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Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease.
Lipsky PE, Brooks P, Crofford LJ, DuBois R, Graham D, Simon LS, van de Putte LB, Abramson SB
(2000) Arch Intern Med 160: 913-20
MeSH Terms: Animals, Brain, Cyclooxygenase 1, Cyclooxygenase 2, Digestive System Physiological Phenomena, Female, Genitalia, Female, Humans, Isoenzymes, Kidney, Membrane Proteins, Prostaglandin-Endoperoxide Synthases, Thrombosis
Show Abstract · Added September 18, 2013
Originally suggested to function mainly in inflammatory situations, recent data have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive biologic processes, renal and neurologic function, and the antithrombotic activities of endothelial cells. As cyclooxygenase-2-specific inhibitors have recently become available as analgesic and anti-inflammatory drugs, a comprehensive view of this rapidly evolving field is necessary to anticipate both the potential therapeutic benefits and toxic effects associated with these agents.
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13 MeSH Terms
Spatial requirements for 15-(R)-hydroxy-5Z,8Z,11Z, 13E-eicosatetraenoic acid synthesis within the cyclooxygenase active site of murine COX-2. Why acetylated COX-1 does not synthesize 15-(R)-hete.
Rowlinson SW, Crews BC, Goodwin DC, Schneider C, Gierse JK, Marnett LJ
(2000) J Biol Chem 275: 6586-91
MeSH Terms: Acetylation, Animals, Arachidonic Acid, Aspirin, Binding Sites, Chromatography, High Pressure Liquid, Cyclooxygenase 1, Cyclooxygenase 2, Hydroxyeicosatetraenoic Acids, Isoenzymes, Membrane Proteins, Mice, Models, Molecular, Mutagenesis, Site-Directed, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Spodoptera
Show Abstract · Added March 5, 2014
The two isoforms of cyclooxygenase, COX-1 and COX-2, are acetylated by aspirin at Ser-530 and Ser-516, respectively, in the cyclooxygenase active site. Acetylated COX-2 is essentially a lipoxygenase, making 15-(R)-hydroxyeicosatetraenoic acid (15-HETE) and 11-(R)-hydroxyeicosatetraenoic acid (11-HETE), whereas acetylated COX-1 is unable to oxidize arachidonic acid to any products. Because the COX isoforms are structurally similar and share approximately 60% amino acid identity, we postulated that differences within the cyclooxygenase active sites must account for the inability of acetylated COX-1 to make 11- and 15-HETE. Residues Val-434, Arg-513, and Val-523 were predicted by comparison of the COX-1 and -2 crystal structures to account for spatial and flexibility differences observed between the COX isoforms. Site-directed mutagenesis of Val-434, Arg-513, and Val-523 in mouse COX-2 to their COX-1 equivalents resulted in abrogation of 11- and 15-HETE production after aspirin treatment, confirming the hypothesis that these residues are the major isoform selectivity determinants regulating HETE production. The ability of aspirin-treated R513H mCOX-2 to make 15-HETE, although in reduced amounts, indicates that this residue is not an alternate binding site for the carboxylate of arachidonate and that it is not the only specificity determinant regulating HETE production. Further experiments were undertaken to ascertain whether the steric bulk imparted by the acetyl moiety on Ser-530 prevented the omega-end of arachidonic acid from binding within the top channel cavity in mCOX-2. Site-directed mutagenesis was performed to change Val-228, which resides at the junction of the main cyclooxygenase channel and the top channel, and Gly-533, which is in the top channel. Both V228F and G533A produced wild type-like product profiles, but, upon acetylation, neither was able to make HETE products. This suggests that arachidonic acid orientates in a L-shaped binding configuration in the production of both prostaglandin and HETE products.
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17 MeSH Terms
Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development.
K├Âmhoff M, Wang JL, Cheng HF, Langenbach R, McKanna JA, Harris RC, Breyer MD
(2000) Kidney Int 57: 414-22
MeSH Terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Dinoprostone, Female, Gastric Mucosa, Gene Expression Regulation, Developmental, Gene Expression Regulation, Enzymologic, In Situ Hybridization, Isoenzymes, Kidney Cortex, Kidney Glomerulus, Membrane Proteins, Mice, Mice, Inbred C57BL, Organic Chemicals, Pregnancy, Prostaglandin-Endoperoxide Synthases, Pyrazoles, RNA, Messenger, Rats, Rats, Sprague-Dawley, Sulfonamides
Show Abstract · Added September 9, 2013
BACKGROUND - Antenatal exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with renal dysgenesis in humans.
