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1
Sato, Hiroyuki. "Identification and biological validation of natural TGR5 agonists." Université Louis Pasteur (Strasbourg) (1971-2008), 2007. http://www.theses.fr/2007STR13232.
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Les acides biliaires agissent comme des molécules anti-obésité, en augmentant la dépense énergétique via l’activation d’un récepteur membranaire pour les acides biliaires, le TGR5. Dans ce travail de thèse, nous avons étudié extensivement différents agonistes pour le TGR5, ainsi que leurs propriétés pharmacologiques, en particulier pour leur utilisation potentielle dans le traitement des maladies métaboliques. Dans la première étude, nous avons établi les relations structure / activité sur le TGR5 pour plus de 80 acides biliaires (et dérivés) naturels. Ce travail a permis d’identifier les caractéristiques structurales que devaient présenter les acides biliaires pour activer le TGR5, et en outre a permis l’identification de plusieurs agonistes puissants pour le TGR5. Dans une deuxième étude, nous nous sommes intéressés à un phytostérol, la gugulstérone (GS), connue pour ses effets régulateurs sur le métabolisme. Nous avons montré que GS est également un puissant agoniste du TGR5. Biologiquement, GS active Dio2 et augmente la consommation d’oxygène chez l’animal et dans des modèles cellulaires. Dans la troisième étude, nous avons criblés des extraits de plantes afin d’identifier d’autres agonistes du TGR5. Ce criblage a permis d’identifier 21 plantes activant le TGR5 dont une pour laquelle une sélection bio-guidée nous a permis d'identifier une molécule originale agoniste du TGR5 dont la structure a été confirmé par RMN. Cette molécule a été testée chez l’animal et a révélé des propriétés anti-obésité. L’ensemble de ce travail a permis d‘identifier plusieurs agonistes puissants du TGR5, lesquels pourraient servir de base à un développement pharmaceutique dans le futurBile acids were shown to have antiobesity properties by increasing energy expenditure via activation of a membrane bile acid receptor, TGR5. In this thesis studies, potent TGR5 agonist was widely explored for pharmacological applications of the treatment of metabolic diseases. In the first study, the structure-activity relationship study was performed using 80 natural bile acids, bile acid derivatives. Not only structural feature of bile acid on TGR5 activation, but also several TGR5 agonists were identified as potent TGR5 selective agonists in this study. In the second study, the author paid an attention to a phytosterol, gugulsterone (GS) known as a metabolic modulator. Its effect was reported to be mediated by another bile acid receptor FXR but the author found that GS was a potent TGR5 ligand. Biological activity of GS on Dio2 activation and enhancement of oxygen consumption was observed in animal model and in cell model. This study showed diversity of drug development targeted to the two bille acid receptor, TGR5 and FXR. In the third study, the author attempted screening of TGR5 agonists using 29 plant extracts as a source of compound library. This assay revealed that 21 out of 29 crude extracts were positive. The author succeeded to purify and identify an active compound from one of the positive extract by means of flash chromatography and subsequently NMR analysis. The active compound showed antiobesity effects in an animal. Thus the author could identify the several compounds as potent TGR5 agonists, which could find the pharmacological applications in the future
2
Strehle, Axelle. "Characterisation of triterpenoids as TGR5 agonists and their effects on metabolism." Strasbourg, 2009. http://www.theses.fr/2009STRA6149.
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Les dysfonctionnements mitochondriaux sont impliqués dans le développement du diabète mais ne sont pas ciblés par les thérapies disponibles. Les mitochondries sont activées par un RCPG activé par les acides biliaires, le TGR5, une cible intéressante à deux niveaux : pour prévenir les maladies métaboliques (mitochondries) et pour traiter ces maladies (sécrétion de GLP-1). Pour étudier TGR5, il fallait identifier des agonistes sélectifs pour contourner les effets pléiotropiques des acides biliaires, les seuls agonistes connus. Après criblage d’une collection de plantes sur un test d’activité TGR5, les feuilles d’olivier Olea Europaea ont montré une activité TGR5 portée par un triterpène, l’acide oléanolique. In vivo, l’acide oléanolique a une activité anti-hyperglycémique, améliore la tolérance au glucose et empêche la prise de poids. L’acide oléanolique stimule les fonctions mitochondriales dans les muscles in vitro et in vivo. Une étude de SAR sur le squelette des triterpènes nous a permis de synthétiser RG239, un puissant agoniste TGR5 in vitro mais inactif in vivo, probablement à cause d’une faible biodisponibilité. RG239 est un outil pharmacologique intéressant pour étudier la biologie du TGR5. Nous avons ainsi montré que RG239 induit les fonctions mitochondriales de façon TGR5-dépendante. Par ailleurs, RG239 stimule la sécrétion de GLP-1 dans les cellules entéroendocrines intestinales, et cet effet est également TGR5-dépendant. Ces résultats confirment TGR5 comme cible thérapeutique et les triterpènes comme agents thérapeutiques potentiels pour prévenir (mitochondries) et traiter (GLP-1) les maladies métaboliquesMitochondrial dysfunction is implicated in the early stages of diabetes but is not targeted by the available therapies. Mitochondrial functions can be activated by the bile acids-activated GPCR TGR5, in muscle and in adipose tissue. This double effect of TGR5, on mitochondria and GLP-1 secretion, positions this receptor as an interesting target to prevent the early onset of metabolic diseases. To further explore TGR5 potential, our principal challenge was to identify more potent and more selective TGR5 agonists devoid of the pleiotropic effects of bile acids, the only TGR5 agonists known so far. To this end, we used a TGR5 activity assay to screen a plant library. Among the plant extracts tested, Olea Europaea leaves was shown to exhibit an activity supported by the triterpenoid oleanolic acid. In vivo, oleanolic acid showed anti-hyperglycemic activity, improved glucose tolerance and decreased weight gain. Furthermore, oleanolic acid enhanced mitochondria in muscle both in vitro and in vivo. A SAR study based on the triterpenoid scaffold led us to synthetize RG239, a more potent TGR5 agonist in vitro which is inactive in vivo, probably because of poor bioavailability. RG239 is an interesting pharmacological tool to understand TGR5 biology. Indeed, RG239 was shown to induce mitochondria activity and number in muscle and intestinal cell lines in a TGR5 dependant manner. In addition, RG239 stimulated GLP-1 secretion in intestinal enteroendocrine cells in a TGR5 dependant-manner. Altogether, these results confirm TGR5 as therapeutical target and triterpenoids as potential therapeutical agents in the prevention/mitochondria and treatment/GLP-1 of metabolic diseases
3
Baptissart, Marine. "Impacts de concentrations supraphysiologiques d'acides biliaires sur la physiologie testiculaire et les fonctions de reproduction." Thesis, Clermont-Ferrand 2, 2014. http://www.theses.fr/2014CLF22526/document.
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Chez l’homme, des données cliniques décrivent une association entre des pathologies hépatiques et des désordres de la fertilité masculine. Plusieurs modèles expérimentaux de cholestase ont permis de confirmer ce lien et de souligner un impact sur la physiologie testiculaire. De manière intéressante, une telle corrélation existe aussi bien à l’âge adulte que dans des modèles animaux en période pré-pubertaire. Pour autant, le lien moléculaire pouvant expliquer cette association physiopathologique n’a pas été exploré. L’ensemble des hépatopathies a pour dénominateur commun une augmentation des taux plasmatiques d’acides biliaires et ce dès les stades les plus précoces de la maladie. Dans ce contexte, l’hypothèse de l’impact délétère des acides biliaires sur la fonction reproductrice reste à définir. Notre projet de recherche s’articule autour de l’analyse d’un modèle murin d’atteinte hépatique induite par un régime supplémenté en acide cholique. Nos résultats principaux montrent que : 1) lors d’une exposition pubertaire, l’activation supra-physiologique des signalisations Fxrα conduit à un défaut de maturation sexuelle associé à une altération de la fonction endocrine du testicule ; 2) dans un contexte d’exposition à l’âge adulte, l’activation excessive du récepteur membranaire Tgr5 par les acides biliaires est associées à une hypofertilité. Celle-ci s’accompagne d’une altération de la spermatogenèse consécutive à un détachement progressif de l’épithélium séminifère et à une apoptose spécifique des spermatides ; 3) enfin, nos conclusions démontrent pour la première fois l’impact transgénérationnel de l’exposition aux acides biliaires. Sur deux générations successives, les descendants des mâles adultes nourris par un régime supplémenté en acide cholique présentent des anomalies développementales et métaboliques. Dépendantes de l’action de Tgr5, ces dernières sont attribuées à des altérations de l’épigénome des spermatozoïdes issus des mâles exposés aux acides biliaires. En conclusion, nos données démontrent que, dans des conditions cholestatiques, les acides biliaires altèrent les fonctions de reproduction notamment par leurs impacts sur les fonctions testiculaires. Au regard du nombre croissant de personnes souffrant de troubles hépatiques, ces effets délétères des acides biliaires pourraient contribuer à l’augmentation de l’incidence de l’infertilité masculine. Des molécules agonistes des signalisations FXRα et TGR5 sont aujourd’hui envisagées dans le cadre du traitement de pathologies courantes de notre société. Dans ce contexte, notre étude permettra d’alerter les instances sanitaires quant aux conséquences de l’accès à de tels traitements sur la fertilité et la santé des générations futuresClinical data describe an association between liver diseases and disorders of male fertility. Several experimental models of cholestasis have confirmed this link and highlight an impact on testicular physiology. Interestingly, such correlation exists in adult as well as in during pre-pubertal animals. However, the molecular links have not been explored yet. The increase of plasma bile acids levels is a common feature of liver diseases. In this context, the hypothesis of the deleterious impact of bile acids on reproductive function remains to be defined. For that purpose, we used a mouse model of liver injury induced by a diet supplemented with cholic acid. Main results show that: 1) supra-physiological activation of Fxra, during pubertal period, alters endocrine function of the testis and then sexual maturation. 2) during adult age excessive activation of membrane receptor TGR5 by bile acids leads to subfertility. This is associated with impaired spermatogenesis due to a detachment of the seminiferous epithelium and specific apoptosis of spermatids. 3) Finally, we show for the first time the transgenerational impact of bile acid exposure. Two generations of progenies from males exposed to bile acid-diet show developmental and metabolic abnormalities. These effects, mediated by TGR5, are correlated with alterations of the spermatozoa epigenome. In conclusion, our data demonstrate that bile acids affect reproductive functions with impacts on testicular functions. In line with the increasing number of people with liver diseases, the deleterious effects of bile acids may contribute to the incidence of male infertility. Interestingly, agonists of FXRα and TGR5 are now considered in the treatment of several diseases. In this context, our study might alert health authorities regarding the potential consequences of these treatments on fertility and health futures generations
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Pean, Noémie. "Récepteur TGR5 des acides biliaires : impact sur la régénération du foie et l'homéostasie biliaire." Paris 7, 2014. http://www.theses.fr/2014PA077055.
