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Inskip, Jessica Ann. "Cardiovascular and metabolic function after thoracic spinal cord injury." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/23500.
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Spinal cord injury (SCI) has the potential to disrupt autonomic pathways in the spinal cord leading to a range of autonomic dysfunctions. The cardiovascular (CV) and metabolic sequelae can restrict the lives of individuals with SCI and contribute to the deterioration of their cardiometabolic health.
Here I investigated the whole-body CV and metabolic ramifications of experimental SCI in rats. Complete thoracic SCI was performed at two different levels in order to determine whether these outcomes demonstrated a level dependence. High-(T3) and low-(T10) thoracic SCI both result in flaccid hindlimb paralysis, but have different effects on the level of supraspinal autonomic control. CV and metabolic function were assessed at several times post-injury to investigate changes over time.
Animals with acute high-thoracic SCI displayed resting hypotension that resolved with time post-injury. However, their capacity to control blood pressure (BP) in response to physiological stimuli remained deficient; animals with high-thoracic SCI displayed pronounced orthostatic hypotension (OH) and severe episodes of sensory stimulation-induced hypertension known as autonomic dysreflexia (AD). The resting BP and heart rate of animals with low-thoracic SCI, and their ability to respond to orthostatic stress, was indistinguishable from sham controls.
Lipid metabolism was also disordered by SCI in a level-dependent pattern. Animals with high-thoracic SCI carried increased white adipose tissue and had higher circulating triacylglycerol levels compared to animals with low-thoracic SCI and sham controls. However, there was no difference in the distribution of cholesterol-carrying lipoproteins.
Carbohydrate metabolism in animals with SCI did not support the diabetic profile suggested by the lipid results. Overall, animals with SCI were more sensitive to glucose and insulin than sham-injured animals. The pronounced ketone response to fasting in animals with high-thoracic SCI suggests that there are diverse effects on substrate metabolism.
This work introduces simple tests that can be performed to investigate several important and understudied autonomic outcomes of SCI. The results reveal the importance of the intact autonomic nervous system in regulating CV and metabolic function. The disparity between motor and autonomic function encourages modifying our current conventions so that we stratify subjects by their autonomic injury level and their motor deficits.
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Kuzmanov, Uros. "Metabolic function of cytoplasmic methylenetetrahydrofolate Dehydrogenase-Cyclohydrolase-Synthetase activities." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98741.
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The NADP-dependent trifunctional methylenetetrahydrofolate Dehydrogenase-Cyclohydrolase-Synthetase (DCS) is responsible for the interconversion of one-carbon substituted tetrahydrofolates (THFs) required for methylation reactions and nucleotide synthesis in the cytoplasm of mammalian cells. A spontaneously immortalized DCS null fibroblast cell line was found to be a purine auxotroph due to a lack of 10-formylTHF required for de novo purine synthesis (Christensen et al. 2005). Using a retroviral infection system the DCS null fibroblasts were infected with constructs designed to express wild type DCS or proteins with D and S activities inactivated by point mutations. Western analysis and activity assays confirmed protein expression. All constructs rescued the cell line from purine auxotrophy showing that one-carbon substituted THF derived from cytoplasmic serine and mitochondrial formate can be utilized in purine synthesis. Supported by previous studies, radiolabeling experiments tracing incorporation of exogenous 3-14C serine and 14C formate demonstrated that mitochondrial formate is the preferred source of one-carbon units for purine synthesis in these cells.
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Olagaray, Katie E. "Bioactive nutrients for improved metabolic function of dairy cattle." Thesis, Kansas State University, 2017. http://hdl.handle.net/2097/35448.
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Master of ScienceDepartment of Animal Sciences and Industry
Barry J. Bradford
Dairy cows undergo many homeorhetic adaptations during the transition to lactation. Although many of the physiological processes - including increased lipolysis and postpartum inflammation - are adaptive, exaggerated responses can contribute to metabolic disease and reduced milk production. L-carnitine has been shown to increase hepatic oxidation of fatty acids and reduce hepatic lipid accumulation in early lactation cows; however, L-carnitine is degraded in the rumen. An experiment using 4 ruminally-cannulated Holstein heifers in a split plot design demonstrated that the relative bioavailability of L-carnitine was greater when delivered abomasally than ruminally. There was a dose × route interaction and a route effect for increases in plasma carnitine above baseline, with increases above baseline being greater across all dose levels (1, 3, and 6 g L-carnitine/d) when infused abomasally compared to ruminally. A second experiment used 56 lactating Holstein cows in a randomized complete block design to evaluate 2 rumen-protected products (40COAT and 60COAT) compared to crystalline L-carnitine at doses targeting 3 and 6 g/d carnitine. Although crystalline and 40COAT were effective in linearly increasing carnitine concentrations, only subtle responses were seen for the 60COAT, which were less than that for crystalline carnitine in plasma, milk, and urine. Ineffectiveness of rumen-protected products to increase carnitine concentrations beyond crystalline may have been due to over-encapsulation that hindered liberation of the carnitine and its absorption in the small intestine. Although L-carnitine has the potential to reduce postpartum hepatic lipidosis, effective rumen protection of L-carnitine while maintaining intestinal availability needs further investigation. Plant polyphenols have anti-inflammatory properties and when administered during the transition period, have been shown to increase milk production. An experiment used 122 multiparous Holstein cows in a randomized block design to determine the effect of short term (5-d; SBE5) and long term (60-d; SBE60) administration of Scutellaria baicalensis extract (SBE)on whole-lactation milk yield, 120-d milk component yield, and early lactation milk markers of inflammation. Whole-lactation milk yield was increased for SBE60 compared to control, but was not different for SBE5 compared to control. Greater total pellet intake, milk lactose yield, and reduced SCC during wk 1-9 for SBE60 compared to control, all could have contributed to the observed sustained increase in milk yield. Milk production parameters were not different for SBE5 compared to control. No treatment effects were observed for BCS or milk markers of inflammation (haptoglobin) and metabolic function (β-hydroxybutyrate). Overall, long term administration of S. baicalensis effectively increased milk production, however the mechanism by which this was achieved is unknown. Although routes of administration to effectively achieve their physiological responses were different between L-carnitine (abomasal delivery) and SBE (feeding), both bioactive nutrients can improve the metabolic function of early lactation dairy cows.
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Dubé, Nadia Marie-Noël. "Protein tyrosine phosphatase 1B regulates metabolic, oncogenic, and hematopoietic function." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85155.
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Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed enzyme that is involved in multiple signaling pathways. Biochemical and substrate trapping studies have implicated PTP1B in the dephosphorylation of various tyrosine kinases, including the EGFR, PDGFR, IR, IGF-IR, JAK2, p210Bcr-Abl, and Src. Of particular interest, gene-targeting studies in mice have established PTP1B as a critical physiological regulator of metabolism by attenuating insulin and leptin signaling. Indeed, PTP1B null mice exhibit resistance to diet-induced diabetes and obesity. Although PTP1B is involved in signaling pathways that contribute to oncogenesis, PTP1B null mice do not develop spontaneous tumors. Therefore, my doctoral research focuses on identifying the physiological significance of PTP1B in these pathways. Our laboratory has previously demonstrated that PTP1B modulates leptin signaling via the tyrosine kinase JAK2. Accordingly, I have shown that PTP1B dephosphorylates JAK2 in a growth hormone (GH)-dependent manner, thus negatively regulating GH signaling and downstream effectors such as STAT3 and STAT5. Consequently, mice lacking PTP1B remain sensitive to GH action after starvation. In addition, I showed that the absence of PTP1B could improve glycemia during streptozotocin-induced type 1 diabetes. In the second part of my research, I have elucidated the mechanism for the previously reported decreased ERK activation in PTP1B null fibroblasts. I demonstrated that Ras activity is reduced in these cells, which is due to increased p120RasGAP expression and p62Dok hyperphosphorylation. Both of these molecules negatively regulate Ras activity by promoting the intrinsic GTPase activity of Ras, leading to decreased ERK activation. Finally, I developed a mouse model of cancer to study the role of PTP1B in tumorigenesis. Since the majority of cancers harbor mutations in p53, I generated p53/PTP1B double null mice. In the absence of p53, PTP1B heterozygous
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Sharma, Rakesh. "Cellular immune function and metabolic abnormalities in chronic heart failure." Thesis, Imperial College London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406373.
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Kohlhaas, Christine Frederike. "Metabolic regulation of human vascular endothelial cell function in vitro." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/348/.
