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Sellers, Kathleen Walworth. "Role of brain soluble epoxide hydrolase in cardiovascular function." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0008356.
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Thesis (Ph.D.)--University of Florida, 2004.Typescript. Title from title page of source document. Document formatted into pages; contains 156 pages. Includes Vita. Includes bibliographical references.
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Davis, Benjamin Boyce. "Novel treatments for atherosclerosis with inhibitors of soluble epoxide hydrolase /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2005. http://uclibs.org/PID/11984.
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Sandberg, Martin. "Mammalian soluble epoxide hydrolase : studies on gene structure and expression /." Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 2000. http://epsilon.slu.se/avh/2000/91-576-5747-5.pdf.
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Varennes, Olivier. "Le rôle de l'Epoxyde hydrolase soluble (sEH) dans la physiopathologie des calcifications vasculaires." Thesis, Amiens, 2018. http://www.theses.fr/2018AMIE0046/document.
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L'Epoxide Hydrolase soluble (sEH) est une enzyme exprimée dans les vaisseaux. Elle possède un domaine hydrolase à l'extrémité COOH-term (sEH-H) qui métabolise des facteurs vasodilatateurs et anti-inflammatoires comme les acides époxyeicosatriénoïques (EETs). Elle possède également un domaine phosphatase à l'extrémité NH2-term (sEH-P) dont le rôle biologique n'est pas totalement élucidé. Afin de comprendre le rôle de sEH-H et sEH-P dans la calcification vasculaire, des anneaux aortiques de rats et des cellules musculaires lisses vasculaires humaines (CMLVh) ont été exposés à des conditions procalcifiantes pendant 7 et 14 jours respectivement. Le N-acétyl-S-farnesyl-L-cystéine (AFC), un inhibiteur de sEH-P, et le trans-4-(4-(3-adamantan-1-yl-ureido)-)cyclohexyloxy) acide benzoïque (t-AUCB), un inhibiteur de sEH-H, ont été utilisés entre 0,1 et 10 μM. En condition procalcifiante, l'AFC réduit de façon dose-dépendante la calcification vasculaire. Au contraire, le t-AUCB augmente de façon dose-dépendante la minéralisation au sein des anneaux aortiques. Une augmentation de l'activité TNAP a été observée dans les surnageants de culture des anneaux aortiques avec le t-AUCB. Sur les anneaux désendothélialisés ou sur les cultures de CMLVh, les inhibiteurs n'ont pas d'effet sur la calcification, soulignant le rôle crucial joué par les facteurs endothéliaux métabolisés par la sEH. L'ensemble de nos résultats montrent que l'inhibition pharmacologique de la sEH-H augmente la calcification vasculaire in vitro en augmentant la biodisponibilité des EETS. Au contraire, l'inhibition de la sEH-P protège contre la calcification vasculaire à travers un mécanisme dépendant de l'endothéliumExpressed in the vasculature, soluble epoxide hydrolase (sEH) exhibits a COOH-terminal hydrolase domain metabolizing endothelial vasodilator and anti-inflammatory factors like epoxyeicosatrienoic acids (EETs) and, a NH2-terminal phosphatase domain whose biological role remains unclear. To assess the role of sEH phosphatase and hydrolase domains in vascular calcification, rat aortic rings and hVSMCs were exposed to procalcifying culture media for 7 and 14 days, respectively. N-acetyl-S-farnesyl-L-cysteine (AFC), an inhibitor of the phosphatase domain, and trans-4-(4-(3-adamantan-1-yl-ureido)-cyclohexyloxy)-benzoic acid (t-AUCB), a hydrolase domain inhibitor, were used at concentrations ranging from 0.1 to 10 μM. Under procalcifying culture condition, AFC significantly and dose-dependently reduces aortic calcification. Conversely, addition of t-AUCB results in a significant and dose-dependent increase in aortic calcification in rats, without modification of tissue viability. A concomitant increase in TNAP activity was observed in supernatants of aortic rings cultured in the presence of t-AUCB. On de-endothelialized aortic rings or hVSMCs cultures, both inhibitors had no significant effect on the calcification process, pointing out the crucial role played by endothelial factors metabolized by sEH in the control of this biomineralization process. Together, our data demonstrates that pharmacological inhibition of sEH hydrolase increases vascular calcification in vitro by majoring the bioavailability of endothelium- derived EETs. Contrarily, the inhibition of sEH phosphatase is protective against vascular calcification through an endothelium-dependent mechanism
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Newman, John William. "Novel tools for the investigation of the endogenous role of soluble epoxide hydrolase /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2002. http://uclibs.org/PID/11984.
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Codony, Gisbert Sandra. "From the design to the in vivo evaluation of novel soluble epoxide hydrolase inhibitors." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/671480.
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Epoxieicosatrienoic acids acids (EETs) are endogenous chemical mediators derived from arachidonic acid that show anti-inflammatory, antihypertensive, analgesic, angiogenic and antiatherosclerotic effects. Soluble epoxide hydrolase (sEH) converts EETs to their corresponding dihydroxyeicosatrienoic acids, whereby the biological effects of EETs are diminished, eliminated, or altered. Therefore, it has been proposed that inhibition of sEH may have therapeutic effects in various inflammatory and pain-related diseases. A number of very potent sEH inhibitors (sEHIs) have been developed, several of them featuring an adamantane moiety that may account for the low solubility and poor pharmacokinetic profile that have hampered their progress into clinics. In this context, the present thesis has been focused on the design and synthesis of novel sEHIs replacing the adamantane moiety by adamantane-like scaffolds in order to improve their drug- like properties. First, the introduction of an oxygen atom in the adamantane nucleus of known sEHI provided a new family of 2-oxaadamantane-based inhibitors endowed with nanomolar potency and improved aqueous solubility and permeability. A screening cascade was conducted in order to biological characterize the new inhibitors and to select a candidate for the in vivo studies, which revealed that the candidate reduced inflammatory and ER stress markers and diminished the pancreatic damage in a murine model of cerulein-induced acute pancreatitis (AP). Second, the exploration of the size of the lipophilic unit of sEHIs showed that the active center of sEH is flexible and can accommodate both larger and smaller polycycles than adamantane, and that the replacement of the adamantane moiety by larger polycyclic rings led to more potent compounds than the replacement by smaller ones. Taking into account these results, the last step was the development of a new family of sEHIs bearing the benzohomoadamantane scaffold, which features in its structure the synthetically versatile homoadamantane unit fused with an aromatic ring. This new family lead to compounds endowed with excellent inhibitory activities in both human and murine sEH, improved water solubility and microsomal stability. Further in vitro profiling and pharmacokinetic studies allowed us to select different candidates for the in vivo efficacy studies. One of them significantly reduced pancreatic damage and improved the health status of the animals after the induction of AP by cerulein. On the other hand, the compound optimized for the treatment of neuropathic pain fully abolished the capsaicin-induced allodynia and outperformed other sEHI tested. Overall, a plethora of very potent sEHIs endowed with improved DMPK properties that present efficacy in several in vivo murine models have been developed in the present Thesis.Los ácidos epoxieicosatrienoicos (EETs) son mediadores químicos endógenos derivados del ácido araquidónico que presentan efectos antiinflamatorios, antihipertensivos y analgésicos entre otros, pero son metabolizados rápidamente por la epóxido hidrolasa soluble (sEH), disminuyendo o alterando sus efectos beneficiosos. Así pues, se ha demostrado que la inhibición de la sEH estabiliza los niveles de EETs in vivo y puede tener efectos terapéuticos en diversas enfermedades que cursan con inflamación y dolor. Recientemente se han desarrollado varios inhibidores de la sEH (sEHIs) muy potentes, y muchos de ellos presentan un adamantano en su estructura, hecho que puede explicar su baja solubilidad y su inadecuado perfil farmacocinético. Por este motivo, la presente tesis doctoral se ha centrado en el diseño y síntesis de nuevos sEHIs, reemplazando el anillo de adamantano por policiclos relacionados, para mejorar las propiedades farmacocinéticas de los compuestos existentes. Primero, la introducción de un oxígeno en el núcleo de adamantano dio lugar a una nueva familia de inhibidores que presentaban mejor solubilidad y permeabilidad manteniendo la potencia inhibidora. Se llevó a cabo una cascada de cribaje para seleccionar un candidato para los estudios in vivo, en los que se demostró que reducía los marcadores de inflamación y de estrés del retículo endoplásmico y disminuía el daño pancreático en un modelo murino de pancreatitis aguda (AP). En segundo lugar, la exploración del tamaño de la unidad lipofílica de los sEHIs mostró que el centro activo del enzima es flexible y puede acomodar policiclos más grandes y más pequeños que el adamantano, siendo los más grandes los que mostraban más potencia. Finalmente, se desarrolló una nueva familia de sEHIs con el núcleo de benzohomoadamantano, dando lugar a compuestos extremadamente potentes, mejorando la solubilidad y la estabilidad microsomal de los sEHIs conocidos. Estudios adicionales nos permitieron seleccionar dos candidatos para los estudios in vivo: el primero para el tratamiento de la AP que produjo una reducción del daño pancreático y mejoró del estado de salud de los animales tratados, mientras que el segundo eliminó por completo la alodinia en un modelo predictivo de dolor neuropático. Así pues, en la presente tesis doctoral se han desarrollado diferentes familias de sEHIs muy potentes con propiedades de DMPK mejoradas y se ha demostrado su eficacia en diferentes estudios in vivo.
