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Epoxide hydrolase

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https://www.readbyqxmd.com/read/29317615/biotransformation-of-polyunsaturated-fatty-acids-to-bioactive-hepoxilins-and-trioxilins-by-microbial-enzymes
#1
Jung-Ung An, Yong-Seok Song, Kyoung-Rok Kim, Yoon-Joo Ko, Do-Young Yoon, Deok-Kun Oh
Hepoxilins (HXs) and trioxilins (TrXs) are involved in physiological processes such as inflammation, insulin secretion and pain perception in human. They are metabolites of polyunsaturated fatty acids (PUFAs), including arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, formed by 12-lipoxygenase (LOX) and epoxide hydrolase (EH) expressed by mammalian cells. Here, we identify ten types of HXs and TrXs, produced by the prokaryote Myxococcus xanthus, of which six types are new, namely, HXB5, HXD3, HXE3, TrXB5, TrXD3 and TrXE3...
January 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29315230/maternal-high-fructose-intake-increases-the-vulnerability-to-post-weaning-high-fat-diet-induced-programmed-hypertension-in-male-offspring
#2
You-Lin Tain, Wei-Chia Lee, Kay L H Wu, Steve Leu, Julie Y H Chan
Widespread consumption of high-fructose and high-fat diets relates to the global epidemic of hypertension. Hypertension may originate from early life by a combination of prenatal and postnatal nutritional insults. We examined whether maternal high-fructose diet increases vulnerability to post-weaning high-fructose or high-fat diets induced hypertension in adult offspring and determined the underlying mechanisms. Pregnant Sprague-Dawley rats received regular chow (ND) or chow supplemented with 60% fructose (HFR) during the entire pregnancy and lactation periods...
January 9, 2018: Nutrients
https://www.readbyqxmd.com/read/29311641/blockade-of-soluble-epoxide-hydrolase-attenuates-post-ischemic-neuronal-hyperexcitation-and-confers-resilience-against-stroke-with-trkb-activation
#3
Li-Hsin Chang, Hui-Ching Lin, Shiang-Suo Huang, I-Chih Chen, Kai-Wen Chu, Chun-Lien Chih, Yao-Wen Liang, Yi-Chung Lee, You-Yin Chen, Yi-Hsuan Lee, I-Hui Lee
Inhibition and deletion of soluble epoxide hydrolase (sEH) has been suggested to ameliorate infarction in experimental ischemic stroke possibly via vasoactive epoxyeicosatrienoic acids. However, it is unknown whether the neuroprotective mechanisms involve alteration of post-ischemic neuronal transmission and neurotrophic signaling. We used a permanent middle cerebral artery occlusion (MCAO) model in adult wild-type mice with the sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA) post-treatment and in sEH knockout (sEH KO) mice...
January 8, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29310082/effects-of-adamantane-alterations-on-soluble-epoxide-hydrolase-inhibition-potency-physical-properties-and-metabolic-stability
#4
Vladimir Burmistrov, Christophe Morisseau, Todd R Harris, Gennady Butov, Bruce D Hammock
Adamantyl groups are widely used in medicinal chemistry. However, metabolism limits their usage. Herein, we report the first systematic study of adamantyl ureas and diureas bearing substituents in bridgehead positions of adamantane and/or spacers between urea groups and adamantane group, and tested their effects on soluble epoxide hydrolase inhibitor potency and metabolic stability. Interestingly, the effect on activity against human and murine sEH varied in opposite ways with each new methyl group introduced into the molecule...
December 30, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29303257/unbiased-molecular-dynamics-of-11-min-timescale-drug-unbinding-reveals-transition-state-stabilizing-interactions
#5
Samuel D Lotz, Alex Dickson
Ligand (un)binding kinetics is being recognized as a determinant of drug specificity and efficacy in an increasing number of systems. However, the calculation of kinetics and the simulation of drug unbinding is more difficult than computing thermodynamic quantities, such as binding free energies. Here we present the first full simulations of an unbinding process at pharmacologically relevant time scales (11 min), without the use of biasing forces, detailed prior knowledge, or specialized processors using the weighted ensemble based algorithm, WExplore...