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The vascular endothelium contributes to the maintenance of vascular health by regulating vascular tone and leukocyte adhesion, amongst others. The vasoregulatory actions of the endothelium are mediated through coordinated release of vasodilators such as nitric oxide (NO) and prostacyclin, and vasoconstrictors such as endothelin-1 and thromboxane A2. Endothelial NO is the principal vasodilator in the vasculature and is produced by endothelial nitric oxide synthase (eNOS). Insulin is a vasoactive hormone that exerts its vasodilatory effects through eNOS-mediated NO production. Endothelial function is impaired in a number of disorders, including insulin resistance, diabetes and atherosclerosis, leading to dysregulated vasodilation as well as increased monocyte adhesion and plaque formation (atherosclerosis). The underlying molecular mechanisms leading to endothelial dysfunction are still in question. The work presented in this thesis addressed this question by investigating how insulin signalling and eNOS-mediated NO and superoxide production in human vascular endothelial cells are affected under experimental hyperinsulinaemia (chapter 3) and experimental hyperglycaemia (chapter 4). Atherogenic processes in human aortic endothelial cells (HAEC) were investigated by assessing monocyte adhesion under experimental hyperinsulinaemia (chapter 3), and by determining the contribution of NO and AMP-dependent kinase (AMPK) activity to the regulation of endothelial chemokine production (chapter 6). The potential of insulin to modify the subcellular distribution of eNOS was investigated in chapter 5. Clinical hyperinsulinaemia correlates with attenuated NO-mediated vasodilation, but it is not clear how hyperinsulinaemia impairs eNOS-mediated NO production. The present study modelled hyperinsulinaemia in HAEC and demonstrated a blunted response of hyperinsulinaemic cells to Ca2+-stimulated, but not insulin-stimulated eNOS-mediated NO synthesis. To address the underlying mechanisms responsible, the protein expression levels of components of the metabolic and mitogenic insulin signalling pathways, and of the metabolic energy sensor, AMPK, were quantified. Experimental hyperinsulinaemia slightly and non-significantly increased basal and insulin-stimulated eNOSS1177 phosphorylation in a time-dependent manner, and the levels of eNOST495 increased following acute insulin stimulation under these conditions. No marked dysregulation of individual insulin signalling pathway components was identified as a potential cause, but increased activating AMPKT172 phosphorylation was found to be a potential cause of increased unstimulated eNOSS1177 phosphorylation under experimental hyperinsulinaemia. Monocyte adhesion to hyperinsulinaemic HAEC did not differ from control HAEC, indicating that experimental hyperinsulinaemia did not act as a proatherogenic factor in the present study. Overt diabetes was simulated by experimental hyperglycaemia in human umbilical vein endothelial cells (HUVEC) and its effect on insulin-stimulated eNOS phosphorylation and endothelial superoxide production assessed. Insulin tended to stimulate phosphorylation of eNOSS615 and eNOSS1177, and decrease phosphorylation of eNOSS114, eNOST495 and eNOSS633 under control conditions. Experimental hyperglycaemia slightly reduced basal phosphorylation of Ser633 and significantly reduced insulin-stimulated phosphorylation of Ser114, but mildly increased basal Ser615 phosphorylation, indicating some dysregulation of eNOS phosphorylation. The upstream components of the metabolic insulin signalling pathway were not impaired in hyperglycaemic conditions. The subcellular localisation of eNOS is thought to have implications for its function. This study showed that eNOS localises to the plasma membrane, the nucleus, the cytoplasm and, primarily, the perinuclear area of HAEC. Insulin stimulation did not affect this distribution. Phospho-eNOS species were found primarily at the plasma membrane, and insulin may modulate the abundance of an intracellular eNOST495 species. Previous work in our laboratory on AMPK-mediated reduction of adhesion molecule expression has lead to the investigation of AMPK- and NO-mediated regulation of chemokine production in the present study. Inhibition of NO synthesis increased the production of monocyte chemoattractant protein (MCP)-1 in HAEC. AMPK activity downregulated TNFα-stimulated MCP-1 expression, and this was NO-dependent in the short-term, but may be NO-independent during prolonged AMPK activation. These data implicate NO and AMPK as antiatherogenic mediators in vascular endothelial cells in vitro. Taken together, the data in this thesis provide further insight into some of the molecular mechanisms involved in endothelial function and their response to hyperinsulinaemia, hyperglycaemia and proatherogenic stimulation.
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Arora, Teresa. "Sleep and its association with metabolic function across the lifespan." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3343/.
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Obesity and accompanied metabolic dysfunction are global public health problems. A better understanding of factors contributing to obesity and metabolic disease development is needed, particularly lifestyle behaviours including sleep. Sleep duration has been suggested to be a contributor to obesity and metabolic dysfunction development. This thesis examines the relationships between sleep, obesity, and metabolic function in different age groups and ethnicities. The thesis also presents a model for experimental sleep manipulation that can be used to understand the underlying mechanisms for the associations among sleep duration, obesity, and metabolic dysfunction. The studies and findings were as follows: 1. Cross-sectional data from young South Asian children in Birmingham showed that ‘inadequate' sleep duration, unlike findings from different population studies, was not associated with overweight/obesity. 2. Cross-sectional data from a population of adolescents in the Midlands showed that short sleep duration was associated with increased odds of overweight/obesity. 3. Cross-sectional data from older Chinese from Guangzhou, China, showed that total long sleep duration was associated with increased odds of the metabolic syndrome. 4. Data from the experimental sleep model revealed that reducing sleep over a prolonged period is more achievable than sleep extension.
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Ferreira, Matias Maria. "Targeting the metabolic environment to modulate T cell effector function." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT020.
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L’activation des cellules T est initiée suite à la rencontre avec un antigène spécifique. Les études réalisées pour mieux comprendre ce processus d’activation se sont principalement focalisées sur le rôle des cellules présentatrices d'antigènes et des cytokines. Toutefois, des données récentes soulignent également l'importance du microenvironnement métabolique pour soutenir l’augmentation des besoins énergétiques et biosynthétiques liés à la stimulation antigénique. Cette reprogrammation métabolique est conditionnée par la disponibilité en nutriments et la teneur en oxygène qui peuvent être altérés en conditions pathologiques, comme dans des tumeurs. En effet, plusieurs groupes dont le nôtre ont montré qu’en cas de faible disponibilité en nutriments, une compétition peut se créer entre les cellules tumorales et les cellules T, impactant de ce fait négativement leurs fonctions anti-tumorales. Cet effet est dû, du moins en partie, aux profils métaboliques distincts des sous-populations de cellules T; alors que les cellules T effectrices (dont les cellules Th1) sont fortement glycolytiques, les cellules T régulatrices suppressives (Treg) présentent un métabolisme plus mixte avec des niveaux accrus d'oxydation lipidique. Il est donc important de déterminer comment les changements métaboliques des cellules T anti-tumorales affectent leur persistance et leur fonctionnalité. Ainsi, j'ai entrepris des travaux afin d’évaluer si le niveau d’expression du transporteur de glucose Glut1 permettait d’identifier et de sélectionner des cellules T ayant des fonctions effectrices distinctes. Nous avons confirmé cette hypothèse et notamment montré que les cellules T exprimant un niveau élevé de Glut1 possèdent un potentiel de sécrétion d’IFNg accru.De plus, nos travaux montrent que la disponibilité en nutriments extracellulaires est un élément clé pour la différenciation terminale des cellules Th1. En effet, l'activation des cellules T CD4 naïves en conditions limitantes en glutamine induit leur différenciation en cellules Treg Foxp3+. Plus surprenant encore, cette carence induit un blocage de la différenciation Th1 même lors d’une polarisation vers ce lignage. De plus, en conditions de carence en glutamine, nous avons découvert que l'alpha-cétoglutarate (aKG), un métabolite dérivé de la glutamine, rétablit cette différenciation terminale Th1. J'ai ensuite évalué l'impact de l’aKG dans les processus de différenciation Th1/Treg en condition non limitante en glutamine. Mes données montrent que, dans des conditions de polarisation Th1, l’ajout d’aKG améliore la différenciation des cellules T CD4 naïfs en cellules Th1 et augmente la production d’IFNg. A l’inverse, l’ajout d’aKG s’accompagne d’une diminution des cellules Foxp3+ et d’une augmentation de la sécrétion de cytokines inflammatoires dans des conditions de polarisation Treg. L'altération de la différenciation des cellules T médiée par l'aKG est notamment associée à une phosphorylation oxydative (OXPHOS) accrue ; ainsi, l'ajout d’un inhibiteur du cycle de Krebs et du complexe mitochondrial II /succinate déshydrogénase, atténue le blocage de la différenciation Treg induit par l'aKG. De façon remarquable, ces modifications de l'équilibre Th1/Treg médiées par l'aKG sont maintenues in vivo et impactent le devenir de cellules T exprimant un récepteur chimérique anti-tumoral (CAR) injectées chez des souris porteuses de tumeurs. En résumé, nos données montrent qu'une faible teneur en aKG intracellulaire liée à une disponibilité limitée en glutamine, favorise un phénotype Treg, alors que des niveaux élevés d’aKG modifient l'équilibre vers un phénotype Th1.En conclusion, les données générées au cours de ma thèse devraient permettre le développement de stratégies permettant de sélectionner des cellules T ayant des propriétés effectrices anti-tumorales amélioréesT cells are stimulated upon interaction with their cognate antigen. While much research has focused on the role of antigen presenting cells (APC) and cytokines as important components of the T cell microenvironment, recent data highlight the importance of the metabolic environment in sustaining the energetic and biosynthetic demands that are induced upon antigen stimulation. The subsequent metabolic reprogramming of the T cell is conditioned by the nutrient composition and oxygen levels. Notably, this environment can be altered by pathological conditions such as tumors and data from our group, as well as others, have shown that the competition of T cells and tumor cells for limiting amounts of nutrients has a negative impact on T cells, inhibiting their anti-tumor effector functions. This effect is due, at least in part, to the distinct metabolic profiles of T lymphocyte subsets; T effector cells (including Th1 cells) are highly glycolytic while suppressive Foxp3+ regulatory T cells (Tregs) display a mixed metabolism with increased levels of lipid oxidation. It is therefore important to determine how changes in the metabolic programming of anti-tumor T cells impacts on their persistence and function. Indeed, in the context of my PhD research, I found that high levels of the glucose transporter Glut1 was associated with a significantly increased level of IFNγ secretion by both CD4 and CD8 T cells. Furthermore, there was a bias of CD8 over CD4 lymphocytes in the Glut1-hi T cell subset. These data point to the importance of metabolic alterations in the fate and effector function of T lymphocytes and during my PhD, I focused on elucidating the metabolic parameters that regulate effector and regulatory T cells, with the goal of improving the efficacy of anti-tumor T cells. In this context, I contributed to initial studies from our group, revealing a critical role for extracellular nutrient availability in terminal CD4+ T cell differentiation. Activation of naïve CD4+ T cells under conditions of glutamine deprivation caused them to differentiate into induced Treg (iTreg). Moreover, the skewing of glutamine-deprived naive CD4+ T cells to a Foxp3+ fate occurred even under Th1-polarizing conditions, blocking terminal Th1 differentiation. Under glutamine-deprived conditions, we found that alpha-ketoglutarate (αKG), a glutamine-derived metabolite, rescued Th1 differentiation. I then evaluated the impact of aKG under glutamine-replete conditions in the Th1/iTreg differentiation processes. My studies showed that, under Th1-polarizing conditions, aKG markedly enhanced naïve CD4+ T cell differentiation into Th1 cells and increased IFNg secretion. Moreover, under Treg-polarizing conditions, αKG decreased Foxp3 expression and increased the secretion of inflammatory cytokines such as IFNg, GM-CSF and IL-17. Notably, the aKG-mediated alteration in T cell differentiation was associated with an augmented oxidative phosphorylation (OXPHOS), and inhibiting the citric acid cycle and the mitochondrial complex II with malonate, an inhibitor of succinate dehydrogenase (SDH), alleviated the αKG-mediated block in Treg differentiation. Impressively, these aKG-mediated changes in the Th1/Treg balance were maintained in vivo, promoting a Th1-like profile in T cells expressing an anti-tumor chimeric antigen receptor (CAR) in tumor-bearing mice. Thus, our data show that low intracellular aKG content, caused by limited external glutamine availability, imposes a Treg phenotype while high aKG levels shift the balance towards a Th1 phenotype.Altogether, the data generated during my PhD will promote the development of metabolic strategies aimed at modulating T cell function and foster the design of nutrient transporter-based approaches that can be used to select T lymphocytes with enhanced anti-tumor effector properties
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Foglesong, Grant. "Lifestyle Improvements Enhance Metabolic Function and Mitigate Breast Cancer Progression." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1490266217799202.
