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Differential cyclooxygenase expression levels and survival associations in type I and type II ovarian tumors.
Beeghly-Fadiel A, Wilson AJ, Keene S, El Ramahi M, Xu S, Marnett LJ, Fadare O, Crispens MA, Khabele D
(2018) J Ovarian Res 11: 17
MeSH Terms: Aged, Biomarkers, Tumor, Cyclooxygenase 1, Cyclooxygenase 2, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Middle Aged, Neoplasm Grading, Neoplasm Staging, Ovarian Neoplasms, Prognosis, Proportional Hazards Models, Prostaglandin-Endoperoxide Synthases
Show Abstract · Added March 21, 2018
BACKGROUND - High cyclooxygenase (COX)-2 expression in ovarian tumors has been associated with poor prognosis, but the role of COX-1 expression and its relation to survival is less clear. Here, we evaluated COX expression and associations with survival outcomes between type I (clear cell, mucinous, low grade endometrioid and low grade serous) and type II (high grade serous and high grade endometrioid) ovarian tumors.
METHODS - We developed and validated a new COX-1 antibody, and conducted immunohistochemical (IHC) staining for COX-1 and COX-2 on a tissue microarray (TMA) of 190 primary ovarian tumors. In addition to standard IHC scoring and H-scores to combine the percentage of positive cells and staining intensity, we also measured COX-1 and COX-2 mRNA expression by QPCR. High expression was defined as greater than or equal to median values. Clinical characteristics and disease outcomes were ascertained from medical records. Associations with disease-free survival (DFS) and overall survival (OS) were quantified by hazard ratios (HRs) and confidence intervals (CIs) from proportional hazards regression.
RESULTS - Type I tumors had high COX-2 expression, while type II tumors had high COX-1 expression. In multivariable adjusted regression models, higher COX-1 mRNA expression was associated with shorter DFS (HR: 6.37, 95% CI: 1.84-22.01) and OS (HR: 2.26, 95% CI: 1.04-4.91), while higher H-scores for COX-2 expression were associated with shorter DFS (HR: 1.92, 95% CI: 1.06-3.49). Stratified analysis indicated that COX-2 was significantly associated with DFS among cases with Type II tumors (HR: 1.93, 95% CI: 1.06-3.53).
CONCLUSIONS - These findings suggest that ovarian tumor type contributes to differences in COX expression levels and associations with survival.
0 Communities
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16 MeSH Terms
Dual cyclooxygenase-fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site.
Goodman MC, Xu S, Rouzer CA, Banerjee S, Ghebreselasie K, Migliore M, Piomelli D, Marnett LJ
(2018) J Biol Chem 293: 3028-3038
MeSH Terms: Amidohydrolases, Catalytic Domain, Cyclooxygenase Inhibitors, Isoenzymes, Phenylcarbamates, Phenylpropionates, Prostaglandin-Endoperoxide Synthases, Protein Binding, Stereoisomerism, Substrate Specificity
Show Abstract · Added April 22, 2018
The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H (PGH). COX-2 also oxygenates the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA) to the corresponding PGH analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy to counter this toxicity is to also inhibit fatty acid amide hydrolase (FAAH), which hydrolyzes bioactive fatty acid ethanolamides (FAEs) into fatty acids and ethanolamine. Here, we investigated the mechanism of COX inhibition by ARN2508, an NSAID that inhibits both COXs and FAAH with high potency, target selectivity, and decreased gastrointestinal toxicity in mouse models, presumably due to its ability to increase levels of FAEs. A 2.27-Å-resolution X-ray crystal structure of the COX-2·()-ARN2508 complex reveals that ARN2508 adopts a binding pose similar to that of its parent NSAID flurbiprofen. However, ARN2508's alkyl tail is inserted deep into the top channel, an active site region not exploited by any previously reported NSAID. As for flurbiprofen, ARN2508's potency is highly dependent on the configuration of the α-methyl group. Thus, ()-ARN2508 is more potent than ()-ARN2508 for inhibition of AA oxygenation by both COXs and 2-AG oxygenation by COX-2. Also, similarly to ()-flurbiprofen, ()-ARN2508 exhibits substrate selectivity for inhibition of 2-AG oxygenation. Site-directed mutagenesis confirms the importance of insertion of the alkyl tail into the top channel for ()-ARN2508's potency and suggests a role for Ser-530 as a determinant of the inhibitor's slow rate of inhibition compared with that of ()-flurbiprofen.
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10 MeSH Terms
Isolevuglandins as a gauge of lipid peroxidation in human tumors.