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La composition en AB était plus hydrophobe chez les souris TGR5-K0 par rapport aux souris WT Après HP, une importante nécrose hépatique, une cholestase prolongée, une réponse inflammatoire excessive et un retard de régénération hépatique ont été observés chez les souriE TGR5-KO. La réponse adaptative rénale et biliaire à la surcharge en AB après HP ont fortement été détériorées chez les souris TGR5-K0 par rapport aux souris WT. Le traitement par la cholestyramine et la déplétion en Kupffer, ont significativement amélioré le phénotype des souris TGR5-K0 après HP. Après une ligature de la voie biliaire principale ou un régime enrichi en CA, les TGR5-K0 avaient des lésions hépatiques plus importantes que les souris WT, ainsi qu'une altération de l'élimination urinaire des AB. Chez les souris TGR5-KO, la synthèse hépatocytaire des AB et le shunt cholécystohépatique n'étaient pas altérés, en revanche, un déficit de relaxation vésiculaire et une hyperperméabilité paracellulaire de l'épithélium biliaire étaient observés par rapport aux WT. Le récepteur TGR5 est crucial pour protéger le foie contre la surcharge en AB après HP, principalement par le contrôle de l'hydrophobicité du pool d'AB et de la sécrétion de cytokines. En absence du récepteur TGR5, la stagnation de bile anormalement hydrophobe et l'excès d'inflammation, associés à l'altération du flux biliaire et de l'élimination urinaire des AB, mènent à une surcharge en AB, à l'origine des lésions hépatiques et du retard de régénération. Le récepteur TGR5 contrôlerait l'hydrophobicité du pool d'AB via le contrôle de la fonction motrice de la vésicule biliaire et régulerait la perméabilité de l'épithélium biliaireBA composition (plasma, liver, bile, urine, stools) was more hydrophobic in TGR5-KO than in W1 mice. After PH, severe hepatocyte necrosis, prolonged cholestasis, exacerbated inflammatory response and delayed regeneration were observed in TGR5-KO mice. Hepatocyte adaptive response to post-PH BA overload was similar in WT and TGR5-KO mice. However, kidney and biliary adaptive responses to post-PH BA overload were strongly impaired in TGR5-KO as compared with WT mice. Cholestyramine treatment, as well as Kupffer cell depletion, significantly improved the post-PH TGR5 KO mice phenotype. After bile duct ligation or upon a cholic acid-enriched diet, TGR5 KO mice exhibited more severe liver injury than WT as well as impaired BA elimination in urine. In TGR5-KO mice, hepatic bile acid synthesis and cholecystohepatic shunt were not altered, but gallbladder relaxation and biliary epithelium hyperpermeability were observed as compared to WT mice. TGR5 is crucial for liver protection against BA overload after PH, primarily through the control of bile hydrophobicity and cytokine secretion. In the absence of TGR5, intrahepatic stasis of abnormally hydrophobic bile and excessive inflammation, in association with impaired bile flow adaptation and deficient urinary BA efflux, lead to BA overload-induced liver injury and delayed regeneration. TGR5 may control both bile acid pool hydrophobicity via the control of gallbladder motor function, and epithelial permeability in the biliary tract
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Prasanna, Kumar Divya. "Regulation of Pancreatic α and β Cell Function by the Bile Acid Receptor TGR5." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3591.
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The discovery that bile acids act as endogenous ligands of the membrane receptor TGR5 and the nuclear receptor FXR increased their significance as regulators of cholesterol, glucose and energy metabolism. Activation of TGR5, expressed on enteroendocrine L cells, by bile acids caused secretion of GLP-1, which stimulates insulin secretion from pancreatic β cells. Expression of TGR5 on pancreatic islet cells and the direct effect of bile acids on the endocrine functions of pancreas, however, are not fully understood. The aim of this study was to identify expression of TGR5 in pancreatic islet cells and determine the effect of bile acids on insulin secretion. Expression of TGR5 was identified by quantitative PCR and western blot in islets from human and mouse, and in α (αTC1-6) and β (MIN6) cells. Release of insulin, glucagon and GLP-1 were measured by ELISA. The signaling pathways coupled to TGR5 activation were identified by direct measurements such as stimulation of G proteins, adenylyl cyclase activity, PI hydrolysis and intracellular Ca2+ in response to bile acids; and confirmed by the use of selective inhibitors that block specific steps in the signaling pathway. Our studies identified expression of TGR5 receptors in β cells and demonstrated that activation of these receptors by both pharmacological ligands (oleanolic acid (OA) and INT-777) and physiological ligand (lithocholic acid, LCA) induced insulin secretion. TGR5 receptors are also expressed in α cells and, activation of TGR5 by OA, INT-777 and LCA at 5 mM glucose induced release of glucagon, which is processed from proglucagon by the selective expression of prohormone convertase 2 (PC2). However, under hyperglycemia, activation of TGR5 in α cells augmented the glucose-induced increase in GLP-1 secretion, which in turn, stimulated insulin secretion. Secretion of GLP-1 from α cells reflected TGR5-mediated increase in PC1 promoter activity and PC1 expression, which selectively converts proglucagon to GLP-1. The signaling pathway activated by TGR5 to mediate insulin and GLP-1 secretion involved Gs/cAMP/Epac/PLC-ε/Ca2+. These results provide insights into the mechanisms involved in the regulation of pancreatic α and β cell function by bile acids and may lead to new therapeutic avenues for the treatment of diabetes.
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Spatz, Madeleine. "Étude du lien entre maladie alcoolique du foie, microbiote intestinal et acides biliaires : rôles spécifiques de la pectine et du récepteur aux acides biliaires TGR5." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS365.
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La maladie alcoolique du foie (MAF) regroupe l’ensemble des lésions qui apparaissent suite à une consommation excessive et chronique d’alcool. A consommation d’alcool égale, les patients n’évolueront pas tous vers les formes sévères de la maladie. Le microbiote intestinal est un cofacteur déterminant dans la sévérité de la MAF. Parmi les métabolites fécaux entre des souris recevant le microbiote intestinal de patients avec des lésions sévères ou non, les acides biliaires ont été identifiés comme les plus discriminants. Le récepteur aux acides biliaires TGR5, exprimé sur les cellules de Kupffer, favorise leur profil anti-inflammatoire.Nous avons évalué l’impact du récepteur TGR5 dans la MAF chez des souris déficientes pour ce récepteur. La déficience en TGR5 aggrave la MAF, sans passer par une modulation de la cellule de Kupffer. C’est en fait le microbiote intestinal qui est impacté chez les souris déficientes pour TGR5, et qui médie cette aggravation.Par ailleurs, afin de moduler le microbiote intestinal au cours de la MAF, nous avons évalué le rôle de la pectine, qui favorise la croissance de certaines bactéries et peut chélater les acides biliaires. Malgré ses propriétés chélatantes, ce sont bien les modifications du microbiote intestinal induites par la pectine qui jouent un rôle protecteur et curatif dans la MAF.Ces différentes études devraient permettre d’identifier des cibles thérapeutiques potentiellement applicables chez des patients alcooliques et basées sur la modulation du microbiote intestinalAlcoholic liver disease (ALD) includes all the liver injuries occurring as a result of excessive and chronic alcohol consumption. Nevertheless, among heavy drinker, only a subset of individuals will develop severe liver injury. Intestinal microbiota was identified as a major player in the mechanisms involved in ALD. Moreover, bile acids were the most discriminant faecal metabolites between mice with or without liver injury. The bile acids receptor TGR5, which is expressed on Kupffer cells, promotes their anti-inflammatory profile.We assessed the role of bile acids receptor TGR5 in ALD using TGR5-deficient mice. TGR5-deficiency worsens ALD, but without modulating the Kupffer cells profile. However, intestinal microbiota is impaired in TGR5-deficient mice, and this is responsible for ALD worsening.Furthermore, in order to modulate the intestinal microbiota during ALD, we assessed the role of pectin, which is known to promote the growth of certain bacteria and that is a bile acids sequestrant. Despite its sequestrant properties, pectin-induced changes in intestinal microbiota play a protective and curative role in ALD.These studies will allow the identification of new therapeutic targets that could be used for alcoholic patients, using intestinal microbiota modulation
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Moullan, Norman. "Identification and validation of a potent synthetic TGR5 agonist that improves metabolism, inflammation and atherosclerosis." Thesis, Paris, EPHE, 2015. http://www.theses.fr/2015EPHE3070.
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L’obésité, le diabète de type 2 et l’athérosclérose sont les principaux problèmes de santé publique affectant les pays développés. Bien que de nombreux traitements soient disponibles contre ces maladies, de nombreux progrès sont encore nécessaire pour le développement de composés plus actif et plus sûr. Mon laboratoire a montré que l’activation du récepteur aux acides biliaires TGR5 par ses ligands entrainait une augmentation de la dépense énergétique et réduisait le niveau des cytokines chez la souris, ce qui pourrait être une nouvelle voie vers le traitement de ces désordres métaboliques. Nous décrivons ici le développement d’un nouvel agoniste synthétique, spécifique et puissant pour TGR5. A partir d’une librairie de 20.000 composés, les composés 50980906, 13008574 et 37525283 ont été caractérisés comme les plus puissants et stables. Le composé 13008574 a montré une réduction significative sur la prise de poids de souris C57BL/6J après un régime alimentaire riche en graisses. Suite à l’activation de TGR5, nous avons observés une augmentation du niveau d'expression des gènes Ucp-1, Dio-2 et Cpt-1 dans le tissu adipeux brun et une augmentation de la clairance du glucose suite à une augmentation de la sécrétion de GLP-1 chez les souris traitées par le composé 13008574. Nous avons également montrés que le composé 13008574 n’a pas d’effet sur les souris TGR5-/- témoignant de sa spécificité. Enfin nous avons par ailleurs confirmé l'effet du composé 13008574 comme agent anti-inflammatoire, avec un effet protecteur face au développement de l'athérosclérose. Notre travail montre ainsi que le développement d’agonistes pour TGR5, puissant et sûr, est possible pour traiter le syndrome métaboliqueObesity, type 2 diabetes and atherosclerosis, are amongst the main driving factors of a public health crisis that impacts developed countries. Although several drugs are available, there is still a large unmet medical need to find better and safer compounds to treat these diseases. In this context, my host laboratory discovered that activation of the membrane bile acid receptor TGR5 induces energy expenditure and reduces inflammation in mice, which would be beneficial to manage the above–mentioned disorders. INT-777, a semi-synthetic bile acid, is until now, one of the most specific TGR5 ligands. Here, we report the identification of a new synthetic, selective and potent TGR5 agonist. From a screen of 20,000 compounds as potential TGR5 activators, the compounds 50980906, 13008574 and 37525283 were the most potent and stable. In particular, 13008574 induced a significant reduction of body weight gain when C57BL/6J mice were exposed to a high fat diet, paralleled by an increase in the expression levels of Ucp-1, Dio-2 and Cpt-1 in brown adipose tissue. In addition, mice treated with 13008574 displayed improved glucose clearance, consequent to increased GLP-1 secretion. We showed furthermore that the effects of 13008574 were lost in TGR5-/- mice, testifying the specificity of the compound. In addition, 13008574 acts as an anti-inflammatory agent, with a protective effect on atherosclerosis development in LDLr-/- mice treated with a high cholesterol diet. Our work hence shows that potent, selective, and safe TGR5 agonists can be developed to cure the metabolic syndrome
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Genet, Cédric. "Identification et développement de triterpènes comme agonistes TGR5 : étude de leurs effets sur le métabolisme." Strasbourg, 2010. http://www.theses.fr/2010STRA6295.
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Les maladies métaboliques sont devenues un fléau ces dernières décennies préfigurant plusieurs maladies graves comme le diabète de type 2. Les disfonctionnements mitochondriaux sont caractéristiques des maladies métaboliques. Cependant, ils ne sont pas ciblés par les thérapies actuelles qui se concentrent plutôt sur les conséquences de ces maladies. Néanmoins, la capacité du récepteur couplé aux protéines G, TGR5 présent dans le tissu adipeux et musculaire à augmenter l’activité mitochondriale ouvre de nouvelles perspectives d’avenir pour prévenir les stades précoce des maladies métaboliques et pour traiter ces maladies. Pour explorer le potentiel de TGR5, notre principal défi était d’identifier des agonistes plus puissants et plus sélectifs que les acides biliaires. En effet, les acides biliaires seuls agonistes connus à ce jour sont aussi actifs sur d’autres récepteurs nucléaires. Dans ce but, nous avons criblé une collection de plantes antidiabétiques par bio-guidage sur TGR5, ce qui nous a permis d’isoler et d’identifier deux principes actifs de la famille des triterpènes, l’acide oléanolique et l’acide corosolique. In vivo, l’acide oléanolique possède une activité hypoglycémiante, améliore la tolérance au glucose et empêche la prise de poids. De plus, l’acide oléanolique augmente l’activité mitochondriale in vitro. Une étude de la relation structure à activité sur une collection plus large de triterpènes naturels nous a permis d’obtenir un chef de file, l’acide bétulinique dont l’hemi-synthèse d’analogues a fourni RG 239, un puissant agoniste TGR5 capable d’induire l’activité mitochondriale de façon TGR5-dépendante. Malgré cela, in vivo il n’a montré aucun effet probablement à cause d’une faible biodisponibilité. Bien que tous ces résultats confirment TGR5 comme une cible thérapeutique, nous nous sommes rendus à l’évidence que les triterpènes ne sont pas des molécules développables pour obtenir un médicament. En effet, leurs châssis hydrophobe et le faible degré de liberté qu’offre leurs fonctions chimiques pour des modifications structurales nous ont poussés à utiliser des outils chémoinformatiques pour découvrir une nouvelle famille d’agoniste TGR5. C’est pourquoi, le criblage des banques de données de produits commerciaux Zinc et Asinex a été réalisé par des recherches pharmacophoriques et topomériques dont les résultats sont en cours d’exploitationMitochondrial dysfunction, a hallmark feature in the early stage of metabolic diseases, is currently not targeted by the available therapies with preferentially focus on the consequence of the diseases. Nevertheless, an early discovered G coupled protein receptor named TGR5 was shown to lead to an increase in mitochondrial activity. This effect reveals TGR5 as an interesting target to prevent the early onset of metabolic diseases. To further explore TGR5 potential, our principal challenge was to identify more potent and more selective TGR5 agonists than the already known bile acids which act on other nuclear receptors. To this end we used a TGR5 activity assay to screen a plant library. Among the plant extracts tested, was have been able to isolated two active principles from the triterpene family, the oleanolic acid and the corosolic acid. In vivo, oleanolic acid showed antihyperglycemic activity, improved glucose tolerance and decrease weight gain. Furthermore, oleanolic acid enhanced mitochondrial activity in vitro. An SAR study based on natural triterpenes has led us to the discovery of betulinic acid used in hemi-synthesis and affords the synthesis of RG 239, a more potent TGR5 agonist which induce mitochondrial activity in a TGR5 dependant manner. Unfortunately, RG 239 was not active in vivo, probably because of poor bioavailability. Although, these results confirm TGR5 as therapeutical target, we have found that triterpenes were not drugable molecules. Indeed, triterpenes are hydrophobic molecules and the degree of liberty of their chemical function for structural modification is very low. That is the reason why we have decided to screen two databases of commercial products, Zinc and Asinex with a scaffold hoping method in order to find new TGR5 agonist family. The selected molecules by this approach are under investigation
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Deutschmann, Kathleen [Verfasser], and Verena [Akademischer Betreuer] Keitel-Anselmino. "Die Rolle des Gallensalzrezeptors TGR5 (GPBAR1) in gastrointestinalen Tumoren / Kathleen Deutschmann ; Betreuer: Verena Keitel-Anselmino." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2021. http://d-nb.info/1236399595/34.