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Pathare, Neeti C. "Metabolic adaptations following disuse and their impact on skeletal muscle function." [Gainesville, Fla.] : University of Florida, 2005. http://purl.fcla.edu/fcla/etd/UFE0010024.
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Thesis (Ph.D.)--University of Florida, 2005.Typescript. Title from title page of source document. Document formatted into pages; contains 171 pages. Includes Vita. Includes bibliographical references.
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Tinson, S. V. "The environmental metabolic function of benthic copepods from Esthwaite Water, Cumbria." Thesis, Lancaster University, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373481.
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Loughrey, Brona Veronica. "Effect of statin therapy on monocyte function in the metabolic syndrome." Thesis, Queen's University Belfast, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.534628.
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Fan, Pengcheng, and 樊鹏程. "Interrelationship between SIRT1 function and biotin homeostasis : implications in metabolic ageing." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196431.
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SIRT1 (sirtuin 1) is a mammalian homolog of the longevity regulator Sir2p in yeast which catalyzes the removal of acetyl groups from protein substrates. Mammalian SIRT1 acts as an energy and stress sensor contributing to the beneficial effects of calorie restriction by regulating the acetylation status of different intracellular protein targets. Selective over-expressing SIRT1 in adipose tissue of mice prevents ageing induced insulin insensitivity and enhances energy homeostasis by inhibiting ageing related biotin accumulation and reduces the level of biotinylated protein including acetyl-CoA carboxylase (ACC) which is a major reservoir of biotin in adipose tissues. On the other hand, chronic biotin supplementation can facilitate the accumulation of ACC and abolish adipose SIRT1-mediated beneficial effects on insulin sensitivity and lipid metabolism. However, the role of biotin in regulating adipose SIRT1-mediated beneficial effects is still elusive and needs further investigations.
The present study shows that overexpression of SIRT1 in adipose tissue downregulates not only the total protein expression of ACC, but also the acetylation and biotinylation of this enzyme. After chronic biotin treatment, both acetylation and biotinylation of ACC are increased, accompanied by elevated total protein expression of this enzyme. Further study using both synthetic peptide and BCCP mutant suggests that the presence of biotin and the biotinylation status of ACC could both influence to the capacity of SIRT1 to regulate the stability of this enzyme.
Then the reciprocal causal relationship between ACC, biotin and SIRT1 in both 3T3-L1 adipocytes and mice adipose tissues is established. The reduced ACC can significantly attenuate the accumulation of biotin and enhance the SIRT1 activity in both 3T3-L1 cells and mice adipose tissues suggesting ACC acts as a central regulator of biotin homeostasis in cells and adipose tissues.
The in vivo study demonstrates that overexpression of adipose SIRT1 significantly reduces the acetylation but not biotinylation level of histone. The biotin supplementation increases the both biotinylation and acetylation level of histone in adipose tissues. The synthetic peptide study further confirms that direct biotinylation of histone inhibits SIRT1 mediated deacetylation. Biotin also regulates the expression and acetylation of two non-biotinylated SIRT1 substrates P53 and LKB1 differentially.
Finally, overexpression dominant negative deacetylase mutant SIRT1 in adipose tissues of mice accelerates ageing induced deterioration of insulin sensitivity and lipid metabolic dysfunction which is restored by fed with biotin deficient diet.
Taken in conjunction, the above findings reveal that biotin antagonizes the beneficial effects of SIRT1 by modulating its deacetylation of diversified substrates which provides a potential therapeutic target for the treatment of ageing related metabolic disorders.published_or_final_version
Pharmacology and Pharmacy
Doctoral
Doctor of Philosophy
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Kensara, Osama Adnan. "Influence of fetal growth on current body structure and metabolic function." Thesis, University of Southampton, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439386.
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Kohlhaas, Kaylee Shevon. "Resveratrol: therapeutic role in metabolic and reproductive function in obese broodmares." Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/23155.
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Resveratrol, a naturally-occurring phytoestrogenic stilbene derivative, has been shown to elicit shifts in physiology of obese animals consuming a high calorie or ad libitum diet toward that of lean counterparts. This study was designed to evaluate effects of oral resveratrol supplementation on parameters of metabolic health and reproductive cyclicity in obese mares on pasture. Seventeen healthy, mares were matched by age and assigned to obese control (OBC; n=5, mean BCS=7.4±0.3), obese supplemented with 5g/d resveratrol (OBR; n=6, mean BCS=7.4±0.2) or non-obese control (NOC; n=6, mean BCS=5.4±0.1) treatments. Control horses received the resveratrol carrier paste. Across three consecutive estrous cycles, morphometric measurements were collected biweekly and follicular dynamics were evaluated via transrectal ultrasonography every other day. Frequently-sampled intravenous glucose tolerance tests were conducted pre- and post- treatment. Insulin and glucose kinetics were analyzed via minimal model. Resveratrol supplementation had no discernible effect on reproductive parameters (P>0.05), however obese mares had more (6 vs. 0) hemorrhagic anovulatory follicles. Neither resveratrol treatment nor time on study influenced morphometric measurements or minimal model parameters (raw data or data adjusted for animal size). As a whole, horses became more insulin resistant over time (Si value < 0.78 (1/[mU/L"min]). NOC horses had lower (P=0.01) acute insulin response to glucose relative to OBC or OBR. Although resveratrol supplementation did not elicit detectable responses in this study, promising results in other species warrant further investigation of the compound in horses, including exploration of bioavailability and possible effects at the tissue or cellular levels.Master of Science
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Asakura, Makoto. "Studies on metabolic function required for infection mechanism of Colletotrichum lagenarium." Kyoto University, 2007. http://hdl.handle.net/2433/136577.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第13454号
農博第1665号
新制||農||949(附属図書館)
学位論文||H19||N4310(農学部図書室)
UT51-2007-S485
京都大学大学院農学研究科応用生物科学専攻
(主査)教授 奥野 哲郎, 教授 遠藤 隆, 准教授 田中 千尋
学位規則第4条第1項該当
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Hooper, Nigel I. "Methylglyoxal, glyoxalases and cell proliferation." Thesis, Aston University, 1987. http://publications.aston.ac.uk/12548/.