Yan HP, Roberts LJ, Davies SS, Pohlmann P, Parl FF, Estes S, Maeng J, Parker B, Mernaugh R
(2017) Free Radic Biol Med 106: 62-68
MeSH Terms: Antibodies, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Free Radicals, Humans, Lipid Peroxidation, Neoplasms, Oxidative Stress, Phospholipids, Prostaglandin-Endoperoxide Synthases, Prostaglandins E, Reactive Oxygen Species
Show Abstract · Added July 17, 2019
The cellular production of free radicals or reactive oxygen species (ROS) can lead to protein, lipid or DNA modifications and tumor formation. The cellular lipids undergo structural changes through the actions of enzymes (e.g. cyclooxygenases) or free radicals to form a class of compounds called Isolevuglandins (IsoLGs). The recruitment and continued exposure of tissue to ROS and IsoLGs causes increased cell proliferation, mutagenesis, loss of normal cell function and angiogenesis. The elevated concentration of ROS in cancerous tissues suggests that these mediators play an important role in cancer development. We hypothesized that tumors with elevated ROS levels would similarly possess an increased concentration of IsoLGs when compared with normal tissue. Using D11, an ScFv recombinant antibody specific for IsoLGs, we utilized immunohistochemistry to visualize the presence of IsoLG in human tumors compared to normal adjacent tissue (NAT) to the same tumor. We found that IsoLG concentrations were elevated in human breast, colon, kidney, liver, lung, pancreatic and tongue tumor cells when compared to NAT and believe that IsoLGs can be used as a gauge indicative of lipid peroxidation in tumors.
Copyright © 2017 Elsevier Inc. All rights reserved.
1 Communities
1 Members
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MeSH Terms
13-Methylarachidonic acid is a positive allosteric modulator of endocannabinoid oxygenation by cyclooxygenase.
Kudalkar SN, Nikas SP, Kingsley PJ, Xu S, Galligan JJ, Rouzer CA, Banerjee S, Ji L, Eno MR, Makriyannis A, Marnett LJ
(2015) J Biol Chem 290: 7897-909
MeSH Terms: Allosteric Regulation, Arachidonic Acids, Endocannabinoids, Kinetics, Oxygen, Prostaglandin-Endoperoxide Synthases
Show Abstract · Added February 22, 2016
Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid (AA) and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonylethanolamide to prostaglandins, prostaglandin glyceryl esters, and prostaglandin ethanolamides, respectively. A structural homodimer, COX-2 acts as a conformational heterodimer with a catalytic and an allosteric monomer. Prior studies have demonstrated substrate-selective negative allosteric regulation of 2-AG oxygenation. Here we describe AM-8138 (13(S)-methylarachidonic acid), a substrate-selective allosteric potentiator that augments 2-AG oxygenation by up to 3.5-fold with no effect on AA oxygenation. In the crystal structure of an AM-8138·COX-2 complex, AM-8138 adopts a conformation similar to the unproductive conformation of AA in the substrate binding site. Kinetic analysis suggests that binding of AM-8138 to the allosteric monomer of COX-2 increases 2-AG oxygenation by increasing kcat and preventing inhibitory binding of 2-AG. AM-8138 restored the activity of COX-2 mutants that exhibited very poor 2-AG oxygenating activity and increased the activity of COX-1 toward 2-AG. Competition of AM-8138 for the allosteric site prevented the inhibition of COX-2-dependent 2-AG oxygenation by substrate-selective inhibitors and blocked the inhibition of AA or 2-AG oxygenation by nonselective time-dependent inhibitors. AM-8138 selectively enhanced 2-AG oxygenation in intact RAW264.7 macrophage-like cells. Thus, AM-8138 is an important new tool compound for the exploration of allosteric modulation of COX enzymes and their role in endocannabinoid metabolism.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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6 MeSH Terms
The role of prostaglandins in allergic lung inflammation and asthma.
Claar D, Hartert TV, Peebles RS
(2015) Expert Rev Respir Med 9: 55-72
MeSH Terms: Animals, Asthma, Cyclooxygenase Inhibitors, Disease Models, Animal, Humans, Lung, Pneumonia, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Receptors, Prostaglandin, Respiratory Hypersensitivity, Signal Transduction
Show Abstract · Added January 20, 2015
Prostaglandins (PGs) are products of the COX pathway of arachidonic acid metabolism. There are five primary PGs, PGD₂, PGE₂, PGF₂, PGI₂ and thromboxane A₂, all of which signal through distinct seven transmembrane, G-protein coupled receptors. Some PGs may counteract the actions of others, or even the same PG may have opposing physiologic or immunologic effects, depending on the specific receptor through which it signals. In this review, we examine the effects of COX activity and the various PGs on allergic airway inflammation and physiology that is associated with asthma. We also highlight the potential therapeutic benefit of targeting PGs in allergic lung inflammation and asthma based on basic science, animal model and human studies.