METHODS - These studies characterized cyclooxygenase-2 (COX-2) versus COX-1-selective inhibition on nephrogenesis in the rodent using histomorphometry, immunohistology, and in situ hybridization.
RESULTS - Administration of a COX-2-selective inhibitor (SC58236), started during pregnancy until weaning, significantly impaired development of the renal cortex and reduced glomerular diameter in both mice and rats. An identical phenotype was demonstrated in COX-2 -/- mice. In contrast to its effects on the developing kidney, a COX-2 inhibitor had no effect on glomerular volume in adult mice. This effect was specific for COX-2 because maternal administration of a COX-1-selective inhibitor (SC58560) did not affect renal development despite significantly inhibiting gastric mucosal prostaglandin E2 (PGE2) synthesis in pups. The expression of COX-2 immunoreactivity peaked in the first postnatal week and was localized to S-shaped bodies and the macula densa in the cortex. Treatment with a COX-2 inhibitor during this period (from postnatal day 0 to day 21) severely reduced glomerular diameter, whereas treatment limited to pregnancy did not affect glomerular size.
CONCLUSION - These data demonstrate an important role for COX-2 activity in nephrogenesis in the rodent, and define a specific time period of susceptibility to these effects.
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26 MeSH Terms
The role of cyclooxygenases in inflammation, cancer, and development.
Williams CS, Mann M, DuBois RN
(1999) Oncogene 18: 7908-16
MeSH Terms: Animals, Anticarcinogenic Agents, Colonic Neoplasms, Colorectal Neoplasms, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Embryonic and Fetal Development, Humans, Isoenzymes, Membrane Proteins, Mice, Mice, Knockout, Prostaglandin-Endoperoxide Synthases
Show Abstract · Added March 5, 2014
The cyclooxygenase (COX) enzymes catalyze a key step in the conversion of arachidonate to PGH2, the immediate substrate for a series of cell specific prostaglandin and thromboxane synthases. Prostaglandins play critical roles in numerous biologic processes, including the regulation of immune function, kidney development, reproductive biology, and gastrointestinal integrity. There are two COX isoforms, which differ mainly in their pattern of expression. COX-1 is expressed in most tissues, whereas COX-2 usually is absent, but is induced by numerous physiologic stimuli. Surprisingly, disruption of Cox1 (Ptgs1) in the mouse did not result in gastrointestinal abnormalities. cox-2 (Ptgs2) null mice show reproductive anomalies and defects in kidney development. Epidemiologic, animal, and human data indicate that NSAIDs, inhibitors of cyclooxygenase, are chemopreventive for colon cancer. COX-2 is overexpressed in 50% of benign polyps and 80-85% of adenocarcinomas. Offspring from cox-2 null by Apcdelta716 matings exhibit an 86% reduction in polyp number when compared to offspring from control animals, thus providing genetic evidence that COX-2 contributes to tumor formation or growth. The in vivo mechanism by which COX-2 affects tumor growth has not been determined. It is possible that both tumor and stromally derived COX-2 could influence tumor angiogenesis and/ or immune function.
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15 MeSH Terms
Biphenotypic B/macrophage cells express COX-1 and up-regulate COX-2 expression and prostaglandin E(2) production in response to pro-inflammatory signals.