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The metabolic function of the glyoxalase system was investigated in (a) the differentiation and proliferation of human tumour cells in vitro, (b) the cell-free assembly of microtubules and (c) in the red blood cells during hyperglycaemia associated with Diabetes Mellitus. Chemically-induced differentiation of human promyelocytic HL60 leukaemia cells to neutrophils, and K562 erythroleukaemia cells, was accompanied by a decrease and an increase in the activity of glyoxalase I, respectively. Growth-arrest of Burkitt's lymphoma Raji cells and GM892 lymphoblastoid cells was accompanied by an increase and a decrease in the activity of glyoxalase I respectively. However, differentiation and growth arrest generally proceeded with an increase in the activity of glyoxalase II. Glyoxalase I activity did not consistently correlate with cell differentiation or proliferation status; hence, it is unlikely that glyoxalase I activity is either an indicator or a regulator of cell differentiation or proliferation. Conversely, glyoxalase II activity consistently increased during cell differentiation and growth-arrest and may be both an indicator and regulator of cell differentiation or proliferation. This may be related to the control of cellular microtubule assembly. S-D-Lactoylglutathione potentiated the cell-free, GTP-promoted assembly of microtubules. The effect was dose-related and was inhibited by glyoxalase II. During assembly, S-D-lactoylglutathione was consumed. This suggests that the glyoxalase system, through the influence of S-D-lactoylglutathione, may regulate the assembly of microtubules in cellular systems The whole blood concentrations of methylglyoxal and S-D-lactoylglutathione were increased in Diabetes Mellitus. There was no significant difference between red blood cell glyoxalase activities in diabetics, compared to healthy controls. However, insulin-dependent diabetic patients with retinopathy had a significantly higher glyoxalase I activity and a lower glyoxalase II activity, than patients without retinopathy. Diabetic retinopathy correlated with high glyoxalase I activity and low glyoxalase II activity and suggests the glyoxalase system may be involved in the development of diabetic complications.
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Ärnlöv, Johan. "Left Ventricular Function in Elderly Men : Metabolic, Hormonal, Genetic and Prognostic Implications." Doctoral thesis, Uppsala University, Department of Public Health and Caring Sciences, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2937.
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Heart failure and left ventricular dysfunction are major causes of morbidity and mortality. In this thesis, metabolic, hormonal, genetic and prognostic aspects of echocardiographically determined left ventricular function were investigated in a fairly large longitudinal population-based study of men. The participants were examined both at age 50 and 70 years and were followed for mortality using the national cause-of-death registry.
Several factors associated with the insulin resistance syndrome predicted left ventricular systolic dysfunction independent of myocardial infarction, hypertension, diabetes and the use of cardiovascular medication after twenty years follow-up. Plasma levels of N-terminal atrial natriuretic peptide (N-ANP) were significantly increased in men with left ventricular dysfunction in comparison to healthy men. However, the diagnostic accuracy was poor due to the extensive overlapping between the groups. Relations between a haplotype of the novel hUNC-93B1 gene and the E/A-ratio were found and validated in separate samples of the cohort. Myocardial performance index (a Doppler derived index of combined left ventricular systolic and diastolic function) and left ventricular ejection fraction were found to be predictors for cardiovascular mortality independent of traditional cardiovascular risk factors in a longitudinal analysis with a mean follow-up of seven years.
In conclusion, this thesis showed that left ventricular function is influenced by metabolic, hormonal and genetic factors and that echocardiographic measurements of left ventricular function, such as the myocardial performance index, are strong independent risk factors for cardiovascular mortality in elderly men.
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Gross, Jeffrey David. "Non-invasive Monitoring of Oxygen Concentrations and Metabolic Function in Pancreatic Substitutes." Diss., Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/14499.
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Design and characterization of tissue engineered substitutes rely on robust monitoring techniques that provide information regarding viability and function when exposed to various environmental conditions. In vitro studies permit the direct monitoring of cellular and construct changes because these substitutes remain accessible. However, upon in vivo implantation, changes in cell viability and function are often detected using indirect or invasive methods that make assessing temporal changes challenging. . Thus, the development of non-invasive monitoring modalities may facilitate improved tissue substitute design and, ultimately, clinical outcome.
The overall objective of this thesis was to establish a method to monitor and track cells and the cellular environment within a tissue engineered substitute in vitro and in vivo. This was accomplished via 31P NMR spectroscopy and through the incorporation of perfluorocarbon (PFC) emulsions for the monitoring of DO concentration by 19F NMR spectroscopy. The first aim of this thesis was to develop a method that tracked the state of cells and of the cellular environment within alginate constructs during perfusion studies in which the perfusing medium DO concentrations were changed over time or cells were exposed to a cytotoxic antibiotic. Due to challenges in acquiring DO concentration gradient information within beads, a second aim was to develop a mathematical model that would calculate gradients from experimentally acquired volume averaged DO concentrations; thus, significantly enhancing the robustness of tracking the alginate beads. Lastly, since the PFC emulsions used in the study may affect cell viability and function, a third aim was to characterize, experimentally and via modeling, the effect of several PFC emulsion concentrations on the encapsulated and #946;TC-tet cells.
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Pourhamidi, Kaveh. "Peripheral nerve function : metabolic features, clinical assessment, and heat shock protein 27." Doctoral thesis, Umeå universitet, Allmänmedicin, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-79469.
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Peripheral neuropathy is a common complication among patients with diabetes mellitus, but whether peripheral neuropathy is present in individuals with impaired glucose tolerance (IGT) is debatable. In order to identify and diagnose peripheral neuropathy correctly, it is important to evaluate diagnostic tools that can be implemented in routine health care to assess both large and small nerve fibre function. There is currently limited knowledge about neuroprotective factors that could be useful for measuring peripheral nerve function in individuals at risk of developing neuropathy such as those with diabetes mellitus. Thus, studies are needed to investigate potential neuroprotective factors in relation to peripheral nerve function in humans. Objectives: The overall goal of this thesis was to study the metabolic features and clinical assessment of peripheral nerve function and the potential relationship between the neuroprotective factor heat shock protein 27 (HSP27) and peripheral nerve function. Methods: Thirty-nine participants with normal glucose tolerance (NGT) and 29 participants with IGT were recruited from the population-based Västerbotten Intervention Programme in 2003–2004. Patients with type 2 diabetes mellitus (T2DM, n = 51) were recruited from primary health care centres. NGT and IGT individuals underwent two separate oral glucose tolerance tests to verify their glucose status. The peripheral nerve function in the lower limb was assessed by nerve conduction studies, neuropathy disability scoring, quantitative sensory tests, and skin biopsies with subsequent quantification of intraepidermal nerve fibre density (IENFD). The concentrations of HSP27 in serum were determined in the NGT, IGT, and T2DM individuals. Patients with type 1 diabetes mellitus (T1DM) were recruited from the Diabetes Clinic, Skåne University Hospital in Malmö, Sweden (n = 27) in 1992 and were followed-up in 2005. Baseline and follow-up concentrations of HSP27 were determined in T1DM patients as well as in healthy non-diabetic controls (n = 397). The T1DM patients underwent nerve conduction studies and thermal and vibration perception threshold tests at baseline and at follow-up. Delta changes in HSP27 concentrations and small and large nerve fibre function were calculated. Results: There was no difference between IGT and NGT in sural nerve conduction, intraepidermal nerve fibre density, or thermal thresholds. The biothesiometer had a sensitivity of 82% and a specificity of 72% in identifying peripheral neuropathy with a cut-off value of ≥24.5 V at the medial malleolus. Adding the quantification of IENFD to the combination of the tuning fork and biothesiometer increased the diagnostic sensitivity from 81% to 95%, the negative predictive value from 87% to 94%, and the positive likelihood ratio from 1.8 to 1.9 when identifying small nerve fibre dysfunction. T2DM patients had lower HSP27 concentrations (mean HSP27 = 412 pg/mL, 95% CI 284–598 pg/mL) than NGT (mean HSP27 = 722 pg/mL, 95% CI 564–922 pg/mL) and IGT (mean HSP27 = 1010 pg/mL, 95% CI 638–1300 pg/mL) individuals (p <0.05 for both comparisons). T1DM patients had lower HSP27 concentrations at baseline (mean HSP27 = 547 pg/mL, 95% CI 421–711 pg/mL) and at follow-up (mean HSP27 = 538 pg/mL, 95% CI 417–693 pg/mL) compared to healthy controls (mean HSP27 = 785 pg/mL, 95% CI 732–842 pg/mL), p <0.05 for both comparisons). High concentrations of HSP27 were associated with better large nerve fibre function (Odds ratio = 2.51, 95% CI 1.25–5.05, p <0.05). Deteriorating large nerve fibre function correlated with decreasing HSP27 concentrations over time in T1DM patients (r = 0.50, p = 0.01). Conclusions: Measures of large and small nerve fibre function in IGT individuals do not differ significantly from NGT individuals. The existence of peripheral neuropathy as a consequence of IGT is not likely, and extensive control of neuropathy in IGT individuals is not advocated by this thesis. The biothesiometer is a useful clinical tool to identify peripheral neuropathy in routine health care. Quantification of IENFD using skin biopsies in combination with methods measuring vibrotactile sense, such as the biothesiometer and the tuning fork, increase the diagnostic usefulness of identifying small nerve fibre dysfunction. High HSP27 concentrations are associated with better peripheral large nerve fibre function. Patients with diabetes mellitus have lower HSP27 concentrations than healthy non-diabetic controls, and deterioration of large nerve fibre function correlates with a decrease in HSP27 concentrations over time in T1DM. This could be indicative of insufficient neuroprotection in patients with diabetes mellitus.
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Loganathan, Arunan. "Relationship between Human Instestinal Permeability and Potassium Channel Function during Metabolic Stress." Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.507636.
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Wehrens, Sophie Michelle Tisia. "Effect of sleep deprivation and shift work on metabolic and cardiovascular function." Thesis, University of Surrey, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531388.
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McClean, Conor Michael. "Exercise and metabolic disturbances : effects on oxidative stress generation and vascular function." Thesis, University of Ulster, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486610.