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Spengler, Joseph R. "Diabetes-Induced Expression and Regulation of GLP-1 levels by Bile Acid Receptors (TGR5 & FXR)." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4776.
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Diabetes Mellitus has continued to drastically affect the health of the world and many complications can prove fatal. As long as this metabolic disease persist, research discoveries will need to continue to be made so that patient outcomes and healthcare are dramatically enhanced. In recent years, GLP-1 has been the topic of conversation for diabetes research, due to its promising effects in promoting insulin sensitivity. Furthermore, bile acids and their receptors (TGR5 & FXR) have shown promise in their actions in the regulation of GLP-1, and thus glucose homeostasis. Here we have shown the detection and increased expression of TGR5 and GLP-1, and decreased expression of FXR in diabetic mouse intestinal mucosa tissues. We have also shown the detection and increased expression of these receptors in STC-1 cells. More importantly we have linked the connection of increased glucose concentration (hyperglycemia) to increased TGR5 activation to increased GLP-1 release, thus leading to increased insulin sensitivity and altered diabetic outcomes.
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Hoguet, Vanessa. "Optimisation de nouveaux agonistes topiques intestinaux du récepteur aux acides biliaires TGR5 pour le traitement du diabète de type 2." Thesis, Lille 2, 2017. http://www.theses.fr/2017LIL2S024/document.
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Le récepteur membranaire TGR5 (Takeda G Protein-coupled Receptor 5), est un récepteur ubiquitaire sensible aux acides biliaires. Il est exprimé dans de nombreux tissus et organes dont l’intestin (dans les cellules entéroendocrines L), la vésicule biliaire, les muscles lisses et squelettiques, le tissu adipeux brun et dans certaines cellules immunitaires. Des études menées in vitro et in vivo chez l’animal ont montré des effets bénéfiques de l’activation de TGR5 sur l’homéostasie énergétique et glucidique. Il est maintenant communément admis que les effets bénéfiques de TGR5 sur l'homéostasie du glucose sont, au moins en partie, médiés par sa capacité à promouvoir la sécrétion de l'incrétine intestinale glucagon-like peptide-1 (GLP-1) au niveau des cellules entéroendocrines L.Cependant, de récentes expériences ont montré que l’activation de TGR5 par des agonistes systémiques dans des modèles animaux peut induire des effets non souhaités tels qu’une augmentation du volume de la vésicule biliaire, des démangeaisons et des effets cardiovasculaires. Afin de s’affranchir des effets non désirés d’agonistes systémiques de TGR5, le projet s’est orienté vers le développement d’agonistes de TGR5 présentant une distribution tissulaire ciblée et limitée à l’intestin et dont la biodisponibilité orale serait très faible, voire nulle. Nous avons alors émis l’hypothèse qu’une activation de TGR5 limitée à l’épithélium intestinal sans exposition systémique permettrait d’obtenir des effets bénéfiques sur l’homéostasie du glucose via l’effet GLP-1 sécrétagogue, tout en minimisant les effets non souhaités sur d’autres tissus ou organes exprimant TGR5.A partir des études de relations structure-activités obtenues au laboratoire sur une série d’agonistes de TGR5, nous avons conçu des composés chimériques de la façon suivante : le pharmacophore responsable de l’activité sur le récepteur TGR5 est lié via un bras espaceur à des éléments structuraux appelés kinétophores qui ajustent les propriétés physicochimiques et pharmacocinétiques de nos agonistes pour limiter leur absorption intestinale. Ainsi, l’objectif de ce travail était d’obtenir des agonistes non systémiques de TGR5, puissants et originaux, exerçant leur action dans l’intestin afin de générer la preuve de concept in vivo de l’intérêt d’utiliser de tels agonistes dans le traitement du diabète de type 2.Une étude systématique de l’effet de kinétophores variés a été réalisée. Une trentaine de composés ont été synthétisés en 8 à 12 étapes permettant l’identification d’agonistes puissants et présentant des propriétés pharmacocinétiques en accord avec notre stratégie de composés topiques intestinaux. Des études in vivo ont ensuite permis de valider l’effet GLP-1 sécrétagogue de tels composés. Enfin, l’évaluation d’un des meilleurs composés dans un modèle murin de diabète nous a permis de valider l’hypothèse qu’un agoniste topique intestinal de TGR5 peut avoir un effet bénéfique sur l’homéostasie énergétique et glucidiqueThe membrane receptor TGR5 (Takeda G Protein-coupled Receptor 5) is an ubiquitous receptor sensitive to bile acids. It is expressed in many tissues and organs including the intestine (in enteroendocrine L cells), the gallbladder, smooth and skeletal muscles, brown adipose tissue and in some immune cells. In vitro and in vivo studies in animals have shown beneficial effects of TGR5 activation on energy and glucose homeostasis. It is now commonly accepted that the beneficial effects of TGR5 on glucose homeostasis are, at least in part, mediated by its ability to promote the secretion of the intestinal incretin glucagon-like peptide-1 (GLP-1) in enteroendocrine L cells.However, recent experiments have shown that the activation of TGR5 by systemic agonists in animal models can induce unwanted effects such as increased gallbladder volume, itching and cardiovascular issues. In order to avoid the undesired effects of systemic agonists of TGR5, the project focused on the development of TGR5 agonists with an intestine targeted distribution and a very low oral bioavailability. Then, we hypothesized that the activation of TGR5 limited to the intestinal epithelium without systemic exposure would promote the beneficial effects on glucose homeostasis via the GLP-1 secretagogue effect, while minimizing systemic effects on other tissues or organs expressing TGR5.On the basis of structure-activity relationships on a series of TGR5 agonists developed in the laboratory, we have designed chimeric compounds as follows: the pharmacophore responsible for activity on the TGR5 receptor is bound, via a linker, at structural elements called kinetophores that fine-tune the physicochemical and pharmacokinetic properties of our agonists to limit their intestinal absorption. Thus, the aim of this work was to obtain powerful and original non-systemic TGR5 agonists acting in the intestine to generate the in vivo proof of concept of the therapeutic potential of such agonists in the treatment of type 2 diabetes.A systematic study of the effect of various kinetophores was performed. About thirty compounds have been synthesized in 8 to 12 steps allowing the identification of powerful agonists with pharmacokinetic properties in accordance with our strategy of topical intestinal compounds. In vivo studies were then used to validate the GLP-1 secretagogue effect of such compounds. Finally, evaluation of one of the best compounds in a murine model of diabetes allowed us to validate the hypothesis that a topical intestinal agonist of TGR5 can have a beneficial effect on energy and glucose homeostasis
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Schäfer, Sven [Verfasser], Anselmino Verena [Gutachter] Keitel-, and Miriam [Gutachter] Cortese-Krott. "Bedeutung von Mutationen im Gen des Gallensalzrezeptors TGR5 (Gpbar-1) bei Lebererkrankungen / Sven Schäfer ; Gutachter: Verena Keitel- Anselmino, Miriam Cortese-Krott." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2018. http://d-nb.info/1163804673/34.
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Lasalle, Manuel. "TGR5, cible thérapeutique pour le traitement du diabète de type 2 et ses complications métaboliques : de la chimie aux effets biologiques." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S023/document.
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Les acides biliaires sont depuis longtemps connus pour leur propriété d’agents solubilisant des graisses et des vitamines liposolubles, permettant ainsi une absorption efficace de ces nutriments lors de la digestion. Depuis les années 2000, plusieurs équipes ont montré que ces molécules étaient également dotées de propriétés de signalisation, en particulier via l’activation de deux récepteurs : le récepteur nucléaire FXR, et le récepteur membranaire TGR5. Le récepteur TGR5 est exprimé dans de très nombreux tissus, dont les muscles lisses et squelettiques, le tissu adipeux brun, la vésicule biliaire, mais aussi certaines cellules immunitaires et certaines populations cellulaires intestinales telles que les cellules entéroendocrine L. Selon le tissu étudié, l’activation de TGR5 peut être suivie de nombreux effets biologiques. En particulier, au niveau intestinal, l’activation de ce récepteur stimule la sécrétion de l’hormone incrétine GLP-1.Les hormones incrétines sont impliquées dans la régulation de la glycémie, en particulier dans la phase postprandiale, où elles concourent à potentialiser l’action de l’insuline, hormone hypoglycémiante majeure. Or, dans un contexte de diabète, et en particulier de diabète de type 2, l’organisme est devenu moins sensible à l’insuline, ce qui se traduit par un défaut de gestion de la glycémie, pouvant entrainer à terme des complications graves, telles que des amputations, une cécité, ou encore des problèmes cardiovasculaires. La prévalence et l’incidence de cette pathologie ont conduit l’OMS à la considérer comme la première épidémie d’origine non-infectieuse, ce qui illustre son impact sur la santé publique et le besoin médical constant qu’elle génère.Dans ce contexte, TGR5 apparait comme cible thérapeutique potentielle attrayante, de par l’effet GLP-1 sécrétagogue consécutif à son activation. En effet, parmi les thérapies antidiabétiques, deux classes de molécules basent leur efficacité sur une augmentation de la signalisation de la voie incrétine : les incrétinopotentiateurs (inhibiteurs de la DDP4, enzyme responsable de la faible demi-vie du GLP-1) et les incrétinomimétiques (agonistes synthétiques du récepteur au GLP-1). Récemment, cette dernière classe a également fait son apparition dans l’arsenal thérapeutique de l’obésité, confirmant l’intérêt de cette voie de signalisation dans les pathologies issues d’un désordre métabolique. L’obtention de composés GLP-1 sécrétagogues s’avère ainsi prometteuse et représente une approche complémentaire aux deux autres classes.L’objectif de ce travail était donc d’obtenir des agonistes puissants, sélectifs et originaux du récepteur TGR5. Afin de diminuer les risques d’effets indésirables, on-target ou off-target, nous avons choisi de profiter de la localisation intestinale de notre cible d’intérêt en concevant nos composés de manière à limiter l’exposition au seul tractus gastro-intestinal, en limitant leur absorption. Ainsi, nous avons cherché à obtenir des composés non systémiques GLP-1 sécrétagogues.La stratégie employée pour aboutir à ces composés a été le développement de molécules chimériques constituées d’une partie agoniste de TGR5, le pharmacophore, liée à un groupement permettant de limiter la perméabilité membranaire et donc l’absorption intestinale, le kinétophore. Après avoir optimisé la partie pharmacophore et identifié une position permettant l’ajout de différents types de kinétophores sans impact majeur sur l’activité du composé, nous avons pu obtenir plusieurs agonistes de TGR5 puissants, originaux, et dotés d’une très faible perméabilité membranaire. L’étude in vivo de ces molécules a ensuite permis de valider d’une part leur activité GLP-1 sécrétagogue, et d’autre part leur faible exposition systémique. Enfin, l’évaluation du potentiel thérapeutique d’un des meilleurs composés dans des modèles murins de diabète a récemment pu être initiéeBile acids have long been known as lipid solubilizing agents, enabling efficient absorption of nutrients and vitamins during digestion. Since 2000, several teams have demonstrated the signaling properties of these molecules, especially through the activation of two receptors : the nuclear receptor FXR and the membrane receptor TGR5.The TGR5 receptor is expressed in various tissues, such as smooth and skeletal muscles, brown adipose tissue, gallbladder, but also on some immune or intestinal cell lines such as the enteroendocrine L cells. Depending on the studied tissue, TGR5 activation can trigger various biological effects. In the intestine, its activation can stimulate the secretion of an incretin hormone, the GLP-1.Incretin hormones play a role in glycaemia regulation, especially during the postprandial phase during which they potentiate the action of the insulin, the main hypoglycemic hormone. Diabetes mellitus correspond to a decreased response of the organism to insulin signaling. This leads to a default in the glycaemia handling that can lead to serious complications, such as amputation, blindness, or cardiovascular problems. Prevalence and incidence of this disease have lead the WHO to define diabetes as the first non-infectious epidemic, illustrating its impact on public health and the constant need for new therapeutic opportunities.In this context, TGR5 appears as an appealing potential therapeutic target, especially because of the GLP-1 secretagogue effect triggered by its activation. Indeed, among the antidiabetic therapeutic options, two classes of drugs work by increasing the incretin signaling: the incretinopotentiators (inhibitors of the DPP4, which is the enzyme responsible for the very short half-life of GLP-1), and the incretinomimetics (synthetic agonists of the GLP-1 receptor). Recently, this last class has also been approved to treat obesity. This demonstrates the interest of this signaling pathway in the treatment of metabolic disorders. Hence, GLP-1 secretagogue compounds may prove to be an interesting approach, and could complement the two other classes.The aim of this work was then to obtain potent, selective and original agonists of the TGR5 receptor. In order to decrease the risk of on-target and off-target effects, we decided to take advantage of the intestinal localization of our target by designing compounds that would only expose the gastro-intestinal tract, by limiting their absorption. Thus, we wanted to obtain non systemic GLP-1 secretagogue compounds.Our strategy was to develop chimeric compounds consisting of a pharmacophore part, which would be a potent and selective agonist of TGR5, linked to a kinetophore part, which would decrease membrane permeability. After having optimized the pharmacophore part and having identified a position where we could link various kinetophore moieties with only weak impact on the activity, we obtained several potent TGR5 agonists with very low membrane permeability. In vivo evaluations of these compounds have validated both their GLP-1 secretagogue activity and their low systemic exposure. In the end, evaluation of our lead compound on mouse model of diabetes was recently started
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Castellanos, jankiewicz Ashley. "Bile acids signaling as a novel mechanism in the hypothalamic control of energy balance." Thesis, Bordeaux, 2019. http://www.theses.fr/2019BORD0218.
