Relevant bibliographies by topics / Soluble epoxide hydrolase subdomains

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Academic literature on the topic 'Soluble epoxide hydrolase subdomains'

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Published: 18 May 2024

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Journal articles on the topic "Soluble epoxide hydrolase subdomains"

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Gupta, Nandita C., Catherine M. Davis, Jonathan W. Nelson, Jennifer M. Young, and Nabil J. Alkayed. "Soluble Epoxide Hydrolase." Arteriosclerosis, Thrombosis, and Vascular Biology 32, no. 8 (August 2012): 1936–42. http://dx.doi.org/10.1161/atvbaha.112.251520.

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Sontakke, Pooja M., Suraj G. Malpani, Pooja R. Tange, MD Rayees Ahmad, and Vishweshwar M. Dharashive. "Soluble Epoxide Hydrolase." Asian Journal of Pharmaceutical Research and Development 12, no. 2 (April 15, 2024): 87–95. http://dx.doi.org/10.22270/ajprd.v12i2.1369.

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Epoxyeicosatrienoic acids (EETs) have numerous cardiovascular benefits, including vasodilation, anti-inflammatory actions, and anti-migratory effects on vascular smooth muscle cells. However, sEH, an enzyme that breaks down EETs into diols, limits these benefits. The development of sEH inhibitors (sEHIs), particularly those based on 1,3-disubstituted urea, has shown promise in enhancing the therapeutic properties of EETs. These inhibitors are antihypertensive and anti-inflammatory and can protect the heart, brain, and kidneys from damage. While there are still challenges to overcome, such as improving the drug-like properties of sEHIs and finding better ways to target specific tissues, the initiation of clinical trials for sEHIs highlights their potential as therapeutic agents.
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Yu, Zhigang, Benjamin B. Davis, Christophe Morisseau, Bruce D. Hammock, Jean L. Olson, Deanna L. Kroetz, and Robert H. Weiss. "Vascular localization of soluble epoxide hydrolase in the human kidney." American Journal of Physiology-Renal Physiology 286, no. 4 (April 2004): F720—F726. http://dx.doi.org/10.1152/ajprenal.00165.2003.

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Epoxyeicosatrienoic acids are cytochrome P-450 metabolites of arachidonic acid with multiple biological functions, including the regulation of vascular tone, renal tubular transport, cellular proliferation, and inflammation. Epoxyeicosatrienoic acids are converted by soluble epoxide hydrolase into the corresponding dihydroxyeicosatrienoic acids, and epoxyeicosatrienoic acid hydration is regarded as one mechanism whereby their biological effects are eliminated. Previous animal studies indicate that soluble epoxide hydrolase plays an important role in the regulation of renal eicosanoid levels and systemic blood pressure. To begin to elucidate the mechanism of these effects, we determined the cellular localization of soluble epoxide hydrolase in human kidney by examining biopsies taken from patients with a variety of non-end-stage renal diseases, as well as those without known renal disease. Immunohistochemical staining of acetone-fixed kidney biopsy samples revealed that soluble epoxide hydrolase was preferentially expressed in the renal vasculature with relatively low levels in the surrounding tubules. Expression of soluble epoxide hydrolase was evident in renal arteries of varying diameter and was localized mostly in the smooth muscle layers of the arterial wall. Western blot analysis and functional assays confirmed the expression of soluble epoxide hydrolase in the human kidney. There were no obvious differences in soluble epoxide hydrolase expression between normal and diseased human kidney tissue in the samples examined. Our results indicate that soluble epoxide hydrolase is present in the human kidney, being preferentially expressed in the renal vasculature, and support an essential role for this enzyme in renal hemodynamic regulation and its potential utility as a target for therapeutic intervention.
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Borhan, Babak, A. Daniel Jones, Franck Pinot, David F. Grant, Mark J. Kurth, and Bruce D. Hammock. "Mechanism of Soluble Epoxide Hydrolase." Journal of Biological Chemistry 270, no. 45 (November 10, 1995): 26923–30. http://dx.doi.org/10.1074/jbc.270.45.26923.

