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Epoxide hydrolase

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https://www.readbyqxmd.com/read/28218273/discovery-of-the-first-dual-inhibitor-of-the-5-lipoxygenase-activating-protein-and-soluble-epoxide-hydrolase-using-pharmacophore-based-virtual-screening
#1
Veronika Temml, Ulrike Garscha, Erik Romp, Gregor Schubert, Jana Gerstmeier, Zsofia Kutil, Barbara Matuszczak, Birgit Waltenberger, Hermann Stuppner, Oliver Werz, Daniela Schuster
Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28199961/proteomic-analysis-of-laser-capture-microdissected-focal-lesions-in-a-rat-model-of-progenitor-marker-positive-hepatocellular-carcinoma
#2
Adeola O Adebayo Michael, Nagib Ahsan, Valerie Zabala, Heather Francois-Vaughan, Stephanie Post, Kate E Brilliant, Arthur R Salomon, Jennifer A Sanders, Philip A Gruppuso
We have shown previously that rapamycin, the canonical inhibitor of the mechanistic target of rapamycin (mTOR) complex 1, markedly inhibits the growth of focal lesions in the resistant hepatocyte (Solt-Farber) model of hepatocellular carcinoma (HCC) in the rat. In the present study, we characterized the proteome of persistent, pre-neoplastic focal lesions in this model. One group was administered rapamycin by subcutaneous pellet for 3 weeks following partial hepatectomy and euthanized 4 weeks after the cessation of rapamycin...
February 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28188798/in-silico-investigation-of-cycloartane-triterpene-derivatives-from-cimicifuga-dahurica-turcz-maxim-roots-for-the-development-of-potent-soluble-epoxide-hydrolase-inhibitors
#3
Nguyen Phuong Thao, Jang Hoon Kim, Bui Thi Thuy Luyen, Nguyen Tien Dat, Young Ho Kim
In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, we found that an ethanolic extract of the roots of Cimicifuga dahurica (Turcz.) Maxim. significantly inhibits sEH in vitro. A phytochemical study on the dichloromethane fraction of C. dahurica resulted in the isolation of two new cycloartane triterpenoids (1 and 6), together with 13 known cycloartane analogues (2-5 and 7-15). The structures of compounds were determined by spectroscopic methods. All of the triterpenoid derivatives inhibited sEH enzymatic activity in a concentration-dependent manner, and 13 of the tested compounds showed significant activity...
February 7, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28185955/endothelial-nox4-based-nadph-oxidase-regulates-atherosclerosis-via-soluble-epoxide-hydrolase
#4
Pingping Hu, Xiaojuan Wu, Alok R Khandelwal, Weimin Yu, Zaicheng Xu, Lili Chen, Jian Yang, Robert M Weisbrod, Kin Sing Stephen Lee, Francesca Seta, Bruce D Hammock, Richard A Cohen, Chunyu Zeng, Xiaoyong Tong
: Nox4-based NADPH oxidase is a major reactive oxygen species-generating enzyme in the vasculature, but its role in atherosclerosis remains controversial. OBJECTIVE: Our goal was to investigate the mechanisms of endothelial Nox4 in regulating atherosclerosis. APPROACH AND RESULTS: Atherosclerosis-prone conditions (disturbed blood flow, type I diabetes, and Western diet) downregulated endothelial Nox4 mRNA in arteries. To address whether the downregulated endothelial Nox4 was directly involved in the development of atherosclerosis, we generated mice carrying a human Nox4 P437H dominant negative mutation (Nox4DN), driven by the endothelial specific promoter Tie-2, on atherosclerosis-prone genetic background (ApoE deficient mice) to mimic the effect of decreased endothelial Nox4...
February 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28140329/the-role-of-cytochrome-p450-epoxygenases-soluble-epoxide-hydrolase-and-epoxyeicosatrienoic-acids-in-metabolic-diseases
#5
REVIEW
Xizhen Xu, Rui Li, Guangzhi Chen, Samantha L Hoopes, Darryl C Zeldin, Dao Wen Wang
Metabolic diseases are associated with an increased risk of developing cardiovascular disease. The features comprising metabolic diseases include obesity, insulin resistance, hyperglycemia, hyperlipidemia, and hypertension. Recent evidence has emerged showcasing a role for cytochrome P450 epoxygenases, soluble epoxide hydrolase, and epoxyeicosatrienoic acids (EETs) in the development and progression of metabolic diseases. This review discusses the current knowledge related to the modulation of cytochrome P450 epoxygenases and soluble epoxide hydrolase to alter concentrations of biologically active EETs, resulting in effects on insulin resistance, lipid metabolism, obesity, and diabetes...