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Introduction : Les acides biliaires (AB) sont des molécules connues pour digérer les lipides. En activant le récepteur couplé à la protéine G Takeda 5 (TGR5) dans les tissus périphériques, ils peuvent également servir de molécules de signalisation pour réduire le poids corporel et améliorer le profil glycémique. L'activation de TGR5 peut aussi augmenter la dépense énergétique dans le tissu adipeux, mais les voies métaboliques impliquées dans ces effets sont encore mal connues. Ces observations impliquent une action anti-obésité du TGR5. Cependant, toutes les études sur les AB dans la balance énergétique se sont concentrées exclusivement sur des tissus périphériques. Comme le principal centre de convergence des signaux nutritifs, hormonaux et environnementaux se trouve dans le cerveau, et en particulier dans l'hypothalamus, nous avons émis l'hypothèse que l'activité hypothalamique du TGR5 pourrait moduler la balance énergétique, en particulier dans un contexte d’obésité. Objectif : Démontrer la fonction du système AB – TGR5 dans des populations de cellules hypothalamiques connues pour contrôler l’homéostasie énergétique et étudier sa pertinence pour le traitement de l’obésité. Méthodes : Des canules intra-cérébro-ventriculaires (ICV) ont été implantées sur des souris mâles C57Bl6/J minces (sous régime standard) ou obèses (sous régime riche en graisses) pour permettre l'administration pharmacologique aiguë ou chronique des agonistes du TGR5. Des souris TGR5flox/flox ont été utilisées pour provoquer la délétion du récepteur dans l'hypothalamus médio-basal (HMB), par l’injection in situ d’un AAV-Cre. Nous avons mesuré le poids corporel, prise alimentaire, composition corporelle, sensibilité à l'insuline, niveaux des AB hypothalamiques et plasmatiques et dépense énergétique. Pour bloquer la signalisation sympathique, nous avons exposé les souris à un environnement de thermoneutralité (30°C) ou à une sympathectomie chimique. Des marqueurs de la lipolyse, de la thermogenèse ou du métabolisme thyroïdien ont été mesurés dans le foie, le tissu adipeux et l’hypothalamus par qPCR ou western blot. Toutes les études ont été approuvées par le comité d'éthique en expérimentation animale de l'Université de Bordeaux. Résultats : Nous montrons que les transporteurs du TGR5 et des AB s’expriment dans l’HMB et que les souris obèses ont une diminution des AB dans la circulation et l’hypothalamus. L'administration aiguë d'agonistes du TGR5 (ICV ou intra-HMB) réduit la prise alimentaire et le poids corporel chez les souris obèses, tout en améliorant leur sensibilité à l'insuline. De plus, l'administration chronique ICV de l’agoniste réduit le poids corporel et l'adiposité, tout en augmentant la dépense énergétique et les marqueurs de l'activité sympathique dans le tissus adipeux. La thermo-neutralité ainsi que la sympathectomie chimique atténuent ces effets, démontrant que l’activité du récepteur TGR5 nécessite un tonus sympathique accru. La délétion de TGR5 dans le HMB (souris TGR5flox/flox) n'a aucun effet chez les souris minces. Cependant, l’exposition à une nourriture riche en graisse augmente rapidement leur poids, prise alimentaire et adiposité. Lors de l’exposition au froid (4 heures à 4°C), l’expression des marqueurs de lipolyse et thermogenèse dans le tissu adipeux était atténuée, suggérant une interruption de la signalisation sympathique. Enfin, la suppression du TGR5 dans le HMB de souris déjà obèses augmente l'adiposité en induisant une hyperphagie, aggravant l’obésité. Conclusions : Nos résultats prouvent l’existence d’un système fonctionnel du TGR5 hypothalamique, un récepteur des AB. Nous montrons pour la première fois que l'activation du TGR5 dans le HMB induit une myriade d'effets qui améliorent des paramètres métaboliques, et que cela dépend de l'activation du système nerveux sympathique. Ainsi, nous dévoilons un nouveau mécanisme d'action pour des potentiels traitements contre l'obésitéIntroduction: Bile acids (BA) are cholesterol-derived molecules mostly known for their role in digesting lipids. By activating the Takeda G protein coupled receptor 5 (TGR5) in peripheral organs, they can also act as signaling molecules to reduce body weight and improve glucose homeostasis. Notably, TGR5 activation can increase energy expenditure in brown adipocytes, although the metabolic pathways involved in these effects are not yet clear. These outcomes imply an anti-obesity function for TGR5. However, all studies investigating BA in energy balance have exclusively focused on peripheral tissues. Since the major center of convergence of nutrient, hormonal, and environmental cues is the brain, particularly the hypothalamus, we hypothesized a role for TGR5 in this brain structure, suggesting that hypothalamic TGR5 activity may participate in energy balance, specifically under dietinduced obesity. Objective: To demonstrate the function of the BA – TGR5 system in hypothalamic populations known to control energy homeostasis, and disentangle its relevance for the treatment of diet-induced obesity. Methods: C57Bl6/J male mice that were either lean (standard chow) or diet-induced obese (60% high-fat diet; HFD) were implanted with an intra-cerebroventricular (ICV) cannula for the pharmacological delivery of TGR5 agonists. TGR5flox/flox mice were used to target the sitespecific deletion of the receptor within the mediobasal hypothalamus (MBH), through the stereotaxic delivery of AAV-Cre. The following metabolic outputs were measured: body weight, food intake, body composition (EchoMRI analyzer), insulin sensitivity, serum and hypothalamic BA (liquid mass spectrometry), and energy expenditure (TSE Phenomaster system). To block sympathetic signaling, we exposed mice to thermoneutrality (30°C) or performed chemical sympathectomy (6-hydroxydopamine; 80mg/kg i.p.). Markers of lipolysis, thermogenesis, and thyroid metabolism were measured in the liver, adipose and hypothalamic tissues by qPCR or western blots. All studies received the approval from the animal ethical committee of the University of Bordeaux. Results: We demonstrate that TGR5 and BA transporters are expressed in the MBH and that diet-induced obese mice have decreased circulating and hypothalamic BA. Acute ICV or intra-MBH administration of TGR5 agonists reduced food intake and body weight in dietinduced obese mice only, and improved insulin sensitivity. Accordingly, chronic ICV administration of the TGR5 agonist in obese mice reduced their body weight and adiposity, while increasing energy expenditure and mRNA markers of sympathetic activity in the adipose tissue. Indeed, experiments conducted at thermoneutrality or chemical sympathectomy blunted these effects, demonstrating that central TGR5 effects require an enhanced sympathetic tone. By using TGR5flox/flox mice coupled with the delivery of an AAVCre, we observed that the deletion of TGR5 in the MBH had no effect in chow-fed mice. However, a HFD switch rapidly increased their body weight, food intake and adiposity. When exposed to the cold (4 h at 4°C), protein levels of lipolysis and thermogenesis markers in the adipose tissue were blunted, implying an interruption in sympathetic signaling to the periphery due to hypothalamic downregulation of TGR5. Lastly, Cre-dependent deletion of TGR5 in the MBH of already obese mice rapidly increased adiposity by inducing hyperphagia, worsening their obese phenotype. Conclusions: Our work proves the existence of a functional hypothalamic BA – TGR5 receptor system. We show for the first time that the activation of TGR5 in the MBH decreases body weight and adiposity, while increasing energy expenditure through recruitment of the sympathetic nervous system. Taken together, these results expose a new mechanism of action for potential anti-obesity therapies
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Queniat, Gurvan. "Rôle des acides biliaires et de leur récepteur TGR5 dans la régulation de la somatostatine pancréatique et intestinale : conséquences fonctionnelles sur les îlots pancréatiques humains." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S024/document.
