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Zhang, Xinping, Scott G. Morham, Robert Langenbach, and Donald A. Young. "Malignant Transformation and Antineoplastic Actions of Nonsteroidal Antiinflammatory Drugs (Nsaids) on Cyclooxygenase-Null Embryo Fibroblasts." Journal of Experimental Medicine 190, no. 4 (August 16, 1999): 451–60. http://dx.doi.org/10.1084/jem.190.4.451.
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In this study, we use primary embryonic fibroblasts derived from cyclooxygenase-deficient transgenic embryos to further investigate the role of the two cyclooxygenases, cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2), in the process of neoplastic transformation. Cells with either, neither, or both of the cyclooxygenases were transformed by Ha-ras and/or SV40. Our results show that when a cyclooxygenase enzyme is present, the transformed cells have marked increases in COX-2 and/or COX-1 expression. Nevertheless, each type of cell, deficient in either or both cyclooxygenases, can be readily transformed at almost equal efficiency. Different nonsteroidal antiinflammatory drugs (NSAIDs) were used to examine their possible antineoplastic effects on the transformed cells, which have various levels of expression of COX-1 or COX-2. Our results show that NSAIDs suppress the colony formation in soft agar in a dosage-dependent manner in the absence of the cyclooxygenase(s). Thymidine incorporation and apoptosis analyses further demonstrate that the NSAIDs are effective in the cyclooxygenase-null cells. Our findings with cyclooxygenase knockout cells confirm recent reports that some of the antiproliferative and antineoplastic effects of NSAIDs are independent of the inhibition of either COX-1 or COX-2. They also show that transformation is independent of the status of cyclooxygenase expression, suggesting that the involvement of the cyclooxygenases in tumorigenesis may occur at later steps.
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Kutil, Zsofia, Veronika Temml, David Maghradze, Marie Pribylova, Marcela Dvorakova, Daniela Schuster, Tomas Vanek, and Premysl Landa. "Impact of Wines and Wine Constituents on Cyclooxygenase-1, Cyclooxygenase-2, and 5-Lipoxygenase Catalytic Activity." Mediators of Inflammation 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/178931.
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Cyclooxygenases and lipoxygenases are proinflammatory enzymes; the former affects platelet aggregation, vasoconstriction, vasodilatation and later the development of atherosclerosis. Red wines from Georgia and central and western Europe inhibited cyclooxygenase-1 (COX-1) activity in the range of 63–94%, cyclooxygenase-2 (COX-2) activity in the range of 20–44% (tested at a concentration of 5 mL/L), and 5-lipoxygenase (5-LOX) activity in the range of 72–84% (at a concentration of 18.87 mL/L). White wines inhibited 5-LOX in the range of 41–68% at a concentration of 18.87 mL/L and did not inhibit COX-1 and COX-2. Piceatannol (IC50= 0.76 μM) was identified as a strong inhibitor of 5-LOX followed by luteolin (IC50= 2.25 μM), quercetin (IC50= 3.29 μM), and myricetin (IC50= 4.02 μM).trans-Resveratrol was identified as an inhibitor of COX-1 (IC50= 2.27 μM) and COX-2 (IC50= 3.40 μM). Red wine as a complex mixture is a powerful inhibitor of COX-1, COX-2, and 5-LOX, the enzymes involved in eicosanoid biosynthetic pathway.
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Reitz, David B., and Peter C. Isakson. "Cyclooxygenase-2 Inhibitors." Current Pharmaceutical Design 1, no. 2 (September 1995): 211–20. http://dx.doi.org/10.2174/1381612801666220917221427.
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Prostaglandins are synthesized by the enzyme cyclooxygenase (COX), which is the target for nonsteroidal anti-inflammatory drugs (NSAIDs). Recently a second form of COX was discovered (COX-2) that is induced by inflammatory stimuli. The identification of an inducible form of COX led to the hypothesis that COX-2 is responsible for inflammatory prostaglandins, whereas the constitutive COX-I produces physiologically important prostaglandins, e.g., in stomach and kidney. Selective COX- 2 inhibitors have been shown to be anti-inflammatory but do not cause ulcers in the stomach or intestines. It is anticipated that drugs which selectively inhibit COX-2 will be superior anti-inflammatory agents with clear benefits over existing NSAIDs. In this review, the expression of human COX-I and COX-2 are discussed. A survey of the different chemical classes of COX-2 inhibitors with structure-activity relationships (SAR) and relevant pharmacological profiles are also presented.
