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Argueso, Cristiana Morgado dos Guimarães Teixeira. "Identificação e purificação parcial de isoenzimas da aspartato quinase (AK) e homoserina desidrogenase (HSDH) de sementes de arroz (Oriza sativa) : evidencias para a existencia de um polipeptideo bifuncional com atividades de AK e HSDH." [s.n.], 1997. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317254.
Texte intégralRésumé :
Orientador: RIcardo Antunes de Azevedo<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia<br>Made available in DSpace on 2018-07-23T00:01:31Z (GMT). No. of bitstreams: 1
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Previous issue date: 1997<br>Mestrado<br>Genetica de Plantas<br>Mestre em Ciências Biológicas
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BERTULETTI, SUSANNA. "EXPLOITING OXIDOREDUCTASES, HYDROLASES AND TRANSAMINASES AS STEREO- AND REGIO-SELECTIVE BIOCATALYSTS IN ORGANIC SYNTHESIS." Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/886073.
Texte intégralRésumé :
The thesis concerns the use of different enzyme classes (namely, oxidoreductases, transferases, and hydrolases) as biocatalysts to achieve the chemo-, regio- and stereo-selective green synthesis of pharmaceutically relevant compounds. The main work has been done with hydroxysteroid dehydrogenases, redox enzymes that naturally work on steroids, which were studied with two main purposes: to shorten the synthesis of valuable bile acids already sold as drugs or with potential biomarker application, and to synthesize active pharmaceutical ingredients of non-steroidal nature. The work has been completed by the study on a peculiar, extremely resistant, redox enzyme, which was isolated from a metagenome in search for novel thermostable hydroxyxsteroid dehydrogenases.
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Baum, Oliver. "HSOH an elusive species with many different traits." Göttingen Cuvillier, 2008. http://d-nb.info/991202996/04.
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Pereira, Laura E. "11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2), molecular structure and regulation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0006/MQ32501.pdf.
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White, Christopher Iain. "Cardiovascular 11β-HSD1 : its role in myocardial physiology and pathophysiology". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/23391.
Texte intégralRésumé :
Glucocorticoid production by the adrenal gland is regulated by hypothalamicpituitary- adrenal (HPA) axis activity. Within cells, glucocorticoid levels are modulated by 11β-hydroxysteroid dehydrogenase (11β-HSD), which interconverts active and intrinsically inert glucocorticoids. Glucocorticoids have widespread physiological effects and, in the cardiovascular system, they play a crucial role in heart development and maturation, blood pressure control, and myocardial calcium cycling. Mice which are unable to regenerate the physiological glucocorticoid, corticosterone, from 11-dehydrocorticosterone due to deletion of the type 1 11β-HSD isozyme (11β-HSD1) have previously been shown to have smaller, lighter hearts but unaltered systolic function. Moreover, a single nucleotide polymorphism (SNP) in the Hsd11b1 gene has been associated with reduced left ventricular mass in humans, suggesting a role for 11β-HSD1 in regulating cardiac size. After myocardial infarction (MI), 11β-HSD1 deficient mice have an augmented inflammatory response, increased numbers of pro-reparative alternatively-activated macrophages in the heart, enhanced peri-infarct angiogenesis and improved cardiac function compared to C57BL/6 controls. However, the role of ‘cardiovascular’ 11β-HSD1 in the development of these phenotypes, both basally and after MI, is unknown. It was hypothesised that ‘cardiovascular’ 11β-HSD1 deficiency would result in smaller hearts, and that this selective deletion would lead to altered calcium handling protein expression and diastolic abnormalities. Furthermore, it was hypothesised that ‘cardiovascular’ 11β-HSD1 deletion would reproduce the beneficial post-MI phenotype previously seen in global 11β-HSD1 deficient mice. The first aim was to characterise the cardiac phenotype of mice with global deletion of 11β-HSD1 (DelI mice), and mice in which deletion is restricted to cardiomyocytes and vascular smooth muscle cells (SMAC mice). SMAC mice have ‘floxed’ 11β- HSD1 alleles and a Cre recombinase transgene inserted into the Sm22α gene. Sm22α is expressed in vascular smooth muscle cells, and transiently in cardiomyocytes during development. Thus, Cre expression in these cells results in deletion of exon three of the Hsd11b1 gene and gives rise to a non-functional protein. Controls for DelI mice were C57BL/6 mice, and controls for SMAC mice were their Cre- littermates. DelI, but not SMAC, mice have smaller, lighter hearts, which may be explained by their shorter cardiomyocytes measured following isolation using a Langendorff preparation. Cardiomyocyte cross-sectional area is unchanged. In vivo measurement of cardiac function using ultrasound imaging showed systolic function is comparable between DelI mice and SMAC mice and their respective controls. However, there is mild diastolic dysfunction in both DelI and SMAC mice, characterised by reduced E wave deceleration and an increased mitral valve deceleration time. This phenotype occurred following pharmacological inhibition of 11β-HSD1, by administration of UE2316, a selective 11β-HSD1 inhibitor, to adult C57BL6/SJL mice. While ventricular collagen content is unaltered in DelI, SMAC and UE2316-treated mice compared to their respective controls, expression of sarcoplasmic reticulum Ca2+ ATPase (SERCA) is reduced, suggesting that altered calcium handling, rather than changes in stiffness, may underlie this phenotype. The second aim was to determine whether the beneficial acute outcomes seen previously in 11β-HSD1 deficient mice after MI could be reproduced by selective cardiovascular deletion of the enzyme. Seven days after MI, compared to Cre- littermate controls, SMAC mice have similar peri-infarct angiogenesis, total macrophage and alternatively-activated macrophage infiltration into the heart, infarct size, ventricular dilatation and systolic function. This suggests 11β-HSD1 deletion in another cell type, or types, is responsible for the phenotype seen in global 11β-HSD1 deficient mice. The final aim was to assess the impact of global 11β-HSD1 deficiency and ‘cardiovascular’ 11β-HSD1 deletion on the development of heart failure, using magnetic resonance imaging to determine structure and function. Eight weeks after MI, mice globally deficient in 11β-HSD1 have attenuated expression of ANP and β- MHC, RNA markers of heart failure, and show attenuated pulmonary oedema, reduced chamber dilatation, preserved systolic function and smaller infarcts compared to control. None of these parameters are altered in SMAC mice relative to control. In conclusion, the data presented in this thesis shows that cardiovascular 11β-HSD1 influences physiological cardiac function, potentially through regulation of calcium handling. 11β-HSD1 in other cells influences cardiomyocyte length, resulting in smaller hearts in its absence. Despite this, global 11β-HSD1 deficiency prevents heart failure development after MI, suggesting that pharmacological inhibition of 11β-HSD1 may be of benefit in treating this condition. Cardiovascular 11β-HSD1 does not, however, account for the changes in infarct healing or remodelling associated with this beneficial outcome, therefore these effects must be related to 11β-HSD1 deficiency elsewhere, such as fibroblasts or myeloid cells.
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Leiva, Martínez Rosana. "Polycyclic group optimization in 11β-HSD1 inhibitors and their pharmacological evaluation". Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/457770.
Texte intégralRésumé :
The present PhD Thesis evolves around the design, synthesis and pharmacological evaluation of novel 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. Given that the enzyme active site includes a hydrophobic pocket to accommodate bulky lipophilic scaffolds, the main objective was focused on the study of new 11β-HSD1 inhibitors exploring different hydrophobic polycyclic substituents.
11β-HSD1 catalyzes the cortisol regeneration from its inactive form cortisone in tissues mainly expressing glucocorticoid (GC) receptors, such as liver, adipose and brain. GCs are well known hormones that play a major role in our organism. It is well accepted that the GC concentration in peripheral tissues not only depends on the adrenal secretion but also on the intracellular metabolism in these tissues, namely by 11β-HSD1. During the last years, both academia and industry have made great efforts to develop 11β-HSD1 inhibitors to target diseases such as type 2 diabetes and Alzheimer’s. The general structure of these molecules consists on a bulky lipophilic group –usually an adamantyl- linked by an amide core to a right-hand side (RHS) substituent.
The first goal was the development of a new polycyclic amine, the 2-oxaadamantan-5- amine, to add to our library of polycyclic substituents (Chapter 3). The target amine was envisioned to contain an oxygen atom in its hydrophobic skeleton to mimic the structure of some hydroxylated adamantyl derivatives in development. Its synthesis involved consecutive Criegee rearrangements on 2-methyl-2-adamantanol to deliver the 2- oxaadamantane, which was then functionalized by C-H activation using phase-transfer catalysis. Finally, a Ritter reaction followed by deprotection with thiourea delivered the desired 2-oxaadamantan-5-amine.
The second objective of the present thesis was the synthesis of a small series of 1- and 2-adamantyl-based 11β-HSD1 inhibitors, as most of the 11β-HSD1 inhibitors evaluated are 2-adamantyl substituted derivatives and no comparison with their C-1 isomers was available. Moreover, considering that very few heteroadamantanes have been studied in 11β-HSD1 inhibitors, we also evaluated the introduction of the previously synthesized 5-substituted 2-oxaadamantane (Chapter 4).
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Focusing on the main goal, it is reported the exploration of other hydrophobic polycyclic substituents as replacement of adamantane with a design supported by molecular modeling studies in order to optimize the filling of the hydrophobic pocket in the binding site (Chapter 5). This work let us to a new family of potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. The in vitro biological profiling of the compounds permitted us to select a proper candidate for an in vivo study in a rodent model of cognitive dysfunction. The results supported the neuroprotective effect of 11β- HSD1 inhibition in cognitive decline related to the aging process, since the treatment prevented memory deficits through a reduction of neuroinflammation and oxidative stress, and an increase of the abnormal proteins degradation in the brain. An additional in vivo study in a model of cognitive dysfunction and metabolic disease is currently ongoing to study how 11β-HSD1 inhibition can modulate these two linked disorders, as so-called type 3 diabetes.
Finally, the focus was on the exploration of different substituents in the RHS of the molecule to further improve potency, selectivity and metabolic stability. The endeavour started integrating different aromatic, heteroaromatic, heterocycloalkyl and branched alkyl substituents generating diversity to build some structure-activity relationship (SAR) information (Chapter 6). From this work we obtained potent nanomolar inhibitors but still without the needed selectivity and stability properties. In light of these results, we started a rational design of new substitution patterns in order to establish additional interactions that would deliver more potent and selective inhibitors (Chapter 7). The pharmacological tests revealed some low nanomolar activities together with good metabolic stabilities, although selectivity over the isoenzyme 11β-HSD2 remains a challenge to be accomplished.
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Craigie, Eilidh. "Investigating mechanisms of salt-sensitive hypertension in 11β-HSD2 heterozygote mice". Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5565.
Texte intégralRésumé :
The mineralocorticoid hormone, aldosterone, classically acts via the Mineralocorticoid Receptor (MR) to promote sodium transport in aldosterone target tissues, such as the kidney, thereby controlling long-term electrolyte homeostasis and blood pressure (BP). Aldosterone biosynthesis by the adrenal gland is regulated by a negative feedback loop called the Renin Angiotensin Aldosterone System (RAAS). The glucocorticoid cortisol (corticosterone in rodents), which has a very similar structure to aldosterone, shares with aldosterone an equal affinity for the MR. Typically, plasma cortisol levels are approximately 1000-fold higher than plasma aldosterone, and so the ligand specificity for aldosterone must be imposed on MR by other, non-structural, means. This specificity is important in order to retain electrolyte and BP balance within the control of the RAAS. The co-localisation of the enzyme 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2) with the MR in aldosterone target tissues provides the MR with the aldosterone specificity it inherently lacks. 11β-HSD2 achieves this by converting active cortisol to its inactive 11-keto metabolite, cortisone (dehydrocorticosterone in rodents). In humans with the monogenetic Syndrome of Apparent Mineralocorticoid Excess (SAME), inactivating mutations in the HSD11B2 gene allows cortisol unregulated access to the MR. Resultant symptoms include severe hypertension and life-threatening hypokalemia. Individuals heterozygous for SAME display no overt phenotypes. However, some studies have associated SAME heterozygosity and loss-of-function polymorphisms within the HSD11B2 gene with essential and/or salt-sensitive hypertension in the general population. Targeted disruption of the Hsd11b2 gene in mice (Hsd11b2-/-) faithfully reproduces with all the major phenotypes of SAME patients. Mice heterozygote for the targeted gene (Hsd11b2+/-) have no phenotype and display a normal BP. In the present study, Hsd11b2+/- mice were used to explore the relationship between reduced 11β-HSD2 enzyme activity and salt-sensitive hypertension. On a high salt diet, Hsd11b2+/- mice were found to have increased BP and impaired natriuresis, compared to wild-type controls (Hsd11b2+/+). Further studies used pharmacological blockade of the Epithelial Sodium Channel (ENaC) and MR to ascertain the contributions of these pathways towards the observed phenotypes. These identified a deregulation of ENaC activity pertaining to an inability to regulate sodium appropriately. Investigations into the contributions of the RAAS and the Hypothalamus Pituitary Adrenal (HPA) axis have revealed valuable insights into their roles in this model. There is an implication that the RAAS has increased sensitivity in Hsd11b2+/-, further exacerbated by increased dietary sodium, and that the regulation of corticosteroids may also be altered. Novel observations have suggested that oxidative stress in response to a high salt diet could also be involved, as a study administering an antioxidant drug in conjunction with a high salt diet prevented the manifestation of a phenotype in Hsd11b2+/-. Finally, the generation of a floxed Hsd11b2 targeting construct for tissue-specific deletion of 11β-HSD2 will allow future studies into the contributions of specific 11β-HSD2 expression sites (such as the kidney) towards the phenotypes of both homozygous and heterozygous mice.
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Andres, Janin. "Untersuchungen über Regulationsmechanismen der 11beta-Hydroxysteroid Dehydrogenase Typ 1." Phd thesis, Universität Potsdam, 2008. http://opus.kobv.de/ubp/volltexte/2009/3303/.
Texte intégralRésumé :
Die 11beta-HSD1 reguliert intrazellulär die Cortisolkonzentration durch Regeneration von Cortison z.B. aus dem Blutkreislauf, zu Cortisol. Daher stellt diese ein wichtiges Element in der Glucocorticoid-vermittelten Genregulation dar. Die 11beta-HSD1 wird ubiquitär exprimiert, auf hohem Niveau besonders in Leber, Fettgewebe und glatten Muskelzellen. Insbesondere die Bedeutung der 11beta-HSD1 in Leber und Fettgewebe konnte mehrfach nachgewiesen werden. In der Leber führte eine erhöhte Aktivität aufgrund einer Überexpression in Mäusen zu einer verstärkten Gluconeogeneserate. Des Weiteren konnte gezeigt werden, dass eine erhöhte Expression und erhöhte Enzymaktivität der 11beta-HSD1 im subkutanen und viszeralen Fettgewebe assoziiert ist mit Fettleibigkeit, Insulinresistenz und Dyslipidämie. Über die Regulation ist jedoch noch wenig bekannt.
Zur Untersuchung der Promotoraktivität wurde der Promotorbereich von -3034 bis +188, vor und nach dem Translations- und Transkriptionsstart, der 11beta-HSD1 kloniert. 8 Promotorfragmente wurden mittels Dual-Luciferase-Assay in humanen HepG2-Zellen sowie undifferenzierten und differenzierten murinen 3T3-L1-Zellen untersucht. Anschließend wurde mittels nicht-radioaktiven EMSA die Bindung des TATA-Binding Proteins (TBP) sowie von CCAAT/Enhancer-Binding-Proteinen (C/EBP) an ausgewählte Promotorregionen analysiert. Nach der Charakterisierung des Promotors wurden spezifische endogene und exogene Regulatoren untersucht. Fettsäuren modifizieren die Entstehung von Adipositas und Insulinresistenz. Ihre Wirkung wird u.a. PPARgamma-abhängig vermittelt und kann durch das Inkretin (Glucose-dependent insulinotropic Peptide) GIP modifiziert werden. So wurden die Effekte von unterschiedlichen Fettsäuren, vom PPARgamma Agonisten Rosiglitazon sowie dem Inkretin GIP auf die Expression und Enzymaktivität der 11beta-HSD1 untersucht. Dies wurde in-vitro-, tierexperimentell und in humanen in-vivo-Studien realisiert. Zuletzt wurden 2 Single Nucleotide Polymorphismen (SNP) im Promotorbereich der 11beta-HSD1 in der Zellkultur im Hinblick auf potentielle Funktionalität analysiert sowie die Assoziation mit Diabetes mellitus Typ 2 und Körpergewicht in der MeSyBePo-Kohorte bei rund 1.800 Personen untersucht.
Die Luciferase-Assays zeigten basal eine zell-spezifische Regulation der 11beta-HSD1, wobei in allen 3 untersuchten Zelltypen die Bindung eines Repressors nachgewiesen werden konnte. Zudem konnte eine mögliche Bindung des TBPs sowie von C/EBP-Proteinen an verschiedene Positionen gezeigt werden. Die Transaktivierungsassays mit den C/EBP-Proteinen -alpha, -beta und -delta zeigten eben-falls eine zellspezifische Regulation des 11beta-HSD1-Promotors. Die Aktivität und Expression der 11beta-HSD1 wurde durch die hier untersuchten endogenen und exogenen Faktoren spezifisch modifiziert, was sowohl in-vitro als auch in-vivo in unterschiedlichen Modellsystemen dargestellt werden konnte. Die Charakterisierung der MeSyBePo-Kohorte ergab keine direkten Assoziationen zwischen Polymorphismus und klinischem Phänotyp, jedoch Tendenzen für eine erhöhtes Körper-gewicht und Typ 2 Diabetes mellitus in Abhängigkeit des Genotyps.