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Le rôle des acides biliaires a évolué ces dernières années passant de simples molécules solubilisatrices des lipides à des composés à activité métabolique. En plus de leur fonction dans l’absorption des lipides post-repas, ils ont été montrés comme stimulant de nombreuses voies de signalisation modulant l’expression de gènes clefs du métabolisme et de nombreux mécanismes physiologiques via l’activation de récepteurs spécifiques tels que les récepteurs « Farnesoid X receptor » (FXR) et le récepteur membranaire couplé à une protéine G, TGR5. La protéine TGR5 codée par le gène GPBAR1, aussi connue sous le nom de « G-protein-membrane-type receptor for bile acids » (M-BAR) est le premier récepteur couplé à une protéine G spécifique aux acides biliaires ayant été mis en évidence. Cette protéine est exprimée dans de nombreux tissus clefs du métabolisme énergétique tels que les cellules L intestinales, le tissu adipeux, les reins, le muscle squelettique et le pancréas. En réponse à la fixation des acides biliaires au récepteur TGR5, celui-ci va être internalisé et sa sous-unité GαS va être libérée. Ce mécanisme va ensuite activer l’adénylate cyclase et augmenter la production d’AMPc à l’origine de l’activation des voies de signalisations liées à la protéine kinase A (PKA). Une fois activée, la PKA va induire la phosphorylation des protéines « cAMP-response element-binding » (CREB) et permettre la modulation de l’expression de gènes cibles.Ces dernières années de nombreux travaux ont eu pour but d’étudier le rôle du récepteur TGR5 dans le métabolisme. Chez la souris, l’activation du récepteur TGR5 stimule la dépense énergétique dans le tissu adipeux brun et dans le muscle squelettique et prévient le développement de l’obésité et de l’insulino-résistance induites par un régime riche en graisses. Le récepteur TGR5 est également impliqué au niveau des cellules L intestinales sécrétrices du GLP-1. Il y joue un rôle essentiel dans l’homéostasie glucidique via la régulation de l’activité pancréatique, des sécrétions de l’insuline et du glucagon, de l’inhibition de la vidange gastrique ou encore de la modulation des messages de satiété via des voies neuroendocrines. TGR5 présente également des fonctions immunologiques avec une expression connue dans les cellules de l’immunité telles que les monocytes, les macrophages alvéolaires ou encore les cellules de Kupffer. TGR5 a également été mis en évidence comme régulateur des mécanismes d’inflammations via les macrophages avec une diminution de l’expression des cytokines pro-inflammatoires. A l’opposé, l’activation de TGR5 serait impliquée dans de nombreux processus pathologiques tels que, le développement de carcinomes gastro-intestinaux, les pancréatites, la lithiase biliaire, suggérant un rôle potentiel du récepteur TGR5 dans la régulation de voies de signalisation responsables de la prolifération et de la mort cellulaire [...]Bile acids (BAs) have evolved over the years from being considered as simple lipid solubilizers to metabolically active molecules. In addition to their function in dietary lipid absorption, they have also been shown to activate farnesoid X receptor (FXR) and TGR5 receptors to initiate signaling pathways and regulate metabolic gene transcription. TGR5 (encoded by the GPBAR1 gene), also known as G-protein-membrane-type receptor for bile acids (M-BAR) or G-protein-coupled bile acid receptor 1 (GPBAR1), was the first identified G-protein coupled receptor specific for bile acids. In normal individuals, the highest level of GPBAR1 mRNA expression was reported in the gallbladder, placenta and spleen, followed by moderate expression in other tissues including lungs, liver, stomach, small intestine and adipose tissue, with a relatively low level of expression in kidney, skeletal muscles and pancreas. In response to binding of BAs to the ligand-binding pocket of the TGR5 protein, the TGR5 receptor is internalized and the GαS subunit is released. This mechanism leads to activation of adenylate cyclase and an increase in cAMP production resulting in induction of the protein kinase A (PKA) pathway. Subsequently, PKA phosphorylates the cAMP-response element-binding protein (CREB) and enhances the transcription of its target genes in response to extracellular signals.To date, extensive work has been done to investigate the role of TGR5 in metabolism. In rodents, BA-activated TGR5 receptor stimulates energy expenditure in brown adipose tissue and skeletal muscle and prevents obesity and insulin resistance induced by a high fat diet. TGR5 is also implicated in intestinal L-cells secreted GLP-1, which plays an essential role in glucose homeostasis through the stimulation of glucose-dependent-insulin-secretion and inhibition of glucagon secretion, inhibition of gastric emptying and increasing satiety through neuroendocrine pathways. In terms of the immunological function of TGR5, it is now known that TGR5 is expressed in several immune cells such as monocytes, alveolar macrophages and Kupffer cells. The beneficial effects of TGR5 on macrophage-driven inflammation include reduced proinflammatory cytokine expression, thus protecting against atherosclerosis and liver steatosis. On the contrary, TGR5 activation has also been implicated in itch and analgesia, gastrointestinal-tract cell carcinogenesis, pancreatitis, and cholelithiasis, suggesting a potential role for TGR5 as a regulator of signal transduction pathways responsible for cell proliferation and apoptosis. BAs may also influence islet function via both direct and indirect mechanisms as recent studies have shown that Farnesoid X receptor (FXR) is expressed by pancreatic beta cells, and regulates insulin signaling in cultured cell lines. Kumar et al., [14] also reported that the TGR5 agonists INT-777 + oleanolic acid (OA) stimulated glucose-mediated insulin release via TGR5 activation, also in cultured cells. Still, little is known about the regulation of TGR5 expression or its involvement in pancreatic hormone secretion in response to physiological or pathological conditions such as T2D, as these studies have been performed mainly in cultured cell lines. In these contexts, the biological function of TGR5 remains enigmatic. The aim of the present study was first to establish the specific expression of TGR5 in human pancreatic islet cell subtypes. Then, a cross-sectional cohort of human islets isolated from individuals with various degrees of insulin resistance was exploited to determine if TGR5 expression and function was modified in T2D. Finally to determine if targeting TGR5 is clinically relevant, human islets were treated in-vitro with a specific agonist of TGR5 or with siRNA directed against TGR5 and hormone secretion assessed to establish whether TGR5 activation or inhibition modulate pancreatic hormone secretion
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Pachhain, Sudhan. "Analysis of gene expression associated with drug-induced hyperthermia in rat." Bowling Green State University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1562330027757666.
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Colliva, Carolina <1981>. "New synthetic bile acid analogue agonists of FXR and TGR5 receptors: Analytical methodologies for the study of their physico-chemical properties, pharmacokinetic activity and metabolism." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5612/1/COLLIVA_CAROLINA_TESI.pdf.
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This thesis reports an integrated analytical approach for the study of physicochemical and biological properties of new synthetic bile acid (BA) analogues agonists of FXR and TGR5 receptors. Structure-activity data were compared with those previous obtained using the same experimental protocols on synthetic and natural occurring BA.
The new synthetic BA analogues are classified in different groups according also to their potency as a FXR and TGR5 agonists: unconjugated and steroid modified BA and side chain modified BA including taurine or glycine conjugates and pseudo-conjugates (sulphonate and sulphate analogues).
In order to investigate the relationship between structure and activity the synthetic analogues where admitted to a physicochemical characterization and to a preliminary screening for their pharmacokinetic and metabolism using a bile fistula rat model. Sensitive and accurate analytical methods have been developed for the quali-quantitative analysis of BA in biological fluids and sample used for physicochemical studies.
Combined High Performance Liquid Chromatography Electrospray tandem mass spectrometry with efficient chromatographic separation of all studied BA and their metabolites have been optimized and validated. Analytical strategies for the identification of the BA and their minor metabolites have been developed. Taurine and glycine conjugates were identified in MS/MS by monitoring the specific ion transitions in multiple reaction monitoring (MRM) mode while all other metabolites (sulphate, glucuronic acid, dehydroxylated, decarboxylated or oxo) were monitored in a selected-ion reaction (SIR) mode with a negative ESI interface by the following ions.
Accurate and precise data where achieved regarding the main physicochemical properties including solubility, detergency, lipophilicity and albumin binding . These studies have shown that minor structural modification greatly affect the pharmacokinetics and metabolism of the new analogues in respect to the natural BA and on turn their site of action, particularly where their receptor are located in the enterohepatic circulation.
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Colliva, Carolina <1981>. "New synthetic bile acid analogue agonists of FXR and TGR5 receptors: Analytical methodologies for the study of their physico-chemical properties, pharmacokinetic activity and metabolism." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5612/.
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This thesis reports an integrated analytical approach for the study of physicochemical and biological properties of new synthetic bile acid (BA) analogues agonists of FXR and TGR5 receptors. Structure-activity data were compared with those previous obtained using the same experimental protocols on synthetic and natural occurring BA.
The new synthetic BA analogues are classified in different groups according also to their potency as a FXR and TGR5 agonists: unconjugated and steroid modified BA and side chain modified BA including taurine or glycine conjugates and pseudo-conjugates (sulphonate and sulphate analogues).
In order to investigate the relationship between structure and activity the synthetic analogues where admitted to a physicochemical characterization and to a preliminary screening for their pharmacokinetic and metabolism using a bile fistula rat model. Sensitive and accurate analytical methods have been developed for the quali-quantitative analysis of BA in biological fluids and sample used for physicochemical studies.
Combined High Performance Liquid Chromatography Electrospray tandem mass spectrometry with efficient chromatographic separation of all studied BA and their metabolites have been optimized and validated. Analytical strategies for the identification of the BA and their minor metabolites have been developed. Taurine and glycine conjugates were identified in MS/MS by monitoring the specific ion transitions in multiple reaction monitoring (MRM) mode while all other metabolites (sulphate, glucuronic acid, dehydroxylated, decarboxylated or oxo) were monitored in a selected-ion reaction (SIR) mode with a negative ESI interface by the following ions.
Accurate and precise data where achieved regarding the main physicochemical properties including solubility, detergency, lipophilicity and albumin binding . These studies have shown that minor structural modification greatly affect the pharmacokinetics and metabolism of the new analogues in respect to the natural BA and on turn their site of action, particularly where their receptor are located in the enterohepatic circulation.
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Gertzen, Christoph Gerhard Wilhelm [Verfasser], Holger [Akademischer Betreuer] Gohlke, and Anselmino Verena [Gutachter] Keitel-. "Integrative Modeling to Determine the Activity, Molecular Recognition, and Membrane Trafficking of the G-Protein Coupled Bile Acid Receptor TGR5 / Christoph Gerhard Wilhelm Gertzen ; Gutachter: Verena Keitel- Anselmino ; Betreuer: Holger Gohlke." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2017. http://d-nb.info/1123713170/34.
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Chavez, Talavera Oscar Manuel. "Rôle des acides biliaires dans la physiopathologie de l'obésité, la résistance à l'insuline, le diabète de type 2, la stéatose hépatique non alcoolique et dans le contexte de la chirurgie bariatrique Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease Bile Acid Alterations in Nonalcoholic Fatty Liver Disease, Obesity, Insulin Resistance and Type 2 Diabetes: What Do the Human Studies Tell?” Bile acids associate with glucose metabolism, but do not predict conversion to diabetes Bile acid alterations are associated with insulin resistance, but not with NASH in obese subjects Roux-en-Y gastric bypass increases systemic but not portal bile acid concentrations by decreasing hepatic bile acid uptake in minipigs The functional relevance of bile acids in the improvement of HDL-mediated endothelial protection after bariatric surgery Metabolic effects of bile acid sequestration: impact on cardiovascular risk factors." Thesis, Lille, 2019. http://www.theses.fr/2019LILUS057.
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En plus de leur rôle dans la solubilisation des lipides alimentaires, les acides biliaires sont des molécules de signalisation régulant leur propre métabolisme, l'homéostasie du glucose et des lipides, la dépense énergétique, la fonction cardiovasculaire et l’inflammation, en modulant le Farnesoid X Receptor (FXR) et le Takeda G protein coupled Receptor 5 (TGR5). En effet, des modifications dans les concentrations des acides biliaires sont associées aux maladies métaboliques et ce sont des candidats pour participer à la pathophysiologie de ces maladies ou prédire leur progression.Dans la première partie de cette thèse nous avons étudié les modifications des acides biliaires dans le contexte de l'obésité, l'insulinorésistance, le diabète de type 2 et la stéatohépatite non alcoolique. Nous avons montré que les acides biliaires sont corrélés avec l’homéostasie du glucose chez l’Homme, mais qu’ils ne sont pas des prédicteurs de la bascule du prédiabète en diabète de type 2 dans un étude de cohorte.La deuxième partie de cette thèse est dédiée à l’étude des acides biliaires dans la chirurgie bariatrique. Nos résultats ont montré que la chirurgie bariatrique réduit la recapture hépatique des acides biliaires, provoquant leur augmentation dans la circulation systémique, et que ce n’est pas l’anse biliaire mais l’anse commune qui est responsable des modifications métaboliques après la chirurgie bariatrique chez le minipig. Ensuite, nous avons montré chez l’Homme que les acides biliaires liés aux lipoprotéines de haute densité (HDL) augmentent après la chirurgie bariatrique, et que cette augmentation est corrélée avec la restauration de leurs fonctions vaso-protectricesIn addition to their role in the solubilization of dietary lipids, bile acids are signaling molecules regulating their own metabolism, glucose and lipid homeostasis, energy expenditure, cardiovascular function and inflammation via the activation of the Farnesoid X Receptor (FXR) and the Takeda G protein coupled Receptor 5 (TGR5). Indeed, changes in bile acid concentrations are associated with metabolic diseases and therefore they are candidates to participate in the pathophysiology of these diseases or predict their progression.In the first part of this thesis, we studied bile acid changes in the context of obesity, insulin resistance, type 2 diabetes and non-alcoholic steatohepatitis. We demonstrated that bile acids are correlated with glucose homeostasis in humans, but that they are not predictors for the progression from prediabetes to type 2 diabetes in a longitudinal cohort study.In the second part of this thesis, we studied the bile acids in the context of bariatric surgery. Our results showed that bariatric surgery reduces the hepatic recapture of certain bile acids, causing them to increase in the systemic circulation. Additionally, we showed that it is not the bile limb but the common limb the one responsible for metabolic changes after bariatric surgery in the minipig. Finally, we showed in humans that bile acids linked to high-density lipoproteins (HDL) increase after bariatric surgery, and that this increase is correlated with the restoration of their vasoprotective functions
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Franck, Silke. "Untersuchungen des Angstverhaltens der transgenen Ratte TGR(mRen2)27." [S.l.] : [s.n.], 2001. http://www.diss.fu-berlin.de/2001/272/index.html.
