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K Cizkova, Z Tauber
CYP2C and CYP2 J enzymes, commonly named as cytochrome P450 (CYP) epoxygenases, convert arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs), biologically active eicosanoids with many functions in organism. EETs are rapidly hydrolysed to less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). We investigated spatio-temporal expression pattern of CYP2C8, CYP2C9, CYP2 J2 and sEH in normal human placenta by immunohistochemical method. In the villous trophoblast, CYP2C8 was the most abundant protein...
June 13, 2018: Acta Histochemica
Anita Matic, Ivana Jukic, Ana Stupin, Lidija Baric, Zrinka Mihaljevic, Sanela Unfirer, Ivana Tartaro Bujak, Branka Mihaljevic, Julian H Lombard, Ines Drenjancevic
The goal of this study was to examine the effect of 1-week of high salt (HS) intake and the role of oxidative stress in changing the mechanisms of flow-induced dilation (FID) in isolated pressurized middle cerebral arteries (MCA) of male Sprague-Dawley rats (N=15-16/per group). Reduced FID in the HS group was restored by intake of the superoxide scavenger TEMPOL (HS+TEMPOL in vivo group). Nitric oxide synthases (NOS) inhibitor Nω -nitro-L-arginine methyl ester (L-NAME), COX inhibitor indomethacin (INDO) and selective inhibitor of microsomal CYP450 epoxidase activity N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) significantly reduced FID in the LS group, while FID in the HS group was mediated by NO only...
June 15, 2018: American Journal of Physiology. Heart and Circulatory Physiology
M H Napimoga, E P Rocha, C A Trindade-da-Silva, A P D Demasi, E F Martinez, C G Macedo, H B Abdalla, A Bettaieb, F G Haj, J T Clemente-Napimoga, B Inceoglu, B D Hammock
BACKGROUND AND OBJECTIVE: Soluble epoxide hydrolase (sEH) is an enzyme in the arachidonate cascade which converts epoxy fatty acids (EpFAs), such as epoxyeicosatrienoic acids (EETs) produced by cytochrome P450 enzymes, to dihydroxy-eicosatrienoic acids. In the last 20 years with the development of inhibitors to sEH it has been possible to increase the levels of EETs and other EpFAs in in vivo models. Recently, studies have shown that EETs play a key role in blocking inflammation in a bone resorption process, but the mechanism is not clear...
May 31, 2018: Journal of Periodontal Research
Jiong Hu, Timo Frömel, Ingrid Fleming
Angiogenesis and inflammation are hallmarks of cancer. Arachidonic acid and other polyunsaturated fatty acids (PUFAs) are primarily metabolized by three distinct enzymatic systems initiated by cyclooxygenases, lipoxygenases, and cytochrome P450 enzymes (CYP) to generate bioactive eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acids, and epoxyeicosatrienoic acids. As some of the PUFA metabolites playing essential roles in inflammatory processes, these pathways have been widely studied as therapeutic targets of inflammation...
May 28, 2018: Cancer Metastasis Reviews
M Hamzaoui, D Guerrot, Z Djerada, T Duflot, V Richard, J Bellien
Cardiovascular events are more prevalent in chronic kidney disease than in the general population, being the main cause of morbi-mortality. The physiopathology explaining this association remains complex. Thus, research for new therapies to prevent cardiovascular events in chronic kidney disease is a major issue. Epoxyeicosatrienoic acids, products of the arachidonic acid metabolism, are endothelium-derived hyperpolarizing factors with vasodilatory, anti-inflammatory, thrombolytic, pro-angiogenic and anti-apoptotic properties...
May 21, 2018: Annales de Cardiologie et D'angéiologie
Joseph Schragenheim, Lars Bellner, Jian Cao, Shailendra P Singh, David Bamshad, John A McClung, Omri Maayan, Aliza Meissner, Ilana Grant, Charles T Stier, Nader G Abraham
BACKGROUND: We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on renal and adipose tissue function, in addition to its vasodilatory action; it increases insulin sensitivity and inhibits inflammation. In an examination of the signaling mechanisms by which EET reduces renal and peri-renal fat function, we hypothesized that EET ameliorates obesity-induced renal dysfunction by improving sodium excretion, reducing the sodium-chloride cotransporter NCC, lowering blood pressure, and enhancing mitochondrial and thermogenic gene levels in PGC-1α dependent mice...
May 19, 2018: Prostaglandins & Other Lipid Mediators
Sang Kyu Park, Anja Herrnreiter, Sandra L Pfister, Kathryn M Gauthier, Benjamin A Falck, John R Falck, William B Campbell
Endothelium-derived epoxyeicosatrienoic acids (EETs) have numerous vascular activities mediated by G protein--coupled receptors. Long-chain free fatty acids and EETs activate GPR40, prompting us to investigate the role of GPR40 in some vascular EET activities. 14,15-EET, 11,12-EET, arachidonic acid, and the GPR40 agonist GW9508 increase intracellular calcium concentrations in human GPR40-overexpressing HEK293 cells (EC50 = 0.58 ± 0.08 μM, 0.91 ± 0.08 μM, 3.9 ± 0.06 μM and 19 ± 0.37 nM, respectively)...