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Chandrakirana Krisnamurti, Gabriella, and Fatchiyah Fatchiyah. "The Biological Function Prediction of The 10-gingerol Compound of Ginger in Inhibiting Cyclooxygenase-2 Activity." Journal of Pure and Applied Chemistry Research 9, no. 3 (December 31, 2020): 222–32. http://dx.doi.org/10.21776/ub.jpacr.2020.009.03.547.
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Anti-inflammatory agents inhibit prostaglandin synthesis by blocking cyclooxygenases (COXs). The compounds extracted from ginger, 10-gingerol and 10-shogaol can inhibit inflammation but the mechanism of inhibition remains unclear. Here we used molecular docking to predict the molecular interactions between COXs and the three inhibitors, acetaminophen (CID1983), 10-gingerol (CID168115) and 10-shogaol (CID6442612). By using that acetaminophen as a gold standard, the results demonstrated that acetaminophen, 10-gingerol, and 10-shogaol could bind catalytic domain and membrane binding domain of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The 10-shogaol did not show significantly different binding energy to bind to COX-1 and COX-2. The 10-gingerol posed a stronger and more specific binding to the membrane-binding domain of COX-2 than acetaminophen and 10-shogaol. The specific binding of the 10-gingerol to COX-2 could prevent the binding of the natural substrate, arachidonic acid. The results provide useful information to improving activities of anti-inflammatory.
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Belton, Orina, and Desmond J. Fitzgerald. "Cyclooxygenase isoforms and atherosclerosis." Expert Reviews in Molecular Medicine 5, no. 9 (March 7, 2003): 1–18. http://dx.doi.org/10.1017/s1462399403005842.
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Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and pain. However, their long-term use is limited by gastrointestinal (GI) side effects such as gastric ulcers. NSAIDs act by inhibiting an enzyme called cyclooxygenase. Cyclooxygenase (COX) catalyses the generation of prostaglandins from arachidonic acid. Two isoforms of the enzyme exist – COX-1 and COX-2 – both of which are targets for NSAIDs. Although they are associated with GI toxicity, NSAIDs have important antithrombotic and anti-inflammatory effects. The GI injury has been attributed to COX-1 inhibition and the anti-inflammatory effects to COX-2 inhibition. As COX-2 is traditionally viewed as an inducible enzyme, selective inhibition of COX-2 by ‘coxibs’ (selective COX-2 inhibitors) has been employed to achieve anti-inflammatory and analgesic effects without GI side effects. However, recently there have been suggestions that chronic administration of coxibs might increase the risk of cardiovascular events, such as atherosclerosis, compared with traditional NSAIDs. In vascular disease, there is increased expression of both COX-1 and COX-2, resulting in enhanced prostaglandin generation. The specific role of COX-1 and COX-2 in vascular regulation is still unknown but such knowledge is essential for the effective use of coxibs. Although more evidence is pointing to selective COX-1 inhibition as a therapeutic measure in inflammatory atherosclerosis, there are some studies that suggest that inhibition of COX-2 might have a potential benefit on atherosclerosis.
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Brannon, Timothy S., Amy N. MacRitchie, Marina A. Jaramillo, Todd S. Sherman, Ivan S. Yuhanna, Linda R. Margraf, and Philip W. Shaul. "Ontogeny of cyclooxygenase-1 and cyclooxygenase-2 gene expression in ovine lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 274, no. 1 (January 1, 1998): L66—L71. http://dx.doi.org/10.1152/ajplung.1998.274.1.l66.
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Prostacyclin is a key mediator of pulmonary vascular and parenchymal function during late fetal and early postnatal life, and its synthesis in whole lung increases during that period. The rate-limiting enzyme in prostacyclin synthesis in the developing lung is cyclooxygenase (COX). We investigated the ontogeny and cellular localization of COX-1 (constitutive) and COX-2 (inducible) gene expression in lungs from late-gestation fetal lambs, 1-wk-old newborn lambs (NB1), and 1- to 4-mo-old newborn lambs (NB2). COX-1 mRNA abundance rose progressively from fetal to NB1 to NB2, increasing 12-fold overall. In parallel, immunoblot analysis revealed a progressive increase in COX-1 protein, rising fourfold from fetal lambs to NB2. COX-2 mRNA levels increased fivefold from fetal to NB1 but were similar in NB1 and NB2. However, COX-2 protein was not detectable by immunoblot analysis in any age group. Immunohistochemistry for COX-1 showed intense immunostaining in endothelial cells at all ages. COX-1 was also expressed in airway epithelium at all ages, with a greater number of epithelial cells staining positively in NB2 compared with fetal and NB1 groups. In addition, COX-1 was expressed in airway smooth muscle from NB1. COX-2 immunostaining was absent in all age groups. These findings indicate that there is differential expression of COX-1 and COX-2 in the developing lung and that the enzymes are expressed in a cell-specific manner. The developmental upregulation in COX-1 may optimize the capacity for prostaglandin-mediated vasodilation, bronchodilation, and surfactant synthesis in the newborn lung.
