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G Proietti, K K Abelak, D Bishop-Bailey, A Macchiarulo, I Nobeli
An experimentally determined structure for human CYP2J2-a member of the cytochrome P450 family with significant and diverse roles across a number of tissues-does not yet exist. Our understanding of how CYP2J2 accommodates its cognate substrates and how it might be inhibited by other ligands thus relies on our ability to computationally predict such interactions using modelling techniques. In this study we present a computational investigation of the binding of arachidonic acid (AA) to CYP2J2 using homology modelling, induced fit docking (IFD) and molecular dynamics (MD) simulations...
November 2016: Journal of Molecular Modeling
Marco Sisignano, Carlo Angioni, Chul-Kyu Park, Sascha Meyer Dos Santos, Holger Jordan, Maria Kuzikov, Di Liu, Sebastian Zinn, Stephan W Hohman, Yannick Schreiber, Béla Zimmer, Mike Schmidt, Ruirui Lu, Jing Suo, Dong-Dong Zhang, Stephan M G Schäfer, Martine Hofmann, Ajay S Yekkirala, Natasja de Bruin, Michael J Parnham, Clifford J Woolf, Ru-Rong Ji, Klaus Scholich, Gerd Geisslinger
Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
Sarah E Allison, Yongjuan Chen, Nenad Petrovic, Stefanie Zimmermann, Bjoern Moosmann, Mirko Jansch, Pei H Cui, Colin R Dunstan, Peter I Mackenzie, Michael Murray
Secondary metastases are the leading cause of mortality in patients with breast cancer. Cytochrome P450 (CYP) 2J2 (CYP2J2) is upregulated in many human tumors and generates epoxyeicosanoids from arachidonic acid that promote tumorigenesis and metastasis, but at present there is little information on the genes that mediate these actions. In this study MDA-MB-468 breast cancer cells were stably transfected with CYP2J2 (MDA-2J2 cells) and Affymetrix microarray profiling was undertaken. We identified 182 genes that were differentially expressed in MDA-2J2 cells relative to control (MDA-CTL) cells (log[fold of control] ≥2)...
October 5, 2016: International Journal of Biochemistry & Cell Biology
Katerina Cizkova, Jana Steigerova, Jan Gursky, Jiri Ehrmann
BACKGROUND: Fibrates are widely used hypolipidemic drugs, which serve as ligand of peroxisome proliferator-activated receptor α (PPARα). Recently, they have also been considered as potential anticancer agents. We studied effect of fibrates treatment on cell proliferation, expression of CYP2J2 and concomitant changes in expression of cell cycle regulatory proteins in three different human cell lines: HEK293, HepG2, and HT-29. METHODS: We used WST-1 viability test, western blot and immunocytochemistry for detection of proteins of interests and analysis of cell cycle...
2016: Lipids in Health and Disease
Yunxia Zhao, Ye Hou, Fei Liu, An Liu, Lu Jing, Changzhi Zhao, Yu Luan, Yuanxin Miao, Shuhong Zhao, Xinyun Li
Feed efficiency (FE) is essential for pig production. In this study, 300 significantly differentially expressed (DE) transcripts, including 232 annotated genes, 28 cis- natural antisense transcripts (cis-NATs), and 40 lncRNAs, were identified between the liver of Yorkshire pigs with extremely high and low FE. Among these transcripts, 25 DE lncRNAs were significantly correlated with 125 DE annotated genes at a transcriptional level. These DE genes were primarily enriched in Vitamin A (VA), fatty acid, and steroid hormone metabolism...
September 15, 2016: G3: Genes—Genomes—Genetics
Chi Zhou, Jin Huang, Junxiong Chen, Jinsheng Lai, Fasheng Zhu, Xizhen Xu, Dao Wen Wang
BACKGROUND: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids (AA) to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the treatment of cardiovascular diseases, but little is known about its role on adventitial remodeling. METHODS: We used C57BL/6J mice in vivo and primary rat adventitial fibroblasts (AFs) in vitro treated with Angiotensin II to investigate the effects of CYP2J2 gene delivery and exogenous EETs administration on adventitial remodeling...
2016: Cellular Physiology and Biochemistry
Bei Wang, Hesong Zeng, Zheng Wen, Chen Chen, Dao Wen Wang
Cytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5'-AMP-activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1...
October 2016: Aging Cell
Shuang Geng, Yutong Wang, Yongmei Sun, Jinfeng Li, Honglei Yin, Zhilei Zeng, Xiaopeng Yang, Yuzhen Zhang, Yunliang Wang
AIMS: To investigate the impact of PPAR -γ and CYP2J2 gene single nucleotide polymorphisms (SNPs) and gene- gene interactions on late-onset Alzheimer's disease (LOAD) risk in Chinese Han population. METHODS: A total of 880 participants (514 males, 366 females), with a mean age of 81.7±15.9years old are selected, including 430 LOAD patients and 450 normal participants. Generalized multifactor dimensionality reduction (GMDR) is used to examine interaction among six SNPs, odds ratio (OR) and 95% confident interval (95%CI) are calculated by Logistic regression model...