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Wang, Yi-Xin Jim, Arzu Ulu, Le-Ning Zhang, and Bruce Hammock. "Soluble Epoxide Hydrolase in Atherosclerosis." Current Atherosclerosis Reports 12, no. 3 (April 13, 2010): 174–83. http://dx.doi.org/10.1007/s11883-010-0108-5.

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Ma, Liang, Hailing Zhao, Meijie Yu, Yumin Wen, Tingting Zhao, Meihua Yan, Qian Liu, et al. "Association of Epoxide Hydrolase 2 Gene Arg287Gln with the Risk for Primary Hypertension in Chinese." International Journal of Hypertension 2020 (February 28, 2020): 1–7. http://dx.doi.org/10.1155/2020/2351547.

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Background. Epoxide hydrolase 2 (EPHX2) gene coding for soluble epoxide hydrolase is a potential candidate in the pathogenesis of hypertension. Objectives. We aimed to assess the association of a missense mutation, R287Q, in EPHX2 gene with primary hypertension risk and examine its association with enzyme activity of soluble epoxide hydrolase. Methods. This study involved 782 patients with primary hypertension and 458 healthy controls. Genotyping was done using TaqMan technique. Activity of soluble epoxide hydrolase fusion proteins was evaluated by the conversion of 11,12-EET to corresponding 11,12-DHET using ELISA kit. Results. After taking carriers of R287Q variant GG genotype as a reference, those with GA genotype had a significantly reduced risk of hypertension (adjusted odds ratio: 0.72, 95% confidence interval: 0.56 to 0.93, P = 0.013). Five significant risk factors were identified, including age, body mass index, total cholesterol, homocysteine, and R287Q variant. These five risk factors for hypertension were represented in a nomogram, with a descent prediction accuracy (C-index: 0.833, P<0.001). Enzyme activity of soluble epoxide hydrolase was significantly lower in the R287Q group than in the wild type group. Conclusions. We provide evidence that R287Q mutation in EPHX2 gene was associated with reduced risk of primary hypertension and low activity of soluble epoxide hydrolase.
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He, Xin, Wen-Yu Zhao, Bo Shao, Bao-Jing Zhang, Tian-Tian Liu, Cheng-Peng Sun, Hui-Lian Huang, Jia-Rong Wu, Jia-Hao Liang, and Xiao-Chi Ma. "Natural soluble epoxide hydrolase inhibitors from Inula helenium and their interactions with soluble epoxide hydrolase." International Journal of Biological Macromolecules 158 (September 2020): 1362–68. http://dx.doi.org/10.1016/j.ijbiomac.2020.04.227.

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Anita, Natasha Z., and Walter Swardfager. "Soluble Epoxide Hydrolase and Diabetes Complications." International Journal of Molecular Sciences 23, no. 11 (June 2, 2022): 6232. http://dx.doi.org/10.3390/ijms23116232.

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Type 2 diabetes mellitus (T2DM) can result in microvascular complications such as neuropathy, retinopathy, nephropathy, and cerebral small vessel disease, and contribute to macrovascular complications, such as heart failure, peripheral arterial disease, and large vessel stroke. T2DM also increases the risks of depression and dementia for reasons that remain largely unclear. Perturbations in the cytochrome P450-soluble epoxide hydrolase (CYP-sEH) pathway have been implicated in each of these diabetes complications. Here we review evidence from the clinical and animal literature suggesting the involvement of the CYP-sEH pathway in T2DM complications across organ systems, and highlight possible mechanisms (e.g., inflammation, fibrosis, mitochondrial function, endoplasmic reticulum stress, the unfolded protein response and autophagy) that may be relevant to the therapeutic potential of the pathway. These mechanisms may be broadly relevant to understanding, preventing and treating microvascular complications affecting the brain and other organ systems in T2DM.
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Bellevik, Stefan, Jiaming Zhang, and Johan Meijer. "Brassica napus soluble epoxide hydrolase (BNSEH1)." European Journal of Biochemistry 269, no. 21 (October 17, 2002): 5295–302. http://dx.doi.org/10.1046/j.1432-1033.2002.03247.x.