Der Promotor der 11beta-HSD1 konnte aufgrund der Daten aus den Luciferaseassays sowie den Daten aus den EMSA-Analysen näher charakterisiert werden. Dieser zeigt eine variable und zell-spezifische Regulation. Ein wichtiger Regulator stellen insbesondere in den HepG2-Zellen die C/EBP-Proteine -alpha, -beta und -delta dar. Aus den in-vivo-Studien ergab sich eine Regulation der 11beta-HSD1 durch endogene, exogene und pharmakologische Substanzen, die durch die Zellkulturversuche bestätigt und näher charakterisiert werden konnten.<br>The enzyme 11beta-HSD1 regulates intracellular the cortisol concentration by regeneration of cortisone to cortisol. Hence, 11beta-HSD1 is an important factor in glucocorticoid-mediated gene expression. It is ubiquitously expressed, but high levels have been specifically described in liver, adipose tissue and smooth muscle cells. A pivotal role for 11beta-HSD1 has been demonstrated with respect to metabolism in liver and adipose tissue. Thus, a liver-specific overexpression results in an elevated gluconeogenesis and hepatic glucose output. Furthermore, a fat-specific overexpression was associated with obesity, insulin resistance and dyslipidemia. Despite these intriguing data, the regulation of the human 11beta-HSD1 gene is still in its infancies.
8 promoter fragments from -3034 to +188 of 11beta-HSD1-gene were cloned to analyze promoter activity. Dual-Luciferase-Assay was used in humane HepG2 cells and in undifferentiated and differentiated 3T3-L1 cells. Furthermore, the region close to the transcription start was studied with a non-radioactive EMSA for binding of TATA-binding protein (TBP) and CCAAT/enhancer-binding-protein (C/EBP). The role of the endogenous and exogenous regulators fatty acids, PPARgamma and the incretin (Glucose-dependent insulinotropic Peptide) GIP was investigated in-vitro and in-vivo. Finally, the functional consequences of 2 Single Nucleotide Polymorphisms (SNP) within the promoter region were studied in cell culture and the MeSyBePo-cohorts for association with diabetes mellitus type 2 and body weight.
The Luciferase-assay revealed a cell-specific regulation of 11beta-HSD1 and a repressor, which was active in all 3 cell models. Accordingly, a cell-specific regulation was observed in transactivation-assays with C/EBP-proteins -alpha, -beta and -delta. The 11beta-HSD1 enzyme expression and activity was specifically modified by the here investigated endogenous and exogenous factors, which was demonstrated in-vitro but also in-vivo in various experimental settings. The characterisation of the MeSyBePo-cohorte revealed no association between genotype and clinical phenotype, although a trend for an increased body weight and diabetes mellitus type 2 was detected.
This work demonstrated a cell-specific regulation of the 11beta-HSD1 promoter. Furthermore, a binding site for TATA-binding proteins was detected in HepG2 and undifferentiated 3T3-L1 cells. A pivotal role in regulation of 11beta-HSD1 promoter activity was demonstrated for the C/EBP-proteins, especially in liver cells. The in-vivo-Studies revealed a regulation of enzyme expression and activity by endogenous, exogenous and pharmacological substances, which was confirmed and analyzed in more detail in cell culture experiments.
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Coutinho, Agnes Elizabeth. "Consequences of 11β-hydroxysteroid dehydrogenase deficiency during inflammatory responses". Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4190.
Texte intégralRésumé :
Glucocorticoids profoundly influence the immune system and pharmacological doses exert potent anti-inflammatory actions. During inflammation, glucocorticoids limit oedema and influence cell trafficking, differentiation programmes and gene transcription in glucocorticoid-sensitive leukocytes. Within cells, glucocorticoid action is modulated by a pre-receptor mechanism; glucocorticoid metabolism by the enzyme 11β- hydroxysteroid dehydrogenase (11β-HSD). Two 11β-HSD isozymes exist: 11β-HSD1, which catalyses amplification of glucocorticoid levels in intact cells by oxo-reduction of intrinsically inert cortisone (11-dehydrocorticosterone in rodents) into active cortisol (corticosterone in rodents) and 11β-HSD2, which performs the opposite reaction. Thus, amplification of intracellular glucocorticoid levels by 11β-HSD1 may represent an endogenous anti-inflammatory mechanism. This hypothesis has been tested in Hsd11b1-/- mice (homozygous for a targeted disruption in the Hsd11b1 gene, encoding 11β-HSD1), using carageenan-induced pleurisy and experimental model of arthritis induced by injection of arthritogenic antibodies. In both models, Hsd11b1-/- mice showed more severe acute inflammation than control mice. During carrageenan-induced pleurisy, Hsd11b1-/- mice recruited more inflammatory cells to the pleural cavity than congenic controls, with a greater proportion of viable cells, at the onset and peak of pleurisy, suggesting a worse inflammatory response. Histological examination suggested impaired resolution of inflammation in Hsd11b1-/- mice with persistence of inflammation in the visceral pleura, activation of lymphoid aggregates, and uniquely in Hsd11b1-/- mice, formation of fibrous adhesions between lung lobes 48h after initiation of pleurisy. During experimental arthritis induced by injection of serum from arthritic K/BxN mice, clinical signs of inflammation occurred earlier in Hsd11b1-/- mice and were slower to resolve than in control mice. Histological assessment of the acute phase (2d) of arthritis showed no difference in joint pathology between genotypes, despite greater oedema and higher clinical scores in the Hsd11b1-/- mice. However, when the inflammation had resolved (21d following injection of serum), compared to control mice, Hsd11b1-/- mice showed more severe exostosis, intense periarticular inflammation, more collagen deposition and uniquely, ganglion cyst formation. At 21d, whereas basal (morning) plasma corticosterone levels were normal in control mice, they remained elevated in Hsd11b1-/- mice, suggesting ongoing inflammation and persistent activation of the hypothalamic-pituitary-adrenal axis. Mast cells are critical in the initiation of an inflammatory response and are essential in this model of arthritis. Mast cells expressed 11β-HSD1 (but not 11β-HSD2) mRNA and activity. Although mast cell number did not differ in joints or peritoneum of Hsd11b1-/- mice, 11-HSD1-deficient mast cells had a lower threshold for degranulation induced by K/BxN arthritogenic serum. As well as implicating a role for mast cell 11β-HSD1 in limiting initial inflammation in arthritis, these findings also have implications for infection, allergy and tolerance. Collectively, these data suggest that 11β-HSD1 deficiency worsens acute inflammation and results in slower resolution. Therefore, amplification of intracellular glucocorticoids levels, by 11β-HSD1, may represent an important mechanism to limit the acute inflammatory response and programme its subsequent resolution. Increasing leukocyte 11β-HSD1 or local delivery of substrate affords a novel approach for anti-inflammatory therapy.
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Zhang, Zhenguang. "Role of macrophage 11β-HSD1 in inflammation mediated angiogenesis, arthritis and obesity". Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9553.
Texte intégralRésumé :
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by Hsd11b1) is an enzyme that predominantly converts inactive glucocorticoids (cortisone in human and most mammals, 11dehydro-corticosterone in mice and rats) into their active forms (cortisol and corticosterone, respectively). Thus 11β-HSD1 amplifies intracellular levels of glucocorticoids. Studies in globally 11β-HSD1 deficient mice have revealed changes in glucocorticoid-regulated physiological and pathological processes, including metabolism, aging, arthritis and angiogenesis. The function of macrophages, which play an important role in inflammation, is also altered. For example, 11β-HSD1 deficiency in macrophages causes a delay in their acquisition of phagocytic capacity. To dissect the role of macrophage 11β-HSD1 in angiogenesis, arthritis and obesity, both in vitro macrophage stimulation and in vivo functional assays in macrophage-specific 11β-HSD1 knockout mice, were conducted. Thioglycollate-elicited peritoneal macrophages from globally 11β-HSD1 deficient and control C57BL/6 mice were used for in vitro studies. In M1/M2 macrophage polarisation experiments, 11β-HSD1 deficient macrophages showed increased expression of mRNAs encoding pro-inflammatory factors upon lipopolysaccharide and interferon-ϒ treatment and decreased expression of pro-resolution genes with interleukin-4 stimulation. However, at cytokine or protein levels, there was little difference between the genotypes except for decrease IL12 p40 levels in 11β-HSD1 deficient macrophages. Hypoxic stress failed to show differences between genotypes in hypoxia-regulated gene expression. These data do not support a strong role for macrophage 11β-HSD1 in inflammation regulation, nor in response to hypoxia, at least when measured in vitro. The discrepancy between transcriptional and translational responses is currently unexplained, but may reflect altered posttranscriptional activity. To investigate the role of macrophage 11β-HSD1 in vivo, macrophage-specific Hsd11b1 knockout mice, LysM-Cre Hsd11b1 flox/flox (MKO) mice and Hsd11b1flox/flox littermate controls were generated. In MKO mice, 11β-HSD1 protein levels and enzyme activity were reduced by >80% in resident peritoneal macrophages. However, 11β-HSD1 protein and enzyme activity levels were unchanged or only modestly reduced in thioglycocollate-elicited peritoneal neutrophils, monocytes/macrophages, or in bone marrow-derived macrophages, despite >80% decrease in Hsd11b1 mRNA levels in these cells. A relatively long half-life of 11β-HSD1 protein compared to that of circulating myeloid cells may underlie this mismatch between transcriptional and translational expression. Furthermore, following 12 days of inflammatory arthritis induced by K/BxN serum transfer, the reduction in 11β-HSD1 protein levels in circulating neutrophils of MKO mice is consistently around 50%, which corroborates the above explanation. MKO mice and littermate controls were subjected to inflammatory models which may involve resident macrophages. First, to address the role of 11β-HSD1 in macrophages in angiogenesis, sponge implants were inserted subcutaneously into the flanks of adult male mice and harvested after 21 days. Chalkley counting on hematoxylin and eosin stained sponge sections showed significantly increased angiogenesis in MKO mice (scores: 5.2±1.0 versus 4.3±0.7; p<0.05, n=9-11). Cdh5 expression (encoding VE-cadherin, a marker of endothelial cells) was higher in sponges from MKO mice (relative expression: 1.5±0.9 versus 0.8±0.6; p<0.05), as was Il1b (encoding IL-1 beta, a marker of inflammation, relative expression: 6.5±6.4 versus 1.5±0.9; p<0.05). Vegfa mRNA (encoding vascular endothelial growth factor alpha) was unchanged, with a trend for higher Angpt1 (encoding angiopoietin 1, p=0.09) expression levels in the MKO group. These results suggest that lack of 11β- HSD1 in resident macrophages increases their pro-angiogenic activity, independently of VEGF-. The K/BxN serum transfer model of arthritis was used to investigate the role of macrophage 11β-HSD1 in arthritis. Adult male MKO and control mice received a single i.p. injection of 125μl K/BxN serum per mouse, followed by 21 days of clinical scoring to assess joint inflammation. The onset of inflammation (d1-8) was similar between MKO and control mice, but MKO mice exhibited greater clinical inflammation scores in the resolution phase of arthritis (d13-21; area-under-the-curve: 86.6±14.7 versus 60.1±13.4; p<0.005), indistinguishable from globally 11β-HSD1- deficient mice. Hematoxylin and eosin staining revealed pronounced fibroplasia predominantly in the supporting mesenchyme associated with the tenosynovium, with new bone and blood vessel formation. These results suggest that macrophage 11β-HSD1 deficiency is fully accountable for the worse arthritis resolution phenotype in the globally 11β-HSD1 deficient mice, but not the earlier onset of inflammation with global 11β-HSD1 deficiency. Macrophage activation states are closely linked with adipose insulin sensitivity. Globally 11β-HSD1 deficient mice are protected from high fat diet induced insulin resistance and adipose tissue hypoxia and fibrosis. To study the effect of macrophage 11β-HSD1 deficiency on insulin sensitivity, adult male MKO and control mice were given a 14 week high fat diet, which typically causes insulin resistance in control but not globally 11β-HSD1 KO mice. The level of fibrosis in subcutaneous adipose tissues was reduced as indicated by quantification of picrosirius red staining of collagen, though GTT data so far does not support protection from insulin resistance in MKO mice. In summary, in vitro macrophage polarisation experiments do not support a strong role of 11β-HSD in M1/M2 macrophage polarisations or response to hypoxia. However, MKO mice reveal, for the first time, an important in vivo role of macrophage 11β-HSD1 to promote angiogenesis and facilitate resolution of K/BxN serum transfer induced arthritis. Modulation of fibrosis is context dependent. Reduced adipose fibrosis may be one of the mechanisms that improve insulin sensitivity. Meanwhile, these findings suggest caution regarding the potential side effects of 11β-HSD1 inhibitors in treating metabolic disease in patients with inflammation-related co-morbidities, such as rheumatoid arthritis.
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Weber, Agnes Johanna [Verfasser]. "Fracture healing and glucocorticoids in HSD2 transgenic mouse model / Agnes Johanna Weber." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2012. http://d-nb.info/1026694914/34.
Texte intégral
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Wamil, Małgorzata. "Protective role of 11β-HSD1 inhibition in the metabolic syndrome and atherosclerosis". Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/3891.
Texte intégralRésumé :
Obesity is associated with an increased risk of diabetes type 2, dyslipidaemia and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by dietary fats such as cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) are also implicated in the pathogenesis of obesity, metabolic syndrome and atherosclerosis. Transgenic mice over-expressing 11β-HSD1 selectively in adipose tissue develop the metabolic syndrome whereas 11β-HSD1-/- mice have a ‘cardioprotective’ phenotype, deriving in part from improved adipose tissue function. Consistent with this, prototypical therapeutic 11β-HSD1 inhibitors ameliorate metabolic disturbances associated with obesity. 11β-HSD1 also inter-converts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7β-HC). Work presented in the first part of the thesis defines the impact of these alternative substrates on the metabolism of glucocorticoids in adipocyte cell lines (3T3-L1 and 3T3-F442A). 11β-HSD1 catalyses the reduction of 7KC in mature adipocytes leading to accumulation of 7β-HC. Oxysterol and glucocorticoid conversion by 11β-HSD1 was competitive and occurred within a physiologically-relevant IC50 range of 450nM for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11β-HSD1 activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of preadipocyte differentiation. 7-oxysterols did not display intrinsic activation of the glucocorticoid receptor (GR). However, when co-incubated with glucocorticoid, 7KC repressed, and 7β-HC enhanced GR transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11β-HSD1 reaction direction, at least in transfected HEK293 cells, and could be abrogated by over-expression of hexose 6-phosphate dehydrogenase, which supplies NADPH to drive the reductase activity of 11β-HSD1. 11β-HSD1 inhibition protects from atherosclerosis, yet it is unknown whether it is an effect of alterations in the metabolism of 7-oxysterols. 7KC and 7β-HC did not activate the potential cognate receptor LXRα and FXR/RXR in transactivation assays. No differential regulation of key gene targets of LXRα, FXR and RORα in the liver and fat depots of high fat fed 11β-HSD1-/- and wild type mice was observed. To further determine the molecular basis for the metabolically beneficial phenotype of 11β-HSD1-/- mice I analysed global gene expression in subcutaneous and mesenteric adipose tissues of high fat-fed (4 weeks) 11β-HSD1-/- and congenic C57BL/6J mice by microarrays, followed by pathway analysis, gene clustering and realtime-PCR validation of transcripts with >1.5-fold difference between genotypes. 11β-HSD1-/- mice gained less weight and distributed adipose tissue to subcutaneous rather than visceral depots. Broadly, high fat-fed 11β-HSD1-/- mice showed up-regulation of transcripts in subcutaneous fat (70% of 1622 differentially-expressed transcripts), but down-regulation in mesenteric adipose tissue (73% of 849 transcripts). Genes up-regulated in 11β-HSD1-/- subcutaneous adipose were associated with β-adrenergic signaling, glucose metabolism, lipid oxidation, oxidative phosphorylation, MAPK, Wnt/β-catenin, EGF, and PI3K/AKT insulin signaling pathways. Increased subcutaneous fat insulin signaling was confirmed by increased IRS-1 and Akt phosphorylation in vivo. Down-regulated genes in 11β-HSD1-/- mesenteric fat were associated with immune cells, NK-kappaB, Jak/Stat, SAPK/JNK, chemokine, toll-like-receptor and Wnt signaling pathways suggesting reduced immune cell infiltration in mesenteric adipose in high fat-fed 11β-HSD1-/- mice. 11β-HSD1 deficiency protects against metabolic disease by increasing peripheral fat insulin sensitivity and through a novel mechanism involving reduction in visceral fat immune/inflammatory cell function. Data presented in this thesis contribute to the understanding of the role of 11β-HSD1 in adipose tissues in obesity and, potentially, atherosclerosis.
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Mitić, Tijana. "Role of murine 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in the metabolism of 7-oxysterols". Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4416.