November 2016: Advances in Nutrition
https://www.readbyqxmd.com/read/28132911/effect-of-alpha-lipoic-acid-on-leukotriene-a4-hydrolase
#6
María José Torres, Angélica Fierro, C David Pessoa-Mahana, Javier Romero-Parra, Gonzalo Cabrera, Mario Faúndez
Leukotriene A4 hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A4 to leukotriene B4 and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B4 synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B4 or to block its receptors. Here we show the inhibitory profile of alpha lipoic acid on the activity of leukotriene A4 Hydrolase...
January 26, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28120429/structural-insights-into-human-microsomal-epoxide-hydrolase-by-combined-homology-modeling-molecular-dynamics-simulations-and-molecular-docking-calculations
#7
Patricia Saenz-Méndez, Aline Katz, María Lucía Pérez-Kempner, Oscar N Ventura, Marta Vázquez
A new homology model of human microsomal epoxide hydrolase was derived based on multiple templates. The model obtained was fully evaluated, including MD simulations and ensemble-based docking, showing that the quality of the structure is better than that of only previously known model. Particularly, a catalytic triad was clearly identified, in agreement with the experimental information available. Analysis of intermediates in the enzymatic mechanism led to the identification of key residues for substrate binding, stereoselectivity, and intermediate stabilization during the reaction...
January 24, 2017: Proteins
https://www.readbyqxmd.com/read/28115652/candidate-risk-factors-and-mechanisms-for-tolvaptan-induced-liver-injury-are-identified-using-a-collaborative-cross-approach
#8
Merrie Mosedale, Yunjung Kim, William J Brock, Sharin E Roth, Tim Wiltshire, J Scott Eaddy, Gregory R Keele, Robert W Corty, Yuying Xie, William Valdar, Paul B Watkins
Clinical trials of tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk factors and mechanisms underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated animals in 3 of the 45 strains...
January 23, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28112313/soluble-epoxide-hydrolase-inhibitors-might-prevent-ischemic-arrhythmias-via-microrna-1-repression-in-primary-neonatal-mouse-ventricular-myocytes
#9
Qiong Liu, Xuan Zhao, Ran Peng, Mi Wang, Wang Zhao, Ya-Jun Gui, Cai-Xiu Liao, Dan-Yan Xu
Ischemic arrhythmias are the main causes of sudden cardiac death. It has been reported that soluble epoxide hydrolase inhibitors (sEHis) could prevent arrhythmias; however, the underlying molecular mechanisms remain unclear. In recent years, the proarrhythmic role of microRNA-1 (miR-1) has been investigated. This study aimed to elucidate whether sEHis prevented ischemic arrhythmias by suppressing miR-1. The primary neonatal mouse ventricular myocyte model of miR-1 overexpression was established by incubating with agonist microONTM mmu-miR-1a-3p agomir (DAEDstain(TM) Dye) (agomiR-1)...
January 23, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28104457/genetic-deletion-of-soluble-epoxide-hydrolase-provides-cardioprotective-responses-following-myocardial-infarction-in-aged-mice
#10
REVIEW
K Lockhart Jamieson, Victor Samokhvalov, Maria Akhnokh, Kyra Lee, Woo Jung Cho, Abhijit Takawale, Xiuhua Wang, Zamaneh Kassiri, John M Seubert
BACKGROUND: Pathophysiological responses, including cardiovascular complications, often alter with age. Cardioprotective effects of epoxyeicosatrienoic acids (EETs) toward acute myocardial ischemia-reperfusion injury have been well documented. However, biological relevance of EET-evoked cardioprotection in the ageing myocardium remains unknown. EETs are metabolized to less active metabolites by the enzyme soluble epoxide hydrolase (sEH). This study uses permanent occlusion of the left anterior descending artery (LAD) in young and aged sEH null and WT mice to compare cardiac and mitochondrial function following ischemic injury...