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Odau, Simone, Christoph Gabler, Christoph Holder, and Ralf Einspanier. "Differential expression of cyclooxygenase 1 and cyclooxygenase 2 in the bovine oviduct." Journal of Endocrinology 191, no. 1 (October 2006): 263–74. http://dx.doi.org/10.1677/joe.1.06761.
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The aim of the present study was to investigate the enzymes for the local prostaglandin (PG) biosynthesis present in the bovine oviduct during the estrous cycle to influence early reproductive events. Bovine oviducts were classified into four phases: pre-ovulatory, post-ovulatory, early-to-mid luteal, and late luteal phase, subdivided further into ipsi- or contralateral site and separated into ampulla or isthmus. Oviductal cells were gained by flushing the oviductal regions. Quantitative real-time reverse transcriptase-PCR was performed for the secretory and cytosolic phospholipases A2 (sPLA2IB, cPLA2α, and cPLA2β) and cyclooxygenases (COX-1 and COX-2) as the first step enzymes of PG synthesis. COX-1 and cPLA2β showed significant highest mRNA expression around and before ovulation compared with the luteal phase respectively. sPLA2IB and cPLA2α mRNA expression was unregulated during the estrous cycle. Regional differences in mRNA content were found for sPLA2IB with higher mRNA expression in the ampulla than in the isthmus. Western blot analysis revealed the highest COX-1 protein content in the early-to-mid luteal phase. Immunohistochemistry demonstrated that COX-1 was localized in epithelial and smooth muscle cells, whereas COX-2 was only localized in epithelial cells. COX-2 showed a differential distribution within the epithelial cell layer suggesting a regulation on a cellular level, although the COX-2 mRNA and protein amounts did not vary throughout the estrous cycle. A COX activity assay of oviductal cells revealed that COX activity originated predominantly from COX-1 than from COX-2. Treatment of primary oviductal cells with 10 pg/ml 17β-estradiol or 10 ng/ml progesterone resulted in a higher expression of COX-2 and cPLA2α, but not of the other enzymes. The expression pattern of these enzymes suggests that an estrous-cycle dependent and region-specific PG synthesis in the bovine oviduct may be required for a successful reproduction.
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Hofer, Michal, and Milan Pospíšil. "Stimulated recovery of perturbed haematopoiesis by inhibition of prostaglandin production — promising therapeutic strategy." Open Life Sciences 1, no. 4 (December 1, 2006): 584–93. http://dx.doi.org/10.2478/s11535-006-0033-3.
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AbstractInhibitors of prostaglandin production, designated as classical non-steroidal anti-inflammatory drugs (NSAIDs) and acting on the base of non-selective inhibition of cyclooxygenases, have been found in numerous studies to potentiate recovery of perturbed haematopoiesis by removing the negative feedback control mediated by prostaglandins. However, classical NSAIDs show pronounced undesirable gastrointestinal side effects, which limits the possibility of their utilization for various pathophysiological states including myelosuppression. Specific cyclooxygenase-2 (COX-2) inhibitors, targeted at selective inhibition of this inducible cyclooxygenase isoform and having much better gastrointestinal side effect profile, have been found in recent studies to retain the haematopoiesis-stimulating effects of classical NSAIDs. These results suggest that the indication spectrum of selective COX-2 inhibitors may be extended to the indication of myelosuppression of various etiology. Combining the anti-tumour and haematopoiesis-stimulating activities in a single COX-2 inhibitor may have a positive clinical impact.
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Ray, Neelanjana, Margaret E. Bisher, and L. W. Enquist. "Cyclooxygenase-1 and -2 Are Required for Production of Infectious Pseudorabies Virus." Journal of Virology 78, no. 23 (December 1, 2004): 12964–74. http://dx.doi.org/10.1128/jvi.78.23.12964-12974.2004.
