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Epoxide hydrolase

Babak Behnam Azad, Daniel P Holt, Hayden T Ravert, Andrew G Horti, Robert F Dannals
In this concise practitioner protocol, the radiochemical synthesis of [18 F]FNDP suitable for human PET studies is described and the results from validation productions are presented. The high specific activity radiotracer product is prepared as a sterile, apyrogenic solution that conforms to current Good Manufacturing Practice (cGMP) requirements.
March 12, 2018: Journal of Labelled Compounds & Radiopharmaceuticals
Věra Čertíková Chábová, Petr Kujal, Petra Škaroupková, Zdeňka Varňourková, Šárka Vacková, Zuzana Husková, Soňa Kikerlová, Janusz Sadowski, Elzbieta Kompanowska-Jezierska, Iwona Baranowska, Sung Hee Hwang, Bruce D Hammock, John D Imig, Vladimír Tesař, Ludek Červenka
BACKGROUND/AIMS: We found recently that increasing renal epoxyeicosatrienoic acids (EETs) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, shows renoprotective actions and retards the progression of chronic kidney disease (CKD) in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX). This prompted us to examine if additional protection is provided when sEH inhibitor is added to the standard renin-angiotensin system (RAS) blockade, specifically in rats with established CKD...
March 6, 2018: Kidney & Blood Pressure Research
P Kala, L Sedláková, P Škaroupková, L Kopkan, Z Vaňourková, M Táborský, A Nishiyama, S H Hwang, B D Hammock, J Sadowski, V Melenovský, J D Imig, L Červenka
We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR...
March 12, 2018: Physiological Research
Arun Bahadur Gurung, Bishwarjit Mayengbam, Atanu Bhattacharjee
Soluble epoxide hydrolase (sEH), a key enzyme belonging to cytochrome P450 pathway of arachidonic acid cascade is a novel therapeutic drug target against atherosclerosis. The enzyme breaks down epoxyeicosatrienoic acid (EETs) to dihydroxy-eicosatrienoic acids (DHETs) and reduces beneficial cardiovascular properties of EETs. Thus, the present work is aimed at identification of potential leads as sEH inhibitors which will sustain the beneficial properties of EETs in vivo. PubChem and ZINC databases were screened for drug-like compounds based on Lipinski's rule of five and in silico toxicity filters...
March 6, 2018: Computational Biology and Chemistry
Pearl Z Fernandes, Marija Petricevic, Lukasz Sobala, Gideon J Davies, Spencer John Williams
Endo-α-1,2-mannosidases and -mannanases, members of glycoside hydrolase family 99 (GH99), cleave α-Glc/Man-1,3-α-Man-OR structures within mammalian N-linked glycans and fungal α-mannan, respectively. They are proposed to act through a two-step mechanism involving a 1,2-anhydrosugar 'epoxide' intermediate, involving two conserved catalytic residues. In the first step Glu333 acts as general base to deprotonate the 2-hydroxyl group adjacent to the fissile glycosidic bond, while Glu336 provides general acid assistance to departure of the aglycon...
March 5, 2018: Chemistry: a European Journal
Marta Martins, Ana Silva, Maria H Costa, Célia Miguel, Pedro M Costa
Addressing the risk of mixed carcinogens in vivo under environmentally-realistic scenarios is still a challenge. Searching for adequate biomarkers of exposure requires understanding molecular pathways and their connection with neoplasia-related benchmark pathologies. Subjecting the zebrafish model to realistic concentrations of two genotoxicants and carcinogens, cadmium and benzo[a]pyrene, isolated and combined, yielded low levels of DNA damage. Altogether, the organisms' mechanisms of DNA repair, oxidative stress and phases I and II were not overwhelmed after two weeks of treatment...
