inositol 1,3,4,5-tetrakisphosphate [InsP4, the inositol head group of PtdIns(3,4,5)P3] led to the design of PtdIns(3,4,5)P3 and InsP4 analogues as potential PKB PH domain inhibitors. The synthesis of PtdIns(3,4,5)P3 analogues modified at the C-4 position was investigated, but it was discovered that such compounds were prone to migration of the 1-position phosphate. Subsequently, a range of racemic InsP4 analogues, modified at the C-1 or C-4 position, were successfully synthesised. Advanced progress has also been made towards the synthesis of enantiomerically pure analogues of InsP4.
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Ionic, cellular and molecular mechanisms underlying the QT prolongation and arrhythmias in diabetic cardiocomplicationsZhang, Yiqiang January 2005 (has links)
Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.
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MECHANISMS OF HEME-OXYGENASE-1 CYTOPROTECTION FOR GENE AND CELL BASED THERAPIES AGAINST CARDIOVASCULAR DISEASEBrunt, KEITH 23 April 2009 (has links)
Establishing the cellular and molecular basis for cardiovascular disease and the application of tools to manipulate the cardiovascular system genetically provide potential for new forms of treatment against cardiovascular disease, including: atherosclerosis, myocardial ischemia, cardiac hypertrophy and heart failure. Heme oxygenase-1 (HO-1) is an enzyme that has potential for the treatment of cardiovascular diseases (CVD).
Atherosclerotic plaques express high levels of HO-1. Advanced plaques are stabilized in part through the separation of plaque constituents from the blood by the fibrous cap made up of smooth muscle cells. Protection of smooth muscle cells from apoptosis in the fibrous cap may be a means of promoting plaque stability in patients. Here we show that expression of HO-1 in human vascular smooth muscle cells renders them resistant to apoptosis mediated by oxidative stress. The cytoprotective mechanism mediated by HO-1 is mediated in part through protein kinase B (Akt).
Plaque rupture may lead to myocardial infarction. Tissue recovery after mycocardial infarction requires neovascularization for improved tissue perfusion. A novel cell type recently discovered in the circulation has been characterized as an endothelial progenitor cell (EPC) and appears capable of promoting neovascularization of post-infarct tissue, thereby enhancing tissue recovery and perfusion. Most EPCs transplanted into the infarct environment do not survive or are not retained to function in neovascularization. Here we show that expression of HO-1 and its cytoprotective partner Akt protect EPCs in an infarct environment and promote EPC function in an infarct environment.
Oxidative stress can result in maladaptive cardiomyocyte hypertrophy. In a model of oxidative stress-induced myocyte hyperterophy we demonstrate the expression of HO-1 prevents cellular hypertrophy through antioxidant mechanisms and regulation of the transcription nuclear factor kappa B (NF-κB).
Atherosclerotic plaque vulnerability is determined by the composition of the lesion. We demonstrate that HO-1 deficient mice have more calcified and fibrotic lesions. This may have implications in the management of late stage atherosclerosis.
Collectively, this work demonstrates new insights into the molecular mechanisms of cardiovascular cells under stress that may have implications for strategies aimed at treating CVD using HO-1. / Thesis (Ph.D, Physiology) -- Queen's University, 2009-04-21 15:31:14.05
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Brain Derived Neurotrophic Factor Modulates Behavioral and Brain Responses to Social StressJeffress, Elizabeth 11 May 2015 (has links)
Social stress is a prevalent factor in society that can cause or exacerbate neuropsychiatric disorders including depression and posttraumatic stress disorder. According to the National Institutes of Health, 6.9% of adults in this country currently suffer from depression, and 4.1% suffer from an anxiety disorder. Unfortunately, current treatments are ineffective in reducing or alleviating symptoms in a majority of these patients. Thus, it is critical to understand how social stress changes in brain and behavior so that we might develop alternative treatments. Brain derived neurotrophic factor (BDNF), which binds to tyrosine kinase B (TrkB) receptors, plays a role in fear learning and in behavioral responses to stress, although we do not currently know whether BDNF promotes or prevents these responses. The purpose of this project was to understand how BDNF alters brain and behavior in response to social stress using a model of social stress in Syrian hamsters, termed conditioned defeat (CD). CD refers to the marked increase in submissive and defensive behavior following social defeat. Specific Aim (SA) 1 tested the hypothesis that BDNF, via TrkB receptors, promotes CD learning. Instead, we found that BDNF and a selective TrkB receptor agonist reduced CD and that a TrkB receptor antagonist enhanced CD. SA 2 tested the hypothesis that the behavioral response observed following systemic administration of TrkB-active drugs is mediated via their action in specific nodes of the neural circuit underlying CD. Unfortunately, the vehicle in which these drugs are dissolved independently activates immediate early gene expression making interpretation of these data impossible. Finally, SA 3 tested the hypothesis that BDNF alters defeat-induced neural activation at least in part by acting in the medial prefrontal cortex (mPFC). We demonstrated that BNDF microinjected into the mPFC site-specifically altered defeat-induced neural activation in the CD neural circuit supporting this hypothesis. Overall, these data suggest that BDNF acts to prevent social stress-induced changes in behavior, at least in part via the basolateral amygdala and the mPFC, and that BDNF-active drugs might be a useful avenue to pursue to discover new treatments for patients that suffer from stress-related neuropsychiatric disorders.