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2 Members
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12 MeSH Terms
Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling.
Zhou W, Goleniewska K, Zhang J, Dulek DE, Toki S, Lotz MT, Newcomb DC, Boswell MG, Polosukhin VV, Milne GL, Wu P, Moore ML, FitzGerald GA, Peebles RS
(2014) J Allergy Clin Immunol 134: 698-705.e5
MeSH Terms: Air Pollution, Allergens, Animals, Enzyme Inhibitors, Epoprostenol, Humans, Hypersensitivity, Immune Tolerance, Indomethacin, Mice, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Ovalbumin, Prostaglandin-Endoperoxide Synthases, Receptors, Epoprostenol, Signal Transduction
Show Abstract · Added January 20, 2015
BACKGROUND - The prevalence of allergic diseases has doubled in developed countries in the past several decades. Cyclooxygenase (COX)-inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses. However, whether COX inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known.
OBJECTIVE - To determine the role of the COX pathway and prostaglandin I2 (PGI2) signaling through the PGI2 receptor (IP) in aeroallergen-induced immune tolerance.
METHODS - Wild-type (WT) BALB/c mice and IP knockout mice were aerosolized with ovalbumin (OVA) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA/alum. The COX inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase. Two weeks after sensitization, the mice were challenged with OVA aerosols. Mouse bronchoalveolar lavage fluid was harvested for cell counts and TH2 cytokine measurements.
RESULTS - WT mice treated with indomethacin had greater numbers of total cells, eosinophils, and lymphocytes, and increased IL-5 and IL-13 protein expression in BAL fluid compared to vehicle-treated mice. Similarly, IP knockout mice had augmented inflammation and TH2 cytokine responses compared to WT mice. In contrast, the PGI2 analog cicaprost attenuated the anti-tolerance effect of COX inhibition.
CONCLUSION - COX inhibition abrogated immune tolerance by suppressing PGI2 IP signaling, suggesting that PGI2 signaling promotes immune tolerance and that clinical use of COX-inhibiting drugs may increase the risk of developing allergic diseases.
Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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18 MeSH Terms
Neurosensory perception of environmental cues modulates sperm motility critical for fertilization.
McKnight K, Hoang HD, Prasain JK, Brown N, Vibbert J, Hollister KA, Moore R, Ragains JR, Reese J, Miller MA
(2014) Science 344: 754-7
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Environmental Exposure, Female, Fertilization, Male, Neurons, Afferent, Neurosecretory Systems, Oocytes, Ovum, Perception, Pheromones, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Sperm Motility, Spermatozoa, Transforming Growth Factor beta
Show Abstract · Added May 19, 2014
Environmental exposures affect gamete function and fertility, but the mechanisms are poorly understood. Here, we show that pheromones sensed by ciliated neurons in the Caenorhabditis elegans nose alter the lipid microenvironment within the oviduct, thereby affecting sperm motility. In favorable environments, pheromone-responsive sensory neurons secrete a transforming growth factor-β ligand called DAF-7, which acts as a neuroendocrine factor that stimulates prostaglandin-endoperoxide synthase [cyclooxygenase (Cox)]-independent prostaglandin synthesis in the ovary. Oocytes secrete F-class prostaglandins that guide sperm toward them. These prostaglandins are also synthesized in Cox knockout mice, raising the possibility that similar mechanisms exist in other animals. Our data indicate that environmental cues perceived by the female nervous system affect sperm function.
Copyright © 2014, American Association for the Advancement of Science.
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18 MeSH Terms
An ancient relative of cyclooxygenase in cyanobacteria is a linoleate 10S-dioxygenase that works in tandem with a catalase-related protein with specific 10S-hydroperoxide lyase activity.
Brash AR, Niraula NP, Boeglin WE, Mashhadi Z
(2014) J Biol Chem 289: 13101-11
MeSH Terms: Bacterial Proteins, Catalase, Nostoc, Nuclear Magnetic Resonance, Biomolecular, Oxidation-Reduction, Prostaglandin-Endoperoxide Synthases
Show Abstract · Added January 21, 2015
In the course of exploring the scope of catalase-related hemoprotein reactivity toward fatty acid hydroperoxides, we detected a novel candidate in the cyanobacterium Nostoc punctiforme PCC 73102. The immediate neighboring upstream gene, annotated as "cyclooxygenase-2," appeared to be a potential fatty acid heme dioxygenase. We cloned both genes and expressed the cDNAs in Escherichia coli, confirming their hemoprotein character. Oxygen electrode recordings demonstrated a rapid (>100 turnovers/s) reaction of the heme dioxygenase with oleic and linoleic acids. HPLC, including chiral column analysis, UV, and GC-MS of the oxygenated products, identified a novel 10S-dioxygenase activity. The catalase-related hemoprotein reacted rapidly and specifically with linoleate 10S-hydroperoxide (>2,500 turnovers/s) with a hydroperoxide lyase activity specific for the 10S-hydroperoxy enantiomer. The products were identified by NMR as (8E)10-oxo-decenoic acid and the C8 fragments, 1-octen-3-ol and 2Z-octen-1-ol, in ∼3:1 ratio. Chiral HPLC analysis established strict enzymatic control in formation of the 3R alcohol configuration (99% enantiomeric excess) and contrasted with racemic 1-octen-3-ol formed in reaction of linoleate 10S-hydroperoxide with hematin or ferrous ions. The Nostoc linoleate 10S-dioxygenase, the sequence of which contains the signature catalytic sequence of cyclooxygenases and fungal linoleate dioxygenases (YRWH), appears to be a heme dioxygenase ancestor. The novel activity of the lyase expands the known reactions of catalase-related proteins and functions in Nostoc in specific transformation of the 10S-hydroperoxylinoleate.