Graf BA, Nazarenko DA, Borrello MA, Roberts LJ, Morrow JD, Palis J, Phipps RP
(1999) Eur J Immunol 29: 3793-803
MeSH Terms: Animals, B-Lymphocytes, Blotting, Western, Cells, Cultured, Cyclooxygenase 1, Cyclooxygenase 2, Dinoprost, Dinoprostone, Gene Expression Regulation, Enzymologic, Immunohistochemistry, Immunophenotyping, Isoenzymes, Macrophages, Membrane Proteins, Mice, Prostaglandin D2, Prostaglandin-Endoperoxide Synthases, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Up-Regulation
Show Abstract · Added December 10, 2013
B/macrophage cells are biphenotypic leukocytes of unknown function that simultaneously express B lymphocyte (IgM, IgD, B220, CD5) and macrophage (phagocytosis, F4/80, Mac-1) characteristics. B/macrophage cells can be generated from purified mouse B lymphocytes incubated in fibroblast-conditioned medium. A potential role for B/macrophage cells in inflammation was shown by their ability to express prostaglandin H synthase-1 (COX-1) and prostaglandin H synthase-2 (COX-2) and by their production of prostaglandin (PG) E(2). COX-1 and COX-2 mRNA expression is not observed in the precursor B lymphocytes and is not known to be a property of B lineage cells. In contrast, COX-2 and the prostanoids PGE(2), PGF(2alpha) and PGD(2) are highly inducible in B/ macrophage cells upon stimulation with lipopolysaccharide, CD40 ligand, or via engagement of surface IgM, supporting a role for these cells in inflammation. PGD(2) and its metabolites are of interest because they activate the nuclear receptor PPARgamma that regulates lipid metabolism. The B/macrophage represents the first instance of a normal B-lineage cell capable of expressing COX-2. Importantly, B/macrophage cells were identified in vivo, providing evidence that they may play a significant role in immune responses. Since PGE(2) blunts IL-12 production, its synthesis by B/macrophage cells may shift the balance of an immune response towards Th2 and humoral immunity.
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21 MeSH Terms
Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition.
Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA
(1999) J Biol Chem 274: 22903-6
MeSH Terms: Animals, Arachidonic Acid, Catalysis, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Humans, Isoenzymes, Membrane Proteins, Models, Molecular, Oxygen, Prostaglandin-Endoperoxide Synthases
Added March 5, 2014
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13 MeSH Terms
COX-2 compensation in the uterus of COX-1 deficient mice during the pre-implantation period.
Reese J, Brown N, Paria BC, Morrow J, Dey SK
(1999) Mol Cell Endocrinol 150: 23-31
MeSH Terms: Animals, Cattle, Cyclooxygenase 1, Cyclooxygenase 2, Embryonic Development, Female, Gene Expression Regulation, Developmental, Gene Expression Regulation, Enzymologic, Isoenzymes, Membrane Proteins, Mice, Mice, Knockout, Pregnancy, Prostaglandin-Endoperoxide Synthases, Uterus
Show Abstract · Added April 9, 2015
Prostaglandins (PGs) produced by cyclooxygenase (COX) participate in many aspects of female reproduction. The two isoforms of cyclooxygenase, COX-1 and COX-2, have distinct expression patterns in the mouse uterus during the peri-implantation period and suggest their independent contribution to uterine PGs. Using wild type and COX-1(-/-) mice, we examined the role of COX-1-derived PGs on day 4 of pregnancy, when its expression is maximal. Uterine vascular permeability was measured by 125I-labeled bovine serum albumin (BSA) uptake, and PG content was measured by gas chromatography-mass spectrometry. Vascular permeability and PG concentrations were reduced in COX-1(-/-) mice, but by less than the expected amount. After ovariectomy, uterine vascular permeability declined in both groups, but returned to baseline in wild type and was exaggerated in COX-1(-/-) females after treatment with ovarian steroids. Most importantly, COX-1(-/-) uteri displayed COX-2 expression on the morning of day 4, when COX-2 is normally absent. This hybridization pattern resembles the native expression of COX-1, and may partially offset the loss of COX-1-derived PGs. These data indicate that COX-1-derived PGs are important during uterine preparation for implantation, and that COX-2 compensation occurs in the absence of COX-1.
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15 MeSH Terms
Coordinate regulation of cyclooxygenase-2 and TGF-beta1 in replication error-positive colon cancer and azoxymethane-induced rat colonic tumors.