Texte intégralRésumé :
7-Oxysterols constitute the major component (40%) of oxidized low-density lipoprotein (oxLDL). They arise in the body via auto-oxidation of cholesterol and are known to induce endothelial dysfunction, oxidative stress and apoptosis in the vascular wall, prior to development of atherosclerosis. A novel pathway has been described for hepatic inter-conversion of 7-ketocholesterol (7-KC) and 7β -hydroxycholesterol (7β OHC) by the enzyme 11β-hydroxysteroid dehydrogenase type-1 (11β HSD1), better known for metabolizing glucocorticoids. Inhibition of 11βHSD1 is atheroprotective and the potential underlying mechanism for this may involve altered metabolism and actions of glucocorticoids. However, alterations in the metabolism of 7-oxysterols may also play an important role in this atheroprotective effect. The work described here addresses the hypotheses that (i) 7-oxysterols are substrates for murine 11βHSD1; (ii) inhibition of 11β HSD1 may abolish cellular metabolism of 7-oxysterols; (iii) this route of metabolism may modulate the actions of 7-oxysterols and glucocorticoids on murine vascular physiology. Murine 11β HSD1 inter-converted 7-oxysterols (Km=327.6±98ìM, Vmax=0.01±0.001pmol/ìg/min) but the regulation of reaction direction is different from that for glucocorticoids. Predominant dehydrogenation of 7β OHC to 7-KC was quantified in several models (recombinant protein, cultured cells stably transfected with 11β HSD1), in which predominant reduction of glucocorticoids was measured. Furthermore, in murine hepatic microsomes, dehydrogenation of 7β OHC occurred exclusively. In aortic rings in culture, however, both reduction and dehydrogenation of 7-oxysterols were evident. 7-Oxysterols and glucocorticoid substrates competed for metabolism by 11β HSD1, with 7β OHC inhibiting dehydrogenation of glucocorticoids (Ki=908±53nM). The circulating concentrations of 7-oxysterols in the plasma of C57Bl6 and 11β HSD1-/- mice were in the ìM range (0.02 – 0.13ìM). The disruption of 11β HSD1 has resulted in increased ratios of 7-KC and 7β OHC over total plasma cholesterol levels (*p<0.05). This finding suggested that 11β HSD1 is involved in metabolizing and determining the plasma levels of 7-KC and 7β OHC. To assess the consequences of these alterations for vascular function, studies were undertaken in aortic rings. Prolonged incubation with 7-oxysterols (20-25 ìM) showed a tendency to attenuate noradrenaline-mediated contractions of C57Bl6 aortae, but had no effect on contractions in response to 5-hydroxytryptamine or KCl. Similarly, endothelium-dependent and -independent relaxations of murine aortae were unaltered after exposure to 7-oxysterols. Thus in the mouse, 11β HSD1 may influence the balance of circulating and cellular 7-oxysterols which may have consequential effects on glucocorticoid action. Although this work suggests that concentrations present in murine tissues are unlikely to cause vascular dysfunction, they may influence further cellular events as yet undescribed. Under pathological conditions where high concentrations of 7-oxysterols occur, 11β HSD1 may influence the extracellular-transport and delivery of 7-KC and 7β OHC to the plaque. This work therefore proposes that inhibition of metabolism of 7-oxysterols by 11β HSD1 inhibitors, may contribute to the atheroprotective effects of these drugs.
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Lye, Mei Xuan. "The role of 11β-HSD1 in reference and working memory in ageing : investigating underlying mechanisms and biomarkers of age-associated cognitive decline". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/22057.
Texte intégralRésumé :
Glucocorticoids (GC) have a negative effect on age-associated cognitive decline and the GC metabolising enzyme 11β-hydroxysteroid dehydrogenase Type 1 (11β- HSD1) plays a key role in these effects. Increased glucocorticoids exert detrimental effects on the volume and function of brain regions such as the prefrontal cortex (PFC) and hippocampus that are necessary for cognitive functions such as memory and working memory. Previous research has identified changes in cell populations, metabolite levels and structure within the brain as well as altered levels of inflammation with age, and studies have suggested these biomarkers to be associated with cognitive impairments. Aged mice with a deletion in 11ß-HSD1 (11β-HSD1-/- mice), resulting in lower levels of glucocorticoids within the brain, exhibit attenuated cognitive decline in hippocampal dependent spatial learning and memory with age. However, the mechanisms through which 11β-HSD1 contribute to age-associated cognitive decline remain unknown. However, previous genetic models of 11β-HSD1- /- mice have demonstrated residual 11β-HSD1 activity in the brain which may still exert some effects on cognitive processes. Furthermore, the effect of 11ß-HSD1 on working memory – a more cognitively demanding process essential for everyday decision making - has yet to be determined. This thesis tests the hypothesis that glucocorticoid action mediates age-associated cognitive impairment in spatial learning and memory and spatial working memory through alterations in cell activity, brain metabolite levels and neuroinflammatory processes. Therefore, we aimed to investigate if complete lifelong 11β-HSD1 deficiency would protect against age-associated working memory deficits as well as spatial learning and memory deficits, and its effect on associated neural markers. In particular, we determined changes in hippocampal metabolite levels, cell activity and inflammation as a function of ageing in a longitudinal manner. At 6, 12, 18 and 22 months, male 11β- HSD1-/- and C57BL/6J control mice were cognitively assessed in the Morris Water Maze (MWM) and Radial Arm Water Maze (RAWM) – tests for spatial reference memory and spatial working memory respectively. Magnetic resonance spectroscopy (1H-MRS) was performed to examine the hippocampal metabolite profile in the same mice at 6, 18 and 22 months. Following their final scan, mice were culled and brains dissected for analysis. Results revealed unaltered spatial learning with age in C57BL/6J and 11β-HSD1-/- mice and pointed to a development of alternative strategies for task completion as a result of repeated testing. Spatial memory was more susceptible to age-associated effects with impairments in wild-type mice but not 11β-HSD1-/- mice, though not completely immune from the effects of repeated testing. These impairments were correlated with glutamate/glutamine levels and glial fibrillary acidic protein (GFAP), whilst GFAP was further correlated with 11β-HSD1 protein expression. Working memory was impaired with age in both 11β-HSD1-/- and wild-type mice, suggesting 11β-HSD1 deletion may be detrimental to cognitive processes in the prefrontal cortex. In conclusion, impaired memory with age may be attributed to increased glial reactivity and altered glutamate/glutamine cycling in the hippocampus, and lifelong removal of 11β-HSD1 may alter these processes. However, lifelong removal of 11β-HSD1 may not be as beneficial to working memory processes suggesting that 11β-HSD1 and glucocorticoid action play a key role in working memory processes.
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Verma, Manu. "Deficiency of 11β-HSD1 modulates energy homeostasis in the brain following systemic inflammation". Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/33323.
Texte intégralRésumé :
Chronically elevated brain glucocorticoid (GC) levels impair cognition. Age-related cognitive deficits or "sickness" behaviour is often associated with neuroinflammation. In rodents, raised GC levels prior to lipopolysaccharide (LPS) administration potentiate neuroinflammation although GC suppresses neuroinflammation if administered after LPS. 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) reductase activity can increase intracellular GC levels, including in the brain, without alteration in circulating levels. Deficiency/pharmacological inhibition of 11β-HSD1 is protective against age related cognitive impairment in both rodent and humans. However, the underlying mechanism remains unclear. 11β-HSD1 reductase activity is coupled to hexose-6-phosphate dehydrogenase activity, itself dependent on cellular energy status. Processes affected by deficiency/inhibition of 11β- HSD1 (e.g. acute inflammation, angiogenesis) are associated with increased glycolysis. Additionally, compared to C57BL/6J controls, adipose tissue of 11β-HSD1 deficient mice shows increased expression of glycolytic and oxidative metabolism genes in a rodent model of obesity, characterised by low-grade chronic inflammation. I hypothesised that 11β-HSD1 has a role in regulation of cellular energetics basally and following inflammation. 11β-HSD1 expression in the brain will be up-regulated during systemic inflammation. Following inflammation, 11β-HSD1 deficiency will attenuate the pro-inflammatory response and subsequently alter energy substrate uptake and/or utilisation in the key areas of brain (i.e. hypothalamus and the hippocampus) that sense and respond to inflammation and energy balance. To test my hypothesis, global 11β-HSD1 KO mice, primary macrophages in vitro and murine models of inflammations were utilised. 11β-HSD1 mRNA and protein expression were confirmed in the hypothalamus and the hippocampus of C57BL/6J mice. In the absence of inflammation, expression of inflammatory markers is low or negligible in the brains of Hsd11b1-/- mice similar to C57BL/6J controls. However, compared to C57BL/6J, Hsd11b1-/- mice show altered mRNA levels of metabolic transporters and enzymes in the hypothalamus and the hippocampus. Overall, the mRNA profiling suggests reduced dependence on glucose in the brains of Hsd11b1-/- mice, either through increased lactate availability (in the whole brain and hippocampus) or through increased glycolysis and mitochondrial number/function (in the hypothalamus). Primary macrophages were utilised to investigate the role of 11β-HSD1 in cellular energetics in vitro. In these cell based assays, glycolysis was found to be the predominant glucose metabolising pathway in C57BL/6J primary macrophages, consistent with the literature. Preliminary data suggested reduced glycolytic activity in Hsd11b1-/- compared to C57BL/6J primary macrophages. However, initial attempts to utilise these cell based assays on primary microglia were unsuccessful. Moreover, Hsd11b1 mRNAs in the brain (down-regulation with inflammation, discussed later) was found to be differentially regulated in comparison to Hsd11b1 mRNA levels in the macrophages (up-regulation with inflammation) hence further investigation was not pursued. To identify a model of peripheral inflammation where 11β-HSD1 is regulated in the brain in vivo, Staph. aureus induced acute lung inflammation and the K/BxN serum transfer induced model of arthritis were utilised. Increased expression of inflammatory markers in the brain was associated with reduced Hsd11b1 mRNA levels in the hippocampus of control mice in these models. Comparison of Hsd11b1-/- and C57BL/6J mice showed increased levels of mRNAs encoding metabolic transporters in the hypothalamus and the hippocampus of Hsd11b1-/- mice following inflammation in the K/BxN serum transfer model of arthritis suggesting increased energy substrate availability. Additionally, increased levels of mRNA encoding metabolic enzymes suggested increased glycolytic capacity and mitochondrial oxidative phosphorylation activity in the hippocampus but not the hypothalamus of Hsd11b1- /-, compared to C57BL/6J mice, following K/BxN serum induced arthritis. Overall, these data suggest that the reduction in expression of 11β-HSD1 could be a potential mechanism to increase energy substrate availability, glycolytic capacity and mitochondrial activity in the hippocampus to provide metabolic support for neuronal metabolism and function following peripheral inflammation. The role of 11β-HSD1 in the pro-inflammatory response and cellular energetics in the hippocampus was further investigated in a well characterised sterile peritonitis model of systemic inflammation in which a low to moderate dose of LPS was used. Mice were administered LPS or vehicle (0.9% saline) by a single i.p. injection and culled 3h, 6h or 9h post injection. Inflammation resulted in significant reduction in burrowing activity both in Hsd11b1-/- and C57BL/6J mice suggesting sickness behaviour.. The number of circulating immune cells, as a measure of peripheral inflammation, did not differ between genotypes. Similarly, plasma corticosterone levels were elevated following inflammation but no genotype difference was observed. However, levels of plasma 11-dehydrocorticosterone, the inert substrate for 11β- HSD1, were significantly elevated in the Hsd11b1-/-, compared to C57BL/6J mice, following inflammation. Levels of mRNA encoding inflammatory markers were lower in the hippocampus of Hsd11b1-/-, compared to C57BL/6J mice, following inflammation. Also, Hsd11b1 mRNA levels were reduced in the hippocampus of C57BL/6J mice following inflammation, consistent with the finding above. Principal component analysis on levels of mRNA encoding metabolite transporters and enzymes revealed a distinct metabolic response in the hippocampus of Hsd11b1-/-, compared to C57BL/6J mice, 6h post LPS. At the same time point in the hippocampus, levels of mRNAs encoding metabolite transporters and enzymes suggested an attenuated switch to aerobic glycolysis with maintenance of mitochondrial function/activity. Quantification of hippocampal energy metabolites using targeted metabolomics in the Hsd11b1-/- compared to C57BL/6J mice 6h post LPS showed correspondence with the mRNA results. Overall, these results suggest that reduced expression of 11β-HSD1 could be a potential mechanism to reduce the pro-inflammatory response and provide better metabolic support for neuronal function and metabolism in the hippocampus, following systemic inflammation. In summary, the current work provides evidence for neuroprotection with 11β-HSD1 deficiency, following systemic inflammation. The suggestive neuroprotection is at least in part mediated via an attenuated pro-inflammatory responses and increased energy substrate uptake and/or utilisation providing better metabolic support for neuronal function following inflammation. It argues for the development of tissue specific small molecule inhibitors of 11β-HSD1 that can cross the blood brain barrier as therapeutic agents against the adverse cognitive effects of systemic inflammation and/or inflammaging.
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Liu, Bin. "Numerical investigation and evaluation of applying PPCI combustion in a HSDI diesel engine." Thesis, University of Sussex, 2014. http://sro.sussex.ac.uk/id/eprint/49394/.
Texte intégralRésumé :
In this study, the Partially Premixed Compression Ignition (PPCI) combustion strategy in the high-speed, direct-injection diesel engine was investigated numerically by KIVA-3V code coupled with detailed chemistry, aiming to find the solution to meet the increasingly stringent emission regulations. Using split-injection, the parameters including injection timing, split-proportion, spray angle and injection pressures have been studied for their effects on combustion performance and emissions. The effects of swirl ratio, EGR rate and boost pressure are evaluated for improving the mixing and combustion of PPCI. The Homogeneity Factor (HF) was proposed for evaluating the quality of mixing and for quantitatively investigating the effects of injection parameters and in-cylinder air motion on mixture formation. Relationships between the quality of mixing and combustion performance and emissions were discussed using this factor. The results showed that HF had well revealed overall quality of mixture and the effects of operating parameters explicitly. Different EGR compositions with varied fractions of CO2 or H2O were applied in PPCI combustion in order to evaluate the effects of EGR constituents on the combustion performance and emissions. Moreover, the parametric study was conducted under a sweep of the 2nd injection timing and EGR rate, for the understanding of the effects of CO2 and water vapour in EGR at different operating modes. The speed range and load range for the PPCI diesel combustion using split injection was investigated. The results showed that the high level of EGR rate limited the implementation of PPCI combustion at high engine load, while the engine speed was limited by increased CO emissions. The application of high level cooled EGR had the potential for extending operating limits. The proposed Premixed Rate (PR) has revealed the correlations between the degree of premixed combustion and ignition delay, together with overall equivalence ratio. Good responses in fuel consumption have been shown with increase PR. And the significant reduce in PR indicated low degree of premixed at high engine load.
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Liu, Xiaoxia. "Regulation and function of 11β-hydroxysteroid dehydrogenase (11β-HSD1) in pancreatic β-cells". Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5582.
Texte intégralRésumé :
Diabetes Mellitus is characterized by high blood sugar and is caused by resistance to (type 2) or insufficiency of (type 1) the pancreatic β-cell hormone insulin. Most commonly, type 2 diabetes is associated with obesity whereas type 1 diabetes is largely a result of immune-mediated destruction of the β-cell. One rare but significant cause of type 2 diabetes is excess blood glucocorticoid levels (Cushing’s syndrome). High circulating glucocorticoids potently induce metabolic disorders including peripheral insulin resistance in key metabolic tissues (muscle, liver and fat) as well as directly suppressing β-cell function and can precipitate type 2 diabetes. However, in common forms of metabolic syndrome (visceral obesity, type 2 diabetes, increased cardiovascular disease risk) it appears that amplification of local tissue glucocorticoid action by increased levels of the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), particularly in adipose tissue, is a key driver of the adverse metabolic phenotype rather than altered circulating glucocorticoid levels. 11β-HSD1 is also elevated in pancreatic islets from obese rodents. This thesis aimed to determine the role of 11β-HSD1 in pancreatic islets (β-cells) under normal conditions and its potential pathogenic role in the development of diabetes. We first determined that 11β-HSD1 acted primarily as a reductase (amplifying glucocorticoid action) in pancreatic islets. We then determined that islet 11β-HSD1 transcription is under the control of the promoters that express in other tissues like liver. Islet 11β-HSD1 is significantly regulated by factors relevant to the diabetic state; high glucose and insulin suppressed whereas fatty acids and TNFα increased 11β-HSD1 activity. To test whether the high islet 11β-HSD1 found in obese rodents was directly diabetogenic, we generated transgenic mice specifically overexpressing β-cell 11β-HSD1 under the mouse insulin promoter (MIP-HSD1 mice) in a mouse strain prone to develop β-cell failure when subjected to diabetic challenge (eg. chronic high fat feeding). Unexpectedly, MIP-HSD1tg/+ mice (expressing ~2 fold elevated 11β-HSD1 activity) exhibited markedly improved β-cell insulin secretory responses, whereas MIP-HSD1tg/tg mice had partially impaired β-cell insulin secretory function in vivo and in vitro. Moreover, MIP-HSD1tg/+ mice completely resisted the mild hyperglycaemia induced by multiple-low doses of the β-cell toxin streptozotocin (40mg/kg i.p. for 5 days) and partially resisted the profound hyperglycaemia induced by a single high dose of streptozotocin (180mg/kg). Notably, MIP-HSD1tg/+ mice exhibited lower macrophage infiltration (MAC-2) and higher T-regulatory cell (Foxp3) infiltration after these challenges with evidence of increased insulin-positive cells and maintenance of normal levels of proliferation-competent β-cells. Overall, MIP-HSD1tg/tg exhibited a partial protection from the streptozotocin challenge. Modestly increased 11β-HSD1 expression in β-cells unexpectedly supports compensatory insulin hypersecretion preventing type 2 diabetes and protects β-cells from inflammatory mediated damage in the setting of type 1 diabetes. Above a protective threshold, elevated β-cell 11β-HSD1 may result in β-cell dysfunction and diabetes. These findings have important implications for the currently advocated therapeutic strategies to inhibit 11β-HSD1 in the context of obesity and diabetes.
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Hein, Anna Caroline. "11ß-HSD2 dependent and independent signalling pathways in trophoblast biology and glucocorticoid responsiveness." Thesis, University of Warwick, 2015. http://wrap.warwick.ac.uk/77309/.