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Duflot, Thomas. "Rôle de l'époxyde hydrolase soluble dans les maladies cardiovasculaires." Thesis, Normandie, 2018. http://www.theses.fr/2018NORMR037.
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L’époxyde hydrolase soluble (sEH) est une enzyme ubiquitaire, bifonctionnelle, codée par le gène EPHX2. La partie hydrolase (sEH-H) est responsable de la dégradation de facteurs endothéliaux vasodilatateurs, les acides époxyeicosatriénoïques (EETs), alors que la partie phosphatase (sEH-P) est impliquée dans le métabolisme des acides lysophosphatidiques (LPAs).L’objectif de ce travail a été de développer des outils méthodologiques permettant d'évaluer le rôle de la sEH dans la physiopathologie des maladies cardiovasculaires.Nous avons développé une méthode de quantification par CLHP-MS² des EETs et de leurs métabolites, les acides dihydroxyeicosatrienoic acids (DHETs). L'application de cette méthode montre que la dysfonction endothéliale des patients atteints d’hypertension artérielle et de diabète de type 2 est associée à une diminution de la libération locale des EETs lors de l'augmentation du débit sanguin, notamment liée à une augmentation d’activité de la sEH-H. L’inhibition pharmacologique de la sEH-H a permis de diminuer l’inflammation et l’atteinte glomérulaire dans un modèle murin d’insulino-résistance. De plus, l’étude des polymorphismes génétiques du gène EPHX2, codant la sEH, a permis de démontrer que la fonction sEH-H joue probablement un rôle important dans le contrôle de la fonction rénale et vasculaire des patients transplantés rénaux. Enfin, les résultats expérimentaux obtenus dans un modèle d’inactivation génétique de la sEH-P et l'étude des polymorphismes génétiques d'EPHX2 chez les patients insuffisants cardiaques suggèrent un rôle important de cette partie dans la régulation du métabolisme des lipides ainsi que dans le contrôle de l’homéostasie cardiovasculaire.Ainsi, les résultats obtenus au cours de ce travail soutiennent l’intérêt de développer des inhibiteurs pharmacologiques de la sEH-H pour traiter les maladies cardiovasculaires, rénales et métaboliques chez l’homme et suggèrent que la modulation de la sEH-P pourrait également constituer une nouvelle cible d'intérêt dans la prise en charge de ces pathologiesSoluble epoxide hydrolase (sEH) is an ubiquitous bifunctional enzyme that is encoded by the EPHX2 gene. The hydrolase activity (sEH-H) is responsible for the conversion of the endothelial vasodilator epoxyeicosatrienoic acids whereas the phosphatase activity (sEH-P) is involved in the metabolism of lysophosphatidic acids (LPAs).The aim of this work was to develop chromatographic methods and molecular biology techniques to evaluate sEH activities in cardiovascular diseases.We developed a LC-MS/MS method to quantify EETs and their metabolites, the dihydroxyeicosatrienoic acids (DHETs). Using this method, we showed that the endothelial dysfunction of hypertensive and type 2 diabetic patients is associated with a decrease in the local production of EETs during flow increase notably due to increased sEH-H activity. In a murine model of insulin resistance, pharmacological inhibition of sEH-H improved renal function by decreasing inflammation, oxidative stress and glomerular lesions. Moreover, genetic investigations of EPHX2 revealed that sEH-H may play a substantial role in the control of renal and vascular function in kidney recipients. Finally, experimental results obtained in knock-in sEH-P deficient rats and genetics findings in patients with heart failure strongly suggest that sEH-P is involved in lipid metabolism and cardiovascular homeostasis.Taken together, these results strengthen the interest of developing pharmacological inhibitors of sEH-H to be tested in patients with cardiovascular, renal or metabolic diseases and suggest that the modulation of sEH-P represents a new therapeutic target to treat these pathologies
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Leuillier, Matthieu. "Rôle de l'activité phosphatase de l'époxyde hydrolase soluble dans la régulation de l'homéostasie métabolique et cardiovasculaire. In vivo inactivation of the phosphatase activity of soluble epoxide hydrolase potentiates brown adispose thermogenesis and protects against cardiovascular damage and remodeling Discovery of the first in vivo active inhibitors of the soluble epoxide hydrolase phosphatase domain Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR150.
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Près de 40 ans après sa découverte initiale en 1972, il a été montré en 2003 que l'époxyde hydrolase soluble (sEH), codée par le gène EPHX2, est une protéine bifonctionnelle qui présente non seulement une activité époxyde hydrolase au niveau de sa partie C-terminale mais également une activité lipidophosphatase sur son domaine N-terminal. En effet, au niveau de sa partie C-terminale, l’activité hydrolase métabolise des époxydes d'acides gras polyinsaturés. Notamment, elle transforme les acides époxyeicosatriénoïques, facteurs vasodilatateurs et anti-inflammatoires biologiquement actifs générés par les cytochromes P450, en acides dihydroxyeicosatriénoïques qui sont des composés biologiquement moins actifs. Cette activité, est aujourd’hui la cible d’une nouvelle classe pharmacologique d’inhibiteurs. Contrairement à la fonction biologique de l’activité hydrolase, celle de l’activité phosphatase de la sEH reste, à ce jour, peu connue. Bien qu’à l’origine, il ait été montré que cette activité participait à la stabilisation de l’activité hydrolase ou à la dimérisation de l’enzyme, certaines données récentes révèlent que l’activité phosphatase de la sEH métabolise d'autres médiateurs lipidiques importants, comme les acides lysophosphatidiques intracellulaires, qui sont impliqués dans un large éventail de fonctions biologiques telles que le tonus vasculaire et l'inflammation, en monoacylglycérols. De plus, des études in vitro ont également suggéré que les deux activités de la sEH possèdent un rôle complémentaire dans la régulation du taux de cholestérol ainsi que dans l’homéostasie vasculaire. Même si les souris recombinantes qui n'expriment pas le gène EPHX2 existent depuis un certain temps, elles ne permettent pas d'étudier spécifiquement l’activité phosphatase car les deux activités de l’enzyme sont éliminées. Toutefois, des études portant sur les différences entre les effets de la délétion génétique de la sEH et ceux de l'inhibition pharmacologique de son activité hydrolase indiquent que l'activité phosphatase de la sEH possède probablement un rôle physiologique. Dans notre étude, afin de pouvoir étudier le rôle de l’activité phosphatase de la sEH et en raison de l’absence d’inhibiteur de cette activité utilisable in vivo, des rats transgéniques originaux exprimant une sEH sans activité phosphatase ont été générés grâce à la méthode CRISPR/Cas9. Un phénotypage métabolique et cardiovasculaire approfondi a été effectué sur ces animaux. Les résultats de cette étude ont mis en évidence que les rat Knock-In (KI) pour la sEH phosphatase présentent une diminution de leur poids corporel et de leur masse grasse comparativement à des rats sauvages du même âge. De plus, leur sensibilité à l’insuline est augmentée. Ce profil métabolique bénéfique est expliqué d’une part par une diminution de la consommation alimentaire et, d’autre part, par une augmentation de l'oxydation des graisses, potentialisant la thermogenèse dans le tissu adipeux brun, et de la dépense énergétique. Par ailleurs, lorsque les rats KI sont nourris avec un régime riche en graisses saturées, la prise de poids reste inférieure à celle des rats sauvages. De plus, ils ne développent pas d’insulino-résistance ou de stéatose hépatique. D’autre part, au niveau cardiaque, les rats KI présentent une activité mitochondriale basale plus élevée associée à une contractilité ventriculaire gauche accrue. Par ailleurs, les animaux KI sont protégés contre les lésions cardiaques d’ischémie-reperfusion et contre le développement de l'hypertension artérielle pulmonaire. Notre étude révèle ainsi que l’activité phosphatase de la sEH est un acteur clé du métabolisme lipidique et énergétique contribuant ainsi, comme l’activité hydrolase, à la régulation de l'homéostasie cardiométaboliqueNearly 40 years after its initial discovery in 1972, soluble epoxide hydrolase (sEH), encoded by the EPHX2 gene, was shown in 2003 to be a bifunctional protein that exhibits not only an epoxide hydrolase activity on its C-terminal domain but also a lipid phosphatase activity on its N-terminal domain. Indeed, the hydrolase activity metabolizes epoxides of polyunsaturated fatty acids. In particular, sEH converts the vasodilator and anti-inflammatory epoxyeicosatrienoic acids converts, generated by cytochromes P450, into dihydroxyeicosatrienoic acids, which are less biologically active. This activity is now the target of a new class of pharmacologicla inhibitors. Unlike the biological function of the hydrolase activity, the biological function of sEH phosphatase activity remains, this time, unknown. Although shown originally to contribute to the stabilization of hydrolase activity or dimerization of the protein, some recent data indicate that the sEH phosphatase metabolizes also important lipid mediators, such as intracellular lysophosphatidic acids, involved in a wide range of biological functions such as vascular tone and inflammation, into monoacylglycerols. In addition, in vitro studies also suggested that the two activities of sEH have a complementary role in cholesterol regulation and vascular homeostasis. Although recombinant mice that do not express the EPHX2 gene have been around for some time, they do not allow to specifically study the phosphatase activity because both activities are eliminated. However, studies examining the differences between the effects of the genetic deletion of sEH and those of the pharmacological inhibition of its hydrolase activity indicate that the phosphatase activity of sEH probably has also a distinct physiological role. In our study, to assess the role of sEH phosphatase activity in absence of an inhibitor of this activity usable in vivo, original transgenic rats expressing sEH without phosphatase activity were generated using the CRISPR/Cas9 method. A thorough metabolic and cardiovascular phenotyping was performed on these animals. The results of this study showed that Knock-In (KI) rats for the sEH phosphatase have a decrease in body weight and fat mass compared to wild type rats of the same age. In addition, their sensitivity to insulin is increased. This beneficial metabolic profile is explained on one hand by a decrease in food consumption and, on the other hand, by an increase in fat oxidation, potentiating thermogenesis in brown adipose tissue enhancing energy expenditure. In addition, when KI rats were fed a high fat diet, weight gain remains lower than that of the wild type rats. In addition, they do not develop insulin resistance or hepatic steatosis. Finally, at the cardiac level, KI rats have higher basal mitochondrial activity associated with increased left ventricular contractility. In addition, KI animals are protected against cardiac ischemia-reperfusion lesions and the development of pulmonary arterial hypertension. Our study thus reveals that the phosphatase activity of sEH is a key player in lipid and energy metabolism, thus contributing, like the sEH hydrolase activity, to the regulation of cardiometabolic homeostasis
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Kamynina, Alisa. "Furthering the understanding of the redox control of soluble epoxide hydrolase and protein kinase G in the cardiovascular system." Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/furthering-the-understanding-of-the-redox-control-of-soluble-epoxide-hydrolase-and-protein-kinase-g-in-the-cardiovascular-system(f6909a1e-6b09-4c3b-8d36-b7e417f45a1d).html.