January 5, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29298899/epoxide-hydrolase-1-ephx1-hydrolyzes-epoxyeicosanoids-and-impairs-cardiac-recovery-after-ischemia
#6
Matthew L Edin, Behin Gholipour Hamedani, Artiom Gruzdev, Joan P Graves, Fred B Lih, Samuel J Arbes, Rohanit Singh, Anette C Orjuela Leon, J Alyce Bradbury, Laura M DeGraff, Samantha L Hoopes, Michael Arand, Darryl Zeldin
Stimuli such as inflammation or hypoxia induce cytochrome P450 epoxygenase-mediated production of arachidonic acid-derived epoxyeicosatrienoic acids (EETs). EETs have cardioprotective, vasodilatory, angiogenic, anti-inflammatory, and analgesic effects, which are diminished by EET hydrolysis yielding biologically less active dihydroxyeicosatrienoic acids (DHETs). Previous in vitro assays have suggested that epoxide hydrolase 2 (EPHX2) is responsible for nearly all EET hydrolysis; EPHX1, which exhibits slow EET hydrolysis in vitro, is thought to contribute only marginally to EET hydrolysis...
January 3, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29295935/estrogen-dependent-epigenetic-regulation-of-soluble-epoxide-hydrolase-via-dna-methylation
#7
Yang-Ming Yang, Dong Sun, Sharath Kandhi, Ghezal Froogh, Jian Zhuge, Weihua Huang, Bruce D Hammock, An Huang
To elucidate molecular mechanisms responsible for the sexually dimorphic phenotype of soluble epoxide hydrolase (sEH) expression, we tested the hypothesis that female-specific down-regulation of sEH expression is driven by estrogen-dependent methylation of the Ephx2 gene. Mesenteric arteries isolated from male, female, ovariectomized female (OV), and OV with estrogen replacement (OVE) mice, as well as the human cell line (HEK293T) were used. Methylation-specific PCR and bisulfite genomic sequencing analysis indicate significant increases in DNA/CG methylation in vessels of female and OVE compared with those of male and OV mice...
January 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29288567/isothiocyanates-and-xenobiotic-detoxification
#8
REVIEW
Ahmad Faizal Abdull Razis, Nattaya Konsue, Costas Ioannides
The potential of isothiocyanates to antagonise the carcinogenicity of structurally-diverse chemicals has been established in animals. A feasible mechanism of action involves protecting DNA by reducing the availability of the genotoxic metabolites of chemical carcinogens by either inhibiting their generation and/or stimulating their detoxification. In vivo as well as in vitro studies conducted in rat/human primary hepatocytes and precision-cut tissue slices have revealed that isothiocyanates can impair cytochrome P450 activity, including the CYP1 family which is the most active in the bioactivation of carcinogens, by virtue of being mechanism-based inactivators...
December 30, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/29285425/active-maintenance-of-endothelial-cells-prevents-kidney-fibrosis
#9
Seung Hee Yang, Yong Chul Kim, Jung Nam An, Jin Hyuk Kim, Juhoh Lee, Hee-Yoon Lee, Joo-Youn Cho, Jin Ho Paik, Yun Kyu Oh, Chun Soo Lim, Yon Su Kim, Jung Pyo Lee
Background: Soluble epoxide hydrolase (sEH) expressed by endothelial cells catalyzes the metabolism of epoxyeicosatrienoic acids (EETs), which are vasoactive agents. Methods: We used a unilateral ureteral obstruction mouse model of kidney fibrosis to determine whether inhibition of sEH activity reduces fibrosis, the final common pathway for chronic kidney disease. Results: sEH activity was inhibited by continuous release of the inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA) for 1 or 2 weeks...
December 2017: Kidney Research and Clinical Practice
https://www.readbyqxmd.com/read/29284644/cox-2-seh-dual-inhibitor-ptupb-potentiates-the-anti-tumor-efficacy-of-cisplatin
#10
Fuli Wang, Hongyong Zhang, Ai-Hong Ma, Weimin Yu, Maike Zimmermann, Jun Yang, Sung Hee Hwang, Daniel Zhu, Tzu-Yin Lin, Michael Malfatti, Kenneth W Turteltaub, Paul T Henderson, Susan Airhart, Bruce D Hammock, Jianlin Yuan, Ralph W de Vere White, Chong-Xian Pan
Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in anti-tumor activity, and has organ protective effects. The goal of this study was to determine the anti-tumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC or combinations thereof...