February 26, 2018: Scientific Reports
Jan Madacki, Françoise Laval, Anna Grzegorzewicz, Anne Lemassu, Monika Záhorszká, Michael Arand, Michael McNeil, Mamadou Daffé, Mary Jackson, Marie-Antoinette Lanéelle, Jana Korduláková
Mycolic acids are the hallmark of the cell envelope in mycobacteria, which include the important human pathogens Mycobacterium tuberculosis and M. leprae Mycolic acids are very long C60-C90 α-alkyl β-hydroxy fatty acids having a variety of functional groups on their hydrocarbon chain that define several mycolate types. Mycobacteria also produce an unusually large number of putative epoxide hydrolases, but the physiological functions of these enzymes are still unclear. Here, we report that the mycobacterial epoxide hydrolase EphD is involved in mycolic acid metabolism...
February 22, 2018: Journal of Biological Chemistry
Haruto Yamanashi, William E Boeglin, Christophe Morisseau, Robert W Davis, Gary A Sulikowski, Bruce D Hammock, Alan R Brash
Lipoxygenase-catalyzed oxidation of the essential fatty acid linoleate represents a vital step in construction of the mammalian epidermal permeability barrier. Analysis of epidermal lipids indicates the linoleate is converted to a trihydroxy derivative by hydrolysis of an epoxy-hydroxy precursor. We evaluated different epoxide hydrolase (EH) enzymes in the hydrolysis of skin-relevant fatty acid epoxides and compared the products to those of acid-catalyzed hydrolysis. In the absence of enzyme, exposure to pH 5 or pH 6 at 37 deg C for 30 min hydrolyzed fatty acid allylic epoxyalcohols to four trihydroxy products...
February 19, 2018: Journal of Lipid Research
Jang Hoon Kim, In Sook Cho, Jaihyuk Ryu, Ji Sun Lee, Jong Seong Kang, Si Yong Kang, Young Ho Kim
Anthocyanin derivatives are well-known secondary constituents contained in fruits. The inhibitory activity of anthocyanin derivatives toward soluble epoxide hydrolase (sEH) was tested for potential applications in the treatment of cardiovascular diseases. Anthocyanin derivatives 1-5 showed dose-dependent inhibitory activity toward sEH, with IC 50 values ranging from 4.3 ± 0.2 to 25.3 ± 2.6 μM. Lineweaver-Burk plots showed that all anthocyanin derivatives preferentially interacted with allosteric sites instead of active sites as noncompetitive (1-3) and mixed (4 and 5) inhibitors...
February 12, 2018: International Journal of Biological Macromolecules
Julian Zaugg, Yosephine Gumulya, Mikael Boden, Alan Edward Mark, Alpeshkumar K Malde
Molecular dynamics simulations and free energy calculations have been used to investigate the effect of ligand binding on the enantioselectivity of an epoxide hydrolase (EH) from Aspergillus niger. Despite sharing a common mechanism, a wide range of alternative mechanisms have been proposed to explain the origin of enantiomeric selectivity in EHs. By comparing the interactions of (R)- and (S)-glycidyl phenyl ether (GPE) with both the wild type (WT, E = 3) and a mutant showing enhanced enantioselectivity to GPE (LW202, E = 193) we have examined whether enantioselectivity is due to differences in the binding pose, the affinity for the (R)- or (S)- enantiomers or a kinetic effect...
February 9, 2018: Journal of Chemical Information and Modeling
Tien Jen Lin, Wilfried J J Karmaus, Mei Lien Chen, Jiin Chyr Hsu, I Jen Wang
PURPOSE: Bisphenol A (BPA) exposure may increase the risk of asthma. Genetic polymorphisms of oxidative stress-related genes, glutathione S-transferases (GSTM1, GSTP1), manganese superoxide dismutase, catalase, myeloperoxidase, and microsomal epoxide hydrolase may be related to BPA exposure. The aim is to evaluate whether oxidative stress genes modulates associations of BPA exposure with asthma. METHODS: We conducted a case-control study comprised of 126 asthmatic children and 327 controls...