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Redox regulation of proteins represents an important control mechanism that can finely tune cell homeostasis or responses to stress. Two proteins regulated in this way include soluble epoxide hydrolase (sEH) and protein kinase G (PKG). sEH hydrolyses epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), which are less potent in terms of their ability to dilate blood vessels and lower blood pressure (BP) or induce angiogenesis. Thus inhibitors of sEH, which include lipid electrophiles, that adduct to C521, increase EET levels. As sepsis is a time of oxidative stress when lipid electrophiles can be generated, the hypothesis that vasodilation and hypotension at this time is mediated by C521-dependent inhibition of sEH was explored. Wild-type (WT) or ‘redox-dead’ C521S sEH knock-in (KI) mice, that are resistant to lipid electrophile-induced inhibition, were subjected to sepsis. There was no difference in BP, heart rate (HR) or activity. Analysis of isolated mesenteries or aortae by myography following sepsis did not identify any differences between genotypes. Similarly, there were no differences in plasma markers of organ damage or metabolic acidosis. Comprehensive comparison of the plasma inflammatory responses of each genotype identified a significant increase solely in granulocyte-colony stimulating factor (G-CSF), together with a similar trend in IL-17A in WT compared to KI. Overall it was concluded that inhibition of sEH by electrophilic lipids is unlikely to mediate blood pressure lowering during sepsis. The attenuated increase in G-CSF and IL-17A in the C521S sEH KI was notable as it is important in vasculogenesis and angiogenesis, in which increased EETs have been implicated. Postischaemic revascularisation in the model of hindlimb ischaemia failed to identify differences between genotypes. Furthermore, the capillary/myofibre ratio in the gastrocnemius muscle, as well as G-CSF levels therein, were also similar between genotypes. Recombinant sEH was also studied with a library of nitro-alkene fatty acids with the position of the double bond or electron-withdrawing nitro moiety altered, potentially allowing for more potent inhibitors of the hydrolase to be identified than previous studies with 10-nitro-oleic acid. Notably it was determined that low concentration of many of the electrophiles actually stimulated sEH, before inhibiting at higher concentrations. Accumulating evidence suggests that C117 and C195 in PKG can be oxidised to from an intraprotein disulfide bond within the high affinity cGMP binding pocket, and this directly mediates oxidant-induced activation. Moreover, recent study has shown that nitroxyl (HNO) can induce intradisulfide-mediated PKG activation. To determine the potential physiological impact of this modification, C195S PKG KI mice were generated and characterised for their haemodynamic function. Basal BP, HR and cardiac function were not different between each group. When each genotype was exposed to a sepsis protocol, no differences in indices of well-being or haemodynamic parameters were observed. Effect of HNO donors, NCA and CXL-1020, on BP and HR was investigated in vivo. While NCA administration resulted in BP lowering in both genotypes to the similar extent, CXL-1020 resulted in attenuated BP only in WT mice and not KI animals, although the differences were not statistically significant and more experiments are required. Although cGMP-dependent vasorelaxation is intact in KI mice, the impact of the C195S mutation on cGMP binding requires further examination. Notably, KI mice basally have enlarged caecum and increased whole gut transit time, which was also reported in mice deficient in the nitric oxide-cGMP pathway.
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Mavrommatis, Ioannis. "The effects of dietary long chain n-3 polyunsaturated fatty acids on soluble epoxide hydrolase and related markers of cardiovascular health." Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=56261.
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Hefke, Lena [Verfasser], Ewgenij [Gutachter] Proschak, and Stefan [Gutachter] Knapp. "Using fingerprints and machine learning tools for the prediction of novel dual active compounds for leukotriene A4 hydrolase and soluble epoxide hydrolase / Lena Hefke ; Gutachter: Ewgenij Proschak, Stefan Knapp." Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2020. http://d-nb.info/122685320X/34.
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Johnson, Clinton L. "Mechanisms of Prenatal High-Salt "Fetal Programming" Resulting in Stress Hyperresponsiveness in The Adult Female Offspring in The Sprague Dawley Rat." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2830.
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Female offspring of Sprague-Dawley rats fed a high-salt diet (HS) during pregnancy show an enhancement of mean arterial pressure (MAP) and heart rate (HR) response to acute stress in adulthood compared to offspring whose mothers were fed a normal-salt diet (NS) [1]. In the present study, we first examined the expression of soluble epoxide hydrolase (SEH) protein in brain tissue. Whole brains were collected and SEH gene (EPHX2) mRNA and SEH protein expression were analyzed using RT-PCR and Western blot, respectively. mRNA levels were relatively decreased in high-salt rats (1.0 ± 0.32 NS vs 0.39 ± 0.07 HS, n=6). However, the relative expression of SEH protein was significantly increased in HS rats (0.97 ± 0.06 NS vs. 1.72 ± 0.32 HS, n=10). SEH is an enzyme that inactivates epoxyeicosatrienoic acids (EETs), which can increase the level of oxygen free radical production and potentially produce an increase in blood pressure. Tempol, a free radical scavenger, was administered ntracerebroventricularly to HS (n=12) and NS (n=11) offspring to determine if the stressinduces cardiovascular hyperresponsiveness could be reversed. We were unable to conclusively show that this was the case. Hence, the expression of SEH protein in the brains of HS offspring was increased, but a role, if any, for this change in explaining the exaggerated response to acute stress remains elusive. Second, the expression of the glucocorticoid receptor (GR) gene was investigated. We focused on the methylation patterns of the exon 17 GR promoter and 17 CpG dinucleotide sites that include the NGFI-A transcription factor binding site. Female rats (HS n=8, NS n=8) were sacrificed and brains were immediately extracted. Tissue from the pituitary, hypothalamus, and hippocampus was removed and DNA was extracted from each of these areas. CT conversion was performed on the DNA samples followed by cloning and sequencing. Methylation patterns between HS and NS in the pituitary, hypothalamus, and hippocampus did not vary. RT-PCR and Western blot were performed to investigate differences in the levels of GR transcription and/or translation. There were no significant differences found. However, the trends found may suggest different levels of GR mRNA and protein between HS and NS female rats. DNA methylation may play a role in the regulation of GR in prenatal high-salt female offspring. Additional studies will be needed to pinpoint the mechanisms responsible for the exaggerated cardiovascular response to acute stress in HS offspring.
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Zhao, Wei. "Further Characterization of Recombinant Epoxide Hydrolase Kau2 Derived from Metagenomic DNA and Application in Biocatalytic Reactions." Thesis, Ecole centrale de Marseille, 2014. http://www.theses.fr/2014ECDM0008/document.