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Vascular dysfunction is a pivotal step in the aetiology of cardiovascular disease, the leading cause of global mortality. Certain metabolic disturbances (postprandial hypertriglyceridemia - PHTG, and impaired glucose tolerance - IGT) have been identified as risk factors for vascular dysfunction, via an oxidative stress mechanism. Exercise has long been regarded as beneficial in tackling CVD but its role on oxidative stress and su~sequent vascular function is less well defined. The principal . . aim of this thesis is to examine the effects of exercise intervention on oxidative stress generation and vascular function in conditions of metabolic disturbance. The findings of Study 1 demonstrate that an acute bout of moderate intensity aerobic exercise did not change arterial function (as measured by pulse wave velocity - PWV) when compared to rest alone. However, a 1 hour bout of moderate exercise did increase the levels of the antioxidants lycopene and retinol suggesting a decrease in oxidative stress. Studies 2 and 3 illustrates that acute moderate intensity exercise can ameliorate the. postprandial vascular dysfunction induced by the ingestion of a highfat meal via a reduction in oxidative stress (LOOH) and an increase in antioxidant activity (Study 2; SOD, Study 3; retinol and lycopene). Study 3 demonstrated that an acute bout ofpre meal exercise had no effect on measures ofgastrointestinal transit. Study 4 illustrates that acute aerobic exercise can improve arterial function in obese individuals with IGT, a group who are known to be more susceptible to vascular disease. These changes were directly correlated with reductions in glucose concentrations but were not associated with changes in lipid metabolism and oxidative stress biomarkers. An exercise training regime (Study 5) was shown to improve arterial function in the same group of obese subjects with IGT. This was in combination to reductions in body mass, glucose and TG concentrations, and oxidative stress. The improvements in arterial function are perhaps due to the effects of exercise on glucose and lipid metabolism and the subsequent effect on free radical generation. The results of the studies described within this thesis provide evidence for acute and chronic exercise as key interventions to modulate the vascular dysfunction associated with PHTG and IGT. However, further research is required to define the precise biochemical mechanisms that perpetuate such adaptations.
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Thakor, Avnesh Sinh. "Nitric oxide and antioxidant modulation of fetal cardiovascular, metabolic and endocrine function." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613851.
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Stewart, Frances Maria. "The impact of maternal obesity on vascular and metabolic function throughout pregnancy." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/426/.
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Maternal obesity increases the risk of numerous maternal and fetal complications of pregnancy. Women were recruited at booking for antenatal care. Each subject was examined in the first, Second and third trimester of pregnancy as well as twelve weeks post partum. Using non invasive techniques microvasular function was measured at each visit. Fasting bloods were taken. This assessment allowed us to observe microvascular function, inflammatory response, dislipidaemia and changes in fatty acid composition with advancing gestation and the degree of recovery in the post partum. By recruitment of women with varying body mass index (BMI) values we were able to examine the influence of maternal BMI on these responses to pregnancy.
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Vaughan, Jeremiah A. "Neuromuscular Function and Fatigue and Metabolic Responses while Cycling in the Heat." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1542212848069694.
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Zheng, Lianqing. "Statistical identification of metabolic reactions catalyzed by gene products of unknown function." Diss., Kansas State University, 2013. http://hdl.handle.net/2097/15594.
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Doctor of PhilosophyDepartment of Statistics
Gary L. Gadbury
High-throughput metabolite analysis is an approach used by biologists seeking to identify the functions of genes. A mutation in a gene encoding an enzyme is expected to alter the level of the metabolites which serve as the enzyme’s reactant(s) (also known as substrate) and product(s). To find the function of a mutated gene, metabolite data from a wild-type organism and a mutant are compared and candidate reactants and products are identified. The screening principle is that the concentration of reactants will be higher and the concentration of products will be lower in the mutant than in wild type. This is because the mutation reduces the reaction between the reactant and the product in the mutant organism. Based upon this principle, we suggest a method to screen the possible lipid reactant and product pairs related to a mutation affecting an unknown reaction. Some numerical facts are given for the treatment means for the lipid pairs in each treatment group, and relations between the means are found for the paired lipids. A set of statistics from the relations between the means of the lipid pairs is derived. Reactant and product lipid pairs associated with specific mutations are used to assess the results. We have explored four methods using the test statistics to obtain a list of potential reactant-product pairs affected by the mutation. The first method uses the parametric bootstrap to obtain an empirical null distribution of the test statistic and a technique to identify a family of distributions and corresponding parameter estimates for modeling the null distribution. The second method uses a mixture of normal distributions to model the empirical bootstrap null. The third method uses a normal mixture model with multiple components to model the entire distribution of test statistics from all pairs of lipids. The argument is made that, for some cases, one of the model components is that for lipid pairs affected by the mutation while the other components model the null distribution. The fourth method uses a two-way ANOVA model with an interaction term to find the relations between the mean concentrations and the role of a lipid as a reactant or product in a specific lipid pair. The goal of all methods is to identify a list of findings by false discovery techniques. Finally a simulation technique is proposed to evaluate properties of statistical methods for identifying candidate reactant-product pairs.
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Rathore, Moeez Ghani. "Metabolic pathways and their function in leukemogenesis : the role of MAPK ERK5." Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON1T022/document.
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Les cellules cancéreuses utilisent une glycolyse anaérobie pour générer l'ATP au lieu de la phosphorylation oxydative. Cette spécificité métabolique offre certains avantages aux cellules cancéreuses: une prolifération rapide et une évasion immune qui implique la sous-régulation de l'expression du CMH-I à la surface des cellules, phénomène lié au changement métabolique. Dans nos expériences, nous forçons les cellules leucémiques à produire de l'énergie par phosphorylation oxydative en les incubant avec de la glutamine comme source d'énergie en absence de glucose. La respiration ainsi forcée induit une augmentation de la transcription et de l'expression du CMH-I. Ce changement de métabolisme induit aussi une augmentation de l'expression de MAPK ERK5 et son accumulation dans les mitochondries. ERK5 intervient dans les changements de l'expression du CMH-I et du métabolisme. La sur-régulation du CMH-I induite par la respiration est bloquée dans les cellules leucémiques exprimant le shRNA shERK5. ERK5 régule la transcription de l'histone désacétylase de classe III Sirtuin 1 par l'activation de sa cible MEF2, ayant pour conséquence la liaison de MEF2 au promoteur de SIRT1. La régulation transcriptionnelle de SIRT1 induite par ERK5 intervient dans la réponse antioxydante des cellules leucémiques, et la sous-régulation d'ERK5 affecte cette réponse antioxydante. L'augmentation du métabolisme de la glutamine observée dans les cellules leucémiques est initiée par la glutaminase (GLS), enzyme qui est le facteur limitant de la vitesse du métabolisme de la glutamine. miR-23a cible l'ARN messager de GLS et inhibe l'expression de GLS. Le milieu glutamine induit la translocation de p65 dans le noyau, qui mène à une augmentation de l'activité transcriptionnelle de p65. NF-KB p65 inhibe l'expression de miR-23a en amenant HDAC4 sur le promoteur de miR-23a. Cela permet aux cellules leucémiques d'augmenter l'utilisation de la glutamine en tant que source alternative de carbone. Ainsi, la respiration forcée dans les cellules leucémiques contrôle l'expression du CMH-I, la réponse antioxydante et facilite la prolifération tumoraleCancer cells have anaerobic-like glycolysis to generate ATPs instead of oxidative phosphorylation. This specific metabolism provides advantages to cancer cells: rapid growth and immune evasion, which involves downregulation of MHC-I at the cell surface and it is linked to metabolic change. In our experiments, we force leukemic cells to produce energy by oxidative phosphorylation by incubating them with glutamine as an energy source in the absence of glucose. The forced respiration increases MHC-I transcription and protein level. This change of metabolism also leads to increase MAPK ERK5 expression and accumulation in mitochondria. ERK5 mediates changes in both MHC-I and metabolism. The respiration-induced upregulation of MHC-I is blocked in leukemic cells stably expressing short hairpin ERK5 (shERK5). ERK5 transcriptionally regulates the class III histone deacetylase Sirtuin 1 through activation of its target MEF2 and subsequently MEF2 binding to SIRT1 promoter. The ERK5-induced transcriptional regulation of SIRT1 mediates the antioxidant response in leukemic cells and downregulation of ERK5 impairs the antioxidant response. The increased glutamine metabolism found in leukemic cells is initiated by glutaminase (GLS), a rate limiting enzyme for glutamine metabolism. miR-23a targets GLS mRNA and inhibits GLS expression. The glutamine medium induces p65 translocation to the nucleus that leads to increase p65 transcriptional activity. NF-KB p65 inhibits miR-23a expression by bringing HDAC4 to the miR-23a promoter. This allows leukemic cells to increase the use of glutamine as an alternative source of carbon. Thus, forcing respiration in leukemic cells controls MHC-I expression, antioxidant response and facilitate tumor growth
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Gibbins, Matthew Thomas George. "Metabolic and vascular effects of thiosulfate sulfurtransferase deletion." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31558.