December 28, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29236467/recent-advances-in-enzymatic-complexity-generation-cyclization-reactions
#11
Christopher T Walsh, Yi Tang
Enzymes in biosynthetic pathways, especially in plant and microbial metabolism, generate structural and functional group complexity in small molecules by conversion of acyclic frameworks to cyclic scaffolds in short, efficient routes. The distinct chemical logic used by several distinct classes of cyclases, oxidative and non-oxidative, has recently been elucidated by genome mining, heterologous expression, and genetic and mechanistic analyses. These include enzymes carrying out pericyclic transformations, pyran synthases, tandem acting epoxygenases and epoxide "hydrolases", as well as oxygenases and radical SAM enzymes that involve rearrangements of substrate radicals under aerobic or anaerobic conditions, respectively...
December 13, 2017: Biochemistry
https://www.readbyqxmd.com/read/29234997/learning-epistatic-interactions-from-sequence-activity-data-to-predict-enantioselectivity
#12
Julian Zaugg, Yosephine Gumulya, Alpeshkumar K Malde, Mikael Bodén
Enzymes with a high selectivity are desirable for improving economics of chemical synthesis of enantiopure compounds. To improve enzyme selectivity mutations are often introduced near the catalytic active site. In this compact environment epistatic interactions between residues, where contributions to selectivity are non-additive, play a significant role in determining the degree of selectivity. Using support vector machine regression models we map mutations to the experimentally characterised enantioselectivities for a set of 136 variants of the epoxide hydrolase from the fungus Aspergillus niger (AnEH)...
December 12, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29232926/differential-effects-of-seh-inhibitors-on-the-proliferation-and-migration-of-vascular-smooth-muscle-cells
#13
Hyo Seon Kim, Sang Kyum Kim, Keon Wook Kang
Epoxyeicosatrienoic acid (EET) is a cardioprotective metabolite of arachidonic acid. It is known that soluble epoxide hydrolase (sEH) is involved in the metabolic degradation of EET. The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in the pathogenesis of atherosclerosis and restenosis. Thus, the present study investigated the effects of the sEH inhibitor 12-(((tricyclo(3.3.1.13,7)dec-1-ylamino)carbonyl)amino)-dodecanoic acid (AUDA) on platelet-derived growth factor (PDGF)-induced proliferation and migration in rat VSMCs...
December 11, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29232125/structural-and-computational-insight-into-the-catalytic-mechanism-of-limonene-epoxide-hydrolase-mutants-in-stereoselective-transformations
#14
Zhoutong Sun, Lian Wu, Marco Bocola, H C Stephen Chan, Richard Lonsdale, Xu-Dong Kong, Shuguang Yuan, Jiahai Zhou, Manfred T Reetz
Directed evolution of limonene epoxide hydrolase (LEH), which catalyzes the hydrolytic desymmetrization reactions of cyclopentene oxide and cyclohexene oxide, results in (R,R)- and (S,S)-selective mutants. Their crystal structures combined with extensive theoretical computations shed light on the mechanistic intricacies of this widely used enzyme. From the computed activation energies of various pathways, we discover the underlying stereochemistry for favorable reactions. Surprisingly, some of the most enantioselective mutants that rapidly convert cyclohexene oxide do not catalyze the analogous transformation of the structurally similar cyclopentene oxide, as shown by additional X-ray structures of the variants harboring this slightly smaller substrate...
December 12, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29212255/soluble-epoxide-hydrolase-inhibitors-t-aucb-regulated-microrna-1-and-its-target-genes-in-myocardial-infarction-mice
#15
Ya-Jun Gui, Tao Yang, Qiong Liu, Cai-Xiu Liao, Jing-Yuan Chen, Ya-Ting Wang, Jia-Hui Hu, Dan-Yan Xu
Purpose: Soluble epoxide hydrolase inhibitors (sEHIs) had been demonstrated to produce cardioprotective effects against ischemia-induced lethal arrhythmias, but the exact mechanisms remain unknown. The present study was designed to investigate whether the beneficial effects of sEHIs are related to regulation of microRNA-1, which was a proarrhythmic factor in the ischemic heart. Methods: A mousemyocardial infarction (MI) model was established by ligating the coronary artery...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29211719/inhibition-of-soluble-epoxide-hydrolase-prevents-diabetic-retinopathy
#16
Jiong Hu, Sarah Dziumbla, Jihong Lin, Sofia-Iris Bibli, Sven Zukunft, Julian de Mos, Khader Awwad, Timo Frömel, Andreas Jungmann, Kavi Devraj, Zhixing Cheng, Liya Wang, Sascha Fauser, Charles G Eberhart, Akrit Sodhi, Bruce D Hammock, Stefan Liebner, Oliver J Müller, Clemens Glaubitz, Hans-Peter Hammes, Rüdiger Popp, Ingrid Fleming
Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid...