Texte intégralRésumé :
The placenta is the interface between the mother and the fetus fulilling important roles such as nutrient transfer, hormone production and barrier functions. Pathological conditions associated with maternal stress during pregnancy can cause placental adaptations which possibly affect fetal health and might lead to long-term effects in later life. The placenta contains an autonomous endocrine system which consists of hormones such as corticotropin-releasing hormone (CRH) and cortisol (the human glucocorticoid) controlling stress responses. Exposure of the fetus and placenta to glucocorticoids (GCs) is finetuned by CRH. The presence of a GC barrier also modulates GC availability. The main component of this GC barrier is the enzyme 11ß-HSD2 which catalyzes active cortisol into cortisone. Expression of this enzyme is decreased in placental diseases such as pre-eclampsia and intrauterine growth restriction (IUGR). This might be associated with elevated levels of trophoblast apoptosis and disturbances of trophoblast differentiation found in pregnancy-related disorders. Very little is known about the specific role of this enzyme and related pathways in placental apoptosis, differentiation, endocrine capacity and the expression of molecules involved in the stress response and glucocorticoid action. These potential effects were investigated in this thesis by using the placental explant culture and the choriocarcinoma BeWo cellular model. Furthermore, the capacity of GCs to regulate transcriptional events in BeWo cells was explored. My results show that CRH treatment and activation of TLR4 have modulating effects on placental hCG production in placental explants. Moreover, the enzyme 11ß-HSD2 seems to be involved in the homeostasis of placental differentiation and apoptotic processes, the maintenance of hCG and progesterone secretion and it might limit overactivation of CRH receptors and CRH secretion. GC insensitivity was identified in the BeWo cells and it appears that in these cells the cAMP pathway is the predominant pathway in regulating GC-responsive genes. Through a series of reporter-gene-assays my results suggest that transfection of exogenous GRα restores the BeWo cell sensitivity to GCs without affecting BeWo cell turnover and hormone secretion. In conclusion, placental CRH and 11ß-HSD2 expression appear to play an important role in the maintenance of placental endocrine function. GCs on the other hand did not have strong regulatory effects in the BeWo cells suggesting a unique mechanism through which trophoblast cells become insensitive to local glucocorticoid action.
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Ota, Takumi. "Regulatory Mechanisms of Adrenal Gland Zona Glomerulosa-Specific 3β-HSD". 京都大学 (Kyoto University), 2015. http://hdl.handle.net/2433/199496.
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Pu, Helen Xiaochun. "Cloning and characterization of 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) in the guinea pig." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ30819.pdf.
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Smith, Melanie Anne. "Biochemical and biophysical characterisation of the domain structure of the HsdS subunit of EcoR124I." Thesis, University of Portsmouth, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323083.
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McCabe, Emma Louise. "Altering adipose tissue responses to glucocorticoids through genetic manipulation of the 11B-HSD1 gene." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6917/.
Texte intégralRésumé :
Glucocorticoids (GC) are regulators of permissive and adaptive physiology. GC excess can lead to metabolic complications including type 2 diabetes and metabolic syndrome. Levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which reactivates GC. 11β-HSD1 activity is deregulated in a range metabolic disorders in which GC levels are normal. I hypothesise that 11β-HSD1 is a critical regulator of adipose tissue sensitivity to GC excess, and that through 11β-HSD1 depletion adipose tissue will be desensitised to GCs and resist metabolic deregulation. Using 11β-HSD1 KO mice in a model of GC excess we demonstrate that 11β-HSD1 mediates the adverse metabolic effects of GC excess on a global scale. I further investigated brown adipose tissue (BAT) with GC excess. I demonstrate that 11β-HSD1 regulates BAT activity and mitochondrial function, possibly suppressing BATs thermogenic potential. I extended my studies to examine the potential for white adipose tissue (WAT) to assume markers of thermogneic and mitochondrial function in the context of 11βHSD1 and GC excess. The data suggest 11β-HSD1 may suppress the potential of WAT to assume a ‘BAT-like’ profile. These data show 11β-HSD1 loss of function confers a protective phenotype with GC excess and demonstrates it’s role in mediating the metabolic phenotype associated with GCs. These data support the idea that GCs can influence BAT and WAT thermogenic potential and may increase knowledge of metabolic dysregulation in humans suffering form GC excess. This therefore highlights 11β-HSD1 as an exciting potential target for the treatment for the metabolic disease associated with GC excess.
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Manwani, Kajal. "The role of hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in cholesterol homeostasis". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/22058.
Texte intégralRésumé :
Chronic glucocorticoid (GC) excess (Cushing’s syndrome, pharmacotherapy) causes metabolic and cardiovascular disease. This might be predicted from the known metabolic (dyslipidaemia, insulin resistance/hyperglycaemia) and hypertensive effects of chronically elevated GC levels. Intracellular GC levels within target tissues are controlled by 11β-hydroxysteroid dehydrogenases. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1, encoded by Hsd11b1) is an enzyme that, in intact cells and in vivo, converts inert GCs (cortisone in humans, and 11- dehydrocorticosterone in mice and rats) into their active forms (cortisol and corticosterone, respectively). Consequently, 11β-HSD1 amplifies intracellular GC levels. Additionally, 11β-HSD1 is also involved in the metabolism of 7-oxysterols; it catalyses the reduction of 7-ketocholesterol (7-KC) to 7β-hydroxycholesterol (7β- HC). 7-KC may inhibit cholesterol biosynthesis through its ability to inhibit cleavage/processing of sterol regulatory element binding protein-2 (SREBP-2), the key regulator of cholesterol synthesis. Alteration of cholesterol homeostasis is a major risk factor for cardiovascular disease. Improvement of metabolic syndrome and attenuation of atherosclerosis are observed in susceptible rodent models with 11β- HSD1 deficiency or inhibition. Conversely, pilot data showed decreased levels of 7- KC as well as increased levels of cleaved SREBP-2 protein (the transcriptionally active form) in liver of mice with hepatic 11β-HSD1 overexpression (LOE mice), suggesting increased cholesterol biosynthesis. It was hypothesised that hepatic 11β- HSD1 promotes cholesterol biosynthesis through hepatic induction of SREBP-2 target genes in the cholesterol biosynthetic pathway. The hypothesis was tested in adult, male LOE and wild-type C57BL/6 mice. In mice fed a standard chow diet, hepatic levels of mRNA encoding hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase and HMG-CoA synthase, SREBP-2 targets in the cholesterol biosynthetic pathway, did not differ between genotypes. Compared to chow, a cholesterol-rich ‘Western’ diet (WD) decreased hepatic levels of mRNA encoding SREBP-2, HMG-CoA reductase and HMG-CoA synthase in wild-type as well as in LOE mice. These data imply that LOE mice show a normal physiological response with respect to cholesterol synthesis when challenged with cholesterol-rich diet, and, contrary to the hypothesis, liver 11β-HSD1 does not increase cholesterol biosynthesis via elevated expression of mRNAs encoding hepatic cholesterol biosynthetic enzymes. The liver X receptors (LXR) are well-known as sensors of oxysterols and regulators of genes involved in processes that decrease total body cholesterol levels i.e. reverse cholesterol transport and cholesterol excretion into bile. Cholesterol is the precursor to oxysterol LXR ligands. It was predicted that liver overexpression of 11β-HSD1 leads to activation of LXRα (the isoform with dominant roles in reverse cholesterol transport and whole-body cholesterol homeostasis) and its downstream targets involved in cholesterol efflux and excretion, in response to increased intracellular cholesterol levels. Indeed, levels of Lxrα mRNA were increased in livers of WD-fed LOE mice compared to wild-type mice on the same diet. There was no evidence for increased cholesterol clearance through bile acid synthesis in LOE mice as indicated by unchanged levels of hepatic Cyp7a1 mRNA between LOE and wild-type mice. However, consistent with being direct targets of LXRα, increased Abcg5 and Abcg8 mRNA levels were observed in livers of WD-fed LOE mice compared to WD-fed wild-type mice. These results corroborate findings in chow-fed LOE mice. Moreover, these data suggest that LOE mice ‘sense’ intracellular cholesterol excess and respond to it by increasing cholesterol efflux into the biliary lumen for excretion, thereby supporting a role for hepatic 11β-HSD1 in promoting biliary cholesterol secretion. To assess the effect(s) of hepatic 11β-HSD1 deficiency on cholesterol homeostasis as well as evaluate the importance of liver 11β-HSD1 in metabolic syndrome, liver-specific 11β-HSD1 knockout (LKO) mice were generated by crossing “floxed” Hsd11b1 mice with Alb-Cre transgenic mice in which Cre expression is restricted to hepatocytes. In liver of LKO mice, 11β-HSD1 mRNA, protein and enzyme activity were reduced by >80%, with no differences in 11β-HSD1 protein levels in kidney, adipose tissue or muscle between LKO and floxed Hsd11b1 littermate controls. These results indicate liver-specificity of Hsd11b1 knockdown in these mice. Body weight and weights of liver, adipose tissue, adrenal, muscle, kidney and brain were unaltered by liver-specific 11β-HSD1 deficiency on a standard chow diet. These mice were subject to a 14-week high fat (HF) diet, which typically causes metabolic syndrome in control but not globally 11β-HSD1 deficient mice. In HF-fed LKO mice, weights of the subcutaneous and epididymal fat depots were decreased compared to HF-fed control mice, resulting in an overall decrease in total white adipose tissue weight. Although no differences were observed in subcutaneous adipocyte hypertrophy between HF-fed LKO and control mice in a small number of samples tested, the above finding suggests that liver 11β-HSD1 influences adiposity and that liver-specific deficiency of 11β-HSD1 may reduce diet-induced adiposity. In terms of cholesterol homeostasis, no differences were observed in hepatic levels of mRNAs encoding cholesterol biosynthetic enzymes as well as those encoding enzymes/transporters for cholesterol catabolism/excretion between LKO and control mice, on either chow or HF diet. In summary, these data do not support a role for hepatic 11β-HSD1 in cholesterol synthesis. However, my evidence suggests that increased hepatic 11β-HSD1 promotes hepatobiliary cholesterol secretion. Finally, knockdown of liver 11β-HSD1, combined with HF feeding, reduces adiposity, suggesting that hepatic 11β-HSD1 may play a key role in adipose tissue lipogenesis/lipolysis and/or lipid storage, and that liver-specific 11β-HSD1 inhibition (or deficiency) may be advantageous in diet-induced obesity. Data presented in this thesis contribute to the understanding of the role of hepatic 11β-HSD1 in cholesterol homeostasis and metabolic syndrome.
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Tran, Van Nam. "Adsorption statique de PCB et de DDT sur charbons actifs en milieux aqueux." Thesis, Lyon 1, 2012. http://www.theses.fr/2012LYO10301.
Texte intégralRésumé :
L’adsorption solide-liquide des PCB et des DDT constitue un moyen efficace pour leur récupération des eaux polluées à condition d’avoir une meilleure connaissance du mécanisme impliqué. Les cinétiques d’adsorption statique ont été principalement réalisées à 25 °C avec le2-PCB, un mélange de tétra-, penta- et hexa-CB et le 4,4’-DDT sur 3 charbons actifs (CA) en poudre différents par le précurseur (houille, bois) et le mode d’activation (H2O, H3PO4) dans l’eau, en présence ou non d’éthanol. Les résultats marquants ont été les suivants : L’adsorption du polluant sur le CA est d’autant plus favorisée que sa solubilité dans la phase liquide est plus faible. Ainsi, l’adsorption du polluant hydrophobe est très augmentée dans l’eau pure. L’adsorption des polluants favorisée par la microporosité développée est essentiellement un phénomène de surface où interviennent les forces de Van der Waals. Une bonne adéquation entre la taille des molécules et la largeur moyenne des pores en forme de fentes montre un confinement maximum des molécules dans la microporosité. L’interaction π−π entre adsorbat et adsorbant, favorisée par le nombre de Cl n’est pas à exclure. Enfin, nous avons montré par la cinétique dans les conditions initiales que l’adsorption y est limitée par le transfert de masse externe. Les modélisations par diffusion superficielle homogène (HSDM), conduisant aux coefficients de diffusion superficielle interne, ont montré que la cinétiqued’adsorption est presque complètement gouvernée par la diffusion intraparticulaire<br>The solid-liquid adsorption of PCBs and DDT is an effective process for the recuperation of wastewaters but a better understanding of the involved mechanism is required. In this study, the static adsorption kinetics were mainly carried out at 25 ° C for 2-PCB, a mixture of tetra-, penta-and hexa-CB, and 4,4 '-DDT onto three different powdered activated carbons (AC) of the precursor (coal, wood) and the activation mode (H2O, H3PO4) in water, with or without ethanol. The prominent results were as follows: The adsorption of the pollutant on the AC is favored if its solubility in the liquid phase is lower. As a result, the adsorption of the hydrophobic pollutant is significantly increased in pure water. Moreover, the adsorption of pollutants favored by the developed microporosity is a surface phenomenon which involved the Van der Waals forces. A good fit between the size of molecules and the average width of the slit-shape pores gave a maximum confinement of molecules in the micropores. The π−π interaction between adsorbate and adsorbent, favored by the number of Cl, is not excluded. Finally, by studying the kinetics of the initial conditions, we found that the adsorption is limited by the external mass transfer. The internal surface diffusion coefficients estimated from applying the homogeneous surface diffusion models (HSDM) showed that the adsorption kinetics are almost completely governed by the intra-particle diffusion
25
Opiyo, Monica Naomi. "The role of glucocorticoid metabolism in bile acid homeostasis." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25673.