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Adhesion Dependent Signals : Cell Survival, Receptor Crosstalk and MechanostimulationRiaz, Anjum January 2013 (has links)
The integrin family of cell surface receptors is evolutionary conserved and found in all multicellular animals. In humans 8-alpha and 18-beta integrins are non-covalently associated into 24 dimers. Integrins mediate cell-extracellular matrix and cell-cell interactions and participate in cell signalling. This ideally places integrins to regulate vital processes such as cell adhesion, migration, differentiation and cytoskeleton dynamics. Integrins also play a fundamental role in regulating cell survival and anoikis. In this thesis molecular mechanisms employed by integrins to induce signal transduction, independently or through crosstalk with other receptors, were characterised. Rictor-mTOR (mTORC2) was required for Akt Ser473 phosphorylation in response to β1 integrin-mediated adhesion as well as EGF-, PDGF- or LPA-stimulation of MCF7 cells. ILK and PAK were dispensable for Akt Ser473 phosphorylation upon β1 integrin-engagement or EGF-stimulation. PAK was needed when this phosphorylation was induced by PDGF or LPA. β1 integrin-promoted cell survival during serum starvation conditions was mTORC2 dependent, indicating the importance of Akt Ser473 phosphorylation. mTORC2 was also required for Akt Ser473 phosphorylation induced upon heparanase treatment of cells. Heparanase preferred PI3K catalytic subunit p110α for the upstream lipid phosphorylation required for Akt activation. Interaction between this subunit and Ras was needed for optimal Akt phosphorylation upon heparanase exposure. Cell adhesion strongly promoted heparanase signalling, which was more efficient in β1 integrin-expressing fibroblasts compared to cells lacking this subunit. The cooperative signalling between integrins and heparanase involved FAK and PYK2 since simultaneous silencing of these kinases suppressed heparanase-triggered Akt activation. Furthermore, the resistance of cells to apoptosis induced by H2O2 or serum starvation was promoted by heparanase. Integrin stimulation by adhesion or cyclic stretching showed divergent downstream signalling responses. Cell attachment on integrin-specific ligands lead to robust phosphorylation of several intracellular integrin-effectors, e.g. p130CAS, FAK, Akt and ERK 1/2. However, mechanical cell stretching only triggered prominent phosphorylation of ERK 1/2. Signalling induced at early stages of integrin-mediated cell adhesion occurred independently of intracellular contraction. Reactive oxygen species (ROS) generated during adhesion and cell stretching influenced integrin signalling. Inhibition of mitochondrial ROS production blocked adhesion-induced Akt phosphorylation. In contrast, stretch-induced ERK 1/2 phosphorylation was elevated when extracellular ROS was scavenged. These results indicate that the two types of integrin stimuli generate signals by different mechanisms.
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Mechanism of glucocorticoid-mediated impairment of glucose transport in adipocytesSherry Ngo Unknown Date (has links)
Glucocorticoids are widely used in clinical therapy. However, they cause adverse effects including insulin resistance and Type 2 diabetes, which are characterised by decreased glucose transport into the muscles and fat. How glucocorticoids inhibit glucose transport remains unclear. Insulin stimulates glucose uptake via the insulin receptor substrate (IRS)-1 / phosphoinositide-3-kinase (PI3K) / protein kinase B (AKT) pathway and promotes the redistribution of GLUT4 from intracellular storage compartments to the plasma membrane (PM). Insulin-stimulated phosphorylation of AKT substrate of 160 kDa (AS160), a Rab-GTPase activating protein is downstream of AKT and appears to be essential for exposure of GLUT4 at the PM and glucose uptake. This is mediated through the association of phosphorylated AS160 (at the key residue T642) with 14-3-3 in the cytosol. The mildly insulin-responsive GLUT1 mediates basal glucose uptake in adipocytes. It is also subject to regulated trafficking like GLUT4. This study aimed to determine the level at which glucocorticoids inhibit glucose uptake in adipocytes. Effects of the synthetic glucocorticoid dexamethasone (Dex) and the natural glucocorticoid cortisol, on GLUT1 and GLUT4 function were examined. Candidates for the glucocorticoid-mediated inhibition of GLUT1- and GLUT4-mediated glucose uptake were investigated. These were glycogen synthase kinase (GSK) 3β (an AKT substrate) for GLUT1-mediated glucose transport; and adaptor protein containing PH domain, PTB domain, and leucine zipper motif (APPL)-1 (an AKT-interacting protein) and AS160 for GLUT4-mediated glucose transport. Dex and cortisol significantly decreased basal glucose uptake by 50% (p<0.05) in SGBS and 3T3-L1 adipocytes. Similarly, insulin-stimulated glucose uptake was decreased by 50% (p<0.001 for SGBS; p<0.05 for 3T3-L1) and 30% (p<0.05 for both) at 1 nM and 100 nM insulin respectively. Similar results were observed with differentiated primary human preadipocytes and human adipose explants. Dex-mediated inhibition of basal glucose