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Przybyla-Zawislak, Beata D., Punit K. Srivastava, Johana Vázquez-Matías, Harvey W. Mohrenweiser, Joseph E. Maxwell, Bruce D. Hammock, J. Alyce Bradbury, Ahmed E. Enayetallah, Darryl C. Zeldin, and David F. Grant. "Polymorphisms in Human Soluble Epoxide Hydrolase." Molecular Pharmacology 64, no. 2 (July 17, 2003): 482–90. http://dx.doi.org/10.1124/mol.64.2.482.

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Dissertations / Theses on the topic "Soluble epoxide hydrolase subdomains"

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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'endothélium
Expressed 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 pathologies
Soluble 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 cardiométabolique
Nearly 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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10

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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Books on the topic "Soluble epoxide hydrolase subdomains"

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Imig, John D., and Christophe Morisseau, eds. Clinical Paths for Soluble Epoxide Hydrolase Inhibitors. Frontiers Media SA, 2020. http://dx.doi.org/10.3389/978-2-88966-161-9.

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Book chapters on the topic "Soluble epoxide hydrolase subdomains"

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Singh, Nalin, and Bruce D. Hammock. "Soluble Epoxide Hydrolase." In Encyclopedia of Molecular Pharmacology, 1–7. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-21573-6_10020-1.

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Singh, Nalin, and Bruce D. Hammock. "Soluble Epoxide Hydrolase." In Encyclopedia of Molecular Pharmacology, 1450–56. Cham: Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-57401-7_10020.

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Nelson, Jonathan W., and Nabil J. Alkayed. "Soluble Epoxide Hydrolase as a Stroke Target." In Translational Stroke Research, 277–94. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-9530-8_13.

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"Soluble epoxide hydrolase." In Class 3 Hydrolases, 228–79. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-540-85703-7_37.

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Nayeem, Mohammed A., Werner J. Geldenhuys, and Ahmad Hanif. "Role of cytochrome P450-epoxygenase and soluble epoxide hydrolase in the regulation of vascular response." In Advances in Pharmacology. Elsevier, 2023. http://dx.doi.org/10.1016/bs.apha.2022.12.003.

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Kandasamy, Ram, and Stevan Pecic. "Treatment of pain with dual fatty acid amide hydrolase (FAAH) enzyme and human soluble epoxide hydrolase (sEH) enzyme inhibitors: Interlinking the endocannabinoid system." In Neurobiology and Physiology of the Endocannabinoid System, 175–87. Elsevier, 2023. http://dx.doi.org/10.1016/b978-0-323-90877-1.00039-5.

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Hung, Shao-Wen, Chia-Chi Chen, Hsiao-Yun Chen, Ying-Ching Hung, Ping-Min Huang, and Chia-Yu Lin. "The Role of Microglia in Neuroinflammation." In Epilepsy - Seizures Without Triggers [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.105865.

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Microglia typically exist in a resting state of a mature brain and monitors the brain environment. In response to brain injuries or immunological stimuli, however, microglia are readily activated. In their activated state, they can serve diverse beneficial functions essential for enhancing neuron survival through the release of trophic and anti-inflammatory factors. Under certain circumstances, such as sustained epilepsy, however, microglia become overactivated and can induce significant and highly detrimental neurotoxic effects by the excessive production of a large array of cytotoxic factors, such as nitric oxide and proinflammatory cytokines. Neuroinflammation has been identified in epileptogenic tissue and is suspected of participating in epileptogenesis. Recent evidence has shown the effects of anti-inflammation and protection against ischemic brain injury by inhibiting soluble epoxide hydrolase (sEH) pharmacologically and genetically. We assume that sEH inhibition might be also beneficial to prevent inflammatory processes caused by seizures and subsequent chronic epilepsy. In the present study, we investigated whether sEH is involved in overactivated microglia-induced neuroinflammation and subsequent epileptogenesis in a mouse model of temporal lobe epilepsy. Overactivated microglia will be detected by using imaging techniques. It is hoped that the results of the present study would provide a better understanding of the roles of sEH and microglia in epileptogenesis.
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Conference papers on the topic "Soluble epoxide hydrolase subdomains"

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Lazaar, Aili, Lucy Yang, Jon Robertson, Navin Goyal, Rebecca Boardley, Ruth Tal-Singer, Joseph Cheriyan, David Newby, Ian Wilkinson, and Ruth Mayer. "Safety and pharmacology of a soluble epoxide hydrolase inhibitor." In Annual Congress 2015. European Respiratory Society, 2015. http://dx.doi.org/10.1183/13993003.congress-2015.pa2120.