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6 MeSH Terms
Cyclooxygenase metabolites in the kidney.
Harris RC, Zhang MZ
(2011) Compr Physiol 1: 1729-58
MeSH Terms: Animals, Arachidonic Acid, Gene Expression, Humans, Kidney, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Receptors, Prostaglandin
Show Abstract · Added February 26, 2014
In the mammalian kidney, prostaglandins (PGs) are important mediators of physiologic processes, including modulation of vascular tone and salt and water. PGs arise from enzymatic metabolism of free arachidonic acid (AA), which is cleaved from membrane phospholipids by phospholipase A2 activity. The cyclooxygenase (COX) enzyme system is a major pathway for metabolism of AA in the kidney. COX are the enzymes responsible for the initial conversion of AA to PGG2 and subsequently to PGH2, which serves as the precursor for subsequent metabolism by PG and thromboxane synthases. In addition to high levels of expression of the "constitutive" rate-limiting enzyme responsible for prostanoid production, COX-1, the "inducible" isoform of cyclooxygenase, COX-2, is also constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. PGs and thromboxane A2 exert their biological functions predominantly through activation of specific 7-transmembrane G-protein-coupled receptors. COX metabolites have been shown to exert important physiologic functions in maintenance of renal blood flow, mediation of renin release and regulation of sodium excretion. In addition to physiologic regulation of prostanoid production in the kidney, increases in prostanoid production are also seen in a variety of inflammatory renal injuries, and COX metabolites may serve as mediators of inflammatory injury in renal disease.
2011 American Physiological Society
1 Communities
2 Members
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8 MeSH Terms
Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer disease.
Shi J, Wang Q, Johansson JU, Liang X, Woodling NS, Priyam P, Loui TM, Merchant M, Breyer RM, Montine TJ, Andreasson K
(2012) Ann Neurol 72: 788-98
MeSH Terms: Age Factors, Alzheimer Disease, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Analysis of Variance, Animals, Animals, Newborn, Aspartic Acid Endopeptidases, Brain, Cells, Cultured, Cognitive Dysfunction, DNA-Binding Proteins, Dinoprostone, Disease Models, Animal, Encephalitis, Female, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microtubule-Associated Proteins, Mutation, Neurons, Oxidative Stress, Peptide Fragments, Prostaglandin-Endoperoxide Synthases, RNA, Messenger, Receptors, Prostaglandin E, EP3 Subtype, Signal Transduction, Synaptosomal-Associated Protein 25, Vesicle-Associated Membrane Protein 2
Show Abstract · Added December 21, 2013
OBJECTIVE - There is significant evidence for a central role of inflammation in the development of Alzheimer disease (AD). Epidemiological studies indicate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the preclinical development of AD. Here, we investigate the function of prostaglandin E(2) (PGE(2) ) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide.
METHODS - The function of PGE(2) signaling through its EP3 receptor was examined in vivo in a model of subacute neuroinflammation induced by administration of Aβ(42) peptides. Our findings were then confirmed in young adult APPSwe-PS1ΔE9 transgenic mice.
RESULTS - Deletion of the PGE(2) EP3 receptor in a model of Aβ(42) peptide-induced neuroinflammation reduced proinflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1ΔE9 model of familial AD, deletion of the EP3 receptor blocked induction of proinflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were β-secretase and β C-terminal fragment levels, suggesting that generation of Aβ peptides may be increased as a result of proinflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in presynaptic proteins seen in APPSwe-PS1ΔE9 mice.
INTERPRETATION - Our findings identify the PGE(2) EP3 receptor as a novel proinflammatory, proamyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE(2) -EP3 signaling in the development of AD.
Copyright © 2012 American Neurological Association.
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35 MeSH Terms