March 2018: Allergy, Asthma & Immunology Research
W Swardfager, M Hennebelle, D Yu, B D Hammock, A J Levitt, K Hashimoto, A Y Taha
The common and severe psychiatric disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are associated with inflammation, oxidative stress and changes in peripheral and brain lipid metabolism. Those pathways are implicated in the premature development of vascular and metabolic comorbidities, which account for considerable morbidity and mortality, including increased dementia risk. During endoplasmic reticulum stress, the soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory fatty acid epoxides generated by cytochrome p450 enzymes into their corresponding and generally less anti-inflammatory, or even pro-inflammatory, diols, slowing the resolution of inflammation...
February 2, 2018: Neuroscience and Biobehavioral Reviews
Sean D Kodani, Saavan Bhakta, Sung Hee Hwang, Svetlana Pakhomova, Marcia E Newcomer, Christophe Morisseau, Bruce D Hammock
Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described herein initially started with t-TUCB (trans-4-[4-(3-trifluoromethoxyphenyl-l-ureido)-cyclohexyloxy]-benzoic acid), a potent sEH inhibitor that was previously shown to weakly inhibit FAAH...
January 4, 2018: Bioorganic & Medicinal Chemistry Letters
Amy A Rand, Patrick O Helmer, Bora Inceoglu, Bruce D Hammock, Christophe Morisseau
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a useful tool to characterize the behavior of natural lipids within biological matrices. We report a LC-MS/MS method developed specifically to analyze CYP products of the arachidonoyl ethanolamide (anandamide, AEA), the epoxyeicosatrienoic acid ethanolamides (EET-EAs) and their hydrolyzed metabolites, and the dihydroxyeicosatrienoic acid ethanolamides (DHET-EAs). This method was used to measure EET-EA biotransformation to DHET-EAs by two human epoxide hydrolases: the soluble EH (sEH) and the microsomal EH (mEH)...
2018: Methods in Molecular Biology
Hae-Seon Kim, Sun Ho Cha, Ho Young Suk, Nyun-Ho Park, Jung-Hee Woo
Sphingorhabdus sp. YGSMI21 is a novel strain exhibiting high enantioselective hydrolysis activity for styrene oxide. Here, we present its complete genome sequence, consisting of one circular chromosome (3.86 Mb) and one plasmid (0.196 Mb).
January 18, 2018: Genome Announcements
Idil Bastan, Xiao Na Ge, Mythili Dileepan, Yana G Greenberg, Alonso G Guedes, Sung Hee Hwang, Bruce D Hammock, Robert J Washabau, Savita P Rao, P Sriramarao
Prevalence of food allergies in the United States is on the rise. Eosinophils are recruited to the intestinal mucosa in substantial numbers in food allergen-driven gastrointestinal (GI) inflammation. Soluble epoxide hydrolase (sEH) is known to play a pro-inflammatory role during inflammation by metabolizing anti-inflammatory epoxyeicosatrienoic acids (EETs) to pro-inflammatory diols. We investigated the role of sEH in a murine model of food allergy and evaluated the potential therapeutic effect of a highly selective sEH inhibitor (trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]-cyclohexyloxy}-benzoic acid [t-TUCB])...
January 17, 2018: Journal of Leukocyte Biology
Mark Howard Barley, Nicholas J Turner, Royston Goodacre
The ability to model the activity of a protein using Quantitative Structure Activity Relationships (QSAR) requires descriptors for the 20 naturally coded amino acids. In this work we show that by modifying some established descriptors we were able to model the activity data of 140 mutants of the enzyme epoxide hydrolase with improved accuracy. These new descriptors (referred to as Physical descriptors) also gave very good results when tested against a series of four dipeptide datasets. The Physical descriptors encode the amino acids using only two orthogonal scales: the first is strongly linked to hydrophillicity/hydrophobicity, and the second to the volume of the amino acid residue...
January 16, 2018: Journal of Chemical Information and Modeling
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
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
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
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