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Yang, Jun, Jennifer Bratt, Lisa Franzi, Junyan Liu, Guodong Zhang, Hua Dong, Keisha Williams, et al. "Soluble Epoxide Hydrolase Inhibitor Attenuates The Ovalbumin-Induced Murine Asthmatic Symptoms." In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1425.

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Achanta, S., A. Marcus, A. Caceres, and S. E. Jordt. "Soluble Epoxide Hydrolase Inhibitors and ACE Inhibitors Ameliorate Phosgene Inhalation Injuries." In American Thoracic Society 2023 International Conference, May 19-24, 2023 - Washington, DC. American Thoracic Society, 2023. http://dx.doi.org/10.1164/ajrccm-conference.2023.207.1_meetingabstracts.a1171.

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Davis, Benjamin B., Jun-Yan Liu, Daniel J. Tancredi, Scott I. Simon, Bruce D. Hammock, and Kent E. Pinkerton. "Anti-inflammatory Effects Of Soluble Epoxide Hydrolase Inhibition Are Independent Of Leukocyte Recruitment." In American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans. American Thoracic Society, 2010. http://dx.doi.org/10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a5751.

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Liao, Jie, Stephanie D. Norwood, Yeon Tae Chung, Haonan Li, Bruce D. Hammock, and Guang-Yu Yang. "Abstract 5702: Soluble epoxide hydrolase: unique biomarker and chemopreventive target of chronic colitis-induced carcinogenesis." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-5702.

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Yang, Jun, Lisa Franzi, Hua Dong, Amir A. Zeki, Junyan Liu, Nicholas J. Kenyon, and Bruce Hammock. "Soluble Epoxide Hydrolase Is A Novel Therapeutic Target In Asthma By Modulating The Inflammatory Response." In American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans. American Thoracic Society, 2010. http://dx.doi.org/10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a4241.

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Yuan, Cassandra, Ashley Murray, Christopher Chin, Alyssa Fernandez, Stephanie Sanchez, Stevan Pecic, and Ram Kandasamy. "Effects of Simultaneous Inhibition of Fatty Acid Amide Hydrolase and Soluble Epoxide Hydrolase on Acute and Persistent Pain in Male Rats." In ASPET 2023 Annual Meeting Abstracts. American Society for Pharmacology and Experimental Therapeutics, 2023. http://dx.doi.org/10.1124/jpet.122.186070.

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Zhang, Wanying, Jie Liao, Haonan Li, Hua Dong, Han Bai, Allison Liao Yang, Bruce D. Hammack, and Guang-Yu Yang. "Abstract 1006: Soluble epoxide hydrolase gene deficiency attenuates colitis-induced carcinogenesis in IL-10 knockout mice." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-1006.

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Rehman, S. F., K. F. Budden, A. Quaranta, D. Fuchs, S. D. Shukla, A. Brown, C. Alemao, et al. "Soluble epoxide hydrolase inhibition alleviates inflammation in cigarette smoke-induced experimental COPD irrespective of dietary fat content." In ERS International Congress 2022 abstracts. European Respiratory Society, 2022. http://dx.doi.org/10.1183/13993003.congress-2022.3378.

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Carlson, A., E. Nixon, K. Messenger, P. Johnson, and K. Keegan. "Anti-nociceptive Efficacy of the Soluble Epoxide Hydrolase Inhibitor t-TUCB in Horses with Mechanically Induced Lameness." In Abstracts of the 6th World Veterinary Orthopedic Congress. Georg Thieme Verlag KG, 2022. http://dx.doi.org/10.1055/s-0042-1758247.

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