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Les chimistes organiciens disposent à l'heure actuelle des outils de la biocatalyse afin d'accéder aux produits de la chimie fine et en particulier à des synthons et des molécules optiquement enrichies. Dans ce cadre, le travail de thèse présenté dans ce mémoire a été conduit afin d'enrichir notre connaissance sur une époxyde hydrolase (EH) découverte après analyse métagénomique d'un bio-filtre. Afin de pouvoir mener une étude de mutagénèse dirigée de sorte à améliorer certaines propriétés de cette enzyme appelée Kau2-EH, un modèle de l'enzyme a été élaboré sur la base de la structure tridimensionnelle de l'EH de souris. Le choix de cette matrice fait suite à des études d'inhibition comparées visant à déterminer laquelle des trois EHs, dont la structure tridimensionnelle était connue (pomme de terre, souris, homme) et dont la séquence était proche de celle de Kau2-EH, présentait l’inhibition la plus proche de celle observée pour Kau2-EH. Il avait été montré précédemment que Kau2-EH présentait un intérêt en biocatalyse permettant une résolution cinétique quasi-parfaite de l'oxyde de trans-méthyl-styrène et une transformation énantioconvergente, elle aussi quasi-parfaite, de l'oxyde de cis-méthyl-styrène. Ainsi des études de bioconversion dédiées à l'évaluation de la diversité des substrats de Kau2-EH ont été réalisées. Cette enzyme se révéla être particulièrement performante lors de l'utilisation d'époxydes cis- et trans-1,2-disubstitués portant sur un des atomes de carbone de la fonction époxyde un groupement phényle ou p-méthoxy-phényle et sur l'autre un groupement variable (méthyl- ou éthyl-ester, cyano, bromo- ou chloro-méthyle, phényle). Pour neuf des dix substrats testés des énantiosélectivités très élevées ont été trouvées permettant des résolutions cinétiques quasi-parfaites de huit d'entre eux et la désymétrisation quasi-parfaite du neuvième. Seul le cis-méthyl-glycidate ne fut pas un substrat de Kau2-EH. Dans les neufs cas précédents une réaction préparative à l'échelle du gramme a pu être conduite à très haute concentration en substrat (de 25 à 75 g/L) et sur une courte période de temps (de 1 à 4h) sauf pour l'oxyde de cis-stilbène (24 h). Finalement et afin d'accéder aux constantes cinétiques fondamentale, une étude préliminaire de « stopped-flow » du comportement de Kau2-EH a été réalisée en utilisant l'oxyde de trans-stilbène comme substratBiocatalysis is nowadays an important tool available to organist chemist to get access to fine chemicals and especially enantiomerically enriched synthons and molecules. Within this framework, the PhD work described in this dissertation was conducted in order to get insights about a newly discovered epoxide hydrolase (EH) from a metagenomic analysis of a biofilter. In order to conduct directed mutagenesis on the so-called Kau2-EH, a model of the enzyme was constructed based on the 3D structure of murine EH. The choice of this template was dictated by comparative inhibition studies aimed at differentiating three otherwise closely Kau2-sequence-related EHs with known crystal structure (potato-, murine- and human-EHs) and showing inhibition behavior the closest to the one found for Kau2. The enzyme was previously shown to display interesting biocatalytic properties such a nearly perfect kinetic resolution of trans-methyl-styrene-oxide and a nearly perfect enantioconvergent transformation of cis-methyl-styrene-oxide. Thus, bioconversion studies dedicated to the evaluation Kau2-EH substrate chemical space were undertaken. The enzyme proved to be particularly useful when using 1,2-disubstituted cis- or trans-aromatic epoxides bearing an aromatic ring (phenyl, p-methoxy-phenyl) on one of the epoxide-bearing carbon atom and various chemical groups (methyl- or ethyl-esters, cyano, chloro- or bromo-methyl or phenyl) on the second carbon atom. For nine of the ten tested substrates very high enantioselectivities were observed allowing nearly perfect kinetic resolutions of eight of them and a nearly perfect desymmetrization of the ninth. Only cis-methyl-glycidate proved to be not a substrate of Kau2-EH. In the all other nine cases a preparative scale reaction could be conducted on the 1g scale, at high to very high substrate concentration (25 to 75 g/L) and in short periods of time (1 to 4h) except for cis-stilbene-oxide (24 h). Finally and in order to get access to fundamental kinetic constants, a preliminary stopped-flow analysis of Kau2-EH behavior was undertaken using trans-stilbene-oxide as substrate
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Wolf, Nicola M. [Verfasser], Bertold [Akademischer Betreuer] Hock, Bruce D. [Akademischer Betreuer] Hammock, and Siegfried [Akademischer Betreuer] Scherer. "Inhibition studies of soluble epoxide hydrolase : Development of two novel fluorescence-based inhibitor assay systems and cellular inhibition by RNAi / Nicola M. Wolf. Gutachter: Siegfried Scherer. Betreuer: Bertold Hock ; Bruce D. Hammock." München : Universitätsbibliothek der TU München, 2006. http://d-nb.info/1058141368/34.
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Silva, Carlos Antonio Trindade da. "O Uso terapêutico de mediadores anti-inflamatórios da via do ácido araquidônico." Universidade Federal de Uberlândia, 2016. https://repositorio.ufu.br/handle/123456789/17681.
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O ácido araquidônico (AA) é precursor na formação dos eicosanoides, que são mediadores lipídicos com uma série de funções na fisiologia e patologia humana. A maioria dos eicosanoides atuam como mediadores pró-inflamatórios e contribuem para o desenvolvimento e proliferação de tumores. Nesta tese foram avaliados dois mediadores: a 15-deoxi-Δ12,14-PGJ2 (15d- PGJ2) e os ácidos Epoxieicosatrienoicos (EETs), ambos apresentam uma atividade oposta a da maioria dos eicosanoides, ou seja, com uma ação anti-inflamatória e antitumoral. Esses dois mediadores distintos da via do AA foram utilizados nesta tese em dois projetos distintos. Primeiro: A 15d- PGJ2 possui uma atividade antiproliferativa e induziu apoptose para diversos tipos de células tumorais, entretanto, o efeito da15d- PGJ2 em células de cancer da tireoide ainda estava desconhecido. Neste sentido, foram cultivadas in vitro células tumorais da tireoide, da linhagem TPC1, e tratadas com diferentes concentrações de 15d- PGJ2 (0 ate 20 μM), as células tratadas demonstraram uma diminuição na proliferação, e aumento na apoptose, e uma diminuição na liberação e expressão relativa de IL-6. Estes resultados em conjunto sugerem que a 15d- PGJ2 pode ser utilizada como uma nova terapia para o cancer da tireoide. Segundo: Os EETs são metabolizados em seus diois pela epóxi hidrolase solúvel (sEH), para manter a estabilidade dos EETs e a sua atividade antiiflamatoria, foi utilizado um inibidor (TPPU) para sEH em um modelo de periodontite induzida por Aggregatibacter actinomycetemcomitans. O tratamento oral com TPPU, assim como o uso de animais sEH Knockout, levou a uma redução na perda óssea acompanhada da diminuição de moléculas osteoclastogenicas como RANK, RANKL e OPG, demonstrando que a inibição farmacológica da sEH pode ter um valor terapêutico na periodontite e doenças inflamatórias que envolvem a reabsorção óssea.Arachidonic acid (AA) a precursor in the formation of eicosanoids which are lipid mediators with a number of functions in human physiology and pathology. The most of the eicosanoids act as proinflammatory mediators and contribute to the development and proliferation of tumors. In this thesis we evaluated two mediators: 15-deoxy-Δ12,14-PGJ2 (15d- PGJ2) and epoxieicosatrienoic acids (EETs) both act with an opposite activity of most eicosanoids, with an anti-inflammatory and and anti-tumoral action these two distinct mediators from AA pathway were used in this thesis in two different projects. First: 15d- PGJ2, was described that to have an antiproliferative activity and to induce apoptosis in several types of tumor cells however, the effect of 15d- PGJ2 in thyroid cancer cells was unknown in this sense, we tested in vitro cultured thyroid tumor cells, here in TPC1 cells, and treated with different concentrations of 15d- PGJ2 (0 to 20 uM) the treated cells showed a decrease in proliferation and an increase in apoptosis and a decrease in IL-6 release and relative expression. These key results together demonstrate that 15d- PGJ2 can be used as a new therapy for thyroid cancer. Second: The EETs are converted to their diols by soluble epoxy hydrolase (sEH) to maintain the stability of EETs and their anti-inflammatory activity, an inhibitor (TPPU) against was used to sEH in a periodontitis model induced with Aggregatibacter actinomycetemcomitans. The oral treatment in mice with TPPU and sEH Knockout animals showed bone loss reduction accompanied by a decrease in the osteoclastogenic molecules, like RANK, RANKL and OPG, demonstrating that pharmacological inhibition of sEH may have therapeutic value in periodontitis and inflammatory diseases that involve bone resorption.