uptake was limited to insulin-sensitive cell types implying that glucocorticoids may regulate GLUTs at steps common to GLUT1 and GLUT4 trafficking. Dex-mediated reduction in glucose uptake correlated with the reduction in basal and insulin-stimulated expression of GLUT1 and GLUT4 to the PM without changes in total GLUT1/4 expression. Dex did not alter total expression or phosphorylation of proximal insulin-signalling molecules up to and including AKT but increased FOXO1 expression, and modified GSK3β-S9 phosphorylation. Dex did not alter total APPL1 expression or subcellular distribution. Dex significantly decreased 1nM-insulin stimulated AS160-T642 phosphorylation by 50% (p<0.05) in SGBS and 3T3-L1 adipocytes via the glucocorticoid repector (GR). This correlated with reduced AS160:14-3-3 interaction. Similar results were obtained for AS160-T642 basal phosphorylation. At 1nM insulin, AS160-T642 phosphorylation is maximal at sub-maximal glucose uptake, i.e. AS160 phosphorylation significantly contributes to glucose uptake. RU486 significantly prevented but did not fully abrogate the Dex-mediated reduction in glucose uptake suggesting additional Dex-induced defects. In conclusion, glucocorticoids inhibit glucose uptake at a level distal to AKT by GR-dependent mechanisms. A role for GSK3β or APPL1 in glucocorticoid-mediated inhibition of glucose uptake requires further investigations. FOXO1 represents a suitable candidate for mediating the Dex-induced defects. Of significance, perturbation in AS160-T642 phosphorylation contributes to Dex-mediated inhibition of glucose uptake. Thus, AS160 presents a novel therapeutic target in the improvement of glucocorticoid-mediated inhibition of glucose uptake.
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Does Olea africana protect the heart against ischemiareperfusion injury?Maliza, Asanda January 2009 (has links)
Magister Scientiae (Medical Bioscience) - MSc(MBS) / Cardiovascular disease is a major health problem and remains the number one cause of death worldwide. For centuries, medicinal plants have been used in different cultures as medicines for the treatment and control of various diseases. Olea africana, also known as the wild olive, is amongst the herbal plants used by people to treat many ailments.Recently, scientific studies on the hypotensive, vasodilatory and antidysarrhythmic effects of O. africana have been reported. Triterpenoids isolated from the O. africana leaves, for example, have antioxidant properties. The aqueous extract from the leaves of O. africana also have angiotensin-converting enzyme (ACE) inhibitory effects. ACE inhibitors and antioxidants protect the heart against ischemic-reperfusion injury. The serine / threonine protein kinase B (PKB) also known as Akt is activated downstream of
phosphoinositide 3- (PI-3) kinase (PI-3-Kinase) and is involved in cardioprotection
against ischemia-reperfusion injury. Angiotensin II (AII) decreases the intrinsic PI-3-kinase activity. In this study, we hypothesized that ACE inhibitors increase PI-3-kinase activity and thus activates PKB. The aims of this study were: 1) to determine whether treatment with the crude aqueous extract of leaves of O. africana protect the heart against ischemic-reperfusion injury and 2) if so, to determine whether the protection is mediated via the PKB signaling mechanism.
Hearts isolated from male Wistar rats were perfused with different concentrations of the plant extract. In one set of experiments, male Wistar rats were treated with the plant extract (1000 mg/kg/day) for 5 weeks for the evaluation of cardiac function before and after ischemia. At the end of the experiments, hearts were freeze-clamped and kept for PKB / Akt determination. In another set of experiments, we determined the effect of O. africana extract (1000 mg/kg/day) or captopril (50 mg/kg/day) on infarct size. Rats fed jelly served as controls for captopril. In a subset of experiments, hearts were frozen immediately after treatment with O. africana extract (1000 mg/kg/day) or captopril (50mg/kg/day) and PKB were determined.Perfusion with the plant extract significantly decreased coronary flow (p<0.05). The heart function was decreased as evidenced by observed decreases in the force of contraction and heart rate, although these were not measured. Chronic treatment with the crude aqueous plant extract had no effect on cardiac function before ischemia, functional recovery (% left ventricular developed pressure and % rate pressure product) and PKB /Akt phosphorylation (p>0.05). Both the aqueous extract of O. africana leaves and captopril had no effect on infarct size compared to the control group (p>0.05). Captopril,however, improved the recovery of the left ventricular developed pressure. Non-perfused
hearts isolated from rats treated with O. africana extract and captopril did not show any response to both captopril and the O. africana extract treatment as measured by PKB /Akt phosphorylation. The results of the present study suggest that the crude aqueous extract of O. africana is not cardioprotective against ischemia-reperfusion injury in this system of the isolated perfused rat heart.
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