December 6, 2017: Nature
https://www.readbyqxmd.com/read/29206762/soluble-epoxide-hydrolase-plays-a-vital-role-in-angiotensin-ii-induced-lung-injury-in-mice
#17
Wei Tao, Ping-Song Li, Gang Xu, Yi Luo, Yu-Sheng Shu, Yong-Zhong Tao, Liu-Qing Yang
BACKGROUND: Angiotensin II plays a vital role in the pathogenesis of acute respiratory distress syndrome (ARDS). However, its mechanism is not well defined. Angiotensin II up-regulates the expression of soluble epoxide hydrolase (sEH; Ephx2). sEH is suggested as a potential pharmacologic target for ARDS. The present study investigates whether the sEH is involved in the angiotensin II triggered pulmonary inflammation and edema using an angiotensin II-induced lung injury animal model. METHODS: Lung injury was induced by angiotensin II intratracheally instillation in wild-type or Ephx2 deficient mice...
December 4, 2017: Shock
https://www.readbyqxmd.com/read/29196978/the-role-of-soluble-epoxide-hydrolase-enzyme-on-daunorubicin-mediated-cardiotoxicity
#18
Zaid H Maayah, Ghada Abdelhamid, Osama H Elshenawy, Ahmed A El-Sherbeni, Hassan N Althurwi, Erica McGinn, Doaa Dawood, Ahmad H Alammari, Ayman O S El-Kadi
Several studies have demonstrated the role of cytochrome P450 (CYP) and its associated arachidonic acid (AA) metabolites in the anthracyclines-induced cardiac toxicity. However, the ability of daunorubicin (DNR) to induce cardiotoxicity through the modulation of CYP and its associated AA metabolites has not been investigated yet. Therefore, we hypothesized that DNR-induced cardiotoxicity is mediated through the induction of cardiotoxic hydroxyeicosatetraenoic acids and/or the inhibition of cardioprotctive epoxyeicosatrienoic acids (EETs)...
December 1, 2017: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/29193961/chemical-proteomics-reveals-soluble-epoxide-hydrolase-as-a-therapeutic-target-for-ocular-neovascularization
#19
Rania S Sulaiman, Bomina Park, Sardar Pasha Sheik Pran Babu, Yubing Si, Rakshin Kharwadkar, Sayak K Mitter, Bit Lee, Wei Sun, Xiaoping Qi, Michael E Boulton, Samy O Meroueh, Xiang Fei, Seung-Yong Seo, Timothy W Corson
The standard-of-care therapeutics for the treatment of ocular neovascular diseases like wet age-related macular degeneration (AMD) are biologics targeting vascular endothelial growth factor signaling. There are currently no FDA approved small molecules for treating these blinding eye diseases. Therefore, therapeutic agents with novel mechanisms are critical to complement or combine with existing approaches. Here, we identified soluble epoxide hydrolase (sEH), a key enzyme for epoxy fatty acid metabolism, as a target of an antiangiogenic homoisoflavonoid, SH-11037...
December 1, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29178914/genetic-deletion-or-pharmacological-inhibition-of-soluble-epoxide-hydrolase-reduces-brain-damage-and-attenuates-neuroinflammation-after-intracerebral-hemorrhage
#20
Chun-Hu Wu, Song-Kun Shyue, Tai-Ho Hung, Shin Wen, Chao-Chang Lin, Che-Feng Chang, Szu-Fu Chen
BACKGROUND: Inflammatory responses significantly contribute to neuronal damage and poor functional outcomes following intracerebral hemorrhage (ICH). Soluble epoxide hydrolase (sEH) is known to induce neuroinflammatory responses via degradation of anti-inflammatory epoxyeicosatrienoic acids (EET), and sEH is upregulated in response to brain injury. The present study investigated the involvement of sEH in ICH-induced neuroinflammation, brain damage, and functional deficits using a mouse ICH model and microglial cultures...
November 25, 2017: Journal of Neuroinflammation
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