July 7, 2016: Behavioural Brain Research
Michael Murray
Polyunsaturated fatty acids (PUFAs) undergo cytochrome P450 (CYP)-dependent oxidation to epoxides that modulate important physiological functions, including vasoactivity, inflammation, nociception, proliferation and viability. One of the most important human CYP epoxygenases is human CYP2J2 that is widely expressed in tissues, especially heart, vascular smooth muscle, salivary glands and placenta. Recent studies have shown that overexpression of CYP2J2 in vivo reverses several pathological processes in animals, including hypertension and other cardiovascular pathologies and insulin resistance...
August 2016: Drug Metabolism Reviews
Nicholas I Mundy, Jessica Stapley, Clair Bennison, Rachel Tucker, Hanlu Twyman, Kang-Wook Kim, Terry Burke, Tim R Birkhead, Staffan Andersson, Jon Slate
Bright-red colors in vertebrates are commonly involved in sexual, social, and interspecific signaling [1-8] and are largely produced by ketocarotenoid pigments. In land birds, ketocarotenoids such as astaxanthin are usually metabolically derived via ketolation of dietary yellow carotenoids [9, 10]. However, the molecular basis of this gene-environment mechanism has remained obscure. Here we use the yellowbeak mutation in the zebra finch (Taeniopygia guttata) to investigate the genetic basis of red coloration...
June 6, 2016: Current Biology: CB
Lukasz Przybyl, Nadine Haase, Michaela Golic, Julianna Rugor, Maria Emilia Solano, Petra Clara Arck, Martin Gauster, Berthold Huppertz, Christoph Emontzpohl, Christian Stoppe, Jürgen Bernhagen, Lin Leng, Richard Bucala, Herbert Schulz, Arnd Heuser, M Susanne Weedon-Fekjær, Guro M Johnsen, Dirk Peetz, Friedrich C Luft, Anne Cathrine Staff, Dominik N Müller, Ralf Dechend, Florian Herse
RATIONALE: We hypothesized that cluster of differentiation 74 (CD74) downregulation on placental macrophages, leading to altered macrophage-trophoblast interaction, is involved in preeclampsia. OBJECTIVE: Preeclamptic pregnancies feature hypertension, proteinuria, and placental anomalies. Feto-placental macrophages regulate villous trophoblast differentiation during placental development. Disturbance of this well-balanced regulation can lead to pathological pregnancies...
June 24, 2016: Circulation Research
Francesco Dalle Vedove, Cristiano Fava, Houli Jiang, Giovanni Zanconato, John Quilley, Matteo Brunelli, Valeria Guglielmi, Gaetano Vattemi, Pietro Minuz
BACKGROUND: Epoxyeicosatrienoic acids (EETs) derived from cytochrome P450 (CYP)-dependent metabolism of arachidonic acid are increased in the plasma of women with preeclampsia as compared with normal pregnancy and are significantly higher in fetal than in maternal plasma and erythrocytes. We hypothesized that differences in EET synthesis or metabolism in the feto-placental unit contributed to the observed differences in circulating EETs. METHOD: To evaluate EETs, formation as well as the expression of relevant CYP isoforms and the metabolizing enzyme, soluble epoxide hydrolase (sEH), biopsies of placenta were collected from 19 normal pregnancy and 10 preeclampsia at the time of cesarean section delivery...
July 2016: Journal of Hypertension
Vyvyca J Walker, Alisha P Griffin, Dagan K Hammar, Paul F Hollenberg
According to the Centers for Disease Control and Prevention, the incidence of inflammatory bowel diseases (IBD) is about 1 in 250 people in the United States. The disease is characterized by chronic or recurring inflammation of the gut. Because of the localization of the endocannabinoid system in the gastrointestinal tract, it may be a potential pharmacologic target for the treatment of IBD and other diseases. Fatty acid amide hydrolase (FAAH) is a potential candidate because it is upregulated in IBD. FAAH hydrolyzes and, as a consequence, inactivates anandamide (AEA), a prominent endocannabinoid...
June 2016: Journal of Pharmacology and Experimental Therapeutics
Aneesh Karkhanis, Hui Yuan Lam, Gopalakrishnan Venkatesan, Siew Kwan Koh, Christina Li Lin Chai, Lei Zhou, Yanjun Hong, Pipin Kojodjojo, Eric Chun Yong Chan
Dronedarone, a multiple ion channel blocker is prescribed for the treatment of paroxysmal and persistent atrial fibrillation. While dronedarone does not precipitate toxicities like its predecessor amiodarone, its clinical use has been associated with idiosyncratic hepatic and cardiac adverse effects and drug-drug interactions (DDIs). As dronedarone is a potent mechanism-based inactivator of CYP3A4 and CYP3A5, a question arose if it exerts a similar inhibitory effect on CYP2J2, a prominent cardiac CYP450 enzyme...