Texte intégralRésumé :
Alterations in glucocorticoid (GC) biosynthesis and metabolism are associated with a variety of pathophysiological disorders including cholestasis, diabetes and other metabolic disorders. Bile acids (BA) are also important modulators of metabolic functions and regulate cholesterol, triglyceride and glucose homeostasis as well as being critical for dietary fat digestion, enterohepatic function, and postprandial thermogenesis. In intact cells and in vivo, the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme converts inactive GC precursors (cortisone in humans, and 11-dehydrocorticosterone in mice and rats) into their active forms (cortisol and corticosterone, respectively) thereby amplifying local intracellular GC levels. Interconversion by 11β-HSD1 of other sterols has also been described. These include conversions of 7keto-cholesterol to 7β-hydroxycholesterol, 7-oxodehydroepiandrosterone (7-oxo-DHEA) to 7α-hydroxy- and 7β-hydroxy DHEA, 7- oxo-lithocholic acid (LCA, a bile acid; BA) to chenodeoxycholic acid (CDCA, a 7α- hydroxylated BA) and ursodeoxycholic acid (UDCA, a 7β-hydroxylated BA) in human liver microsomes. In the liver, BA inhibit 11β-HSD1 but whether 11β-HSD1 regulates BA homeostasis is unclear. Evidence of molecular regulation of the enterohepatic recycling of bile acids by liver glucocorticoid receptor (GR) in mice does suggest a role for 11β-HSD1. It was therefore hypothesised that disruption of 11β-HSD1 expression in mice would impair BA recycling and might affect the relative concentrations of BA within the enterohepatic circuit. The primary objective of the current work was to investigate the impact of altered 11β-HSD1 on BA homeostasis. This was achieved using genetically modified mouse models with altered 11β-HSD1 expression, either globally or restricted to hepatocytes. BA are stored in the gall bladder and are released postprandially, to aid digestion. It was hypothesised that 11β-HSD1 deficiency might the affect the process of postprandial gall bladder emptying/refilling. Mice with global 11β-HSD1 knockout (Hsd11b1-/-) and age-matched control mice (C57Bl/6) were either fasted for 4h and culled or fasted for 4h and re-fed for another 4h before culling. Their response to fasting and re-feeding was assessed with specific focus on organs associated with BA recycling in the enterohepatic circuit (liver, gall bladder, serum and small intestine). Gall bladders of fasted Hsd11b1-/- and C57Bl/6 mice had similar volumes of bile but in fasted Hsd11b1-/- mice, BA concentrations were higher in serum and liver. As expected, re-feeding caused gall bladder emptying in C57Bl/6 mice with consequent increased serum and liver bile acid concentrations. In Hsd11b1-/- mice, the gall bladder did not empty and serum and liver BA concentrations were similar to the fasted state. To explore possible reasons for this, levels of mRNA encoding proteins known to be involved in hepatic BA transport were quantified using real-time q-PCR. Levels of mRNA encoding NTCP/ SCL10A1/ SCL10A1, the transporter responsible for most hepatocyte BA uptake, were increased in livers of fasted Hsd11b1-/- mice whereas levels of Slc51b mRNA, encoding the OST- transporter that facilitates BA removal from liver to the systemic circulation, and levels of Mrp2 and Atp8b1/FIC1 mRNAs (both encoding proteins which transport BA from liver into gall bladder) were decreased. This suggests that in fasted Hsd11b1-/- mice, BA transporter expression is altered to increase BA influx into hepatocytes and decrease efflux, to compensate for reduced levels of liver BA. These data together imply that bile acid recycling is controlled by 11β-HSD1 activity which regulates gall bladder emptying, hepatic BA concentration and BA transporter activity to ensure continuity of BA recycling within the enterohepatic circuit compartments. These changes may also affect digestion of lipids and fat-soluble micronutrients. Because 11β-HSD1 can directly metabolise secondary BA, it was predicted that 11β-HSD1 deficiency would lead to changes in the BA profile. Profiling of BA in the gall bladder was performed using mass spectrophotometry. In Hsd11b1-/- mice, 7α-hydroxylated BA predominated (cholic acid [CA]>α-muricholic acid [α- MCA]>CDCA>others), in contrast to C57Bl/6 mice in which 7β-hydroxylated BA predominated (ω-MCA>β-MCA>UDCA>others). The ratio of 7α:7β acids was therefore >100-fold greater in Hsd11b1-/- mice. This suggests that 11β-HSD1 either directly or indirectly controls the epimerisation of 7α- to 7β- hydroxylated BAs. Measurement of mRNAs encoding proteins important for hepatic BA biosynthesis in livers of fasted Hsd11b1-/- mice showed decreased expression of Scarb1/SR-B1, Cyp39a1 and Cyp27a1 (though with no change in levels of CDCA, the product of CYP27A1, in liver or bile fluid), compared to fasted control mice. Hepatic levels of Gpbar1/TGR5/GPBAR1 and Cyp3a11 mRNAs, encoding proteins important in BA detoxification, were increased and decreased, respectively. This suggests that Gpbar1/TGR5/GPBAR1, encoding G-protein coupled bile acid receptor (also called TGR5/GPBAR1) and an FXR target, could be induced to detoxify 7α-hydroxylated BA whereas expression of Cyp3a11, which catalyses the conversion of LCA to hyodeoxycholic acid (HDCA) is decreased; bile fluid of Hsd11b1-/- mice contained lower levels of LCA and little to no HDCA, though LCA and HDCA levels in liver were unaltered. Currently, the functional differences between 7α- and 7β- hydroxylated BA are not clear. However, these findings could have significant implications for bile acid-mediated transcription which, in turn, might affect lipid and sterol metabolism. Also, alterations in BA composition may have other physiological consequences via other pathways. Because cholesterol is the precursor of BA synthesis, it was hypothesised that western diet (WD) (containing cholesterol) would exacerbate and/or alter the phenotype of Hsd11b1-/- mice. Gall bladder weights of fasted Hsd11b1-/- and control C57Bl/6 mice did not change with western diet compared to chow diet. In control C57Bl/6 mice, the total BA concentration in the gall bladder increased in response to WD in comparison to chow diet. In contrast, Hsd11b1-/- mice showed no change in total BA concentration when fed on WD in comparison to chow. These data indicate that 11β-HSD1 is required by mice for the normal increase in total BA concentration in bile in response to dietary cholesterol. BA profiling of bile from control mice fed on WD showed no difference in the relative amounts of 7β-hydroxylated BA and 7α-hydroxylated BA to littermates fed on chow diet with the exception of β–MCA which increased, and α–MCA which decreased. Like chow-fed Hsd11b1-/- mice, BA profiling of bile from WD-fed Hsd11b1-/- mice showed a significant decrease in relative levels of 7β-hydroxylated BA (UDCA < β-MCA < others) and an increase in percentage of 7α-hydroxylated BAs (CA>α-MCA>CDCA>others) compared to C57Bl/6 controls. These data show that Hsd11b1-/- mice fail to show the normal increase in 7β-hydroxylated BA and decrease in 7α-hydroxylated BA observed in control mice in response to a cholesterol containing diet, suggesting 11β-HSD1 deficiency blunts the influence of cholesterol on BA composition. Measurement of hepatic mRNAs encoding BA transporters suggest that hepatocyte uptake of BA is decreased in C57Bl/6 on WD compared to those mice on chow diet, whereas this was not the case in Hsd11b1-/- mice where hepatic expression did not change with diet. Thus, Hsd11b1-/- mice failed to increase expression of Ntcp/ Scl10a1/ Scl10a1 appropriately, suggesting impaired hepatic BA uptake, while Slc51b (encoding OST-β) expression was increased, compared to control mice, possibly to reduce hepatic BA concentration by transporting BA out of hepatocytes into the systemic circulation. Therefore, Hsd11b1-/- mice may adapt to a cholesterol-induced increase in hepatic BA by blunting hepatic BA uptake via NTCP/ SCL10A1/ SCL10A1 and increasing hepatic efflux via OST-β. The effects of 11β-HSD1 deficiency upon BA recycling and BA profile and concentration within the enterohepatic circuit, could reflect 11β-HSD1 action within the liver or could be due to actions in other tissues.<br>To investigate the role of hepatic 11β-HSD1 specifically, 11β-HSD1 liver-specific knockout (Hsd11b1LKO), 11β- HSD1 liver-specific over-expressors (Hsd11b1LOE) and control mice with exon 3 of the Hsd11b1 gene “floxed” (Hsd11b1F) were studied. Findings from this study indicate a role for 11β-HSD1 in adaption to dietary cholesterol and suggest that hepatic 11β-HSD1 (as opposed to 11β-HSD1 in extra-hepatic tissues) is the main factor regulating BA metabolism. Also, work from this thesis demonstrates 11β-HSD1 is an important regulator of gall bladder emptying and filling, an important component of enterohepatic bile acid recycling. Based on these findings it is anticipated that therapeutic use of 11β-HSD1 inhibitors will result in BA imbalances within the enterohepatic circuit and therefore BA homeostasis. Care must therefore be observed when implementing therapeutic use of 11β-HSD1 inhibitors, with particular focus on patients with cholestasis, Addison’s disease and critically ill patients who already have known BA imbalances in their enterohepatic system.
26
Pradhan, Devaleena S. "Rapid social regulation of 3β-HSD activity in the songbird brain". Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/1500.
Texte intégralRésumé :
Rapid increases in plasma androgens are generally associated with short-term aggressive challenges in many breeding vertebrates. However, some animals such as song sparrows (Melospiza melodia) are aggressive year-round, even during the non-breeding season, when gonads are regressed and systemic testosterone (T) levels are non-detectable. In contrast, levels of the prohormone dehydroepiandrosterone (DHEA) are elevated year-round in the plasma and brain. The local conversion of brain DHEA to potent androgens may be critical in regulating non-breeding aggression. 3β-hydroxysteroid dehydrogenase/Δ4-Δ5 isomerase (3β-HSD) catalyzes DHEA conversion to androstenedione (AE) and the cofactor NAD⁺ assists in this transformation. In this thesis, I asked whether brain 3β-HSD activity is regulated by social encounters in seasonally breeding male songbirds. In Experiment 1, I looked at the long-term seasonal regulation of brain 3β-HSD activity. 3β-HSD activity was highest in the non-breeding season compared to the breeding season and molt. In Experiment 2, I hypothesized that brain 3β-HSD activity is rapidly regulated by short-term social encounters during the non-breeding season. A 30 min social challenge increased aggressive behavior. Without exogenous NAD⁺, there was ~355% increase in 3β-HSD activity in the caudal telencephalon and ~615% increase in the medial central telencephalon compared to controls (p<0.05). With exogenous NAD⁺, there was no effect of social challenge on 3β-HSD activity. These data suggest that endogenous cofactors play a critical role in the neuroendocrine response to social challenges. The increase in brain DHEA conversion to AE during social challenges may be a mechanism to rapidly increase local androgens in the non-breeding season, when there are many costs of systemic T.
27
Glisson, Katelynn E. "The Ability of the U.S. Army Heat Strain Decision Aid (HSDA) to Predict a Limiting Heat Stress Exposure." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/7027.
Texte intégralRésumé :
Working below the threshold limit value (TLV) for heat stress is not always feasible. When work above the TLV is required, an exposure method is needed that can help protect workers from time limiting heat stress by calculating a safe time for work at certain heat exposures. The purpose of this paper is to determine whether the USARIEM Heat Strain Decision Aid (HSDA) can be used to predict time limiting heat stress exposure in an occupational setting.
Twelve adults participated in time limited heat stress exposures. A range of heat stress conditions were designed using three different ensembles and five different heat stress levels. Safe exposure times were assigned based on limiting criteria for core temperature (38.5°C), high heart rate (90% of age-estimated maximum), or willingness to continue. The HSDA process was adapted to an Excel function using Visual Basic for Applications (VBA) and trial data were input data to the HSDA function. A second HSDA function was used to find a predicted core temperature for fixed a standard person using a height of 170cm, a weight of 70kg, and an initial core temperature of 37°C.
The logistic regression and probability of the individual data as well as the fixed data were compared. We found that the HSDA could be used to assess time limiting exposures in an occupational setting when workers are working above the TLV.
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Yin, Jennifer, and Chris Dehmelt. "A Common Solution to Custom Network Applications." International Foundation for Telemetering, 2007. http://hdl.handle.net/10150/604467.
Texte intégralRésumé :
ITC/USA 2007 Conference Proceedings / The Forty-Third Annual International Telemetering Conference and Technical Exhibition / October 22-25, 2007 / Riviera Hotel & Convention Center, Las Vegas, Nevada<br>The deployment of networks has become ubiquitous in the avionics world, as they have opened
the door to a rich suite of common and open hardware and software tools that provide greater
functionality and interoperability. Unfortunately, a number of networked avionic and other
related applications can be affected by vendor or application specific proprietary
implementations. These “closed” implementations may reduce or eliminate the benefits of a
standardized network, requiring the customization of the data acquisition system to allow it to
properly operate with the other devices.
This paper presents the approach that was recently employed for the development of a network
interface module that can be quickly reconfigured to address the changing requirements of
network applications, including monitoring of industry standard and proprietary networks, or
providing the command and data interface to the data acquisition system itself. This reconfigurability
of the module is shown in a review of four different specific applications.
29
Iqbal, Javaid. "Role of intra-cellular glucocorticoid regulation in vascular lesion development." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4810.
Texte intégralRésumé :
Atherosclerosis and post-angioplasty neointimal proliferation, which are leading causes of cardiovascular morbidity and mortality, develop as a result of chronic or acute vascular injury producing inflammatory and proliferative responses in the vessel wall. Glucocorticoids, the stress hormones produced by the adrenal cortex, have anti-inflammatory and anti-proliferative characteristics and can also influence systemic cardiovascular risk factors. The systemic levels of these hormones are controlled by the hypothalamic pituitary adrenal axis. However, there is also a tissue-specific pre-receptor regulation of these hormones by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD); type 1 regenerates active glucocorticoids within the cells and type 2 inactivates glucocorticoids. Whilst it has been shown that the inhibition of 11β-HSD1 has favourable effect on cardiovascular risk factors and the inhibition of 11β-HSD2 results in hypertension; the effect of these enzymes on vascular lesion development is not known. The work described in this thesis tested the hypothesis that 11β-HSD1 inhibition reduces vascular lesion development due to improvement in cardiovascular risk factors, whereas 11β-HSD2 inhibition leads to adverse vascular remodelling. Apolipoprotein-E deficient (ApoE-/-) mice fed on western diet were used to study atherosclerosis, whereas neointimal proliferation was investigated using a well-established mouse model of wire-angioplasty. Vascular lesions were assessed using novel imaging and standard histological techniques. 11β-HSD1 inhibition reduced the size of atherosclerotic lesions and improved markers of plaque stability with a reduction in lipid content and increase in collagen content of the plaques. This was associated with a reduction in weight gain and blood pressure but without any effect on lipid profile. 11β-HSD1 inhibition did not produce any significant effect on neointimal proliferation in C57Bl/6J mice. However in ApoE-/- mice, 11β-HSD1 inhibition reduced neointimal proliferation with corresponding increase in size of patent lumen and with an associated reduction in macrophage content of neointimal lesions. 11β-HSD2 deletion produced an outward remodelling in un-injured vessels but there was no effect on neointimal proliferation after wire-angioplasty. Administration of a selective mineralocorticoid antagonist, eplerenone, reduced neointimal lesions significantly but to a similar degree in both C57Bl/6J and 11β-HSD2-/- mice, associated with a significant reduction in macrophage content of lesions but without any effect on blood pressure. Data in this thesis highlight the potential therapeutic application of 11β-HSD1 inhibition in reducing the size and vulnerability of atherosclerotic plaques and also reduction in neointimal proliferation (and hence post-angioplasty restenosis) in high risk patients with „metabolic syndrome‟ phenotype. The results also indicate that 11β-HSD2 has a limited, if any, role to play in the development of neointimal lesions.
30
Hibberd, Carina Jayne. "Investigating the significance of 11β-HSD type 1 in the ageing brain". Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/24698.
Texte intégralRésumé :
In-situ-hybridisation of the mouse hippocampus and cerebellum, showed no changes in 11β-HSD1 mRNA with ageing. However, decreases in mRNA of corticosteroid receptors indicated a possible, neuro-protective mechanisms through changes in GC signalling. The improved ageing in a hippocampal –dependent behavioural task, was further investigated on a C57BL/6 background. Middle-aged mice showed improved long-term memory in a Y-maze spatial learning test, with no differences in short-term or working memory. In light of the GC role in anxiety and exploration, the elevated-plus-maze and open-field were investigated. There were no definitive differences in visits to arms of the elevated-plus-maze, but an increase in risk assessment suggested increased anxiety in the young Ko (<i>vs</i> young control). The young Ko were more active than the young control in the open-field, exploring the outer zone proportionally more than young control, again suggesting increased anxiety, certainly behavioural activation. The significance of enzyme expression in the cerebellum was explored using a motor-learning task. Over 5 days of learning, the young Ko were impaired compared with young controls and there was a negative effect of age. Although, 11β-HSD1 has been shown as a reductase in hippocampal neurons, there remains some debate over the activity direction in other cells of the brain. To address this, activity was measured in primary, cultured cells from brain regions of interest. No significant activity was found in cells from the frontal cortex, but cerebellar granular neurons showed reductase activity comparable with hippocampal cultures.
31
Darnel, Andrew D. "Regulation of endometrial 11ß-hydroxysteroid dehydrogenase (11ß-HSD) types I and II." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ39814.pdf.
Texte intégral
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Patel, Jaynish. "The cloning, expression and mutagenesis of the recognition subunit, HsdS, from the EcoR124 R-M system." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316666.
Texte intégral
33
Davies, Graham Peter. "Motifs in the HsdR subunit of EcoKI necessary for ATP-dependent DNA translocation and DNA cleavage." Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/13586.
Texte intégralRésumé :
The type I restriction enzyme <i>Eco</i>KI specifies DNA methyltransferase, ATPase, DNA translocase and endonuclease activities. One subunit (HsdR) of the oligomeric enzyme contributes to those activities essential for restriction. These activities are thought to involve ATP-dependent DNA translocation and DNA cleavage. Analyses of recently predicted amino acid sequences of known and putative type I restriction endonucleases indicates conservation of eight amino acid motifs in the HsdR subunit. Seven are characteristics of the DEAD-box family of proteins that comprise known, or putative, helicases whilst the eighth was identified as a putative endonuclease motif due to its similarity to the active sites of type II restriction endonucleases and other nucleases. Secondary structure predictions based on sequences alignments of HsdR sequences suggest the DEAD-box motifs reside in domains similar to the catalytic domains of DNA helicases of known structure. Mutations affecting each of the DEAD-box motifs, including a new candidate for motif IV, impair or abolish restriction activity <i>in vivo</i> and ATPase activity <i>in vitro</i> (Webb <i>et al</i>., 1996; Webb, 1998; Davies <i>et al.,</i> 1998). Alteration of conserved residues in the putative endonuclease motif resulted in complete loss of restriction <i>in vivo</i> and endonuclease activity <i>in vitro</i>. Enzyme purified from two of these mutants, those with the alterations D298E and E312H, bound DNA with an <i>Eco</i>KI target and hydrolysed ATP at rates equivalent to wild-type on covalently-closed circular DNA with unmodified targets without introducing any nicks or breaks into the DNA. To investigate the role of conserved motifs in HsdR on DNA translocation more directly an assay based on the <i>Eco</i>KI-dependent entry of T7 DNA was used (Garcia and Molineux, 1999). Mutations within the seven DEAD-box motifs abolished translation activity <i>in vivo</i> whereas conservation mutations in the putative endonuclease motif had no significant effect on DNA translocation <i>in vivo</i>.
34
Pan, Tianyuan [Verfasser], Edmund [Akademischer Betreuer] Maser та Sabine [Gutachter] Fuchs. "Isolation and identification of two repressors, TetR AND LuxR, FOR 3,17β-hsd and 3α-hsd/cr gene regulation in Comamonas testosteroni / Tianyuan Pan ; Gutachter: Sabine Fuchs ; Betreuer: Edmund Maser". Kiel : Universitätsbibliothek Kiel, 2019. http://d-nb.info/1202630332/34.
Texte intégral
35
Mbeko, Simaleko Marcel. "Efficacité d’interventions de prévention, basées sur une meilleure prise en compte des besoins perçus et vécus des HSH en République Centrafricaine." Doctoral thesis, Universite Libre de Bruxelles, 2020. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/316093.