Tese (Doutorado)
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Schmidt, Cosima. "Identifizierung, molekulare Eigenschaften und Regulation einer renalen 20-Hydroxyeicosatetraensäure-Synthase." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15876.
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Cytochrom P450 (CYP)-Enzyme hydroxylieren und epoxydieren Arachidonsäure (AA) zu bioaktiven Metaboliten wie 20-Hydroxyeicosatetraensäure (20-HETE) und Epoxyeicosatriensäuren (EETs). Diese CYP-abhängigen Eicosanoide fungieren als Mediatoren bei der Regulation der Gefäß-, Nieren- und Herzfunktion. Hauptziel der vorliegenden Arbeit war es, die Identität der 20-HETE bildenden CYP-Isoformen in der Mausniere aufzuklären. Ein weiterer Schwerpunkt war die Bestimmung von Veränderungen im Metabolismus CYP-abhängiger Eicosanoide in Tiermodellen des akuten Nieren- und Herzversagens. Zur Identifizierung der 20-HETE bildenden CYP-Isoform wurde die Substrat- und Wirkungsspezifität von Cyp4a10, Cyp4a12a, Cyp4a12b und Cyp4a14, sowie ihre geschlechts- und stammspezifische Expression charakterisiert. Die Ergebnisse dieser Arbeit zeigen, dass Cyp4a12a die 20-HETE Synthase der Mausniere ist. Cyp4a12a wird durch Androgene induziert und seine Expressionshöhe ist für geschlechts- und stammspezifische Unterschiede in der 20-HETE Bildung verantwortlich. Im Rattenmodell des Ischämie/Reperfusions (I/R)-induzierten Nierenschadens wird eine 20-HETE Freisetzung durch I/R induziert. Wir konnten zeigen, dass der I/R-Schaden durch Hemmung der 20-HETE Bildung signifikant reduziert wird. Im Rattenmodell der Herzinsuffizienz (SHHF) ist das Herzversagen mit einer Variante des EPHX2 Gens assoziiert. EPHX2 kodiert für die lösliche Epoxidhydrolase (sEH), die den Abbau von EETs katalysiert. Wir konnten zeigen, dass die Genvariation zu signifikant höheren sEH-Aktivitäten im Herzen (3-fachen) und in der Niere (30-fachen) führt, im Vergleich zu Rattenstämmen, die keine Herzinsuffizienz entwickeln. Die vorliegende Arbeit unterstreicht die pathophysiologische Bedeutung von Veränderungen im Metabolismus von 20-HETE und EETs. Daher erscheint es vielversprechend, den CYP-Eicosanoid Stoffwechsel als neuen Angriffspunkt für die pharmakologische Behandlung kardiovaskulärer Erkrankungen zu erschließen.Cytochrome P450 (CYP) enzymes hydroxylate and epoxidize arachidonic acid (AA) to bioactive metabolites such as 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs). These CYP-dependent eicosanoids serve as mediators in the regulation of vascular, renal and cardiac function. The main objective of the present study was to identify the 20-HETE producing CYP isoforms in the mouse kidney. Another focus was to determine changes in the metabolism of CYP-dependent eicosanoids in animal models of acute renal and heart failure. To identify the 20-HETE producing CYP-isoform the substrate and reaction specificity of Cyp4a10, Cyp4a12a, Cyp4a12b and Cyp4a14, as well as their sex- and strain-specific expression were characterized. The present study shows that Cyp4a12a is the predominant AA hydroxylase in the mouse kidney. Cyp4a12a is induced by androgens and its expression determines the sex and strain-specific differences in 20-HETE generation. In a rat model of renal ischemia/reperfusion (I/R) injury, I/R triggered the release of 20-HETE and we were able to ameliorate renal injury by pharmacological inhibition of 20-HETE production. In a rat model of heart failure (spontaneously hypertensive heart failure rats, SHHF) the heart failure phenotype is associated with a variant of the EPHX2 gene. EPHX2 is coding for the soluble epoxide hydrolase (sEH) which catalyze the degradation of EETs. We found that the gene variation leads to significantly higher sEH activities in the heart (3-fold) and in the kidney (30-fold) compared to rat strains not prone to the development of heart failure. The present study emphasizes the pathophysiological relevance of changes in the biosynthesis and degradation of 20-HETE and EETs. Therefore, it appears promising to develop the CYP-eicosanoid pathway as a novel clinical target for the treatment of cardiovascular diseases.
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Yen, Hsin-Ju, and 顏欣如. "Roles of soluble epoxide hydrolase inhibitor in emotional behavior." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/64023860197755509012.
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碩士國立陽明大學
生理學研究所
104
Soluble epoxide hydrolase（sEH）expression is widespread in cortex, striatum and amygdala. It is a bifunctional enzyme with N- and C-terminal domains. The C-terminal domain is responsible for the epoxide hydrolase activity. EETs are hydrolyzed by sEH into less active dihydroxyeicosatrienoic acids (DHET). The sEH C-terminal epoxide hydrolase inhibitor 12-（3-adamantan-1-yl-ureido）-dodecanoic acid（AUDA）elevated the endogenous EETs , i.e. 14,15-EET, be a beneficial therapeutic treatment in various diseases. Previous studies from our laboratory show that AUDA facilitated long-term potentiation （LTP） in prefrontal cortex neurons. However, the role of amygdala activity in the behavioral responses to AUDA has not been examined. In this study, we investigated the role of sEH inhibitor on emotional behavior in the amygdala. The Pavlovian fear conditioning animal models was used to investigate AUDA on emotional behavior and synaptic plasticity underlying learning and memory formation. The results show that male mice received pre-training microinjection of AUDA bilaterally into the amygdala, which facilitates the acquisition, consolidation and expression of fear in the auditory-cue-conditioned fear task. AUDA treatment increased anxiety-like behavior and reduced spontaneous activity in the open-field test and elevated plus-maze test. Western Blotting demonstrated that AUDA treatment increased the expression of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits GluR1, but not GluR2 subunit level. AUDA treatment caused an increase in p38 MAPK and ERK (extracellular signal regulated kinases) phosphorylation. Electrophysiology indicate AUDA enhancing LTP. In addition, mice received pre-training microinjection of 14,15-EET bilaterally into the amygdala, which facilitates fear acquisition. 14,15-EET treatment increased anxiety-like behavior and reduced spontaneous activity in the open-field test and elevated plus-maze test. In summary, we provided evidence suggesting that AUDA within the amygdala circuitry are important to the regulation of fear memory.
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Chen, Yi-Ju, and 陳怡如. "Effect of soluble epoxide hydrolase inhibition on synaptic plasticity." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/336q5s.
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碩士國立陽明大學
生理學研究所
105
The epoxygenases are a subgroup of enzymes in the cytochrome P450 (CYP 450) family that metabolize arachidonic acid (AA) into four regioisomers of epoxyeicosatrienoic acid (5,6-, 8,9-, 11,12-, and 14,15-EETs). EETs are metabolized into dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). Many experimental evidences show that EETs are potent vasodilators, pro-angiogenic and anti-inflammatory effects in rodent. In brain, EETs also protect neurons from ischemia-reperfusion injury. Previous study has demonstrated higher levels of 14,15-EET in sEH–/– mice. Hippocampus is a major region mediates memory such as spatial memory and cognitive behaviors. To date, the role of EETs on hippocampus-related synaptic function and cognitive function is still unclear. To determine the effect of EETs on synaptic function, we investigated the N-[1-(oxopropyl)-4-piperidinyl]-N’-[4-(trifluoromethoxy)phenyl)-urea (TPPU), which is a sEH inhibitor, and 14,15-EET on the high frequency stimulation (HFS)-long-term potentiation (LTP) and forskolin (FSK)-induced LTP in hippocampus. The results showed that TPPU- and 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing HFS-induced LTP and FSK-induced LTP. TPPU and 14,15-EET increased HFS-LTP, which could be blocked by an N-methyl-D-aspartate (NMDA) receptor subunit NR2B antagonist. TPPU- and 14,15-EET-facilitated FSK-mediated LTP can be potentiated by a phosphodiesterase inhibitor, but is prevented by a cAMP-dependent protein kinase (PKA) inhibitor. Furthermore, we found that TPPU and 14,15-EET treatment could enhanced learning and memory, which was assessed by novel object recognition test (NOR). Therefore, this study demonstrated that EETs increased NMDAR- and FSK-mediated LTP via the cAMP-PKA pathway and also enhances the recognition memory.
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Chen, I.-Chih, and 陳奕志. "Soluble Epoxide Hydrolase Inhibition Reduces Ischemic Infarction and Neuroexcitation by TrkB Activation." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/nnbt7h.