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Hydrogen sulfide (H2S), is a gasotransmitter with several key roles in metabolism and vascular function. The effects of H2S are dependent on concentration and target organ. For example, increased H2S concentrations impair liver metabolic function but protect against vascular dysfunction and atherosclerosis. Thiosulfate sulfurtransferase (TST), a nuclear encoded mitochondrial matrix enzyme, is proposed to be a component of the sulfide oxidising unit (SOU) which metabolises H2S. Preliminary data has shown that Tst deletion in mice (Tst-/-) increases circulating H2S levels measured in whole blood. Therefore, it was hypothesised that Tst-/- mice would exhibit worsened metabolic function in the liver but also protection of vascular function under conditions of vascular stress e.g. atherosclerosis. Liver metabolism was assessed by extensive metabolic phenotyping of Tst-/-mice fed control diet and in conditions of metabolic dysfunction induced by a high fat diet (HFD). Tst deletion altered glucose metabolism in mice; gluconeogenesis was increased in liver from Tst-/-mice fed control diet. Glucose intolerance in HFD-fed Tst-/-mice was also more severe than HFDfed C57BL/6 controls. In vitro metabolic investigations in primary hepatocytes isolated from Tst-/-mice demonstrated that mitochondrial ATP-linked and leak respiration were increased compared to controls. The effect of Tst deletion on vascular function was investigated in Tst- /-mice fed control or HFD using myography. Tst deletion did not alter vessel function when mice were maintained on a normal diet. HFD feeding (20 weeks) reduced maximal vessel constriction in the presence of endothelial nitric oxide synthase and cyclooxygenase inhibitors in C57BL/6 aorta. However, in Tst-/-mice fed HFD there was no reduction in maximal constriction suggesting a protective action of Tst deletion. The effects of Tst deletion on atherosclerotic lesions was investigated by generating double knock-out (DKO) mice by deletion of the Tst gene in ApoE-/- mice and (ApoE-/-Tst-/-). Atherosclerotic lesion formation was accelerated by feeding mice a western diet. Within the brachiocephalic branch lesion volume and total vessel volume were reduced in DKO mice fed western diet for 12 weeks, indicating that Tst deletion reduced lesion formation. Plasma cholesterol was reduced in DKO mice compared to ApoE-/- controls and a trend towards reduced systolic blood pressure was also noted. Overall this work supported the hypothesis that Tst deletion engenders metabolic dysfunction but vascular protection. The findings are consistent with the reported effects of increased H2S signalling. Overall inhibition of TST represents a novel target for treatment of atherosclerosis, with the caveat that glycaemia may be worsened due to hepatic metabolic dysfunction.
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van, Harmelen Vanessa. "Metabolic and endocrine function of human adipose tissue with focus on regional differences /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4637-x/.
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Hudson, Emily. "The assessment of mitochondrial function and metabolic activity in pancreatic progenitor derived hepatocytes." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3736.
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Hepatocytes are the primary cell type of the liver, they play a key role in drug toxicity and therefore represent an ideal model for preclinical toxicity testing. However, current primary hepatocyte models resist in vitro proliferation and immortalised models are often not fully metabolically competent. One solution is the rodent B-13 cell line which forms hepatocyte-like B-13/H cells in response to glucocorticoid treatment. This thesis aimed to investigate the metabolic activity of B-13/H cells and assess the role of mitochondrial dysfunction in cytotoxicity. Cells were challenged with the anti-diabetic drug, troglitazone, which was withdrawn from the market following reports of liver injury, mitochondrial liabilities have since been associated with its toxicity. Extracellular flux analysis showed that basal levels of respiration were comparable between B-13 and B-13/H cells, however, reserve capacity was 5-fold greater in the B-13/H cells. In response to troglitazone, there was a concentration dependent decrease in oxygen consumption rate in B-13/H cells compared to a stimulation of respiration in B-13 cells and a concomitant increase in lactate levels and oxygen demand for ATP production. After 24 hours troglitazone treatment, there was a concentration dependent decrease in B-13/H viability. B-13 cell viability was unaffected. A larger baseline reserve capacity suggested a greater mitochondrial mass in B-13/H cells concomitant with a greater role in metabolism, similarly, B-13/H cells were more susceptible to troglitazone than B-13 cells. A drop in oxygen consumption rate suggested that there was mitochondrial dysfunction; this was supported by a drop in total ATP levels. In B-13 cells, troglitazone had a stimulatory effect on respiration and a concentration dependent increase in lactate suggested a switch from oxidative phosphorylation to glycolysis. The data presented indicate that B-13/H cells could potentially form the basis of a toxicity screening platform. This work could also underpin the development of a human equivalent model.
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Stomberski, Colin Thomas. "Molecular Mechanism and Metabolic Function of the S-nitroso-coenzyme A Reductase AKR1A1." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1554372852266484.
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Vasunta, R. L. (Riitta-Liisa). "Ambulatory blood pressure:association with metabolic risk indicators, renal function and carotid artery atherosclerosis." Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789514299605.
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Abstract Blood pressure is usually measured on a clinic visit as a momentary value. It can also be defined as a continuum based on several repeated measurements. Ambulatory blood pressure measurement (ABPM) is a method of repeated BP measurements targeted to evaluate the circadian blood pressure (BP). Nondipping, i.e., the lack of reduction of BP during the night, has been shown to associate with cardiovascular endpoints. The aim of this study was to investigate the association between 24-hour ABPM and cardio-metabolic confounders in a cross-sectional, population-based study design. Particular attention was paid to the nondipping phenomenon. Adiponectin, a hormone secreted by the adipose tissue, has vasoprotective and anti-inflammatory effects. Reduced adiponectin level has been associated with hypertension. In this study adiponectin level was inversely associated with daytime systolic BP, but showed no association with nondipping. Hypertension is one component of metabolic syndrome (MS). MS has been associated with nondipping. The association between ABPM and metabolic abnormalities was studied in subjects without known hypertension or type 2 diabetes. Subjects with impaired glucose metabolism were more likely to belong to the group of nondippers. Fatty liver is considered as the hepatic manifestation of MS. A significantly higher prevalence of fatty liver has been seen in hypertensives compared to normotensive controls, elevating their risk for cardiovascular morbidity. The association between ABPM characteristics and fatty liver was evaluated in the present study. Significantly higher systolic ABPM levels were seen in subjects with fatty liver, but no association with nondipping existed. The kidney vasculature is prone to injury under a high continuous circadian BP load and lacking nighttime drop. This may lead to diminished glomerular filtration rate. Our study showed a significant independent association between renal function and the dipping status. Reduction in renal function was associated with increased risk of nondipping pattern. Carotid intima-media thickness (cIMT), the surrogate marker of early atherosclerosis, has been associated with blunted nocturnal BP drop. The association between cIMT and dipping status was explored. Nondipping pattern was associated with increased cIMT. In conclusion, ABPM specifies the information of circadian and nighttime BP level not achievable with conventional BP measurement. This is especially beneficial in metabolic abnormalities when the risk of cardiovascular morbidity is increasedTiivistelmä Väitöstutkimuksessa osoitettiin, että vuorokausiverenpaineen mittauksella eli ambulatorisella verenpaineenmittauksella on erityistä merkitystä sydän- ja verenpainesairastavuutta lisäävien metabolisten häiriöiden yhteydessä. Työssä haluttiin selvittää 24 tunnin aikana mitatun verenpainetason ja puuttuvan yöaikaisen verenpaineenlaskun eli nondipping-ilmiön yhteyttä tunnettuihin metabolisiin riskitekijöihin ja kaulavaltimoseinämän paksuuntumaan. Kyseessä on suomalaiseen, keski-ikäiseen väestöotokseen kohdistunut poikkileikkaustutkimus. Tavallisesti yöaikainen verenpainetaso laskee 10 % tai enemmän päiväaikaiseen verenpainetasoon nähden (dipping). Verenpaineen lasku voi kuitenkin jäädä puutteelliseksi (nondipping). Nondipping-ilmiön on todettu lisäävän sydän- ja verisuonisairastuvuuden riskiä. Kaulavaltimoseinämän paksuuntumaa on pidetty merkkinä varhaisesta valtimosairaudesta ja maksan rasvakertymä katsottu osaksi metabolista oireyhtymää. Metabolisiin häiriöihin sekä munuaistoiminnan häiriöihin liittyy lisääntynyt valtimosairauden riski. Väitöstutkimuksessa vuorokausiverenpaine mitattiin mukana kannettavalla automaattisella verenpaineenmittausmenetelmällä eli ambulatorisella verenpaineenmittauksella. Lisäksi verenpaine mitattiin tavalliseen tapaan vastaanottokäynnin yhteydessä. Maksan rasvaisuutta ja kaulavaltimon seinämäpaksuutta tutkittiin ultraäänilaitteella. Tavanomaisten taustamuuttujien lisäksi kerättiin laboratoriotietoa sokeriaineenvaihdunnasta, munuaissuodoksen määrästä sekä rasvakudoksen erittämän adiponektiinihormonin määrästä. Nondipping-ilmiön todettiin olevan itsenäisesti yhteydessä sokeriaineenvaihdunnan häiriöön, munuaissuodoksen alenemaan ja kaulavaltimon seinämäpaksuuntumaan. Kohonnut päiväaikainen systolinen verenpainetaso oli yhteydessä verisuoniston kannalta epäedulliseen adiponektiinihormonitasoon. Sekä systolinen että diastolinen verenpainetaso oli korkeampi henkilöillä, joilla todettiin maksan rasvoittuma kuin niillä, joilla ei ollut maksan rasvoittumaa. Tutkimus osoitti ambulatorisen verenpaineenmittauksen tuovan merkittävää lisätietoa etenkin sydän- ja verisuonisairastuvuuden riskiä jo sinällään lisäävissä tiloissa, kuten metabolisissa häiriöissä ja munuaistoiminnan alentumassa. Koska metaboliset häiriöt lisääntyvät jatkuvasti, on todennäköistä, että vuorokausiverenpaineen mittaus yleistyy osana valtimosairastavuuden kokonaisriskin arviointia
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Lim, Sean. "The Relationship Between Metabolic Circumstance and Epigenetic Acetylation in Myoblast Fate and Function." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/42659.