May 18, 2018: Journal of Biological Chemistry
Zhibo Gai, Michele Visentin, Ting Gui, Lin Zhao, Wolfgang E Thasler, Stephanie Hausler, Ivan Hartling, Alessio Cremonesi, Christian Hiller, Gerd A Kullak-Ublick
Inflammation has a recognized role in non-alcoholic fatty liver disease (NAFLD) progression. The present work studied the effect of high fat diet (HFD) on arachidonic acid metabolism in the liver and investigated the role of the farnesoid X receptor (FXR, NR1H4) in eicosanoid biosynthetic pathways and NF-kB signaling, major modulators of the inflammatory cascade. Mice were fed a HFD to induce NAFLD, then, treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue...
May 9, 2018: Molecular Pharmacology
Qian Wang, Yan Liang, Yingjin Qiao, Xiangya Zhao, Yi Yang, Shengnan Yang, Bing Li, Qianru Zhao, Ling Dong, Songxia Quan, Rui Tian, Zhangsuo Liu
Tubulointerstitial inflammatory cell infiltration and activation contribute to kidney inflammation and fibrosis. Epoxyeicosatrienoic acids (EETs), which are rapidly metabolized to dihydroxyeicosatrienoic acids by the soluble epoxide hydrolase (sEH), have multiple biological functions, including vasodilation, anti-inflammatory action, and others. Inhibition of sEH has been demonstrated to attenuate inflammation in many renal disease models. However, the relationship between sEH expression and macrophage polarization in kidney remains unknown...
May 2, 2018: American Journal of Physiology. Renal Physiology
Ji Won Park, Choon-Myung Lee, Joan S Cheng, Edward T Morgan
Nitric oxide (NO) is an essential signaling molecule in the body, regulating numerous biological processes. Beside its physiological roles, NO affects drug metabolism by modulating the activity and/or expression of cytochrome P450 enzymes. Previously, our lab showed that NO generation caused by inflammatory stimuli results in CYP2B6 degradation via the ubiquitin-proteasome pathway. In the current study, we tested the NO-mediated regulation of CYP2J2 that metabolizes arachidonic acids to bioactive epoxyeicosatrienoic acids, as well as therapeutic drugs such as astemizole and ebastine...
June 2018: Free Radical Biology & Medicine
S P Singh, J A McClung, L Bellner, J Cao, M Waldman, J Schragenheim, M Arad, E Hochhauser, J R Falck, J A Weingarten, S J Peterson, N G Abraham
We have previously shown that an Epoxyeicosatrienoic Acid (EET) -agonist has pleiotropic effects and reverses cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that administration of an EET agonist would increase Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), which controls mitochondrial function and induction of HO-1 and negatively regulates the expression of the proinflammatory adipokines CCN3/NOV in cardiac and pericardial tissues...
2018: Cardiovascular Pharmacology: Open Access
Li-Ping Liu, Bin Li, Tian-Kui Shuai, Lei Zhu, Yu-Min Li
BACKGROUND: Recent studies reported that soluble epoxide hydrolase (sEH) plays an important role in lung diseases. However, the role of sEH in hyperoxia-induced ALI is unclear. METHODS: ALI was induced by exposure to 100% oxygen in an airtight cage for 72 h in wild-type (WT) and sEH gene deletion (EPHX2-/- ) mice. ALI was assessed by the lung dry/wet ratio, alveolar capillary protein leak, and the infiltration of inflammatory cells in the lung. RESULTS: Hyperoxia elevated sEH activity in WT mice...
April 27, 2018: BMC Anesthesiology
Meetal Satishkumar Solanki, Amy Pointon, Barry C Jones, Karl E Herbert
Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA) derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesised by cytochrome P450 2J2 (CYP2J2). The biological effects of EETs including its protective effects on inflammation and vasodilation are diverse due, in part, to their ability to act on a variety of cell types. In addition, CYP2J2 metabolises both exogenous and endogenous substrates and is involved in phase I metabolism of a variety of structurally diverse compounds including some antihistamines, anti-cancer agents and immunosuppressants...
April 25, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Metin Kasap, Huseyin Canaz, Gokhan Canaz, Mehmet Tokmak, Alper Bingul, Ibrahim Alatas
Objective: Our aim of this study was to determine effective doses of progesterone which has a vasodilatory effect during the early stage of vasospasm. Cerebral vasospasm (CV) is a predominant cause of morbidity and mortality which develops following subarachnoidal hemorrhage (SAH). Etiopathogenesis of CV is multifactorial. Despite many previously performed studies on this issue, the mechanism by which blood and blood products in the subarachnoidal space induce CV has not been clarified yet...