Texte intégralRésumé :
Résumé français :Problématique :les hommes qui ont des rapports sexuels avec des hommes (HSH) constituent les populations les plus à risque d’infection au VIH dans différents pays d’Afrique subsaharienne. A ce jour, très peu d’interventions sont menées pour réduire le risque d’infection en influant sur les facteurs de risque, en Afrique Centrale et particulièrement en République Centrafricaine. Les objectifs de cette thèse visent à démontrer que les HSH sont identifiables et sont à risque des IST/VIH, que leur simple suivi médical ne permet pas un changement de comportements sexuels et réduire la fréquence des IST/VIH, mais que la combinaison d’interventions comportementale, biomédicale et structurelle permet, même en période de crise humanitaire, le changement de comportement sexuel et la réduction de la fréquence des IST/VIH. Méthodologie :Les HSH ont été enrôlés progressivement depuis 2010 pour atteindre un nombre de 220 en 2014. L’étude préliminaire sur les caractéristiques sociodémographiques et pratiques sexuelles à risque a concerné les 103 premiers HSH enrôlés en 2010. En 2012, la cohorte atteint le nombre de 170 HSH parmi lesquels 99 qui avaient un dossier médical complet ont fait l’objet de la deuxième étude du suivi sur deux ans.En 2013, alors que la cohorte des HSH avait atteint 200, 20 HSH ont été interviewés dans le cadre de l’étude qualitative. En 2014, la cohorte des HSH a atteint le nombre de 220. L’étude d’intervention a concerné 40 HSH sélectionnés sur les 220 et s’est poursuivie jusqu’en 2016.Résultats :L’analyse des caractéristiques socio démographiques des 103 HSH relève la présence de HSH jeunes. L’âge varie entre 15 et 40 ans, avec une médiane à 23 ans. Les pratiques sexuelles à risque sont fréquentes, notamment les premiers rapports sexuels avant 16 ans et sans préservatifs (70%) ;7% n’ont jamais utilisé les préservatifs, 56 % sont bisexuels, 98% pratique la pénétration anale. 31 HSH soit 24 %, étaient séropositifs pour le VIH ;22 soit 17% étaient infectés par le virus de l'hépatite B (VHB), dont 6 cas étaient coinfectés par le VIH et le VHB (M.B. Simaleko, et al.- Médecine d'Afrique Noire 6010 - Octobre 2013 - 409-414).En 2012, après deux ans de suivi médical et de counseling, il n’y a pas eu de changement de comportement et de pratiques sexuelles à risque, notamment en ce qui concerne la fréquence des rapports non protégés et la moyenne du nombre de partenaires occasionnels. La fréquence des principales IST a augmenté. Les prévalences du VIH, de la syphilis et de l’hépatite ont augmenté de manière significative et respectivement de 29% à 41%, de 12% à 21% de 14% à 23%. (Mbeko Simaleko M. et al. Pan Afr Med J. 2018; 29: 132).L’entretien avec les HSH a révélé plusieurs obstacles à l’utilisation des préservatifs, notamment, les ruptures, leur disponibilité, les fausses croyances, les pressions de l’entourage. (Mbeko Simaleko M. et al. Médecine et Santé Tropicale 2018 ;28 :424-429). De 2014 à 2016, l’étude d’interventions sur 40 HSH choisis de manière aléatoire et basée sur la combinaison des interventions comportementale, biomédicale et structurelle a permis d’améliorer le comportement et pratiques sexuelles des HSH par la réduction significative du nombre de partenaires sexuels occasionnels et l’augmentation significative de la fréquence des rapports sexuels protégés. À cet effet, il a été noté un seul cas de nouvelle infection par le VIH parmi les séronégatifs des 40 HSH contre 9 cas dans le groupe témoin. Aucune nouvelle infection au virus de l’hépatite B dans le groupe intervention contre 18, dans le groupe témoin. Il y a une augmentation significative de séropositifs dans le groupe témoin comparativement au groupe intervention en ce qui concerne la sérologie de la syphilis. (Mbeko Simaleko M. et al. Health Sci. Dis. 2020; 21: 94-99). Conclusion :les HSH sont identifiables et à risque. Le simple suivi médical associé au counseling ne permet pas d’améliorer le comportement sexuel et réduire la fréquence des IST. Cependant la combinaison des interventions a permis d’améliorer le comportement et la prise de risques des HSH mais également de réduire la fréquence des IST, même en période de crise humanitaire. Au vu du faible nombre de HSH inclus dans l’étude, il serait nécessaire d’étendre celle-ci, afin de conforter les résultats obtenus.Abstract Issue: Men who have sex with men (MSM) are the most at risk populations of HIV infection in different countries of sub-Saharan Africa. To date, very few interventions have been carried out to reduce the risk of infection by influencing on risk factors in Central Africa and particularly in the Central African Republic. The objectives of this research are to demonstrate that MSM are identifiable and at risk of STI/HIV, that the medical follow-up does not cause a change in sexual behavior and a reduction in the frequency of STI/HIV but that the combination of behavioral, biomedical and structural interventions allows, even in times of humanitarian crisis, behavioral change and reduction in the frequency of STI/HIV. Methodology: MSM have been progressively enrolled since 2010 to reach a number of 220 in 2014. The preliminary study on sociodemographic characteristics and sexual risk practices involved the first 103 MSM recruited until 2011. In 2012, 99 MSM who had a complete medical record were the subject of the second study on a two-year follow-up. In 2013, when the MSM cohort reached 200, 20 MSM were interviewed in the context of the qualitative study. In 2014, the MSM cohort reached 220. The intervention study involved 40 selected MSM out of the 220 and was continued during 2016.Results: MSM are predominantly young Their age varied between 15 and 40 years, with a median of23 years. Risky sexual practices were frequent, including first sexual intercourse before the age of 16 and without condoms (70%); 7% never used condoms, 56% are bisexual, 98% practice anal penetration. 31 MSM, or 24%, were HIV-positive; 22, or 17%, were infected with hepatitis B virus (HBV), of which 6 cases were co-infected with HIV and HBV (M.B. Simaleko, Set al. - Médecine d'Afrique Noire 6010 - Octobre 2013 - 409-414). In 2012, after two years of medical follow-up and counselling, there was no change in risk behavior and sexual practices, including the frequency of unprotected sex and the average number of occasional partners.The incidence of major STIs increased. The prevalence of HIV, syphilis and hepatitis increased significantly and respectively from 29% to 41%, from 12% to 21%, from 14% to 23%, respectively (Mbeko Simaleko M. et al. Pan Afr Med J. 2018; 29: 132). Interviews with MSM revealed several barriers to condom use, including condom breaks, condom availability, false beliefs, and peer pressure (Mbeko Simaleko M. et al. Médecine et Santé Tropicale 2018; 28: 424-429). From 2014 to 2016, the intervention study of 40 randomly selected MSM based on a combination of behavioral, biomedical, and structural interventions improved the sexual behavior and practices of MSM by significantly reducing the number of occasional sexual partners and significantly increasing the frequency of safer sex. Only 1 case of new HIV infection was noted among the 40 HSH HIV-negative compared to 9 cases in the control group. There were no new hepatitis B virus infections in the intervention group versus 18 in the control group. There was a significant increase in seropositivity in the control group compared to the intervention group with respect to syphilis serology (Mbeko Simaleko M. et al. Health Sci. Dis: Vol 21 (7) July 2020 pp 94-99). Conclusion: MSM were identifiable and most of them were at HIV risk. Simple medical follow-up combined with counselling does not allow to improve sexual behavior or to reduce the frequency of STIs. However, the combination of interventions has made it possible to improve the behavior and risk-taking of MSM and also to reduce the frequency of STIs, even in times of humanitarian crisis. In view of the low number of MSM included in the sample study and in order to consolidate the results obtained, it would be necessary to carry out a more in-depth study with a larger sample of MSM.<br>Doctorat en Santé Publique<br>info:eu-repo/semantics/nonPublished
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Puigoriol, Illamola Dolors. "Stress influence in neurodegeneration. Unravelling the mechanisms underlying stress response in brain ageing by 11ß-HSD1 inhibition." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/671427.
Texte intégralRésumé :
The world is facing an unprecedented situation: soon the number of people over 60 years old will exceed the number of children, and more people at extreme old age than ever before. This is due to medical advances that have increased life expectancy and with it, the number of elderly. The latest data published by the WHO predicts that by 2050 the world’s population aged 60 years and older is expected to nearly double from 12% to 22% achieving a total 2 billion, up from 900 million in 2015. A longer life brings with it opportunities, however, there is little evidence to suggest that older people today are experiencing their later years in better health than their parents. While rates of severe disability have declined over the past 30 years, there has been no significant change in mild to moderate disability over the same period. If this added years are dominated by declines in physical and mental capacity, the implications for older people and for society will be more negative. Therefore, in the last years research has focused on the biology of ageing with the purpose of achieving better understanding of its mechanisms for preventing the onset and progression of age-related conditions.
Besides, modern society is experiencing an increasingly common stressful lifestyle together to increased rates of metabolic stress caused, in part, by high-fat diet consumption. Several pieces of evidence state that environmental factors are essential in determining the development of different diseases as well as compromising healthy ageing. With upcoming age, the capability to fight against harmful stimuli decreases and the organism becomes more vulnerable to infections and disease. In agreement, stressful experiences have been identified as an important risk factor for cognitive impairment. Therefore, it is important to study the molecular mechanisms underpinning the effects of chronic stress on cognition and its relationship with ageing in order to unveil what challenges we might have to cope with as a society in the not-so-far future.
In parallel with ageing, stress and neurodegenerative diseases, such as Alzheimer’s disease (AD), there is impaired glucocorticoid (GC) signalling. Disturbances in the GC-mediated stress response and individual’s adaptive abilities appear to increase the vulnerability of elderly to age-related pathologies. In consequence, the present doctoral dissertation has been focused on the study of the mechanisms involved in age-related neurodegeneration modified by GC excess attenuation through the inhibition of the enzyme 11β-HSD1 in an animal model of accelerated ageing, as well as, their response to chronic mild stress exposure. Last but not least, the present doctoral thesis has been devoted to evaluate the GC-mediated stress response to chronic moderate stressful situations and to metabolic stress underlying neurodegeneration and the potential role of 11β-HSD1 inhibition to restore those detrimental effects induced by stress.
In summary, results obtained pointed out a protective role of the 11β-HSD1 inhibitor tested as improved cognitive and behavioural abilities of aged mice, as well as restored the deleterious effects induced by stressful conditions applied. Additionally, some of the molecular pathways related to ageing and neurodegeneration – particularly, AD neurodegeneration – were altered as a consequence of stress, but most of them were re-established after 11β-HSD1 inhibition, such as proteostasis, oxidative stress, neuroinflammation and epigenetics, among others. Overall, GC excess attenuation may become a potential therapeutic strategy for age-related cognitive decline.
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Ketzner, Karissa Marie Wilson David A. "11[beta]-HSD₂ activity in an equine distal limb and thoracic wound model." Diss., Columbia, Mo. : University of Missouri-Columbia, 2009. http://hdl.handle.net/10355/6662.
Texte intégralRésumé :
"December 2009" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on January 5, 2010). Thesis advisor: David A. Wilson. Includes bibliographical references.
38
Trottier, Alexandre. "Étude de l'action du PBRM, un inhibiteur de la 17β-hydroxystéroïde déshydrogénase (17β--HSD) type 1 : ...qui mena à la découverte fortuite d'un 1er activateur de la 17β-HSD type 12". Master's thesis, Université Laval, 2014. http://hdl.handle.net/20.500.11794/25503.
Texte intégralRésumé :
Les 17β-hydroxystéroïdes déshydrogénases (17β-HSD) sont un groupe de 15 enzymes connues avant tout pour leur rôle dans le métabolisme des hormones sexuelles. La 17β-HSD1 est responsable de la toute dernière étape dans la fabrication des estrogènes actifs. Cela en fait une cible intéressante pour traiter l’endométriose et le cancer du sein qui sont stimulées par ces hormones. Le dérivé stéroïdien PBRM, conçu dans notre laboratoire, est l’une des rares molécules ayant démontré une inhibition forte et spécifique de la 17β-HSD1. Lors des présents travaux, l’effet de l’inhibiteur s’est avéré irréversible, sélectif et durable tout en présentant un profil intéressant chez la souris. Durant ce processus, plusieurs composés n’ayant pas les qualités requises ont été mis de côté. Parmi eux, l’un s’est avéré être un activateur de la 17β-HSD12, une enzyme essentielle dans l’élongation des acides gras. Il s’agit là du premier activateur rapporté pour la famille des 17β-HSD.<br>17β-Hydroxysteroid dehydrogenases (17β-HSD) are a group of 15 enzymes known firstly for their involvement in sexual hornomes metabolism. 17β-HSD1 is responsible of the last step in the biosynthesis of potent estrogens. It is thus an interesting target to treat diseases stimulated by those hormones such as endometriosis and breast cancer. PBRM, a steroidal inhibitor developed in our laboratory, is one of the few molecules that shown a strong and specific inhibition of 17β-HSD1. The present works showed that the inhibitory effect is irreversible, selective and long-lasting while showing an interesting profil in mice. During that process, many other compounds were tested but didn’t have the required qualities. Among them, one seemed to stimulate the activity of 17β-HSD12, an essential enzyme for fatty acids elongation also involved in estrogen metabolism. It is the first reported activator for a member of 17β-HSD family.
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Guerra, Enriquez Guillermo José. "Factores conductuales y cognitivos asociados al riesgo de contraer VIH en un grupo de HSH." Bachelor's thesis, Pontificia Universidad Católica del Perú, 2017. http://tesis.pucp.edu.pe/repositorio/handle/123456789/9892.
Texte intégralRésumé :
La presente investigación buscó describir los factores conductuales (conductas sexuales de
riesgo) y factores cognitivos (conocimientos, actitudes negativas y positivas,
susceptibilidad y autoeficacia percibida) asociados al contagio del VIH en un grupo de 56
hombres que tienen sexo con otros hombres (HSH). Ellos asisten a una ONG en Lima, con
edades entre 20 y 54 años (DE= 29.95). Para el objetivo, se usó parte del Cuestionario
Confidencial de Vida Sexual Activa (CCVSA) desarrollado por el Ministerio de Salud de
Colombia con la colaboración de la Organización Panamericana de la Salud (OPS) (1997)
y el VIH-65 (Bermúdez, Buela-Casal y Uribe, 2005). Se encontró que el 89% de los
participantes reportan conductas de riesgo para la práctica de sexo oral, otro 61% con el
sexo anal, 50% con el sexo vaginal y el 46% presentó una ITS en el último año. Los altos
índices de incidencia en este tipo de conductas, anales y orales, son alarmantes ya que
estos ponen en riesgo la salud con respecto al VIH. Por otro lado, se encontró niveles
adecuados de conocimientos correctos, autoeficacia y actitudes frente a aspectos
relacionados al VIH y a personas con dicha condición. Sin embargo, las escalas de
susceptibilidad percibida; autoeficacia y actitudes negativas, mostraron índices de
consistencia interna muy bajos por lo que no se pudieron incorporar al análisis de
correlación luego de realizadas las pruebas de confiabilidad. No se hallaron correlaciones
entre las conductas de riesgo y el nivel de conocimientos, ideas erróneas o las actitudes
positivas en la muestra. Se discute la necesidad de realizar más investigaciones y de
desarrollar y/o adaptar instrumentos más específicos a las poblaciones con las que se
pretende trabajar.<br>This research sought to describe behavioral (risky sexual behavior) and cognitive factors
(knowledge, positive and negative attitudes, susceptibility and perceived self-efficacy)
associated to the infection of HIV in a group of 56 men that have sex with other men
(MSM). They attend an NGO in Lima, and their ages range between 20 and 54 years (M=
29.95). The Confidential Active Sexual Life Questionnaire (CCVSA) developed by the
Colombian Ministry of Health with the collaboration of the Pan American Health
Organization (PAHO) (1997) and HIV-65 (Bermudez, Buela-Casal and Uribe, 2005) were
used to reach this objective. It was found that 89% showed risk behaviors in oral sex,
another 61% had risk in anal sex, 50% in vaginal sex and 46% identified an STD in the last
year. These high incidence rates in this type of behavior are alarming and put these
people's health at risk with respect to HIV/AIDS. On the other hand, accurate levels of
knowledge, self-efficacy and attitudes were found. The need for more research is
discussed, as well the development and/or adaptation of more accurate instruments.<br>Tesis
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Bailey, Helen Victoria. "Drug design and novel anti-cancer therapeutics : inhibitors of 17β hydroxysteroid dehydrogenase type 3". Thesis, University of Bath, 2007. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.512267.
Texte intégralRésumé :
Herein, we describe the design and synthesis of novel inhibitors of 17β-hydroxysteroid dehydrogenase type 3 which convert androstenedione into testosterone, which is then converted into dihydrotestosterone (DHT). This isozyme has been implicated in the growth of prostate cancer. Using an in silico pharmacophore model initial targets were planned, based around a diphenylether hydrophobic head linked to a 4-substituted piperidine ring. Over 45 compounds were synthesised and many show significant biological activity when evaluated in a 17β-HSD type 3 biological assay. The most potent compound in this series is 1-(4-[2-(4-chloro-phenoxy[-phenylamino]-piperidin)1-yl) ethanone with an IC₅₀ of 700 nM. The amine linked compounds are significantly more active than the amide equivalents. Synthesis of the amine-linked compounds was problematic and led to the development of a novel and general microwave assisted procedure for the reductive amination of anilines, enabling aromatic amine-linked compounds to be synthesised in excellent yields. A series of benzylamine linked inhibitors was also prepared. Over 30 analogues were synthesised and several show very promising biological activity. The most active compound is N-(2-([2-(4-Chloro-phenoxy)-phenylamino]-methyl)-phenyl)-acetamide, which exhibits an IC₅₀ of 900 nM. The synthesis of compounds with a benzophenone linked hydrophobic head group led to an unexpected product. X-ray crystallography was used to determine the structure, as a quinoline derivative. This led to optimisation of a novel modification of the Friedländer synthesis of quinolines. The potent inhibitors synthesised are selective over 17β-HASD Types 1 and 2. One inhibitor also shows potentially interesting activity against the leukaemia cell line CCRF-CEM, in the NCI screening, with a GI₅₀ of 10 nM.
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Zou, Xiantong. "The role of 11β-hydroxysteroid dehydrogenase type 1 in liver fibrosis and inflammation in non-alcoholic fatty liver disease". Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/18748.