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Muscle tissue is grown and maintained by muscle stem cells termed satellite cells. Activated satellite cells become myoblasts, which must proliferate then differentiate into functional muscle. This process, known as myogenesis, is controlled by a cascade of epigenetic regulatory events. One facet of this regulation is histone acetylation, which can be influenced by the availability of metabolites within a cell. In this study, the ability of glucose, pyruvate, or glutamine to change histone acetylation levels in cultured myoblasts was investigated. Changing concentrations of glucose or pyruvate had no effect but decreasing the availability of glutamine in cell culture from 2mM to 0.2mM resulted in proliferating myoblasts accruing a hyperacetylated histone phenotype. However, when the same concentration of glutamine was used on differentiating myoblasts the hyperacetylated phenotype was lost and no change to differentiation was observed. This study demonstrates the potentials and limitations of altering epigenetic acetylation with metabolic circumstance. -- Le développement du tissu musculaire est soutenu par les cellules souches musculaires, communément appelées cellules satellites. Les cellules satellites activées se transforment en myoblastes qui doivent ensuite proliférer et se différencier en muscle fonctionnel. Ce processus, connu comme myogenèse, est contrôlé par une cascade de régulation épigénétique. Un aspect de ce processus est l’acétylation d’histones, qui peut être influencée par la disponibilité de métabolites dans la cellule. Dans cette étude de cas, la capacité du glucose, pyruvate, ou glutamine à changer les niveaux d’acétylation d’histones a été examinée. Le changement des concentrations de glucose ou de pyruvate n’a généré aucun effet, mais la diminution de la disponibilité de la glutamine dans la culture cellulaire de 2mM à 0.2mM a eu pour résultat une prolifération de myoblastes présentant un phénotype d’histones hyper-acétylées. Pourtant, quand la même concentration de glutamine a été utilisée pour différencier les myoblastes, le phénotype hyper-acétylé n’a pas été observé et aucun changement de différenciation n’a pu être détecté. Cette étude démontre le potentiel et les limites des modifications de l’acétylation épigénétique selon les circonstances métaboliques.
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Johnson, Andrew William. "Metabolic control of energetics in human heart and skeletal muscle." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:82c0dce6-a162-4c08-b061-3ea7f2e35134.
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Myocardial and skeletal muscle high energy phosphate metabolism is abnormal in heart failure, but the pathophysiology is not understood. Plasma non-esterified fatty acids (NEFA) increase in heart failure due to increased sympathetic drive, and regulate the transcription of mitochondrial uncoupling protein-3 (UCP3), through peroxisome proliferator-activated receptor-α. The aim of the work in this thesis was to determine whether cardiac PCr/ATP ratios and skeletal muscle PCr kinetics during exercise were related to cardiac and skeletal muscle UCP3 levels respectively, thus providing a mechanism for the apparent mitochondrial dysfunction observed in heart failure. Patients having cardiac surgery underwent pre-operative testing, including cardiac and gastrocnemius 31P magnetic resonance spectroscopy. Intra-operatively, ventricular, atrial and skeletal muscle biopsies were taken for measurement of mitochondrial protein levels by immunoblotting, along with mitochondrial function by tissue respiration rates. Fasting plasma NEFA concentrations increased in patients with ventricular dysfunction and with New York Heart Association (NYHA) class. Ventricular UCP3 levels increased and cardiac PCr/ATP decreased with NYHA class, however, demonstrated no relationship to each other. In skeletal muscle, maximal rates of oxidative ATP synthesis (Qmax) related to functional capacity. Skeletal muscle UCP3 levels increased with NYHA class but were unrelated to skeletal muscle Qmax. Tissue respiration experiments revealed no relationship between ventricular function and indices of mitochondrial coupling, furthermore, indices of mitochondrial coupling were unrelated to tissue UCP3 levels. No evidence was found to support mitochondrial uncoupling, mediated through UCP3, as a cause of the abnormalities in cardiac and skeletal muscle high energy phosphate metabolism.
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Lyons, Jeremy D. M. "Effects of anaesthesia and nutrition on immunology and hepatic function in adults and children." Thesis, Queen's University Belfast, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326386.
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Heck, Patrick. "The effects of metabolic manipulation on myocardial function in humans with coronary artery disease." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510433.
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Ali, Seemaab. "Environmental enrichment mitigates hypothalamic inflammation and improves metabolic function across the lifespan of mice." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587632494811204.
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Goh, Kah Lay. "Skin microvascular function in type 2 diabetes and related aspects of the metabolic syndrome." Thesis, University of Leicester, 2001. http://hdl.handle.net/2381/29384.
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Microangiopathy is a major cause of morbidity and mortality in type 2 diabetes. This thesis investigates the factors that may influence the microcirculation in type 2 diabetes and related aspects of the metabolic syndrome, using techniques that interrogate the skin microvascular function. The first study explores the concept of intrinsic microvascular dysfunction. Low birth weight has been linked with the increased risk of developing type 2 diabetes and cardiovascular disease in adult life. Impaired maximum hyperaemic response to local heating was demonstrated in the lowest-quartile birth weight infants compared to the highest-quartile birth weight group. Skin endothelium-dependent vasodilatory function and capillary density were not different between the two groups. In a separate study involving prepubertal and postpubertal subjects, both skin maximum hyperaemic response and postural vasoconstriction response were not related to birth weight. It is possible that extrinsic factors or perhaps the rapid phase of growth and sexual maturation during childhood may have modified the relationship between birth weight and microvascular function. There has been much interest in the role of postprandial dyslipidaemia in macrovascular disease but its effect on the microcirculation is not known. In a group of healthy volunteers, skin microvascular response was not significantly attenuated after a high-fat meal. However, the change in vasodilatory response correlated strongly with the postprandial rise in triglycerides. In a corresponding study in type 2 diabetic subjects, skin microvascular function was significantly reduced after a high-fat meal. Thus it would appear that both intrinsic and extrinsic influences are important factors in determining skin microvascular function and the interplay between the elements that are present at birth and subsequent exposures is one of the essential challenges for future research.
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Henriques, Bárbara J. "Defective protein folding and function in metabolic disorders: studies on the mitochondrial flavoenzyme ETF." Doctoral thesis, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, 2010. http://hdl.handle.net/10362/5150.
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Dissertation presented to obtain the PhD degree in Biochemistry at the Instituto de Tecnologia Química e Biológica, Universidade Nova de LisboaThe work presented in this dissertation concerns the study of the electron transfer flavoprotein (ETF), a protein involved in mitochondrial β-oxidation whose deficiency is associated to multiple acyl-CoA dehydrogenase deficiency (MADD). The thesis will focus on establishing the functional, cellular and molecular consequences of the genetic variability in ETF, and in particular it aims to clarify the basis for the effect of heat stress on disease progression. Moreover, the beneficial effects of vitamin B2 supplementation will be addressed.(...)
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Gautam, Jyotshana. "Genome-Scale Metabolic Network Reconstruction of Thermotoga sp.Strain RQ7." Bowling Green State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1605228158638208.
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Göngrich, Christina. "Metabolic alterations in connexin36 knock-out mice induce gender-specific changes in dentate gyrus function." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:16-opus-87371.
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Gomez-Smith, Mariana. "The Cafeteria Diet Model of Metabolic Syndrome and Its Effects on Cerebrovascular Form and Function." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/36449.
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The global occurrence of metabolic syndrome has reached epidemic proportions and is a contributing factor in the rising incidence of cognitive decline in the aging population. While pre-clinical research has advanced our understanding of many of the mechanisms underlying metabolic syndrome, animal models often do not reflect the complexity of human disease. For example, animal models that investigate the role played by diet in metabolic syndrome have generally focused on a single macronutrient, in particular fat or carbohydrate. As a result, although a balanced diet and increased physical activity are commonly recommended to treat metabolic syndrome symptomatology, their long-term cerebrovascular benefits are uncertain. To address these gaps in knowledge, a “Cafeteria” diet consisting of 16 common ultra-processed grocery store food items was used to model human metabolic syndrome in the rat. I compared rats fed a Cafeteria diet (CAF) to those fed “standard” chow (SD) as well as to a third group that underwent a switch to chow after chronic exposure to the Cafeteria diet (SWT). In a first study, I showed that three months of exposure to the Cafeteria diet produced metabolic syndrome as well as hippocampal neuroinflammation with increased microglial proliferation. These were fully reversed in SWT rats. Nonetheless, the Cafeteria diet did not worsen spatial learning and memory performance as assessed using the Barnes maze. In a second study, brain perfusion was examined using continuous arterial spin labeling magnetic resonance imaging (CASL MRI). Cortical and hippocampal resting perfusion was increased in CAF rats while cerebrovascular reactivity in response to a 10% CO2 vasodilatory challenge was reduced. Furthermore, while resting perfusion improved in SWT rats, cerebrovascular reactivity remained impaired. These cerebral blood flow outcomes were not accompanied by alterations in microvascular architecture or integrity as determined by rat endothelial cell antigen-1 (RECA-1) and immunoglobulin G (IgG) histology. Taken together, these results demonstrate that the Cafeteria diet is an effective model of metabolic syndrome that negatively impacts brain hemodynamic function. Moreover, while a dietary lifestyle intervention can recover peripheral features of metabolic syndrome, neuroinflammation, and resting perfusion, it is insufficient to completely reverse deficits in cerebrovascular reactivity. These findings are compelling as they speak to the detrimental effects of ultra-processed food consumption on cerebrovascular reserve capacity, believed to be an important factor in cognitive decline.