January 16, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28104439/up-regulation-of-cyp1a1-and-phase-ii-enzymes-by-5-ring-isomeric-polycyclic-aromatic-hydrocarbons-in-precision-cut-rat-hepatic-slices-importance-of-molecular-shape
#11
Daphnee Pushparajah, Dfv Lewis, Costas Ioannides
The objectives of the present study were two-fold: (a) to evaluate the role of molecular shape on the interaction of polycyclic aromatic hydrocarbons (PAHs) with the Ah receptor and CYP1A1 upregulation, and (b) to evaluate the potential of PAHs to induce epoxide hydrolase and glutathione S-transferase, two major enzymes involved in their metabolism. In order to achieve these objectives, precision-cut rat liver slices were incubated with a range of concentrations of seven 5-ring isomeric PAHs, namely benzo[c]chrysene, benzo[b]chrysene, benzo[g]chrysene, dibenzo[a,j]anthracene, dibenzo[a,c]anthracene, picene and pentacene, for 24h...
January 16, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28071912/insights-into-the-catalytic-mechanism-of-unsaturated-glucuronyl-hydrolase-of-bacillus-sp-gl1
#12
Jing Xiong, Dingguo Xu
Together with polysaccharide lyases (PLs), the unsaturated glucuronyl hydrolase of Bacillus sp., GL1, is responsible for the metabolism of glycosaminoglycans (GAGs), which plays an important role in various crucial physiological events. More importantly, the degradation mechanism of GAGs often causes extracellular bacterial infection and is thought to be one of the virulence factors. We have previously studied the first degradation step catalyzed by PLs. In this work, we focused on the degradation of the unsaturated chondroitin disaccharide, which is produced from chondroitin by chondroitin lyase...
February 9, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28071611/microsomal-epoxide-hydrolase-gene-polymorphisms-and-susceptibility-to-prostate-cancer-a-systematic-review
#13
REVIEW
Dsl Srivastava
Microsomal epoxide hydrolase (mEH) is a crucial biotransformation enzyme that has capability to metabolize a large number of structurally divergent, highly reactive epoxides, and numerous environmentally exposed carcinogens. It catalyzes the conversion of xenobiotic epoxide compounds into more polar diol metabolites and may play important part of the enzymatic defense against adverse effects of foreign compounds. Most commonly, two functional polymorphisms affecting mEH enzyme activity have been identified: One in exon 3 and other in exon 4 of the mEH gene, which results in His113Tyr and Arg139His amino acid substitutions, respectively...
April 2016: Indian Journal of Cancer
https://www.readbyqxmd.com/read/28065501/synthesis-docking-cytotoxicity-and-lta4h-inhibitory-activity-of-new-gingerol-derivatives-as-potential-colorectal-cancer-therapy
#14
Mai H El-Naggar, Amira Mira, Fatma M Abdel Bar, Kuniyoshi Shimizu, Mohamed M Amer, Farid A Badria
Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene which may play an important role in chronic inflammation associated carcinogenesis. [6]-gingerol, the major bioactive compound of Zingiber officinale, is a potential inhibitor of LTA4H, a highly expressed enzyme in colorectal carcinoma. Eighteen compounds; seven of natural origin (including [4]-, [6]-, [8]-, and [10]-gingerol), five new and six known semi-synthesized [6]-gingerol derivatives were examined using docking, in vitro cytotoxicity against human colon cancer cells (HCT-116) and LTA4H aminopeptidase and epoxide hydrolase inhibitory studies...
December 29, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28057597/depletion-of-juvenile-hormone-esterase-extends-larval-growth-in-bombyx-mori
#15
Zhongjie Zhang, Xiaojing Liu, Takahiro Shiotsuki, Zhisheng Wang, Xia Xu, Yongping Huang, Muwang Li, Kai Li, Anjiang Tan
Two major hormones, juvenile hormone (JH) and 20-hydroxyecdysone (20E), regulate insect growth and development according to their precisely coordinated titres, which are controlled by both biosynthesis and degradation pathways. Juvenile hormone esterase (JHE) is the primary JH-specific degradation enzyme that plays a key role in regulating JH titers, along with JH epoxide hydrolase (JHEH) and JH diol kinase (JHDK). In the current study, a loss-of-function analysis of JHE in the silkworm, Bombyx mori, was performed by targeted gene disruption using the transgenic CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/RNA-guided Cas9 nucleases) system...