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碩士國立陽明大學
腦科學研究所
105
Pharmacological inhibition and gene deletion of soluble epoxide hydrolase (sEH) has been suggested to ameliorate infarction in preclinical ischemic stroke by preventing metabolism of beneficial epoxyeicosatrienoic acids. However, it is unclear whether the neuroprotection of sEH inhibition involves alteration of post-ischemic excitatory transmission and neurotrophic signaling. Here, a permanent middle cerebral artery occlusion (MCAO) model was used in adult wild-type and sEH knockout (sEH KO) mice, and wild-type mice were treated with sEH hydrolase inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA, intraperitoneal injection at 10 mg/kg/day) for 7 days after MCAO. We found that sensorimotor recovery of the paretic limbs was significantly enhanced with decreased sEH activity and infarct volume in the brain relative to controls in both AUDA-treated and sEH KO mice after MCAO. TrkB phosphorylation enhancement rather than glutamate receptor alteration was consistently found in the ipsilesional hemisphere by both sEH inhibition and gene deletion. Immunohistochemistry further revealed augmentation of peri-infarct TrkB activation in cortical neurons and the microvasculature in AUDA-treated and sEH KO mice, suggesting a neurovascular enhancement. An ex vivo ischemia model of hippocampal slices was then used to examine post-ischemic field excitatory postsynaptic potentials. Intriguingly, post-ischemic long-term potentiation was attenuated by sEH inhibition or deletion, and TrkB antagonist ANA12 pretreatment eliminated this effect ex vivo and also abolished the infarct reduction by sEH deletion in vivo. The neuroprotective effects of sEH inhibition and gene deletion are both mediated via enhancement of TrkB signaling that attenuates post-ischemic neuroexcitation and neurological deficits.
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Fife, Kimberly L. "Soluble epoxide hydrolase as a target for modulation of the inflammatory response." Diss., 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3295022.
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Hsiao, Yu-Yieh, and 蕭郁曄. "Role of Soluble Epoxide Hydrolase in Microglia Activation under Oxygen-glucose Deprivation/Reperfusion Stress." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/87845303673907025817.
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碩士國立陽明大學
解剖學及細胞生物學研究所
103
Abstract Key word: ischemic-hypoxia, microglia activation, soluble epoxide hydrolase. Ischemic-hypoxia with lack of blood flow caused vascular diseases including cardiac ischemia and stroke. Mild ischemic-hypoxia stress which resulted from stenosis or blockade at vascular is a cause of morbidity and mortality leading to cell death and neurological disability in the affected brain area. After ischemic-hypoxia stimulation, brain ischemia-reperfusion increases perivascular inflammation and neurovascular unit permeability in penumbra region and contributing to sensitize brain injury. It has been demonstrated that epoxyeicosatrienoic acids (EETs) are cardioprotective after ischemic heart attack and reperfusion, and produced in brain play an important role in cerebral blood flow regulation. However, EETs is limited by their metabolism via a bifunctional enzyme soluble epoxide hydrolase (sEH), which metabolizes EETs to dihydroxyeicosatrienoic acids (DHETs). Inhibition of sEH promoted protection and reduced cell death in multiple cell types such as vascular smooth cells, endothelial cells and neuron, but the complex neuroinflammation mechanisms in ischemic-hypoxia induced brain injury among biofunctions of sEH dual terminal activity enzyme and activated microglia is poor understanding. In this study, we have interesting to investigate whether sEH was involved in microglia activation-induced neuroinflammation following ischemic-hypoxia reperfusion stimulation. In our study, we created in vitro model to mimic ischemic-hypoxia attacked neurovascular units and affected microenvironment through murine microglial cells (BV-2 cells). This model focus on microglia exposed at deprivation of glucose and oxygen environment. Our evidences showed that microglial cells increased cell death in glucose-oxygen deprivation/ reperfusion 24 hours, and processes (filopodia) of microglial cells increased following glucose-oxygen deprivation/ reperfusion. Besides, sEH was upregulated under oxygen-glucose deprivation stimulation. Noteworthy that in this study, we used selective antagonist for N-terminal lipid phosphatase / C-terminal epoxide hydrolase of sEH to elucidate its biofunctions in activated microglia. In our research, sEH was involved in microglial cells activation under ischemic-hypoxia stimulation. The results showed that sEH possibly regulated microglia activation including in morphological changes and process outgrowth. We provide an important evidence for N-terminal lipid phosphatase of sEH for OGD-induced microglial activation.
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Homburg, Shirli [Verfasser]. "Biochemical analysis of the phosphatase domain of the human soluble epoxide hydrolase (sEH) / Shirli Homburg." 2010. http://d-nb.info/101190019X/34.
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Hou, Hsin-Han, and 侯欣翰. "Phosphatase activity of soluble epoxide hydrolase negatively regulates the activation of endothelial nitric oxide synthase." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/58629548340501094245.
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博士國立陽明大學
生理學研究所
100
Soluble epoxide hydrolase (sEH) expresses in endothelial cells (ECs) and is a bifunctional enzyme with C-terminal hydrolase and N-terminal phosphatase activities. The implication of hydrolase activity of sEH in the metabolism of antiinflammative and antihypertensive epoxyeicosatrienoic acid has been well documented and suggested inhibition of sEH hydrolase activity may serve as a therapeutic strategy for treatment with hypertension. However little is known about the protein substrates and associated physiological role of sEH phosphatase. Endothelium-derived nitric oxide (NO), a key regulator for vascular tone, is mainly produced by endothelial nitrite oxide synthase (eNOS) which the activity is tightly regulated by posttranslational mechanism including phosphorylation and protein-protein interaction. In phosphorylation, eNOS could be phosphorylated by vascular endothelial growth factor (VEGF) and simvastatin or dephosphorylated by protein phosphatase 2A. Therefore, we hypothesize that eNOS is a possible protein substrate for sEH phosphatase and sEH phosphatase may play an important role in eNOS-associated physiological function. In this study, we investigated that the phosphorylation of eNOS was higher in artery isolated from sEH knockout mice than wild type mice. In ECs, sEH phosphatase inhibited VEGF- and simvastatin-induced NO production and eNOS phosphorylation. Furthermore, simvastatin-induced protein kinase B (PKB/Akt) and AMP-activated protein kinase (AMPK) phosphorylation was inhibited by sEH phosphatase. Moreover, VEGF and simvastatin-increased sEH tyrosine phosphorylation and sEH-eNOS interaction and simvastatin-induced associations of sEH-Akt and sEH-AMPK were mediated by c-Src family kinase. We also demonstrated that the phosphatase activity of sEH inhibited the VEGF- and simvastatin-induced NO-mediated angiogenesis in vitro and in vivo. In conclusion, sEH phosphatase activity plays a crucial role in the negative regulation of VEGF- and simvastatin-induced eNOS activity and NO-derived angiogenesis.
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WEN, SHIN, and 温芯. "The Neuroprotective Effects and Anti-Inflammatory Mechanisms of Soluble Epoxide Hydrolase Inhibition in Experimental Intracerebral Hemorrhage." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/47385041676452135541.
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碩士國防醫學院
生理學研究所
104
Intracerebral hemorrhage (ICH) accounts for 10–15% of all strokes, but it is associated with high mortality and morbidity. Also, there are no effective drug therapies available at present. Following ICH, danger signals from damaged neurons and blood components such as thrombin and heme trigger inflammatory processes through the MAPK-NF-κB pathway. Epoxyeicosatrienoic acids (EETs), a product of arachidonic acid metabolized through cytochrome P450, have been shown to suppress the NF-κB inflammatory pathway and reduce brain damage after brain injuries. However, EET is rapidly metabolized to less active form by soluble epoxide hydrolase (sEH). In this present study, we hypothesize that inhibition of sEH activity reduces brain damage and inflammatory reaction after experimental ICH. The mouse ICH was induced by injecting collagenase VII-S into the right striatum and the sEH inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA, 10μM), was administered by intracerebroventricular injection. The results show that sEH protein expression increased at 1 h and lasted for 7 days following ICH, and sEH was expressed in microglia, astrocytes, and neurons. Intracerebroventricular injection with AUDA significantly improved the behavior outcomes including rotarod and beam walking latency, and mNSS for 28 days. AUDA treatment also attenuated brain atrophy at day 28 and reduced brain tissue damage and neuronal death at day 1. Furthermore, treated with AUDA attenuated the number of activated microglia, neutrophil infiltration, matrix metalloproteinase-9 (MMP-9) activity and proinflammatory cytokine production at day 1. BV2 cell line and rat microglial cell culture were used to determine if the anti-inflammatory effects of sEH inhibition directly act through microglia. AUDA attenuated LPS, IFN-γ, or thrombin -induced NO production in BV2 cell cell line or primary microglia. AUDA also attenuated proinflammatory cytokine production in primary microglia. In BV2 cell line, AUDA significantly inhibited LPS-induced p38 and pJNK phosphorylation but had no effects on Erk phosphorylation. However, treatment with AUDA did not affect the sEH level in hemorrhagic brain or LPS-stimulated microglia. These results indicate that sEH inhibition improves functional outcomes, provides neuroprotection and reduces inflammation after ICH. The anti-inflammatory effect of sEH inhibition might mediate through p38 and pJNK MAPK signaling. Inhibition of sEH may provide a novel therapeutic strategy for ICH.