Texte intégralRésumé :
Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem which includes steatosis (triglyceride accumulation alone), non-alcoholic steatohepatitis (NASH, with liver inflammation), fibrosis, cirrhosis and hepatocellular carcinoma. Liver fibrosis, which is a reversible response, is the final phase of most chronic liver disease and is characterized by accumulation of extracellular matrix (ECM) from activated hepatic stellate cells (HSCs). Glucocorticoids (GCs) regulate many aspects of metabolism involved in NAFLD. Also, GCs limit HSC activation in vitro. Tissue GC levels are regulated by 11β- hydroxysteroid dehydrogenase-1 (11β-HSD1) which converts inactive 11- dehydrocorticosterone (DHC) into active corticosterone. Previous studies demonstrate that 11β-HSD1 deficiency improves fatty liver in obesity models, but the role of 11β-HSD1 in mechanisms involved in the progression and/or resolution of hepatic injury is largely unknown. I hypothesized that 11β-HSD1 modulates fibrotic and inflammatory responses during hepatic injury and/or the resolution phase. First I sought to address if the levels of 11β-HSD1 during different models of liver injury are dysregulated. In mice, 11β-HSD1 was down-regulated in choline deficient diet (CDD) induced steatosis, methionine and choline deficient diet (MCDD) induced NASH, carbon tetrachloride (CCL4) induced liver fibrosis and thioacetamide (TAA) induced liver fibrosis. In CCL4 injured livers, the down regulation of 11β- HSD1 was observed around the scar area. To test if 11β-HSD1 plays a key role in modulating liver inflammation and fibrosis responses in NAFLD and liver fibrosis I used initially11β-HSD1 knockout (KO) mice. 11β-HSD1 KO showed higher HSC activation only in the High fat feeding model but not in CDD and MCDD models. In the CCL4 injury model, despite reduced hepatocellular injury, 11β-HSD1 KO mice showed enhanced collagen deposition during peak injury and increased fibrotic gene expression during the early resolution phase although unaltered inflammatory markers during both peak injury and resolution. To further dissect cell-specificity on the effect of 11β-HSD1, I repeated the CCL4-injury model using the hepatocyte-specific 11β-HSD1 KO (Alb-HSD1). Alb-HSD1 mice did not show increased susceptibility to fibrosis compared to control littermates suggesting that the 11β- HSD1 possibly modulates fibrotic response by affecting HSC function. To mechanistically address how GCs inhibit HSC activation in vitro I studied the effects of 11β-HSD1 on HSC in vitro. 11β-HSD1 expression was down-regulated during ‘spontaneous’ HSC activation, and 11β-HSD1 deficiency enhanced susceptibility to activation. The GC (11-DHC)’s inhibitory effect on HSC activation was reversed by 11β-HSD1 inhibition. Finally, to address the clinical relevance of 11β-HSD1 in hepatic injury and/or resolution a selective 11β-HSD1 inhibitor, UE2316, was used. UE2316 induced a pro-fibrotic phenotype in ob/ob mice and CCL4-treated C57BL/6 mice, but had no effect when administered only during injury resolution. In conclusion, 11β-HSD1 deficiency causes increased activation of HSCs following diet and chemical injury and promotes liver fibrosis. Effects of 11β-HSD1 inhibitors, which are a potential treatment for metabolic syndrome, are perhaps offset by adverse outcomes in liver.
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Fallou, Hélène. "Adsorption sur des tissus de carbone activé de micropolluants émergents à l'état de traces dans les eaux : Traitements multi-échelles et modélisation." Rennes, Ecole nationale supérieure de chimie, 2015. http://www.theses.fr/2015ENCR0027.
Texte intégralRésumé :
Aujourd’hui, de nombreuses études ont montré la présence de micropolluants dans les eaux. Ces composés ne sont que partiellement éliminés par les procédés conventionnels de traitement des eaux. Les procédés d’adsorption montrent un potentiel intéressant pour éliminer ces polluants. Dans un premier temps, l’étude des capacités d’adsorption sur des tissus de carbone activé de 9 micropolluants émergents a été effectuée dans des réacteurs fermés agités, afin de déterminer les cinétiques et isothermes d’adsorption dans des conditions proches des conditions environnementales (C0 = 1 μg. L-1 et en présence de matières organiques). Cette première étape a permis de montrer une compétition importante entre les matières organiques et les polluants aux faibles concentrations (réduction des capacités d’adsorption de 30 à 95 % en présence de 2 mgC. L-1 pour des concentrations en soluté de 1 μg. L-1). De plus, les matières organiques diminuent la diffusivité de surface des solutés. Ces paramètres fondamentaux, déterminés à l’échelle du laboratoire sont utilisés pour prédire les courbes de percée obtenues à l’échelle pilote. Une unité de filtration sur des tissus de carbone activé d’une capacité de 50 L. H-1 a été réalisée pour traiter des eaux dopées avec une solution de polluants (C0 = 1 μg. L-1). Cette unité pilote est mise en oeuvre pour étudier l'abattement d'une pollution chronique. Différentes conditions opératoires ont été étudiées telles que la vitesse, l’influence des matières organiques, la nature du matériau. Les capacités d’adsorption sont impactées par le passage en dynamique et le possible développement d’un biofilm à la surface des tissus<br>Nowadays, several studies have shown the occurrence of emerging pollutants into aquatic compartments. These compounds are not totally removed using conventional treatments. Adsorption processes are promising to remove these undesirable polluants. The first part of our study focuses on the determination of adsorption kinetics and isotherms of 9 compounds, onto activated carbon fiber cloths (ACFC). These experiments were carried out using batch reactors under synthetic and environmental conditions (i. E. Initial concentrations of 1 μg. L-1 and in the presence of natural organic matter). Competitions of adsorption with natural organic matter were especially critical at trace concentrations (decrease between 30 and 95 % of the adsorption capacities at equilibrium concentration of 1 μg. L-1, with 2 mgC. L-1). The competition with the organic matter led to a large decrease of the surface diffusivity. Then, the second part is dedicated to the efficiency of the adsorption process using a fixed-bed of ACFC. Breakthrough curves were experimentally determined and simulated using fundamental parameters obtained from batch-scale experiments. An adsorption pilot, with a flow of 50 L. H-1, was carried out to treat polluted waters (C0 = 1μg. L-1). This pilot is used to study a chronical pollution removal. Various operating conditions were tested and their influence was evaluated: the type of water (tap water, surface water with different contents of natural organic matter), the velocity of the liquid phase through the filter, and the type of ACFC. Adsorption capacities are impacted by the dynamic conditions and the potential development of a biofilm on the surface of material
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Garcia, Roberto. "Fatores envolvidos nos comportamentos de omissão circunstancial e de recusa do uso do preservativo em homens que fazem sexo com homens." Pontifícia Universidade Católica de São Paulo, 2016. https://tede2.pucsp.br/handle/handle/19132.
Texte intégralRésumé :
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Previous issue date: 2016-07-08<br>This study aimed to identify and understand factors involved in conducts of circumstantial omission and refusal of condom use with casual and/or stable partners by MSM living with HIV+; and as a specific objective, to understand the behavior of intentional and deliberate refusal of condom use among MSM with HIV+. In this research of mixed methods, comparing reports between quantitative and qualitative components, 178 participants were selected for the quantitative stage (total sample = T), who filled out a sociodemographic form with condom usage habits, as well as two scales – Barratt Impulsiveness Scale (BIS-11) and Sexual Compulsivity Scale (SCS). From this universe, 81 participants were selected for the qualitative stage (Subsample = S-2), also answering to three fictional-projective stories and rating a 2014 National Campaign Poster on HIV. For the qualitative analysis we used the Discourse of the Collective Subject; and for the quantitative analysis we opted for the combination of Natural Language Processing and triangulation with qualitative results. Among the main findings we highlight that, in the quantitative stage, from the 73 subjects (41%) (T) that had declared the use of condom in all their sexual relations, only 14 (17.3%) (S-2) effectively admitted its use in the qualitative stage, indicating divergence between the two groups. Similarly, this contradiction was repeated as to the use of psychoactive substances – characterized in this study as the main triggering factor of condom use omission –, since only 28% (T) initially admitted having used them, in contrast to the total of 56% (S- 2) in the qualitative stage. Another difference that would mean a "clear proof" of failure and refusal of condom use occurred in their assertion of having contracted STIs after the HIV diagnosis, identified in 35.5% (T) and 52% (S-2), respectively. Another finding was the intentional and deliberate refusal of condom use associated with signs of compulsive sexual behavior and risk in pleasure, including the barebackers and those practiced in cruising areas. Given the significant divergences between the initial reports of the participants and what was later identified in the two stages of this research, we conclude that clinical guidelines and public policies should be cautious in research interpretation, with proper checkings associated with further investigations. The clinical features observed in this study, including the evidence of impulsive and compulsive sexual behaviors, may constitute determining benchmarks to be taking into account in future actions associated to the use of condoms by MSM with HIV+<br>Cette étude a eu pour but principal d‟identifier et de comprendre les facteurs impliqués dans le comportement de l'omission circonstancielle et le refus de l'utilisation du préservatif avec des partenaires occasionnels et / ou stables des HSH VIH+; et comme objectif spécifique, comprendre le comportement de refus intentionnel et délibéré de l'utilisation du préservatif chez les HSH VIH+. Dans cette recherche utilisant des méthodes mixtes, qui a comparé les récits recueillis chez les composantes quantitatives et qualitatives, 178 participants ont été sélectionnés pour l‟étape quantitative (échantillon total = T), ceux-là ont rempli un formulaire socio-démographique portant également sur leurs habitudes d'utilisation du préservatif, et deux échelles - la Barratt Impulsiveness Scale (BIS-11) et l'Échelle de la Compulsion Sexuelle (ECS). Dans cet univers, 81 participants ont été alors choisis (sous-échantillon = S-2) pour l'étape qualitative, lesquels ont également répondu à trois histoires fictives-projectives et évalué une affiche de la Campagne nationale contre le VIH de 2014. Comme méthode d'analyse qualitative, nous avons utilisé le Discours du sujet collectif; et pour l'analyse quantitative, nous avons choisi la combinaison du Traitement de la langue naturelle et la triangulation avec des résultats qualitatifs. Parmi les principaux résultats, nous soulignons que, au cours de l‟étape quantitative, sur les 73 sujets (41%) (T) qui avaient déclaré initialement avoir utilisé des préservatifs lors de toutes les relations sexuelles, au cours de l‟étape qualitative seulement 14 (17,3%) (S-2) ont admis l‟utiliser effectivement, ce qui montre des divergences entre les deux groupes. Cette contradiction s‟est répétée en ce qui concerne l'utilisation de substances psychoactives - caractérisée dans cette étude comme le principal facteur déclencheur de l'omission de l‟utilisation du préservatif -, car seulement 28% (T) ont initialement admis les utiliser, en contraste avec le total de 56% (S- 2) lors de l‟étape qualitative. Une autre divergence, qui représenterait une «preuve définitive» de l'omission et du refus de l'utilisation du préservatif, a eu lieu lorsqu‟ils ont déclaré avoir contracté les MST après le diagnostic du VIH, identifiée dans 35,5% (T) et dans 52% (S-2) respectivement. Une autre constatation est le refus intentionnel et délibéré de l'utilisation du préservatif associé à des indices de comportement sexuel compulsif et le plaisir du risque, parmi lesquels ceux des barebackers et ceux pratiqués dans les cruising areas. Compte tenu des divergences importantes existant entre les récits initiaux des participants et ce qui a été identifié plus tard au cours des deux étapes de cette recherche, nous avons conclu que les orientations cliniques et celles des politiques publiques doivent être plus prudentes en ce qui concerne l'interprétation des enquêtes, en effectuant les vérifications nécessaires associées à une investigation plus approfondie. Les caractéristiques cliniques observées dans cette étude, parmi lesquelles les indices de comportement sexuel impulsif et compulsif, peuvent constituer des référentiels déterminants à prendre en considération lors des actions futures concernant l'utilisation des préservatifs chez les HSH VIH+<br>Este estudo teve como objetivo principal identificar e compreender fatores envolvidos nos comportamentos de omissão circunstancial e recusa do uso do preservativo com parcerias eventuais e/ou estáveis de HSH HIV+; e, como objetivo específico, compreender o comportamento de recusa intencional e deliberada do uso do preservativo entre HSH HIV+. Nesta pesquisa de métodos mistos, que comparou os relatos entre os componentes quantitativos e qualitativos, foram selecionados 178 participantes para a etapa quantitativa (amostra total = T), que preencheram um formulário sociodemográfico e de hábitos do uso do preservativo, e duas escalas – a Barratt Impulsiveness Scale (BIS-11) e a Escala de Compulsividade Sexual (ECS). Desse universo, foram então selecionados 81 participantes (Subamostra = S-2) para a etapa qualitativa, que também responderam a três histórias fictício-projetivas e avaliaram um cartaz de Campanha Nacional do HIV de 2014. Como método de análise qualitativa, utilizamos o Discurso do Sujeito Coletivo; e para a análise quantitativa optamos pela combinação de Processamento de Língua Natural e triangulação com resultados qualitativos. Dentre os principais resultados encontrados destacamos que, na etapa quantitativa, dos 73 sujeitos (41%) (T) que declararam inicialmente ter usado preservativos durante todas as relações sexuais, na etapa qualitativa apenas 14 (17,3%) (S-2) admitiram efetivamente usá-lo, demonstrando divergências entre os dois grupos. Essa contradição se repetiu no uso de substâncias psicoativas – caracterizado neste estudo como o principal fator desencadeador da omissão do uso do preservativo –, pois somente 28% (T) inicialmente admitiram usá-las, em contraste com o total de 56% (S-2) na etapa qualitativa. Outra divergência, que representaria a “prova cabal” de omissão e recusa do uso do preservativo, ocorreu na declaração de terem contraído DSTs após o diagnóstico do HIV, identificada em 35,5% (T) e em 52% (S-2), respectivamente. Outra constatação foi a recusa intencional e deliberada do uso do preservativo associada a indícios de comportamento sexual compulsivo e prazer no risco, entre eles o dos barebackers, e aqueles praticados nas cruising areas. Considerando as significativas divergências entre os relatos iniciais dos participantes e o que foi identificado posteriormente nas duas etapas desta pesquisa, conclui-se que orientações clínicas e de políticas públicas devem ser cautelosas na interpretação de pesquisas, com as devidas checagens associadas a uma investigação mais aprofundada. As características clínicas observadas neste estudo, entre elas os indícios de comportamentos sexuais impulsivos e compulsivos, podem se constituir em referenciais determinantes a serem considerados em futuras ações quanto ao uso do preservativo em HSH HIV+
44
Adie, Jillian E. "Structure-based drug design of 11β-hydroxysteroid dehydrogenase type 1 inhibitors". Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4673.
Texte intégralRésumé :
The enzyme 11β-Hydroxysteroid Dehydrogenase 1 (11β-HSD1) catalyses the intracellular biosynthesis of the active glucocorticoid cortisol. Tissue specific dysregulation of the enzyme has been implicated in the development of metabolic syndrome and other associated diseases. Experiments with transgenic mice and prototype inhibitors show that inhibition of 11β-HSD1 in visceral adipose tissue and liver leads to a resistance of diet-induced hyperglycemia and a favourable lipid and lipoprotein profile as compared to controls. 11β-HSD1 inhibition has thus been proposed as an effective strategy to decrease intracellular glucocorticoid levels without affecting circulating glucocorticoid levels that are essential for stress responses. The clinical development of selective and potent drugs has therefore become a priority. In this research, a process of virtual screening employing the novel algorithm UFSRAT (Ultra Fast Shape Recognition with Atom Types) was used to discover compounds which had specific physicochemical and spatial atomic parameters deemed essential for inhibition of 11β-HSD1. The top scoring compounds were assayed for inhibitory activity against recombinant human and mouse enzyme, using a fluorescence spectroscopy approach. In addition, HEK-293 cell based assays with either human, mouse or rat enzymes were carried out using a scintillation proximity assay (SPA). The most potent compound competitively inhibited human 11β-HSD1 with a Kiapp value of 51 nM. Recombinant mouse and human enzyme were expressed, purified and characterised and used in a series of ligand binding assays. Further to this, an X-ray crystal structure of mouse 11β-HSD1 in complex with a tight binding inhibitor – carbenoxolone was solved.
45
Dudamel, Wilmer. "Modélisation et simulation de l'influence de la température lors de l'adsorption de micropolluants organiques par du charbon actif dans les eaux naturelles." Rennes 1, 2005. http://www.theses.fr/2005REN1S024.
Texte intégralRésumé :
Le but de ce travail est la modélisation, intégrant l’effet de la température, des équilibres et des cinétiques d’adsorption compétitive des pesticides avec la matière organique naturelle (MON). Des expériences en corps pur à différentes températures ont permis de sélectionner un modèle d’équilibre adapté. Les équilibres en compétition ont pu être modélisés en utilisant la théorie de la solution adsorbée idéale (IAST) et le principe d’un composé fictif équivalent (EBC) représentant la MON. L’ajustement des simulations, par le modèle de la diffusion de surface homogène (HSDM) en association avec l’IAST, aux cinétiques expérimentales a fourni les coefficients de diffusion superficielle des pesticides et de l’EBC. Diverses corrélations ont permis de relier l’évolution de ces coefficients à la température, à celle de la diffusion moléculaire ou de la constante d’équilibre. Des relations entre leurs paramètres et des caractéristiques, soit du charbon ou du pesticide ont été mises en évidence.
46
Abdullah, Ammara. "Inhibitors of cytochrome P450 enzymes CYP17 and 17β-HSD3 : their role in the treatment of hormone-dependent prostate and breast cancer". Thesis, Kingston University, 2012. http://eprints.kingston.ac.uk/25093/.