February 2017: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28056085/vascular-endothelial-over-expression-of-human-soluble-epoxide-hydrolase-tie2-seh-tr-attenuates-coronary-reactive-hyperemia-in-mice-role-of-oxylipins-and-%C3%AF-hydroxylases
#16
Ahmad Hanif, Matthew L Edin, Darryl C Zeldin, Christophe Morisseau, John R Falck, Mohammed A Nayeem
Cytochromes P450 metabolize arachidonic acid (AA) into two vasoactive oxylipins with opposing biologic effects: epoxyeicosatrienoic acids (EETs) and omega-(ω)-terminal hydroxyeicosatetraenoic acids (HETEs). EETs have numerous beneficial physiological effects, including vasodilation and protection against ischemia/reperfusion injury, whereas ω-terminal HETEs induce vasoconstriction and vascular dysfunction. We evaluated the effect of these oxylipins on post-ischemic vasodilation known as coronary reactive hyperemia (CRH)...
2017: PloS One
https://www.readbyqxmd.com/read/28036068/design-synthesis-and-cellular-characterization-of-a-dual-inhibitor-of-5-lipoxygenase-and-soluble-epoxide-hydrolase
#17
Karin Meirer, Daniel Glatzel, Simon Kretschmer, Sandra K Wittmann, Markus Hartmann, René Blöcher, Carlo Angioni, Gerd Geisslinger, Dieter Steinhilber, Bettina Hofmann, Robert Fürst, Ewgenij Proschak
The arachidonic acid cascade is a key player in inflammation, and numerous well-established drugs interfere with this pathway. Previous studies have suggested that simultaneous inhibition of 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH) results in synergistic anti-inflammatory effects. In this study, a novel prototype of a dual 5-LO/sEH inhibitor KM55 was rationally designed and synthesized. KM55 was evaluated in enzyme activity assays with recombinant enzymes. Furthermore, activity of KM55 in human whole blood and endothelial cells was investigated...
December 29, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28028752/cigarette-smoke-induced-pulmonary-inflammation-and-autophagy-are-attenuated-in-ephx2-deficient-mice
#18
Yunxiao Li, Ganggang Yu, Shaopeng Yuan, Chunting Tan, Puqiao Lian, Lixia Fu, Qi Hou, Bo Xu, Haoyan Wang
Cigarette smoke (CS) increases the risk of chronic obstructive pulmonary disease (COPD) by causing inflammation, emphysema, and reduced lung function. Additionally, CS can induce autophagy which contributes to COPD. Arachidonic acid-derived epoxyeicosatrienoic acids (EETs) have promising anti-inflammatory properties that may protect the heart and liver by regulating autophagy. For this reason, the effect of decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on inflammation, emphysema, lung function, and autophagy was here studied in CS-induced COPD in vivo...
December 27, 2016: Inflammation
https://www.readbyqxmd.com/read/28002622/inhibition-of-soluble-epoxide-hydrolase-augments-astrocyte-release-of-vascular-endothelial-growth-factor-and-neuronal-recovery-after-oxygen-glucose-deprivation
#19
Yue Zhang, Gina Hong, Kin Sing Stephen Lee, Bruce D Hammock, Debebe Gebremedhin, David R Harder, Raymond C Koehler, Adam Sapirstein
Epoxyeicosatrienoic acids (EETs) are synthesized in astrocytes, and inhibitors of soluble epoxide hydrolase (sEH), which hydrolyzes EETs, reduce infarct volume in ischemic stroke. Astrocytes can release protective neurotrophic factors, such as vascular endothelial growth factor (VEGF). We found that addition of sEH inhibitors to rat cultured astrocytes immediately after oxygen-glucose deprivation (OGD) markedly increased VEGF concentration in the medium 48 h later and the effect was blocked by an EET antagonist...
March 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27992199/contribution-of-shape-and-charge-to-the-inhibition-of-a-family-gh99-endo-%C3%AE-1-2-mannanase
#20
Marija Petricevic, Lukasz F Sobala, Pearl Z Fernandes, Lluís Raich, Andrew J Thompson, Ganeko Bernardo-Seisdedos, Oscar Millet, Sha Zhu, Matthieu Sollogoub, Jesús Jiménez-Barbero, Carme Rovira, Gideon J Davies, Spencer J Williams
Inhibitor design incorporating features of the reaction coordinate and transition-state structure has emerged as a powerful approach for the development of enzyme inhibitors. Such inhibitors find use as mechanistic probes, chemical biology tools, and therapeutics. Endo-α-1,2-mannosidases and endo-α-1,2-mannanases, members of glycoside hydrolase family 99 (GH99), are interesting targets for inhibitor development as they play key roles in N-glycan maturation and microbiotal yeast mannan degradation, respectively...
January 25, 2017: Journal of the American Chemical Society
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