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Chen, Jia-Wei, and 陳嘉偉. "Dual-Wavelength Optical Neural Image on Functional Recovery of Ischemic Stroke with Soluble Epoxide Hydrolase Inhibitors Treatmen." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/14851404541135899095.
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碩士國立陽明大學
生物醫學工程學系
103
Stroke is a cerebrovascular disease that is caused by the blockage of blood vessels, which can result in permanent neurological damage or death. Previous studies have shown that 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) can lead to protection mechanisms of the brain, heart and kidney. However, the exact mechanism of this phenomenon still remains unclear. Though there has been much research focused on stroke, the treatment options in the acute phase of stroke are still limited. Normally neural activity is accompanied by changes in the local oxygenation and blood flow. When the neurons were stimulated, oxygen and energy is needed to support the reaction. The relationship between neural activity, oxygen metabolism, and hemodynamic can be studied by variable imaging techniques. Simultaneously imaging the changes of blood flow, blood volume, and oxygenation in tissue is important for basic research in biological science, clinical diagnosis, and therapeutic applications. This study demonstrates optical imaging method for in vivo imaging of functional neurovascular activation during the stroke, treated by AUDA. Laser Speckle Contrast Imaging (LSCI) is an easy method to determine the relative blood flow, so we propose to use a synchronized two wavelength imaging system which combines laser speckle contrast imaging with Intrinsic optical signals imaging(IOSI). This system calculated LSCI data from the reflectance of the laser on the surface and records the oxygenation data from laser absorption in hemoglobin simultaneously. Based on this system, we also images changes in vessel density and try to separates arteries and veins in order to get more information by using the same raw data.
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Chang, Yun-Chi, and 張芸綺. "The Role of Soluble Epoxide Hydrolase in High Fat Diet-induced Metabolism and Brain Function in Mice." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/geter5.
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碩士國立陽明大學
生理學研究所
107
High fat diet (HFD) is a common cause of obesity accompanied by not only metabolic syndrome, but also brain insulin resistance and inflammation that altered brain insulin signaling such as insulin receptor substrate-1 (IRS-1), protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β). Moreover, HFD may also increase the risk of impaired memory and hippocampal long-term potentiation (LTP) which forms of synaptic plasticity and plays an important role in the formation of memories. Additionally, soluble epoxide hydrolase (sEH) is an enzyme that metabolizes epoxyeicosatrienoic acids (EETs) which possess anti-inflammatory properties. Previous studies have shown that TPPU, a sEH inhibitor, has potential to increase the availability of EETs and facilitate synaptic plasticity LTP. However, whether HFD-induced metabolic disorder, brain insulin resistance, memory impairment and synaptic plasticity deficits could be recovered through reducing sEH is still unclear. In this study, 8-week-old male sEH-KO mice and intranasal TPPU treatment were used to investigate the improvement effect after feeding 12-week HFD. First, as for the metabolic aspects, HFD induced increased glucose level in oral glucose tolerance test (OGTT), homeostasis model assessment-insulin resistance (HOMA-IR) index and mRNA expression of inflammation-related genes including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and IL-6 were reversed in sEH-KO mice. We found that sEH activity was elevated in HFD-fed mice compared with ND-fed mice. The results also indicated that the increased serine phosphorylation of IRS-1, the decreased phosphorylation of Akt and GSK-3β induced by HFD were rescued by genetic deletion of sEH. In addition, sEH deletion improved memory and hippocampal LTP impairment caused by HFD in behavioral tests and electrophysiology. We also found HFD-induced decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit glutamate-A1 (GluA1) phosphorylation in hippocampus was reversed in sEH-KO mice. Similarly, HFD-induced elevated sEH activity, metabolic makers, brain insulin resistance, memory impairment and the impaired hippocampal LTP and decreased phosphorylation of GluA1 were also recovered by TPPU treatment. Taken together, this study suggests that reducing sEH might have potential to improve the HFD-induced metabolic disorder, brain insulin resistance, memory impairment and synaptic plasticity deficits.
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Wong, Lin-Kin, and 黃勵健. "The Effect of Soluble Epoxide Hydrolase Inhibition on Seizure Generation in Two Mouse Models of Temporal Lobe Epilepsy." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/40294122701077458022.
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碩士國立陽明大學
腦科學研究所
102
Background: Temporal lobe epilepsy (TLE), a common neurological disease with hallucinations and disturbance of consciousness, is the abnormal neurological activity of brain. Although the condition responds well to antiepileptic drugs (AEDs), there are still unresponsive to antiepileptic drug in about 1/3 of cases. Other treatment including surgical discectomy and deep brain stimulation, also limited to the lesion location which is not easily removed or restricted unclear. Thus, the development of new AEDs needs to be discovered for the treatment of drug resistant epilepsy. Previous studies indicated that ictogenesis, large amounts of polyunsaturated fatty acids including arachidonic acid (AA) will be released in brain. AA is a substrate for three major enzymatic routes of metabolism by cyclooxygenase, lipoxygenase and cytochrome P450 enzymes. These enzymes convert AA to potent lipid mediators including prostanoids, leukotrienes and epoxyeicosa-trienoic acids (EETs). The prostanoids and leukotrienes are largely pro-inflammatory molecules that sensitize neurons whereas EETs are anti-inflammatory, anti-apoptotic and reduce the excitability of neuron via modulating different of ion channel. Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolic conversion of EETs into their less active form, dihydroxyeicosatrienoic acids (DHET). Our preliminary data showed that inhibition of sEH hydrolase activity by 12-(3-adamantan-1-yl-ureido) dodecanoic acid butyl ester (AUDA) attenuated neuroinflammation and the frequency and duration of SRS in vivo, suggesting that sEH may play a crucial role in the ictogenesis. Hypothesis: We hypothesized that sEH inhibition might affect the development of epilepsy. Materials and methods: Pretreatment of a single dose of AUDA (80 mg/kg, intranasal administration) was performed in two mice ictogenesis models: pilocarpine induction and electrical kindling. Their electroencephalography (EEG) and behavior responses were recorded and analyzed. Results: The onset time of behavior seizures reach to Racine scale stage 1 and stage 3 were prolonged in both models when the mice were pre-treated with AUDA. Conclusions: Our results demonstrated that inhibition of sEH hydrolase activity reduced the process of ictogenesis in both mice models. Therefore, sEH may play an important role in the generation of epilepsy, suggesting its potential for clinical use in the future.
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Wu, Yi-Chen, and 吳苡禎. "Effects of Soluble Epoxide Hydrolase on Epileptogenesis: A study in A Kindling Model of Temporal Lobe Epilepsy in Mice." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/18378754175983896649.
Full textAbstract:
碩士國立陽明大學
腦科學研究所
101
Temporal lobe epilepsy (TLE), a common neurological disease with hallucinations and disturbance of consciousness, is the abnormal neurological activity in any part of brain. Although the condition responds well to antiepileptic drugs (AEDs), there are still unresponsive to antiepileptic drug in about 1/3 of cases. Other treatment including surgery and deep brain stimulation (DBS), are also limited to the lesion location is not easily removed or restricted unclear. In addition, little is known about the underlying mechanism of the disease, deepened the difficulty of treatment. Previous studies indicated that TLE is associated with a specific structural lesion in the hippocampus called as hippocampal sclerosis, there is selective loss of neurons, gliosis and neuron degeneration. Also, neuroinflammation may be involved in epileptogenesis, and the inflammatory mediators will accelerate the death of neurons, making epilepsy symptoms gradually worse. Epoxyeicosatrienoic acids (EETs) are potent vasodilators for the endothelium-derived hyperpolarizing factor (EDHF), which plays an important role in decrease of blood pressure, anti-inflammation, and anti-apoptosis. Furthermore, arachidonic acid and the eicosanoid metabolites have electrophysiological and anticholinergic properties in the nervous system. However, the soluble epoxide hydrolase (sEH) can hydrate EETs to an inactivated form of dihydroxyeicosatrienoic acid (DHET), which attenuated or eliminated the effects of EETs. More recently, some investigators showed that sEH C-terminal inhibitors decreased plasma levels of proinflammatory cytokines and nitric oxide metabolite while promoting the formation of lipoxins in lipopolysaccharide-induced acute inflammation, thus supporting inflammatory resolution. In the context, studying the role of sEH in epileptogenesis in an important issue. To determine the role of sEH in temporal lobe epilepsy, we evaluated the difference between sEH gene knock-out (sEHKO) and wild-type (WT) mice in electrical kindling-induced epileptogenesis. In this study, we used electrical stimulation in amygdala daily, while recording EEG and behavior changes, comparative sEHKO and WT mice between the numbers of stimulations required to elicit seizure behavior, the latency to seizure onset and the afterdischarge amplitude. Our results showed that both in the seizure-induction threshold, stimulation numbers and severity of seizure, afterdischarge duration and the latency to seizure onset, sEH-KO were serious than WT mice. We suggested that sEH play an important role in epileptogenesis. sEH is a homodimer with a bifunctional enzyme which has hydrolase activity residing in the C-terminus and phosphatase activity in the N-terminus. To determine the function of C-terminus and N-terminus of sEH in epileptogenesis, we measured the seizure-induction threshold changes after 30 min prior to treated C-terminal inhibitor (12-(3-Adamantan-1-yl-ureido)-dodecanoic acid, AUDA) or N-terminal inhibitor (N-acetyl-S-farnesyl-L-cysteine, AFC) to fully kindled WT mice by intranasal and intraperitoneal administration, respectively. After seven consecutive days of administration, data showed that intranasal administration of AUDA (10 mg/kg BW) increased the seizure-induction threshold in fully kindling mice, especially in the fifth day and the sixth day of the most significant increase. However, the results of AFC by intraperitoneal injection did not significantly alter the seizure-evoked threshold. In conclusion, the role of sEH C-terminal domain causes more severe symptoms of epilepsy. Additionally, because N-terminal inhibitor of sEH did not induced significant change in seizure-induction threshold, the reason were suggested that the mistake route of drug administration or the effective doses were not found. In conclusion, further investigations of the role of sEH in TLE and the underlying mechanisms are warranted to provide more information to confirm, and provide clinical management and relevant research in the future.