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Rodwan, Naima Salem. "Light-Limited Access to Fructose Alters Metabolic Function and Adipose Tissue Catecholaminergic Activity in Mice." Wright State University / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=wright1339615527.
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Estrada, Christina M. "The Impact of Obesity and Estrogen on the Brain and Metabolic Function in Female Rats." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535378499166638.
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Politano, Carlos Alberto 1952. "Síndrome metabólica e função sexual em mulheres climatéricas = Metabolic syndrome and sexual function in climacteric women." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312827.
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Orientadores: Lucia Helena Simões da Costa Paiva, Ana Lucia Ribeiro ValadaresDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Introdução: A Síndrome Metabólica é uma condição bastante frequente na população e em especial em mulheres climatéricas. Alguns estudos associam a SM com baixa função sexual, porém com resultados ainda controversos. Objetivo: Avaliar se existe associação entre síndrome metabólica e função sexual e os fatores associados à baixa função sexual em mulheres climatéricas. Sujeitos e métodos: Realizou-se uma análise secundária de um estudo maior de corte transversal sendo que o grupo controle constituiu a presente amostra onde foram incluídas 256 mulheres climatéricas com idade variando entre 40 a 60 anos, acompanhadas nos Ambulatórios de Planejamento Familiar e Menopausa da Faculdade de Ciências Médicas da UNICAMP. As mulheres responderam a um questionário realizado em ambiente confidencial, contendo dados sócio-demográficos, comportamentais e a avaliação da função sexual através do Short Personal Experience Questionnaire (SPEQ) que avalia 9 domínios da função sexual considerando-se baixa função sexual um escore ?7. Foram feitas mensurações antropométricas, de pressão arterial e dosagens séricas de glicemia em jejum, colesterol HDL, triglicérides, FSH e TSH. Resultados: A prevalência de Síndrome Metabólica, considerando-se o critério adotado pelo International Diabetes Federation (IDF)-2005, foi de 62,1% e de baixa função sexual de 31,4%. O único fator relativo à função sexual feminina que se associou à síndrome metabólica foi a disfunção sexual do parceiro. Os fatores associados à baixa função sexual foram idade > 50 anos (p=0,003), não ter companheiro (p<0,001), estar na pós menopausa (p=0,046), presença de fogachos (p=0,02), pior auto-percepção de saúde (p=0,04), idade do parceiro ? a 50 anos e tempo que vive com parceiro ? 21 anos. O relato de relação oral ativa (p=0,02) e oral passiva (p=0,01) foram associados a ausência de disfunção sexual. Na analise de regressão múltipla o único fator que se associou a baixa função sexual foi ter cinquenta anos ou mais. Conclusões: A prevalência de Síndrome Metabólica foi alta e não se associou com a baixa função sexual em mulheres climatéricas. O único fator associado a baixa função sexual foi a idade acima de 50 anos
Abstract: Introduction: Metabolic syndrome is a fairly common condition in the population and especially in perimenopausal women. Some studies associate SM with low sexual function, but with still controversial results. Objective: To evaluate whether there is an association between metabolic syndrome and sexual function and the factors associated with low sexual function in menopausal women. Subjects and methods: We performed a secondary analysis of a larger cross-sectional study and the control group comprised the sample where this 256 menopausal women were included age between 40 to 60 years, accompanied in Ambulatory Family Planning and Menopause Faculty of Medical Sciences, UNICAMP. The women answered a questionnaire conducted in a confidential environment, including socio-demographic, behavioral data and the evaluation of sexual function using the Short Personal Experience Questionnaire (SPEQ) that assesses nine domains of function sexual considerando low sexual function is a score ? 7. Anthropometric measurements, blood pressure, serum fasting glucose, HDL cholesterol, triglycerides, FSH and TSH were made. Results: The prevalence of metabolic syndrome, considering the criterion adopted by the International Diabetes Federation (IDF) -2005, was 62.1% and low sexual function of 31.4%. The only on female sexual function factor associated with metabolic syndrome was sexual dysfunction partner. Factors associated with low sexual function factors were age> 50 years (p = 0.003), not having a partner (p <0.001), being postmenopausal (p = 0.046), presence of hot flushes (p = 0.02), worse self- perception of health (p = 0.04), age of partner ? 50 years and while living with partner ? 21 years. Active oral sex (p = 0.02) and passive oral sex (p = 0.01) were associated with absence of sexual dysfunction. In multivariate regression analysis the only factor associated with low sexual function was age >50 years. Conclusions: The prevalence of metabolic syndrome was high and was not associated with low sexual function in menopausal women. The only factor associated with low sexual function was the age of 50 years
Mestrado
Fisiopatologia Ginecológica
Mestre em Ciências da Saúde
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Cao, Lu. "A genome wide approach to stress response and chronological ageing in yeast." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/285995.
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Caloric restriction (CR) extends lifespan from yeast to mammals. In budding yeast, inhibition of the conserved TOR and/or PKA pathways has been shown to mediate lifespan extension by CR partly through the activation of stress response. However, how the stress response is regulated at the systems level is poorly understood. In this study, by using fluorescent reporters whose expression is dependent on the transcription factors Msn2/4 and Gis1, two separate screenings were conducted to reveal novel regulators of the stress response induced by starvation. A 'focused' screening on the 272 'signalling' mutants revealed that, apart from the previously identified Rim15, Yak1 and Mck1 kinases, the SNF1/AMPK complex, the cell wall integrity (CWI) pathway and a number of cell cycle regulators are necessary to elicit appropriate stress response. The chronological lifespan (CLS) of these signalling mutants correlates well with the amount of accumulated storage carbohydrates but poorly with transition-phase cell cycle status. Subsequent analyses reveal that the levels of intracellular reactive oxygen species are controlled by Rim15, Yak1 and Mck1. Furthermore, CLS extension enabled by tor1 deletion is dependent on the above three kinases. These data suggest that the signalling pathways (SNF1 and CWI) and the kinases downstream of TOR/PKA (Rim15, Yak1 and Mck1) coordinate the metabolic reprogramming (to accumulate storage carbohydrates) and the activation of anti-oxidant defence systems (to control ROS levels) to extend chronological lifespan. A 'genome-wide' screening of a haploid deletion library indicates that less than 10% of the non-essential genes are implicated in the regulation of starvation-induced stress response. Gene ontology analysis suggests that they can be grouped into major clusters including mitochondrial function, r-RNA processing, DNA damage and repair, transcription from RNA polymerase and cell cycle regulation. Further phenotypic assays confirm the previous observation that CLS extension is mostly correlated with the accumulation of storage carbohydrates. Compromised expression of stress response reporters is confirmed by FACS in a variety of mitochondrial mutants, suggesting that mitochondrial respiration also plays a key role in the activation of stress response. Put together, the above findings indicate that stress response and metabolic reprogramming induced by glucose starvation are coordinated by multiple signalling pathways and the activation of mitochondrial respiration is essential to both cellular processes and to CLS extension.
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Crosby, Kevin C. "Macromolecular Organization and Cell Function: A Multi-System Analysis." Diss., Virginia Tech, 2008. http://hdl.handle.net/10919/30259.
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The interior of the cell is a densely crowded and complex arena, full of a vast and diverse array of molecules and macromolecules. A fundamental understanding of cellular physiology will depend not only upon a reductionist analysis of the chemistry, structure, and function of individual components and subsystems, but also on a sagacious exegesis of the dynamic and emergent properties that characterize the higher-level system of living cells. Here, we present work on two aspects of the supramolecular organization of the cell: the controlled assembly of the mitotic spindle during cell division and the regulation of cellular metabolism through the formation of multienzyme complexes.
During division, the cell undergoes a profound morphological and molecular reorganization that includes the creation of the mitotic spindle, a process that must be highly controlled in order to ensure that accurate segregation of hereditary material. Chapter 2 describes results that implicate the kinase, Zeste-white3/Shaggy (Zw3/Sgg), as having a role in regulating spindle morphology.
The congregation of metabolic enzymes into macromolecular complexes is a key feature of cellular physiology. Given the apparent pervasiveness of these assemblies, it seems likely that some of the mechanisms involved in their organization and regulation might be conserved across a range of biosynthetic pathways in diverse organisms. The Winkel laboratory makes use of the flavonoid biosynthetic pathway in Arabidopsis as an experimental model for studying the architecture, dynamics, and functional roles of metabolic complexes. Over the past several years, we have accumulated substantive and compelling evidence indicating that a number of these enzymes directly interact, perhaps as part of a dynamic globular complex involving multiple points of contact between proteins. Chapter 3 describes the functional analysis of a predicted flavonol synthase gene family in Arabidopsis. The first evidence for the interaction of flavonoid enzymes in living cells, using fluorescent lifetime imaging microscopy fluorescent resonance energy transfer analysis (FLIM-FRET), is presented in Chapter 4.Ph. D.
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Petrosino, Jennifer M. "Maximizing the max test: Development of a maximal graded exercise test for the assessment of cardiovascular function in mice." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1428595054.
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Sobetzko, Patrick [Verfasser]. "Impact of global gene regulators in E. coli on cellular proteome and metabolic function / Patrick Sobetzko." Bremen : IRC-Library, Information Resource Center der Jacobs University Bremen, 2013. http://d-nb.info/1035268566/34.
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