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Kopec, David M., Jeff J. Gilbert, Mohammed Pessarakli, and Steve Nolan. "Repeat Applications of Paclobutrazole (TGR) Plant Growth Regulator on Overseeded Bermudagrass Turf: Weed Control and Bermudagrass Transition." College of Agriculture and Life Sciences, University of Arizona (Tucson, AZ), 2009. http://hdl.handle.net/10150/216670.
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TGR (paclobutrazole) was applied to both overseeded and non-overseeded turfs in repeat monthly applications at either 8.0 oz or 12.0 oz product/1000 ft² rates. Applications were made in repeat monthly intervals to apply either three, four or five repeat applications beginning in December 2007, and ending in April 2008. When applied as a post emergent PGR material, TGR caused only a slight decrease in turfgrass color and quality of overseeded turfs in March at the high (and repeated) rate of 12.0 oz/product/acre. This effect was short lived, as overseeded turfs for the remainder of the season maintained fully acceptable color and quality through the spring transition period. Tenacity turfs always had quality scores of 6.0 or higher throughout the test. Seed head suppression was realized from TGR, with greater head suppression at the 12.0 oz rate than that of the 8.0 oz rate. Bermudagrass transition among TGR treated turfs was not different from that of the untreated controls, whether the turfs were overseeded or not. On 20 June 2008, percent bermudagrass plot cover ranged from 29-58% for TGR treated turfs, 40% for Tenacity, while the overseeded UTC had 35%, on average. The percent bermudagrass increased quickly after a 2.0 lb. /N /M application on June 20, to 68% to 90% bermudagrass cover for TGR treated turfs (UTC = 83%). After a scalping event (from 1.25 inches to 0.50 inches) performed on July 1, percent bermudagrass decreased temporarily (from bermudagrass removal), but rebounded within 15 days to yield 96% to 99% bermudagrass cover by the close of the test on 31 July, 2008. Like wise, Tenacity alone did not inhibit transition, as Tenacity treated turfs had bermudagrass cover slightly greater than that of the overseeded controls.
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Wells, Lawrence L., and Robert S. Montgomery. "AN INTEGRATED GPS TRACKING AND TELEMETRY SYSTEM FOR RANGE APPLICATIONS." International Foundation for Telemetering, 1998. http://hdl.handle.net/10150/607360.
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International Telemetering Conference Proceedings / October 26-29, 1998 / Town & Country Resort Hotel and Convention Center, San Diego, CaliforniaThis paper describes a highly integrated and low cost GPS Translator/Telemetry system for use on missile platforms – the Digital GPS Translator (DGT), a component part of the Translated GPS Range System (TGRS). The DGT provides translated GPS tracking capability combined with transmission of telemetry at rates of up to 10 Mbps with optional encoding and/or encryption. This integrated approach to GPS tracking and telemetry results in a significant reduction in hardware size and cost compared to a segregated approach. The TGRS includes a ground-processing unit that provides real time processing of both the GPS and telemetry portions of the DGT transmission.
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Breymaier, Susan M. "The effects of the Reading Academy Intensive Support Education (RAISE) Summer School Program on students' Third Grade Reading Guarantee (TGRG) assessment scores." University of Toledo / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1525986233056296.
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Dobrovolska, Olena. "Structure-functional Characterization of Mammalian Redox Proteins : Methionine sulfoxide reductase B1 (MsrB1), Glutaredoxin domain (Grx) of TGR, and Thioredoxin (Trx)." Doctoral thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for bioteknologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-20125.
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This thesis was written at the Department of Biotechnology of Norwegian University of Science and Technology (NTNU) and made as a completion of the three-year PhD program. It summarises the studies of the thiol redox active mammalian enzymes operating within thioredoxin defence system. Aiming to characterize their structural and functional aspects high resolution NMR spectroscopy technique was mainly used along with other complementary techniques. This study covers four research projects dedicated to the following proteins: methionine sulfoxide reductase B1 (MsrB1), thioredoxin (Trx), methionine sulfoxide reductase B (MsrBs), and Grx domain of mouse TGR (Grx). The reduction mechanism of MsrB1, focusing on structural aspects of the intermolecular protein complex formation between MsrB1 and its functional partner Trx was the subject of the first study. Analysis and systematization of the currently available structural data about the key members of the cellular antioxidant defence system, MsrB enzymes, were presented in the second study. Thioredoxin glutathione reductase (TGR) is a member of the mammalian thioredoxin reductase family that has a monothiol glutaredoxin (Grx) domain attached to the thioredoxin reductase module. Grx structure determination and characterization was performed in the third project. MsrB1 contains zinc ion coordinated by four cysteines. Recombinantly expressed in E.coli cells in cobalt-supplemented medium MsrB1 was demonstrated to uptake cobalt ion. Structural studies of cobalt-containing MsrB1 were described in the fourth project.
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Nadu, Ana Paula. "Avaliação da Cardioproteção em Ratos que Superexpressam uma Proteína de Fusão Produtora de Angiotensina-(1-7) [TGR(A1-7)3292]." Universidade Federal de Minas Gerais, 2006. http://hdl.handle.net/1843/CMCH-7FYNBB.
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Angiotensin-(1-7) (Ang-(1-7) is now considered to be a biologically active member of the renin-angiotensin system. The functions of Ang-(1-7) are often opposite to those attributed to the main effector component of the renin-angiotensin system, Ang II. Recently it has been suggested that Ang-(1-7) has cardioprotective properties. In the present study, we investigated the effect of Ang-(1-7) on cardiac hypertrophy. Heart hypertrophy was induced in male Sprague-Dawley (SD) and TG rats [TGR(A-7)3292] by daily injection of isoproterenol (2 mg/Kg i.p, 7 days). Control groups received daily injection of vehicle (0.9 % NaCl 0.1 ml/100g i.p, 7 days). At the end of the 7-day period, the rats were killed by decaptation and the heart and blood were immediately collected. The atria and right ventricle were dissected. Wet weights of the left ventricles were recorded and normalized for body weight. The left ventricles were used for morphometric analyzes and quantification of collagen I, III and fibronectin proteins by immunofluorescence using confocal microscopy. Angiotensins were determined by radioimmunoassay (RIA) in plasma and left ventricles. In addition, atrial natriuretic peptide was also determined by RIA in the plasma. The isoproterenol-induced hypertrophy was attenuated in TG rats. The expression of collagen I, III and fibronectin proteins in the extracellular matrix were also attenuated in isoproterenol-treated TG rats left ventricles. Expression of left ventricle angiotensinogen, ACE2, collagen I, III, Mas and AT1 receptors mRNA levels were assessed by semi-quantitative polymerase chain reaction. The cardiac Ang II level was significantly decreased in the TG rats. In contrast, the plasma Ang II levels were significantly increased in TG animals .Angiotensiogen mRNA in the left ventricle was significantly decreased in TG rats while ACE2 mRNA was significantly increased in TG rats. No significant changes were observed for Mas receptor mRNA levels and AT1 receptor mRNA levels in the left ventricles of TG rats. A significant increase of plasma ANP concentration was observed in TG rats. Isoproterenol did not change the biochemical alterations observed in the TG rats before the treatment . These results reinforce the hypothesis that Ang-(1-7) plays an important site-specific role within renin-angiotensin system and others peptidic systems.A Ang-(1-7) é descrita como um fragmento biologicamente ativo do sistema renina-angiotensina, tendo diversas de suas ações contrárias aquelas descritas para Ang II. Estudos recentes têm demonstrado que a Ang-(1-7) apresenta efeitos antiproliferativos e cardiproterores. O objetivo desse estudo foi avaliar o papel da Ang-(1-7) na hipertrofia do ventrículo esquerdo. Nesse estudo foram utilizados ratos machos Sprague-Dawley(SD) e ratos machos que superexpressam Ang-(1-7) [TGR(A1-7)3292]. Os ratos foram tratados com injeções diárias de isoproterenol (2mg/Kg/dia, i.p.) durante 7 dias. Após o período de tratamento, os ratos foram sacrificados e foram coletados o VE e o plasma para posteriores análises. Os VE foram utilizados para análise morfométrica e imunofluorescência, dosagens de Ang II e Ang-(1-7), e expressão de mRNA para angiotensinogênio, ECA2, receptores Mas e AT1, colágenos I e III. O plasma foi utilizado para dosagens de Ang II e ANP. Os ratos TG apresentaram menor hipertrofia do VE, acompanhada por menor formação de matriz intersticial em resposta ao ISO. A concentração cardíaca de Ang II estava diminuída no VE dos ratos TG. Em contraste, as concentrações plasmáticas de Ang II estavam aumentadas. Os ratos TG apresentaram diminuição da expressão do mRNA para angiotensinogênio e aumento da expressão do mRNA para ECA2 no VE. Os ratos TG não apresentaram alterações na expressão do mRNA para os receptores Mas e AT1. Os níveis de ANP estavam aumentados no plasma dos ratos TG. Em resposta ao ISO, as características bioquímicas observadas foram mantidas inalteradas nos ratos TG. Os dados sugerem que a Ang-(1-7) induz importantes alterações bioquímicas no coração e no plasma dos ratos TG, reforçando a hipótese de que ela pode modular o SRA e outros sistemas peptídicos, favorecendo a proteção de órgãos alvos do sistema cardiovascular.
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Chagas, Bruna Maria Emerenciano das. "Pir?lise r?pida da cianobact?ria Spirulina para produ??o de combust?veis e qu?micos." PROGRAMA DE P?S-GRADUA??O EM ENGENHARIA QU?MICA, 2016. https://repositorio.ufrn.br/jspui/handle/123456789/21610.
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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES)
Recentemente as microalgas e cianobact?rias vem sendo muito estudadas como fonte de biocombust?veis devido a sua elevada produtividade, elevado teor de ?leo e capacidade de crescer em uma grande variedade de climas e terras sem competir com a produ??o de alimentos. A pir?lise ? um m?todo de convers?o termoqu?mica eficaz capaz de converter biomassa em bio-?leo, carv?o e gases combust?veis. O bio-?leo ? uma mistura l?quida de compostos org?nicos potencial para substituir o ?leo diesel. Tem sido demosntrado que bio-?leos de microalgas e cianobact?rias s?o mais est?veis, apresentam teor de oxig?nio mais baixo e poder calor?fico mais alto que bio-?leos de biomassa lignocelul?sica, embora contenha um alto teor de nitrog?nio devido a presen?a de prote?nas na mat?ria-prima. A Spirulina ? uma cianobact?ria que vem sendo muito estudada nos processos de degrada??o t?rmica por apresentar alto teor de prote?nas (74%) e baixo teor de lip?dios (< 1%) podendo ser totalmente convertida em biocombust?vel. Nesta tese, foi investigado o potencial de produ??o de combust?veis e qu?micos a partir da pir?lise r?pida de Spirulina. Os experimentos de pir?lise r?pida convencional em Py-GC/MS foram conduzidos para investigar a influ?ncia dos par?metros de pir?lise, tais como temperatura, taxa de aquecimento e tempo de resid?ncia nos rendimentos dos produtos. O rendimento dos produtos da pir?lise foi maximizado a 450 ?C e 30 s, independente da taxa de aquecimento. Essas condi??es foram escolhidas para o estudo da pir?lise catal?tica com 9 ze?litas diferentes para avaliar a produ??o de hidrocarbonetos espec?ficos, compostos oxigenados e nitrogenados em func?o da raz?o biomassa/catalisador. O rendimento de hidrocarbonetos arom?ticos aumentou ? medida que a propor??o de catalisador/biomassa aumentou de 1:1 para 10:1. A ze?lita H-ZSM5 (23) apresentou o rendimento m?ximo de hidrocarbonetos e a maior redu??o de f?nois quando comparada as outras ze?litas, por?m os compostos nitrogenados totais n?o foram significativamente reduzidos por nenhum catalisador testado. Posteriormente testes de pir?lise r?pida de Spirulina foram conduzidos em um reator de leito fluidizado da USDA-ARS sob diferentes atmosferas de rea??o. Foram testadas a pir?lise convencional com atmosfera inerte (N2) e um processo de pir?lise com atmosfera reativa compostas por gases reciclados da pi?lise, denominado ?Tail Gas Reactive Pyrolysis? (TGRP). O bio-?leo, carv?o e gases produzidos pelo processo TGRP tiveram suas caracter?sticas melhoradas em rela??o aos produtos obtidos na pir?lise convencional, houve um aumento na concentra??o dos hidrocarbonetos arom?ticos e predominaram compostos nitrogenados com um ?nico ?tomo de nitrog?nio (piridinas, pirroles, indoles, nitrilas e amidas). Devido a esta composi??o, esse bio-?leo apresentou um n?vel suficientemente elevado de estabilidade t?rmica para ser destilado. Al?m disso, o bio-?leo produzido pelo processo TGRP foi mais est?vel, menos ?cido e apresentou um poder calor?fico mais alto que bio-?leos de biomassa lignocelul?sica.