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Yeh, Chien-Fu, and 葉建甫. "Inhibition of soluble epoxide hydrolase regulates microglia polarization and improves neurological outcomes in a rat model of ischemic stroke." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/ttrn5z.
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Hu, Ya-Yu, and 胡雅瑜. "Effects of Genetic and Pharmacological Inhibitions of Soluble Epoxide Hydrolase on Kainic Acid-induced Memory Impairment and Loss of Hippocampal GABAergic Interneurons in Mice." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/6ap3y6.
Full textAbstract:
碩士國立陽明大學
生理學研究所
106
Soluble epoxide hydroxylase (sEH) is a dual activity enzyme with the C-terminal epoxide hydrolase domain and an N-terminal lipid phosphatase domain and is expressed in mammalian brains, especially hippocampus. Inhibition of sEH hydrolase activity has been proven to be protective against ischemic brain injury, but it was also reported to facilitate synaptic plasticity. Synaptic plasticity in the hippocampus is an important role to improve memory function. Also, previous studies demonstrated that inhibition of GABAergic interneuron activity impaired memory function, indicating GABAergic interneuron involved in regulating memory function. However, whether the sEH inhibitor treatment can benefit the recovery of memory function by affecting GABAergic interneurons after excitotoxic insult was unknown. In this study, we examined the post-treatment effect of intranasal delivery (i.n.) of sEH hydrolase inhibitor TPPU (0.5mg/kg once a day for 7 days) on hippocampal damage, with special focus on GABAergic interneurons, and memory impairment 7 days after the intraperitoneal kainic acid (KA) injection, and in comparison with the effect of genetic ablation of Ephx2 (Ephx2-KO). Our results show that the KA-triggered seizure activity 2h after the injection was lower in TPPU-i.n than the vehicle-i.n mice, and also lower in Ephx2-KO than WT mice. Immunohistochemistry staining showed that both Ephx2-KO and TPPU-i.n attenuated KA-induced NeuN+ neuronal loss in hippocampal CA1, CA3 and dentate gyrus (DG). Hippocampus-related pattern separation behavior assessed by the novel object recognition test was impaired by KA, which was ameliorated by TPPU-i.n and also in Ephx2-KO. Another hippocampus-related behavior is the spatial learning memory assessed by the Barnes maze test. The data showed that TPPU-i.n treatment, not Ephx2 deletion, attenuated KA-induced spatial memory 3 days post-injection. However, this memory-improving effect of TPPU-i.n treatment did not sustain to 7-day post-injection. Notably, the Ephx2-KO mice learn faster than the WT mice to find the target hole during the 4-day training period prior to the drug injection; whereas vehicle-injected Ephx2-KO mice spent more time to find the target hole than the vehicle-injected WT mice 7 days after the training, implying that sEH might be involved in both memory acquisition and consolidation. Immunohistochemistry study of the GABAergic interneurons as labeled by the GABA synthesizing enzyme glutamic acid decarboxylase 65 (GAD65) show that GAD65 were reduced by KA and rescued by both TPPUi.n and Ephx2-KO in hippocampal subregions. Next, we examined a subset of GABAergic interneurons in the DG hilus region, which expressed a calcium-buffering protein calretinin (CR) to maintain proper neuronal excitability, found that both TPPU and Ephx2-KO could rescue CR+ interneurons in supragranular layer (SG) and hilus of DG after KA insult. Another subtype of GABAergic interneurons, parvalbumin (PV) expressing neurons in the hippocampus, could not be rescued by TPPU treatment after KA-ip insult significantly. Then we tried to confirm this phenomenon in vitro by using primary glia-neuron mix culture treated with glutamate receptor agonist NMDA to induce excitotoxic neuronal death. The results indicated that TPPU pretreatment could ameliorate NMDA-induced loss of NeuN+ neurons and MAP2+ neurons. Next, we examined GABAergic neurons labeled cell cytosol by GAD67, and we found that TPPU pretreatment could not alter NMDA-induced loss of GAD67 protein level or expression. Further examined one type of GABAergic neuron labeled by calretinin, and we found that TPPU pretreatment can significantly ameliorate NMDA-induced reduction of CR+ neurons but not CR protein level. Also, we examined another type of GABAergic neurons labeled by parvalbumin, and the data indicated that TPPU pretreatment cannot alter NMDA-induced the loss of PV+ neurons. In conclusion, these results suggest that intranasal delivery of sEH inhibitor TPPU and Ephx2 deletion both show moderate protective effects against excitotoxin-induced hippocampal damage and pattern separation deficit accompanied with preservation of CR-expressing GABAergic interneurons in the dentate gyrus. The obtained information may provide clues for the modulation of excitation-inhibition balance in hippocampal circuits.
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Keserü, Benjamin [Verfasser]. "Role of the soluble epoxide hydrolase and cytochrome P450-derived epoxyeicosatrienoic acids in hypoxic pulmonary vasoconstriction and hypoxia induced pulmonary vascular remodelling / von Benjamin Keserü." 2009. http://d-nb.info/992453011/34.
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Jíchová, Šárka. "Úloha metabolitů kyseliny arachidonové v regulaci krevního tlaku u experimentálních modelů ANGII-dependentní formy hypertenze." Doctoral thesis, 2020. http://www.nusl.cz/ntk/nusl-436095.
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Introduction: Two major product groups originate from the arachidonic acid metabolic pathway of cytochromes P450: epoxyeicosatrienoic acid (EETs) and 19 and 20-hydroxyeicosatetraenoic acid (19- and 20-HETE). These metabolites play an important role in the regulation of blood pressure, inflammatory responses, regulation of sodium excretion and other crucial physiological processes. Hypothesis: Our studies were based on the hypothesis that abnormalities in the production and function of these cytochrome P450 metabolites significantly contribute to the pathophysiology of hypertension development, in particular in the angiotensin II-dependent models. Objective: To investigate if the increased bioavailability of the above-mentioned metabolites in the kidney tissue will result in blood pressure reduction in the ANG II - dependent rat model of hypertension. Methods: The two methods to increase the concentration of EETs was chosen. In the first part of the study, we administered a soluble epoxide hydrolase inhibitor cAUCB [cis-4- [4- (3-adamantan-1-yl- ureido) cyclohexyloxy] benzoic acid, at a dose of 26 mg.l-1 administered in drinking water], an enzyme responsible for inactivation of biologically active forms of EETs. In the second series of the experiments we applied a synthetic EET analogue, called...
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Honetschlägerová, Zuzana. "Úloha epoxyeicosatrienových kyselin v regulaci krevního tlaku a renálních funkcí u experimentálních modelů hypertenze." Doctoral thesis, 2018. http://www.nusl.cz/ntk/nusl-389786.
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Introduction: Epoxyeicosatrienoic acids (EETs) are converted by the enzyme soluble epoxid hydrolase (sEH) to the biologically inactive dihydroxyeicosatrienoic acids (DHETs). EETs are significantly involved in the control of blood pressure, they influence vascular tone and renal transport mechanism. sEH inhibitor reduce blood pressure by increasing the bioavailability of EETs in many models of hypertension. Aim of the study: To determine that sEH inhibitor decreases blood pressure and improves the renal function during the development of malignant hypertension in transgenic rats after the induction of the mouse renin gene. Methods: Hypertension in Cyp1a1-Ren-2 transgenic rats was induced through a dietary administration of the natural xenobiotic indole-3-carbinol (I3C, 0.3 %) for 3 and 11 days. I3C activates the renin gene. At the same time, during a three-day induction of hypertension, the inhibitor of nitric oxide synthase L-NAME (600 mg/l) was administered in drinking water. The sEH inhibitor c-AUCB was given in drinking water at a dose of 13 or 26 mg/l, starting 48 hours before the initiation of I3C and L-NAME administration. Radiotelemetric measurement of blood pressure was performed and renal excretory parameters were monitored in the conscious animals. The effects on renal hemodynamics and...