Shao J, Sheng H, Aramandla R, Pereira MA, Lubet RA, Hawk E, Grogan L, Kirsch IR, Washington MK, Beauchamp RD, DuBois RN
(1999) Carcinogenesis 20: 185-91
MeSH Terms: Animals, Azoxymethane, Carcinogens, Colon, Colonic Neoplasms, Cyclooxygenase 1, Cyclooxygenase 2, Enzyme Induction, Epithelial Cells, Humans, Immunohistochemistry, Intestinal Mucosa, Isoenzymes, Liver Neoplasms, Male, Membrane Proteins, Neoplasm Proteins, Prostaglandin-Endoperoxide Synthases, RNA, Messenger, Rats, Rats, Inbred F344, Transforming Growth Factor beta
Show Abstract · Added June 14, 2013
Evidence is accumulating which indicates that cyclooxygenase-2 (COX-2) is involved in the pathogenesis of colorectal cancer. We evaluated the expression of COX-2 in replication error-positive (RER) colon cancers, colon cancers metastatic to liver and azoxymethane (AOM)-induced rat colonic tumors. Immunohistochemistry showed that COX-2 was low to undetectable in normal human mucosa, but abundant in the RER adenocarcinomas we examined. COX-2 immunoreactivity in metastatic colon cancers was less abundant, but clearly detectable. In the colon of AOM-treated rats, COX-2 protein was not detectable in normal mucosa, but present in most of the epithelial cells comprising the tumors. The TGF-beta1 staining pattern in these human and rat tumors was similar to that observed for COX-2. The role of TGF-beta in RER adenocarcinomas is complex because of the increased mutation rate of TGF-beta type II receptors. Northern analysis showed abundant TGF-beta1 mRNA in AOM-induced tumors, but not in paired mucosa. TGF-beta1 induced the expression of COX-2 mRNA and protein in intestinal epithelial cells (IEC-6). Chronic TGF-beta1 treatment caused a TGF-beta-dependent overexpression of COX-2 in rat intestinal epithelial cells (RIE-1). TGF-beta1 may regulate COX-2 expression during the colonic adenoma to carcinoma sequence.
1 Communities
2 Members
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22 MeSH Terms
Meloxicam inhibits the growth of colorectal cancer cells.
Goldman AP, Williams CS, Sheng H, Lamps LW, Williams VP, Pairet M, Morrow JD, DuBois RN
(1998) Carcinogenesis 19: 2195-9
MeSH Terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, Cell Division, Collagen, Colorectal Neoplasms, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Dinoprostone, Drug Combinations, Humans, Isoenzymes, Laminin, Meloxicam, Membrane Proteins, Mice, Mice, Nude, Neoplasm Transplantation, Prostaglandin-Endoperoxide Synthases, Proteoglycans, Thiazines, Thiazoles, Transplantation, Heterologous, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
Cyclooxygenase-2 has been reported to play an important role in colorectal carcinogenesis. The effects of meloxicam (a COX-2 inhibitor) on the growth of two colon cancer cell lines that express COX-2 (HCA-7 and Moser-S) and a COX-2 negative cell line (HCT-116) were evaluated. The growth rate of these cells was measured following treatment with meloxicam. HCA-7 and Moser-S colony size were significantly reduced following treatment with meloxicam; however, there was no significant change in HCT-116 colony size with treatment. In vivo studies were performed to evaluate the effect of meloxicam on the growth of HCA-7 cells when xenografted into nude mice. We observed a 51% reduction in tumor size after 4 weeks of treatment. Analysis of COX-1 and COX-2 protein levels in HCA-7 tumor lysates revealed a slight decrease in COX-2 expression levels in tumors taken from mice treated with meloxicam and no detectable COX-1 expression. Here we report that meloxicam significantly inhibited HCA-7 colony and tumor growth but had no effect on the growth of the COX-2 negative HCT-116 cells.
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25 MeSH Terms
The classification of cyclooxygenase inhibitors.
Lipsky LP, Abramson SB, Crofford L, Dubois RN, Simon LS, van de Putte LB
(1998) J Rheumatol 25: 2298-303
MeSH Terms: Animals, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Humans, Isoenzymes, Membrane Proteins, Prostaglandin-Endoperoxide Synthases
Show Abstract · Added September 18, 2013
In summary, precise classification of COX inhibitors has important clinical implications for efficacy and toxicity. However, classification of these agents clinically is difficult because there are insufficient data to predict correlations between biochemical and pharmacologic properties and the clinical effect of a given agent. In any case, specific COX-2 inhibitors are expected to show antiinflammatory and analgesic activities equivalent to those of NSAID, as well as significant reductions in the incidence of the life threatening side effects (i.e., GI bleeding) associated with COX-1 inhibition. The advantages of preferential COX-2 inhibitors may be more subtle and therefore more difficult to verify in clinical trials.
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9 MeSH Terms