May 1, 2016: Biochemical Pharmacology
Jia Jia, Catherine M Davis, Wenri Zhang, Matthew L Edin, Sari Jouihan, Taiping Jia, J Alyce Bradbury, Joan P Graves, Laura M DeGraff, Craig R Lee, Oline Ronnekleiv, Ruikang Wang, Yun Xu, Darryl C Zeldin, Nabil J Alkayed
OBJECTIVE: Cytochrome P450 epoxygenases (CYP) metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), which exhibit vasodilatory, anti-inflammatory and neuroprotective actions in experimental cerebral ischemia. We evaluated the effect of endothelial-specific CYP overexpression on cerebral blood flow, inflammatory cytokine expression and tissue infarction after focal cerebral ischemia in transgenic mice. APPROACH AND RESULTS: Male and female wild-type and transgenic mice overexpressing either human CYP2J2 or CYP2C8 epoxygenases in vascular endothelium under control of the Tie2 promoter (Tie2-CYP2J2 and Tie2-CYP2C8) were subjected to 60-min middle cerebral artery occlusion (MCAO)...
May 2016: Experimental Neurology
Wanjun Liu, Tao Wang, Xingwei He, Xintian Liu, Bei Wang, Yujian Liu, Zhuxi Li, Rong Tan, Chen Ding, Hongjie Wang, Hesong Zeng
AIMS: The aim of the present study was to investigate how cytochrome P450 (CYP)2J2-derived epoxyeicosatrienoic acids (EETs) regulate the AKT1 and FOXO1 and BIM pathway and protect against endothelial apoptosis in the development and progression of atherosclerosis. METHODS AND RESULTS: Recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression increased EET levels and prevented high-fat diet-induced atherosclerosis in ApoE mice, which was associated with reduced vascular apoptosis...
June 2016: Journal of Cardiovascular Pharmacology
Reni Tzveova, Galya Naydenova, Teodora Yaneva, Georgi Dimitrov, Silviya Vandeva, Yoanna Matrozova, Diana Pendicheva-Duhlenska, Ivan Popov, Olga Beltheva, Cyrill Naydenov, Rumiana Tarnovska-Kadreva, Gencho Nachev, Vanio Mitev, Radka Kaneva
We conducted a case-control study to determine the contribution of polymorphisms in CYP2C8 (CYP2C8*3) and CYP2J2 (CYP2J2*7) to increased risk of coronary artery disease and essential hypertension in Bulgarians. The current analysis included 192 unrelated hypertensive patients, 261 patients with angiographically documented CAD (153 with myocardial infarction and 108 without myocardial infarction), and 496 population controls. The CYP2C8*3 and CYP2J2*7 polymorphisms were genotyped by TaqMan SNP Genotyping Assay...
December 2015: Biochemical Genetics
Lisa Plucinski, Manas Ranjan Gartia, William R Arnold, Abid Ameen, Te-Wei Chang, Austin Hsiao, Gang Logan Liu, Aditi Das
Cytochrome P450s are the primary enzymes involved in phase I drug metabolism. They are an important target for early drug discovery research. However, high-throughput drug screening of P450s is limited by poor protein stability and lack of consistent measurement of binding events. Here we present the detection of substrate binding to cytochrome P450-2J2 (CYP2J2), the predominant P450 in the human heart, using a combination of Nanodisc technology and a nanohole plasmonic sensor called nanoplasmonic Lycurgus cup array (nanoLCA)...
January 15, 2016: Biosensors & Bioelectronics
Ann K Daly
Associations of cytochrome P450 (CYP) polymorphisms with risk of disease development have been reported widely. For lung cancer, a large number of studies on CYP1A1, CYP2D6, and CYP2A6 polymorphisms have been performed. However, recent studies, including meta-analyses and genome-wide association studies, suggest that only the CYP2A6 association, where genotypes associated with low activity decrease susceptibility possibly due to slower nicotine metabolism, appears significant. Associations with lung cancer susceptibility have also been reported for CYP1A2, CYP1B1, and CYP2E1 polymorphisms but these, though biologically plausible, have not been well replicated...
2015: Advances in Pharmacology
Daniel R McDougle, Javier L Baylon, Daryl D Meling, Amogh Kambalyal, Yelena V Grinkova, Jared Hammernik, Emad Tajkhorshid, Aditi Das
CYP2J2 epoxygenase is an extrahepatic, membrane bound cytochrome P450 (CYP) that is primarily found in the heart and mediates endogenous fatty acid metabolism. CYP2J2 interacts with membranes through an N-terminal anchor and various non-contiguous hydrophobic residues. The molecular details of the motifs that mediate membrane interactions are complex and not fully understood. To gain better insights of these complex protein-lipid interactions, we employed molecular dynamics (MD) simulations using a highly mobile membrane mimetic (HMMM) model that enabled multiple independent spontaneous membrane binding events to be captured...
October 2015: Biochimica et Biophysica Acta
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