Texte intégralRésumé :
Androgens play an important part in the initiation and progression of hormone-dependent prostate and breast cancer. These types of cancers can be treated by androgen ablation therapy. However, androgen ablation is associated with short (2-3 years) remission of the disease. Therefore therapies that inhibit the systemic biosynthesis of androgens, by targeting the P450 enzymes (CYP17 and 17-[beta]HSD type 3) which catalyse androgen biosynthesis, may represent a rational approach in the treatment of androgen-dependent cancer. Inhibitors of the enzyme CYP17: ketoconazole and liarozole, have been shown to decrease tumour cell adhesion to the endothelium and expression of adhesion molecules. The adhesion of cancer cells to the endothelium is an important preliminary event that underlies cancer matastasis. Within the this study, the development of assays for the enzymes; CYP17 and 17[beta]-HSD3 and the evaluation of a series of compounds which were designed to inhibit these enzymes have been considered. The preliminary screening of the compounds showed good inhibition of 17[alpha]=OHase and 17, 20 lyase components of the CYP17 enzyme in comparison to the reference drug, ketoconazole (KTZ). The IC[sub]50 of compounds 31, 34, 38, 41, 48 and 51 and KTZ was calculated as 14.40 [Mu]M, 5.82 [Mu]M, 0.18 [Mu]M, 1.35[Mu]M, 1.21[Mu]M, 0.50[Mu]M and 5.65[Mu]M respectively. However, only a few of the compounds designed to inhibit 17[beta]-HSD3 showed ap potent inhibitory activity. Compound 132 showed the highest percentage inhibition (40.51 [plus or minus] 0.14%) of 17[beta]- HSD3 activity when compared to the reference drugs, 7-hydroxy flavone (12.90 [plus or minus] 0.31%) and biacalein (13.66 [plus or minus] 0.31%). CYP17 inhibitors did not have any cytoxic effect on human cancerous and non-cancerous cell lines. The adhesion of DU145, PC3 and MCF7 to a non-stimulated HUVEC monolayers was decreased from 100 [plus or minus] 0.01% cell adhesion to 60.93 [plus or minus] 3.95%, 65.79 [plus or minus] 9.39% and 65.12 [plus or minus] 4.04% by compounds 38. 48 and 51 respectively in the absence of tumour necrosis factor alpha (THF-[alpha]). Similarly, compounds 38, 48 and 51 showed the highest anti-adhesion effect of DU145 on stimulated HUVEC monolayers (69.85 [plus or minus] 2.51%) cells respectively. Flow cytometry and immunostaining of intracellular adhesion molecules showed that CYP17 inhibitors did not have any effect on the expression of ICAM-1. In conclusion, the synthesised compounds were found to be good indicators of the CYP17 enzyme with no cytoxic and better anti-adhesion effects when compared to KTZ. Thus, these compounds can be further investigated as a therapeutic strategy against hormone-dependent prostate and breast cancer.
47
Yang, Fu. "Role and regulation of 11β-hydroxysteroid dehydrogenase in lung inflammation". Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4828.
Texte intégralRésumé :
Glucocorticoids are steroid hormones that have potent anti-inflammatory actions. Endogenous glucocorticoid action is modulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyses the interconversion of active glucocorticoids (cortisol, corticosterone) and intrinsically inert forms (cortisone, 11-dehydrocorticosterone). There are 2 isozymes; 11β-HSD type 1 regenerates active glucocorticoids in vivo whereas 11β-HSD type 2 inactivates glucocorticoids. Although 11β-HSD1 is highly expressed in the lung, its role there has been little explored. In this study, the expression and localization of 11β-HSD1 mRNA in lung was confirmed by in situ hybridization. Immunohistochemical staining of mouse lung localized 11β-HSD1 to the cytoplasm of fusiform cells in alveolar walls, in a multivesicular pattern characteristic of interstitial fibroblasts. A lung fibrosis model of inflammation was used to test the role and regulation of 11β-HSD1. The results suggest that levels of 11β-HSD1 mRNA and enzyme were not changed during bleomycin-induced lung inflammation. However, 11β-HSD1-deficient mice showed a more severe inflammatory response than congenic wild-type controls, with greater inflammatory cell infiltration into the lung, and increased levels of HO-1 and iNOS mRNA 14 days following bleomycin installation into lung. Picrosirius red staining of lung sections suggested more collagen deposition in 11β-HSD1-deficient mice than in wild-type controls during the course of the lung inflammatory response. Moreover, whereas naïve 11β-HSD1-deficient mice had significantly lower collagen content in lung (84% of WT levels, p<0.05). 28d after bleomycin there was no significant difference between genotypes (KO having 94% of WT levels, p=0.42) confirming more collagen production in 11β-HSD1-deficient mice following bleomycin. Fibroblasts are critical in the regulation of inflammatory responses and are essential in the model of bleomycin-induced lung injury. Lung fibroblasts may have a different transcriptional regulation of 11β-HSD1 compared to other tissues. In the majority of tissues, 11β-HSD1 can be transcribed from 2 promoters; the P1 promoter is the main promoter used in lung, with other tissues mainly using the P2 promoter. To address the relevance of the P1 promoter in lung and to identify the cell type using the P1 promoter, mouse lungs were collagenase-digested to isolate primary fibroblast and epithelial cells. Isolated lung fibroblasts highly expressed 11β-HSD1, predominantly from the P1 promoter. During passage, primary lung fibroblasts switched promoter usage from P1 to P2. In fibroblast primary culture, treatment with TGF-β for 72h markedly decreased 11β-HSD1 expression to 38% of untreated levels, an effect which was reversed by SB431542, a TGF-β receptor antagonist. Whilst TGF-β reduced levels of mRNA initiating at the P2 promoter, initiation from the P1 promoter was completely repressed. Treatment with TGF-β receptor antagonist increased levels of P1-initiated 11β-HSD1 mRNA by 6.6-fold compared to untreated cells. These data suggest that the switch in 11β-HSD1 promoter usage may be regulated by TGF-β during an inflammatory response. Furthermore, as the P1 and P2 promoters are differentially regulated (e.g. by C/EBPβ, a cytokine-responsive transcription factor), the promoter switch may place 11β-HSD1 under a different transcriptional regulation during inflammation. Taken together, these results suggest that 11β-HSD1 deficiency worsens lung inflammation and results in greater lung fibrosis. Therefore, amplification of intracellular glucocorticoids levels, by 11β-HSD1, may represent an important mechanism to limit the inflammatory response and shape fibroblast function, limiting subsequent collagen production and fibrosis.
48
Garcia, Roberto. "A experiência de estigma e discriminação em homem que faz sexo com homens (HSH) vivendo com HIV." Pontifícia Universidade Católica de São Paulo, 2012. https://tede2.pucsp.br/handle/handle/15115.
Texte intégralRésumé :
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Previous issue date: 2012-05-09<br>Since its beginning, the Aids epidemic has established a series of social representations which hampers the daily life of men who have sex with men (MSM) living with HIV, who see themselves as doubly stigmatized due to their sexual orientation. The main objective of this study is observing the experience of stigma and discrimination in man who has sex with men living with HIV. With this ample target in mind, the specific objectives are: firstly, to observe the possible implications that HIV may cause on seropositive individuals as regards to perception of disease, self-perception as infected, social network, sexual orientation and involved contexts of vulnerability; and secondly, to observe the differences in the experiences of HIV-positive MSM through diagnosis disclosing to the social network by individuals infected before chronification and those infected after chronification. Based on the Theory of Social Representations, this work adopts the technique of the Discourse of the Collective Subject (LEFEVRE & LEFEVRE, 2010), a method of quali-quantitative nature. The corpus of the study is formed by a sample of thirty three MSM living with HIV, between 20 and 60 years of age, from a municipal clinic at the Greater São Paulo. The results reveal a high index of stigma and discrimination, manifested by sensations of fear, rejection, constant state of alert and guilt, in a social network that is fragile and unreliable. These high indexes were reflected in the increase of vulnerability of these individuals, demonstrated by the non-use of condom, by the fear of aggression, by the discrimination and the isolation, among others<br>A epidemia da aids, desde seu início, vem estabelecendo uma série de representações sociais que dificultam o cotidiano de homens que fazem sexo com homens (HSH) vivendo com HIV, que se veem duplamente estigmatizados devido à sua orientação sexual. O objetivo geral deste estudo é observar a experiência de estigma e discriminação em homem que faz sexo com homens vivendo com HIV. Partindo desse objetivo amplo, os objetivos específicos são: primeiro, observar as possíveis implicações que o HIV pode ocasionar nos indivíduos soropositivos, no que tange à percepção da doença, percepção de si enquanto infectado (autopercepção), à rede social, à orientação sexual e aos contextos de vulnerabilidade envolvidos; e segundo, observar as diferenças nas experiências dos HSH HIV+ por meio da revelação do diagnóstico à rede social, pelos indivíduos que se infectaram antes e os que se infectaram depois da cronificação. Fundamentada na Teoria das Representações Sociais, esta dissertação adota a técnica do Discurso do Sujeito Coletivo (LEFEVRE e LEFEVRE, 2010), que é um método de natureza qualiquantitativa. O corpus de estudo compõe-se de uma amostra de trinta e três HSH vivendo com HIV, entre 20 a 60 anos, de uma clínica municipal da Grande São Paulo. Os resultados mostraram alto índice de estigma e discriminação, manifestadas pelas sensações de medo, rejeição, constante estado de alerta e culpa, em uma rede social frágil e não confiável. Estes índices elevados refletiram-se no aumento da vulnerabilidade desses sujeitos, demonstrado pelo não uso da camisinha, pelo medo de ser agredido, pela discriminação e pelo isolamento, dentre outros
49
Vaz, Aura Maria de Morais. "Descoberta e desenvolvimento de inibidores da 17ß-HSD-1 potencialmente úteis no tratamento do cancro da mama." Master's thesis, Universidade da Beira Interior, 2012. http://hdl.handle.net/10400.6/1133.
Texte intégralRésumé :
Capítulo I
O cancro da mama é o cancro mais comum entre as mulheres. Neste contexto, diversos estudos evidenciam que entre 40 a 60% de todos os cancros da mama são considerados hormono-dependentes, dependendo principalmente de 17β-estradiol para o seu desenvolvimento. No corpo humano, este estrogénio é originado maioritariamente a partir da estrona, um estrogénio com baixa atividade estrogénica, pela ação da enzima 17β-hidroxiesteroide desidrogenase tipo 1 (17β-HSD-1). Como esta enzima se encontra em elevadas quantidades em tecidos cancerígenos dependentes de estrogénios e tem elevada seletividade, a descoberta de inibidores da 17β-HSD-1, com o objetivo de minimizar a formação de estradiol, está a ganhar grande interesse nos dias de hoje.
Assim, baseado no conhecimento prévio de que vários D-homoesteroides têm interessantes propriedades inibitórias da 17β-HSD-1, neste trabalho pretende-se desenvolver vários derivados da estrona como potenciais inibidores da 17β-HSD-1 com elevadas propriedades inibitórias, baixa toxicidade e preparação sintética simples. Para este propósito foram realizados estudos computacionais, tais como o docking molecular e avaliação toxicológica in silico. A partir destes estudos, várias moléculas, em especial derivados da estrona funcionalizados em C2 e C3 e os seus homólogos com anel de D de 6 membros, lactonizado, foram seleccionados como potenciais novos inibidores da 17β-HSD-1.
Os resultados de docking realizados com o programa AutoDock Vina, revelaram que os referidos derivados lactonizados da estrona possuem elevados valores de afinidade para a enzima, quando comparados com os seus homólogos com anel D de 5 membros, e quando comparados com outros homólogos D-Homo, revelaram possuir iguais ou mesmo até superiores afinidades. Todos os compostos funcionalizados em C2 apresentaram valores de afinidade superiores quando comparados com o valor de afinidade da estrona, em especial substituintes hidrofóbicos ou com elevadas propriedades eletronegativas. Este tipo de funcionalização é vantajoso, já que se encontra descrito que diminui a estrogenicidade dos compostos. Adicionalmente descobriu-se também que substituições em C3, com grupos aceitadores em pontes de hidrogénio, como grupos éster ou heterocíclicos, bem como grupos lipofílicos, dão origem a compostos com elevados valores de afinidades. Os estudos de toxicidade in silico revelaram que as moléculas avaliadas são seguras em termos de efeitos mutagénicos, tumorigénicos, irritantes ou em efeitos a nível reprodutivo, exceto para as moléculas substituídas com C6-OH, que apresentaram risco a nível reprodutivo.
Neste momento estão ainda a ser realizadas sínteses químicas e a iniciar-se a avaliação biológica in vitro, com o objetivo de confrontar com os resultados obtidos nos cálculos computacionais e de efetuar estudos de relação-estrutura-atividade (REA) para este tipo de novos compostos inibidores da 17β-HSD-1. Capítulo II
O capítulo II pretende resumir a minha participação no estágio profissional realizado na área da farmácia comunitária na Farmácia Sant’Ana – Covilhã. Nele encontram-se descritas todas as áreas de trabalho e funcionalidades, as funções desempenhadas pelo farmacêutico, entre outros diversos aspetos fundamentais para o funcionamento desta unidade de saúde dirigida para a comunidade.<br>1
st Chapter
Breast cancer is the most common cancer in women. In this context, several studies
evidenced that 40 to 60% of all breast cancers are considered hormone-dependent, relying
especially on estradiol for their development. In the human body, this estrogen is originated
from estrone, an estrogen with low estrogenic activity, by the action of 17β-hydroxysteroid
dehydrogenase type 1 (17β-HSD-1). As this enzyme is encountered in high amounts on
estrogen-dependent cancer tissues and has high selectivity, the discovery of 17β-HSD-1
inhibitors, in order to minimize the formation of estradiol, is gaining high interest nowadays.
Thus, based on previous knowledge that several D-homosteroids have interesting 17β-HSD-1
inhibitory properties, our group has been developing several new estrane derivatives as
potential 17β-HSD-1 inhibitors with higher inhibitory properties, low toxicity and simpler
synthetic preparation. For this purpose, computational studies, like molecular docking and in
silico toxicological evaluation have been performing. From these studies, several molecules,
mainly C2 and C3 functionalized estrone derivatives and their homologues with the lactonized
D-ring have been elected as potentially novel 17β-HSD-1 inhibitors. Interestingly, docking
results performed with AutoDock Vina revealed that the lactonized estrone derivatives have
higher affinity values to the enzyme when compared to all their 5-membered D-ring
homologues as well as equal or higher affinity values compared to the previously reported DHomo derivatives. In silico toxicity tests also revealed that all molecules were safe regarding
on mutagenic, tumorigenic, irritant or reproductive effects, except for C6-OH substituted
molecules that presented risk on reproductive level. At the moment, chemical synthesis and
in vitro biological evaluation are being performed.
2
nd Chapter
This chapter aims to resume the professional traineeship realized in the field of Community
Pharmacy, it’s presented in Chapter 2 an overview of the working areas and fields of this
health unit managed for the society.
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Armour, Danielle Louise. "Role of 11β-hydroxysteroid dehydrogenase type 2 in protection against inflammation during atherogenesis : studies in the Apoe-/- /11β-HSD2-/- double knockout mouse". Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4431.
Texte intégralRésumé :
It is well established that atherosclerosis, an inflammatory response to chronic injury in the blood vessel wall, plays a leading role in the development and progression of cardiovascular disease. Mineralocorticoid receptor (MR) over-activation has been implicated in atherosclerosis. In mineralocorticoid-target tissues, 11β- Hydroxysteroid dehydrogenase type 2 (11β-HSD2) inactivates glucocorticoids, conferring aldosterone specificity upon the normally unselective MR. Recent evidence suggests that 11β-HSD2 may also afford protection of MR in the cells of the vasculature, providing possible mechanisms by which MR activation may directly promote atherosclerosis. Consistent with this, Apoe-/-/11β-HSD2-/- double knockout (DKO) mice show accelerated atheroma development. The present thesis tested the hypothesis that inactivation of 11β-HSD2, allowing inappropriate activation of MR in cells of the vasculature, accelerates atherogenesis through promotion of a pro-inflammatory environment with increased endothelial cell expression of adhesion molecules and subsequent macrophage infiltration into plaques. DKO mice received either the MR antagonist eplerenone (200mg/kg/day) or vehicle in normal chow diet from 2 months of age for 12 weeks. Eplerenone significantly decreased atherosclerotic burden in brachiocephalic arteries of DKO mice, an effect that was accompanied by alterations in the cellular composition of plaques such that a more stable collagen- and smooth muscle cell- rich plaque was formed. Eplerenone treatment was also associated with a reduction in vascular inflammation as demonstrated by a significant reduction in macrophage infiltration into DKO plaques. The accelerated atherogenesis in DKO mice was clearly evident by 3 months of age, a time point at which Apoe-/- mice were completely lesion free. By 6 months, some Apoe-/- mice had developed lesions whilst all DKO mice at this age showed much larger plaques. Compared to Apoe-/- mice, the cellular composition of DKO plaques was altered favouring vulnerability and inflammation, with increased macrophage and lipid content and decreased collagen content. To investigate the possible underlying mechanisms responsible for increased inflammatory cell content, the expression of vascular cell adhesion molecule 1 (VCAM-1) was compared in DKO and Apoe-/- brachiocephalic arteries. VCAM-1 immunostaining was significantly greater on the endothelial cells of DKO arteries at 3 months compared to age-matched Apoe-/- mice. At 6 months, DKO and Apoe-/- mice had similar expression of VCAM-1. Finally, mouse aortic endothelial cells (MAECs) were used to investigate the mechanism of adhesion molecule up-regulation in the absence of 11β-HSD2. Both aldosterone and TNF-α, included as a positive control, dramatically increased VCAM-1 expression in MAECs. Spironolactone pre-treatment blocked the effect of aldosterone, suggesting an MR-mediated mechanism. Corticosterone alone had no effect on VCAM-1 expression. However, inhibition of 11β-HSD2 by pre-treatment with glycyrrhetinic acid allowed corticosterone to induce a significant increase in the number of VCAM-1-stained MAECs, demonstrating functional expression of 11β- HSD2 in MAECs. Consistent with 11β-HSD2 involvement, VCAM-1 up-regulation by corticosterone in the presence of glycyrrhetinic acid was reversed by blockade of MR with spironolactone. In conclusion, loss of 11β-HSD2 activity leading to inappropriate activation of MR in atherosclerotic mice promotes plaque vulnerability and increases vascular infiltration of macrophages which accelerates plaque growth, possibly through enhanced MR- mediated endothelial cell expression of VCAM-1.