April 2018: Asian Journal of Neurosurgery
Haijing Sun, Patrick Lee, Chenxi Yan, Nan Gao, Jiemei Wang, Xianqun Fan, Fu-Shin Yu
EPHX2 (encoding soluble epoxide hydrolase [sEH]) converts biologically active epoxyeicosatrienoic acids (EETs), anti-inflammatory and profibrinolytic effectors, into the less biologically active metabolites, dihydroxyeicostrienoic acids. We sought to characterize the expression and the function of EPHX2 in diabetic corneas and during wound healing. The expression of EPHX2 at both mRNA and protein levels, as well as sEH enzymatic activity, was markedly upregulated in the tissues/cells, including corneal epithelial cells as well as the retina of human type 2 and mouse type 1 (streptozotocin [STZ] induced) and/or type 2 diabetes...
June 2018: Diabetes
Ranran Tu, Jillian Armstrong, Kin Sing Stephen Lee, Bruce D Hammock, Adam Sapirstein, Raymond C Koehler
Epoxyeicosatrienoic acids (EETs) are produced by cytochrome P450 epoxygenases from arachidonic acid, and their rapid metabolism is mainly through soluble epoxide hydrolase (sEH). EETs exert vasodilatory, anti-inflammatory, anti-apoptotic, and pro-angiogenic effects. Administration of sEH inhibitors before or at the onset of stroke is protective, but the effects of post-treatment at reperfusion, when inflammation is augmented, has not been as well studied. We tested the hypothesis that 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent and highly selective sEH inhibitor, suppresses inflammation and protects the brain when administered at reperfusion...
March 27, 2018: Scientific Reports
Yi-Er Qiu, Jun Qin, Yang Luo, Shao-Lan Qin, Yi-Fei Mu, Ran Cun, Hou-Li Jiang, Jian-Jun Chen, Min-Hao Yu, Ming Zhong
BACKGROUND: Previous preclinical evidence has suggested that the elevation of epoxyeicosatrienoic acids (EETs) derived from the cytochrome P450 (CYP) epoxygenases-dependent metabolism of arachidonic acid has important anti-inflammatory effects. However, the levels of EETs and their synthetic and metabolic enzymes in human ulcerative colitis has not been evaluated. METHOD: To evaluate EETs and the expression of relevant CYP isoforms and the metabolizing enzyme, soluble epoxide hydrolase (sEH), tissue biopsies were collected from 16 pairs of ulcerative colitis patients' tissues and matched with adjacent non-inflamed tissues...
May 2018: Prostaglandins & Other Lipid Mediators
Ping-Song Li, Wei Tao, Liu-Qing Yang, Yu-Sheng Shu
Hyperoxic acute lung injury is a serious complication of oxygen therapy that causes high mortality. Inhibition of soluble epoxide hydrolase (sEH) has been reported to have protective effect on lipopolysaccharide-induced acute lung injury (ALI). This study investigates whether sEH plays any role in the pathogenesis of hyperoxic ALI. Wild-type and sEH gene knockout (sEH-/- ) mice were exposed to 100% O2 for 72 h to induce hyperoxic ALI. Hyperoxia caused infiltration of inflammatory cells, elevation of interleukin-1β and interleukin-6 levels, and deterioration of alveolar capillary protein leak as well as wet/dry weight ratio in the lung...
March 24, 2018: Inflammation
Luděk Červenka, Zuzana Husková, Libor Kopkan, Soňa Kikerlová, Lenka Sedláková, Zdenka Vaňourková, Petra Alánová, František Kolář, Bruce D Hammock, Sung H Hwang, John D Imig, John R Falck, Janusz Sadowski, Elzbieta Kompanowska-Jezierska, Jan Neckář
OBJECTIVE: We examined the effects of treatment with soluble epoxide hydrolase inhibitor (sEHi) and epoxyeicosatrienoic acids (EETs) analogue (EET-A), given alone or combined, on blood pressure (BP) and ischemia/reperfusion myocardial injury in rats with angiotensin II (ANG II)-dependent hypertension. METHODS: Ren-2 transgenic rats (TGR) were used as a model of ANG II-dependent hypertension and Hannover Sprague-Dawley rats served as controls. Rats were treated for 14 days with sEHi or EET-A and BP was measured by radiotelemetry...
June 2018: Journal of Hypertension
Jun Wang, Mingyue Tan, Jifu Ge, Ping Zhang, Jie Zhong, Le Tao, Qiong Wang, Xuemei Tong, Jianxin Qiu
OBJECTIVES: Clear cell renal cell carcinoma (ccRCC) is characterized histologically by accumulation of cholesterol esters, cholesterol and other neutral lipids. Lysosomal acid lipase (LAL) is a critical enzyme involved in the cholesterol ester metabolism. Here, we sought to determine whether LAL could orchestrate metabolism of cholesterol esters in order to promote ccRCC progression. MATERIALS AND METHODS: Quantitative reverse-transcription PCR and western blots were conducted to assess the expression of LAL in human ccRCC tissues...
March 23, 2018: Cell Proliferation
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