Recently microalgae and cyanobacteria have been widely studied as a source of biofuels due to its high yield, high oil content and ability to grow on a wide variety of climates and land without competing with food production. Pyrolysis is an effective thermochemical conversion method capable of converting biomass to fuels, including bio-oil, bio-char and gas. Bio-oil is a liquid mixture of organic compounds that can be a source of valuable chemicals and potential to replace diesel oil depending on its quality. It has been shown that bio-oil from microalgae and other proteinaceous biomass are more stable, have a low oxygen content and higher calorific value than those produced from lignocellulosic feedstock, though contains high nitrogen content due to the presence of protein in its constitution. Spirulina is a cyanobacteria that has been studied in the thermal degradation processes due to its high protein and low lipids content. In this thesis, we investigated the potential for production of fuels and chemicals from the fast pyrolysis of Spirulina. Conventional fast pyrolysis experiments in Py-GC/MS were performed to investigate the influence of pyrolysis parameters such as temperature, heating rate and residence time in distribution of products. The pyrolysis yield was maximized at 450 ?C and 30 s, regardless of heating rate. H-ZSM5 (23) showed the maximum hydrocarbon yield and the largest phenols reduction when compared to the other zeolites, but the total nitrogenated compounds were not significantly reduced by any catalyst tested although some specific nitrogenous have been reduced or eliminated. H-? (38) was also able to increase aromatics production, although its effect was less significant when compared to H-ZSM5 (23) and (50). Subsequently tests of Spirulina fast pyrolysis were conducted in USDA?s bubbling fluidized bed pyrolysis reactor under different reaction atmospheres. Conventional (N2 atmosphere) and reactive (Tail Gas Reactive Pyrolysis - TGRP) pyrolysis were tested. Biooil, bio-char and gas obtained from TGRP process had their fuel characteristics improved when compared to the products from conventional pyrolysis. TGRP Spirulina pyrolysis oil showed an increased concentration of aromatics hydrocarbon and the presence of nitrogenous compounds with single nitrogen atom (pyridines, pyrroles, indoles, nitriles and amides), low oxygen content and low acidity being thermally stable therefore a good feedstock for distillation process. Distillation successfully allowed concentrating various chemicals into distillate fractions which, in turn, could be individually isolated for processing to fuels or chemical co-products.
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Ricci, Estelle. "Étude du remodelage morphologique et électrophysiologique des cardiomyocytes ventriculaires chez le rat hypertendu TGR (mREN²)27 et le rat obèse DIO." Lyon 1, 2006. http://www.theses.fr/2006LYO10006.
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Le remodelage cardiaque regroupe les modifications survenant lorsque le cœur est soumis à diverses contraintes. Elles se traduisent notamment au niveau cellulaire par des changements électrophysiologiques. Grâce à la technique du " patch-clamp ", nous les avons étudiées au niveau des cardiomyocytes ventriculaires du rat hypertendu TGR (mREN2)27 et dans un modèle d'obésité, le rat DIOs (Diet Induced Obesity sensitive). Chez le rat TGR de 10 semaines, nos résultats montrent que le facteur surcharge de pression ne peut être seul à l'origine des modifications électrophysiologiques (allongement du potentiel d'action et réduction du courant Ito). De plus, l'étude à 14 mois met en évidence les interactions entre le remodelage lié au vieillissement et celui lié à l'hypertension artérielle. Enfin, chez les rats DIOs nos résultats suggèrent que la résistance à la leptine pourrait conduire l'échangeur Na-Ca à un fonctionnement arythmogène
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Oliveira, Lucas Miranda Kangussu Gomes. "Caracterização dos efeitos cardíacos produzidos pelo aumento crônico dos níveis cerebrais de Angiotensina-(1-7) em ratos hipertensos que superexpressam renina [TGR(mRen2)27]." Universidade Federal de Minas Gerais, 2014. http://hdl.handle.net/1843/BUBD-9MVLR6.
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The renin-angiotensin system (RAS) is a complex hormonal system composed by several enzymes, peptides and receptors. Ang-(1-7) is one of the biologically active peptides of RAS. Chronic intracerebroventricular (ICV) infusion of Ang-(1-7) attenuates arterial hypertension and improves barroreflex control of heart rate. Some initial studies investigated the participation of Ang-(1-7) in the physiopathology of hypertension in transgenic rats that over express tissue renin [TGR(mRen2)27], however, the cardiac effect mediated by Ang-(1-7)/Mas receptor in nervous central system is not well established. The aim of the present study was to characterize the cardiac effects induced by chronic effect of chronic ICV infusion of Ang-(1-7) in TGR(mRen2)27. Sprague-Dawley (SD) and TGR(mRen2)27 rats, with 10 to 12 weeks of age, were divided in four experimental groups: SD subjected to chronic ICV infusion of saline (14 days), hypertensive rats subjected to chronic ICV infusion of saline (14 days), hypertensive rats subjected to chronic ICV infusion of Ang-(1-7) (0,2 g/ h for 14 days) and hypertensive rats subjected to chronic ICV infusion of Ang-(1-7) (0,2 g/ h for 14 days) associated with A779 (1 g/ h for 14 days). It was evaluated: cardiovascular parameters by telemetry, the sensitivity of the barorreflex control of heart rate, cardiac morphology and systolic and diastolic ventricular function by echocardiography, histopathological analysis of left ventricle, determination of the levels of markers of cardiac stress and cellular proliferation by immunoenzymatic assay, evaluation of collagen, fibronectin and RAS components levels by quantitative RT-PCR, measurement of RAS enzymes, ACE and ACE2 activity, determination of RAS peptides levels by radioimmunoassay, evaluation of protein expression of AT1 and Mas receptors by Western blotting and measurement of cardiac autonomic tonus by pharmacologic blockade. We showed that chronic ICV infusion of Ang-(1-7) in TGR(mRen2)27 rats leads to reduction in blood pressure, anti-hypertrophic effects in cardiomyocytes, improvement of barorreflex sensitivity, attenuation of cardiac hyperdinamism, reduction in cardiac levels of ANP, BNP and TGF-, reduction in collagen type 1 and fibronectin levels, that reflects in cardiac remodeling attenuation and alteration in cardiac RAS components (decrease in ACE expression and activity and increased in ACE2 expression and activity, as well as, reduction in Ang II levels). Finally, we showed that these effects might be associated to alteration in the cardiac autonomic tonus, since rats that received Ang-(1-7) showed restoration of its balance. All the effects induced by Ang-(1-7) were prevented or attenuated by the concomitant infusion with the receptor Mas antagonist, A779. Altogether, the results of the present study show that activation of the Ang-(1-7)/ Mas axis in the CNS lowers blood pressure and attenuates the cardiac alterations induced by arterial hypertension, which may constitute an important additional strategy for the treatment of cardiovascular diseases.O sistema renina-angiotensina (SRA) e um complexo sistema hormonal composto por varias enzimas, peptideos e receptores. Entre os peptideos descritos como biologicamente ativos esta a Angiotensina-(1-7) [Ang-(1-7)]. A infusao cronica intracerebroventricular (ICV) de Ang-(1-7) atenua a hipertensao arterial e melhora o controle barorreflexo da frequencia cardiaca (FC). Apesar de alguns estudos iniciais terem sido realizados investigando a participacao da Ang-(1-7) na fisiopatologia da hipertensao em ratos hipertensos que superexpressam o gene da renina [TGR(mRen2)27], o efeito induzido pela Ang-(1-7) via receptor Mas no SNC nas alteracoes cardiacas induzidas pela hipertensao arterial ainda nao estao caracterizadas. Sendo assim, o objetivo deste estudo foi caracterizar os efeitos cardiacos produzidos pelo aumento cronico dos niveis cerebrais de Ang-(1-7) em TGR(mRen2)27. Ratos Sprague-Dawley (SD) e TGR(mRen2)27, entre a 10a e a 12a semana de idade, foram divididos em quatro grupos experimentais: ratos SD com infusao cronica (14 dias) ICV de salina, ratos hipertensos com infusao cronica ICV de salina, ratos hipertensos com infusao cronica ICV de Ang-(1-7) (0,2 g/ hora/ 14 dias) e ratos hipertensos com infusao cronica ICV de Ang-(1-7) (0,2 g/ hora/ 14 dias) associada ao A779 (1 g/ hora/ 14 dias). Foram avaliados os parametros cardiovasculares por telemetria, a sensibilidade do controle barorreflexo da FC, avaliacao da morfologia cardiaca e da funcao ventricular sistolica e diastolica por ecocardiografia, analise histopatologica do ventriculo esquerdo, ensaio imunoenzimatico para determinacao dos niveis de marcadores de estresse cardiaco e proliferacao celular, avaliacao dos niveis de colageno, fibronectina e componentes do SRA por RT-PCR quantitativo, mensuracao da atividade das enzimas ECA e ECA2 do SRA, determinacao dos niveis de peptideos angiotensinergicos por radioimunoensaio, avaliacao da expressao proteica dos receptores AT1 e Mas por Western blotting e avaliacao da atividade autonomica cardiaca atraves de bloqueios farmacologicos. A infusao cronica ICV de Ang-(1-7) em TGR(mRen2)27 reduziu a pressao arterial, melhorou a sensibilidade do controle barorreflexo da FC e atenuou o hiperdinamismo cardiaco. Alem disso, os animais tratados apresentaram efeito anti-hipertrofico, reducao dos niveis de marcadores de estresse mecanico cardiaco (ANP e BNP) e de proliferacao celular (TGF-), reducao dos niveis de colageno I e fibronectina, que reflete na atenuacao do processo de remodelamento cardiaco decorrente da hipertensao arterial. Interessantemente, os animais (mRen2)27 tratados com Ang-(1-7) ICV apresentaram reducao da expressao e atividade da ECA, aumento da expressao e atividade da ECA2 e reducao dos niveis de Ang II no VE. Esses efeitos parecem estar associados a modulacao do tonus autonomico cardiaco. Todos os efeitos induzidos pela Ang-(1-7) foram revertidos ou atenuados pelo antagonismo do receptor Mas utilizando o A779. Em conjunto, os resultados obtidos nesse trabalho mostram que a ativacao do eixo Ang-(1-7)/ Mas no SNC reduz a pressao arterial e atenua as alteracoes cardiacas induzidas pela hipertensao arterial podendo se constituir em uma importante estrategia adicional para o tratamento de doencas cardiovasculares.
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Chen, Zhongli Verfasser], Andreas [Akademischer Betreuer] [Schäffer, and Joost T. van [Akademischer Betreuer] Dongen. "Accumulation and decomposition of the herbicide propanil in the plants dominating in the littoral zone of the Three Gorges Reservoir (TGR), China / Zhongli Chen ; Andreas Schäffer, Joost T. van Dongen." Aachen : Universitätsbibliothek der RWTH Aachen, 2016. http://d-nb.info/1127337084/34.
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Chen, Zhongli [Verfasser], Andreas [Akademischer Betreuer] Schäffer, and Joost T. van [Akademischer Betreuer] Dongen. "Accumulation and decomposition of the herbicide propanil in the plants dominating in the littoral zone of the Three Gorges Reservoir (TGR), China / Zhongli Chen ; Andreas Schäffer, Joost T. van Dongen." Aachen : Universitätsbibliothek der RWTH Aachen, 2016. http://d-nb.info/1127337084/34.
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Thomas, Martin Alexander. "Lokalisation von Komponenten des Renin-Angiotensin-Systems im Hypothalamus von normotensiven (Sprague-Dawley) und transgen-hypertensiven (TGR(MREN2)27) Ratten unter besonderer Berücksichtigung des Nucleus suprachiasmaticus (SCN) ; eine licht- und elektronenmikroskopische Studie /." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972117636.
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Avena, Paola, Ivan Casaburi, and Diego Sisci. "Chenodeoxycholic acid (CDCA) through TGR5-dependent CREB-signaling activation enhances Cyclin D1 expression and promotes human endometrial cancer cell proliferation." Thesis, 2011. http://hdl.handle.net/10955/1024.
Full textAbstract:
Dottorato di Ricerca in Dottorato di Ricerca in Biochimica Cellulare ed Attività dei Farmaci in Oncologia, XXIV Ciclo, a.a. 2010-2011Increasing epidemiologic data in humans as well as many in vitro investigative reports suggest that overweight and obesity are important risk factors for type-I EC which is the most common malignancy in women and accounts for 80% of all ECs. The strongest support for mechanisms to link obesity and cancer risk involves the metabolic and endocrine effects of obesity and the alterations that they induce in the production of peptide and steroid hormones. One way in which fat might exert its effect is stimulation of bile acids (BAs) synthesis and secretion. Bile acids (BAs) are amphipathic detergents that are synthesized in the liver and stored in the gallbladder. An important physiological role of BAs is to facilitate the uptake of lipids together with the fat-soluble vitamins A, D, E and K from the intestine. BAs facilitate these absorptive processes through their detergent properties, which allow the emulsification of lipids. Moreover, BAs have evolved over the past few years from being considered as simple lipid solubilizers to complex metabolic integrators. Beyond the orchestration of bile acids, lipid and glucose metabolism by the nuclear receptor farnesoid X receptor (FXR), BAs also act as signaling molecules through the non-genomic pathway activated by a BAdedicated G protein-coupled receptor (GPCR) TGR5 (also known as BG37 or MBAR). Despite the efficient enterohepatic recirculation of bile acids, a small amount of them can spill over into the systemic circulation particularly during high fat diet. Since in the obese women a strong correlation with endometrial cancer does exist, we investigated the biological effects of different concentrations of the primary bile acid CDCA in a human endometrial type-I cancer cell line, Ishikawa. Ishikawa cell proliferation was determined by [3H]-thymidine incorporation assay after 72 hours of treatment with different concentrations of CDCA. The effects of CDCA on the expression of the cell cycle regulatory proteins were evaluated by RT-PCR and Western blotting assays. Transient transfection method and mutagenesis studies were performed to functionally characterize the Cyclin D1 promoter while ChIP assay was to highlight the direct involvement of the ciselements in CDCA-dependent Cyclin D1 up-regulation. In addition, the effects of impaired expression and function of the proteins involved in CDCA activated signaling were assessed by using small interfering RNAs (siRNAs) technology. Our results indicate that low concentrations (< 30μM) of CDCA were able to stimulate Ishikawa cell growth as evidenced by [3H]Thymidine incorporation and cell cycle analysis by inducing a significant increase in Cyclin D1(CD1) protein and mRNA expression. In contrast, according to previous findings, high doses (> 50μ) of CDCA showed cytotoxic effects concomitantly with an increase of CDK inhibitor p21WAF1/CIP1 expression through a p53-indipendent pathway. Moreover, mutagenesis studies and ChIP analysis revealed that the CDCA-induced CD1 expression requires a cyclic AMP-responsive element (CRE) binding protein motif within the CD1 proximal promoter. Silencing of a cell surface bile acid sensor TGR5 and/or CREB gene expression by RNA interference reversed the CDCA-dependent induction of CD1 expression and proliferation in Ishikawa cells. In conclusion, extrahepatic spillover of BAs following high fat diet particularly in overweight and obese women, could be involved in the onset and/or maintenance of endometrial cancer by stimulation of TGR5 that activates ERK signaling that in turn induces the recruitment of the transcription factor CREB to the Cyclin D1 gene promoter enhancing cell proliferation
Università della Calabria
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corno, chiara. "Studio degli effetti del trattamento con INT-767 sulla capacità differenziativa dei preadipociti." Doctoral thesis, 2019. http://hdl.handle.net/2158/1151891.
Full textAbstract:
La sindrome metabolica (SM) è una patologia caratterizzata da un insieme di fattori di rischio cardio-metabolici. Un
ruolo centrale nella patogenesi è svolto dall'obesità vlscerale e dall'insulino-resistenza che causano, a livello epatico, il
manifestarsi della steatoepatite non alcolica (NASH). Nella SM gli adipociti gravemente disfunzionanti, perdendo la
capacità di rispondere all'insulina, diventano incapaci di sostenere l'aumento dell'apporto energetico. Questo
determina ipertrofia e iperplasia del tessuto adiposo, che inlzia a rilasciare in circolo citochine pro-infiammatorie che
vanno ad alterare la funzionalità degli organi periferici, come ad esempio fegato. ll recettore X del farnesoide (FXR) e il
recettore accoppiato a proteina G (TGR5), entrambi recettori degli acidi biliari, regolano diversi pathway, tra cui il
metabolismo glicidico e lipidico. ln un modello di coniglio di sindrome metabolica indotta da una dieta ricca di grassi
(HFD), il trattamento a lungo termine con INT-767 doppio agonista FXR/TGRs riduce l'accumulo del tessuto adiposo
viscerale, l'iperglicemia, l'ipercolesterolemia e la steatoepatite non alcolica. INT-767 mostra avere un effetto diretto
sulla differenziazione dei preadipociti (rPAD), migliorando il quadro metabolico, principalmente attraverso un
aumento della sensibilità all'insulina dipendente da FXR, e migliorando la funzione mitocondriale e la differenziazione
bruna, dipendenti da TGR5. Nei preadipociti, INT-767 si comporta principalmente come agonista TGR5, attivando
direttamente in modo dose-dipendente la via cAMP/PKA. I preadipociti isolati dal tessuto adiposo viscerale (VAT) di
conigli trattati con INT-767, rispetto ai preadipociti di HFD, mostrano una maggiore espressione dell'mRNA dei
marcatori di adipogenesi bruna (BMP4, CIDEA, HOXC9, LHX8, TMEM26), della biogenesi e motilità mitocondriale (FlS1,
NRF1, TFAM), del signaling del cGMP (GCSA1, GCSBL, PKGl). Questi dati sono stati confermati dall'analisi
dell'espressione genica su omogenati di VAT isolati da animali HFD trattati con INT-767. Nel VAT si osserva un
aumento dei geni relativi alla sopravvivenza (BLC-2), all'adipogenesi bruna (ClDEA, LHX8, PKG1, UCPl), alla
mitocondriogenesi (NRF1, PGC1A, TFAM), al signaling dell'insulina (STAMP2), al metabolismo lipidico (PPARa) e il
rimodellamento delle goccioline lipidiche (PLlN1, STX5, VAMP4). ll trattamento in vivo contrasta, inoltre, le alterazioni
mitocondriali negli rPAD, ne migliora la lunghezza e la dinamicità, promuovendo il processo di fissione e fusione
mitocondriale. INT-767 in vivo riduce la produzione di superossido, la sintesl di ATP, e aumenta il consumo di ossigeno.
Questi miglioramenti della funzionalità mitocondriale sono associati all'aumentata espressione di UCP1, indotta
dall'tNT-767, osservata in campioni omogenati di VAT, isolati da animali trattati in vivo. Anche il rimodellamento delle
goccioline lipidiche risulta nettamente migliorato dal trattamento in vivo.lnfine, INT-767 ha mostrato la capacità di
ridurre le alterazioni istologiche epatiche indotte dalla dieta HFD e di normalizzare l'aumentata espressione dei geni
pro-infiammatori (112, lL6, TNFo). INT-767 induce anche una significativa riduzione dell'espressione genica dei marker
di fibrosi (SNAl2) e di sintesi degli acldi grassi (ACC1, FAS), viceversa aumentando contestualmente l'espressione di
marker legati al corretto immagazzinamento dei lipidi (ABCA1, PLlN1, SNAP23, SRB1, STX5, VAMP4), alla segnalazione
insulinica (lRS1, STAMP2) e dei marcatori mitocondriali (FlS1, MFNL, MFN2, OPA1, SDHB, SLC25A12). ln conclusione,
INT-767 contrasta significativamente le alterazioni indotte da HFD osservate nel fegato e nel grasso, ripristinando la
sensibilità all'insulina e la differenziazione dei preadipociti verso un fenotipo metabolicamente sano.
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Franck, Silke [Verfasser]. "Untersuchungen des Angstverhaltens der transgenen Ratte TGR(mRen2)27 / vorgelegt von Silke Franck." 2001. http://d-nb.info/963666541/34.
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Grosová, Hana. "Variabilita markeru TG5 a asociace k obsahu intramuskulárního tuku a marblingu u skotu." Master's thesis, 2015. http://www.nusl.cz/ntk/nusl-250596.
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The variability of the marker TG5 TG gene and its association with the intramuscular fat and marbling of meat in cattle was studied. Randomly selected population, composed of 237 individuals (bulls) of the Czech Pied cattle breed from four farms in the Czech Republic, waschosen for testing polymorphisms. Polymerase chain reaction was used to amplify a fragment of TG 545 bp in size. After amplification, the fragments digestion was performed using the restriction endonuclease BstYI. To verify the presence of the PCR product and to identify the sizes of digested frag-ments the horizontal agarose electrophoresis was performed. The population's absolute and relative frequencies of alleles and genotypes were calculated. The calculations reve-aled a high frequency of the T allele (25.98 %). In conclusion, statisticalanalysis was performed. As a result, the influence of C422T polymorphism in the 5'promoter region of the gene on the TG and on the IMT marblinghave not been proven, but on the contra-ry there was detected significant effect (p<0.05) of polymorphism content on the region of Lauric acid (C12:0). The results also reveal some evidence of polymorphism having influence on Timnodonic acid and meat pH.
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HUANG, FENG-TUAN, and 黃鳳緞. "Applying Meta Frontier to evaluate the TGR performance of Taiwan's listed tourism industry - Combining with corporate governance." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/7mkvh4.
Full textAbstract:
碩士嶺東科技大學
高階主管企管碩士在職專班
107
This study mainly uses Meta-Frontier method to estimate the technical efficiency value of Taiwan's listed tourism industry. The empirical results indicate that the group production technical efficiency values GCRS, GVRS and GSE are 0.984, 0.994 and 0.990, respectively. During the period, the assessed Taiwan-listed tourism industry had 1.577% of production technology inefficiency, and the small scale of Taiwan-listed tourism industry was the main source of inefficient production technology. The Meta-Frontier production technology efficiency values MCRS, MVRS and MSE are 0.936, 0.981 and 0.955, respectively. This represents that during the estimation period, the assessed Taiwan-listed tourism industry has 6.355% of production technology inefficiency, indicating Taiwan's listed sightseeing tour. The inefficiency of industrial scale is the main source of inefficiency in production technology. The TGR value for the entire period was 0.951, indicating that the travel agency was in an optimal production efficiency during the evaluation period. According to the regression analysis of corporate governance, the TGR gap value of Taiwan's listed tourism industry, Z1, Z2 and Z4 have statistically significant effects.
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CAO, GAO-GUANG, and 曹高光. "The TGR analysis of the Meta Frontier between National joint-stock commercial banks and City commercial banks." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/e5bb4v.
Full textAbstract:
碩士嶺東科技大學
財務金融系碩士班
107
This paper uses the data of the Chinese banking industry in the Bank Scope database to estimate the Meta-Frontier efficiency and TGR(Technology Gap Ratio) of the national joint-stock commercial banks and city commercial bank banks from 2013 to 2017. The empirical results show that the Meta-Frontier index values MCRS, MVRS and MSE and the group production efficiency index values GCRS, GVRS and GSE show that the allocation inefficiency of national joint-stock commercial banks and city commercial banks is the main cause of inefficiency in national joint-stock commercial banks and city commercial banks. The TGR of commercial banks and city commercial banks shows that the TGR of city commercial banks is larger than that of national joint-stock commercial banks, which are 0.999 and 0.989 respectively, that is, the group boundaries of city commercial banks are smaller than national joint-stock commercial banks, to the the meta.
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Müller, Tilo. "Einfluss der Überexpression des zellulären Prionproteins auf ischämisch induzierte neuronale Schädigung in vivo." Doctoral thesis, 2010. http://hdl.handle.net/11858/00-1735-0000-0006-B167-9.
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Thomas, Martin Alexander [Verfasser]. "Lokalisation von Komponenten des Renin-Angiotensin-Systems im Hypothalamus von normotensiven (Sprague-Dawley) und transgen-hypertensiven (TGR(MREN2)27) Ratten : unter besonderer Berücksichtigung des Nucleus suprachiasmaticus (SCN) ; eine licht- und elektronenmikroskopische Studie / von Martin Alexander Thomas." 2004. http://d-nb.info/972117636/34.
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