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ABSTRACT We have recently shown that cyclooxygenase-2 (COX-2) transcription is markedly induced after herpes simplex virus type 1 and pseudorabies virus (PRV) infections of rat embryonic fibroblast (REF) cells (N. Ray and L. W. Enquist, J. Virol. 78:3489-3501, 2004). For this study, we investigated the role of cyclooxygenase induction in the replication and growth of PRV. We demonstrate here a concordant increase in COX-2 mRNA and protein levels after the infection of REF cells. Inhibitors blocking the activity of cyclooxygenases caused a dramatic reduction in PRV growth. Viral growth could be restored if prostaglandin E2, the final product of COX-2 activity, was added simultaneously with the COX inhibitors. Immediate-early protein IE180, major capsid protein VP5, and glycoprotein expression were slightly reduced in the presence of COX-2 inhibitors, but expression of the early protein EP0 was not affected by COX inhibition. Viral DNA replication was marginally reduced in the presence of a COX-1/2 inhibitor, but there was no defect in viral DNA cleavage. Electron microscopy analysis revealed an increased number of unusual empty capsid structures in the nuclei of cells infected with PRV in the presence of a COX-1/2 inhibitor. These capsid structures shared some characteristics with procapsids but had a novel appearance by negative staining. Our data establish a role for COX-1 and COX-2 in facilitating the efficient growth and replication of PRV in primary cells.
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Maloney, Christopher G., William A. Kutchera, Kurt H. Albertine, Thomas M. McIntyre, Stephen M. Prescott, and Guy A. Zimmerman. "Inflammatory Agonists Induce Cyclooxygenase Type 2 Expression by Human Neutrophils." Journal of Immunology 160, no. 3 (February 1, 1998): 1402–10. http://dx.doi.org/10.4049/jimmunol.160.3.1402.
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Abstract The synthesis of prostanoids is regulated by cyclooxygenases (prostaglandin H synthases), which catalyze the conversion of arachidonic acid to PGH2. Cyclooxygenases are the target of aspirin and other nonsteroidal anti-inflammatory agents. In this study, we found that human polymorphonuclear leukocytes (PMNs) express the inducible isoform of cyclooxygenase, COX-2, when stimulated by LPS whereas the protein was not detectable in freshly isolated human PMNs. We also found by immunohistochemical analysis that COX-2 is expressed in PMNs in inflamed human tissues. COX-2 was induced in a time- and concentration-dependent fashion when isolated human PMNs were exposed to LPS; COX-2 was also induced, or its expression was increased, by TNF-α, IL-1, and IL-8. Expression of COX-2 in stimulated PMNs was paralleled by secretion of PGE2. The release of PGE2 was blocked by a selective nonsteroidal inhibitor of COX-2, indicating that the enzyme is responsible for the prostanoids produced, and was inhibited by dexamethasone. The time course of LPS-induced COX-2 expression and other features were different in freshly isolated PMNs, monocytes, and macrophages, indicating that COX-2 expression is differentially regulated in myeloid cells of different lineages and degrees of maturation. Consistent with this, IL-4 and IL-10, which suppressed LPS-induced COX-2 expression in monocytes, had little effect on this response by PMNs. These experiments demonstrate that PMNs express COX-2 when appropriately stimulated. Thus, they may actively influence the eicosanoid composition of the acute inflammatory milieu.
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Krämer, Bernhard K., Martin C. Kammerl, and Martin Kömhoff. "Renal Cyclooxygenase-2 (Cox-2)." Kidney and Blood Pressure Research 27, no. 1 (2004): 43–62. http://dx.doi.org/10.1159/000075811.
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Glomb, Teresa, Benita Wiatrak, Katarzyna Gębczak, Tomasz Gębarowski, Dorota Bodetko, Żaneta Czyżnikowska, and Piotr Świątek. "New 1,3,4-Oxadiazole Derivatives of Pyridothiazine-1,1-Dioxide with Anti-Inflammatory Activity." International Journal of Molecular Sciences 21, no. 23 (November 30, 2020): 9122. http://dx.doi.org/10.3390/ijms21239122.
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Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4. The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases.
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Mengle-Gaw, Laurel J., and Benjamin D. Schwartz. "Cyclooxygenase-2 inhibitors: promise or peril?" Mediators of Inflammation 11, no. 5 (2002): 275–86. http://dx.doi.org/10.1080/09629350290000041.
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The discovery of two isoforms of the cyclooxygenase enzyme, COX-1 and COX-2, and the development of COX-2-specific inhibitors as anti-inflammatories and analgesics have offered great promise that the therapeutic benefits of NSAIDs could be optimized through inhibition of COX-2, while minimizing their adverse side effect profile associated with inhibition of COX-1. While COX-2 specific inhibitors have proven to be efficacious in a variety of inflammatory conditions, exposure of large numbers of patients to these drugs in postmarketing studies have uncovered potential safety concerns that raise questions about the benefit/risk ratio of COX-2-specific NSAIDs compared to conventional NSAIDs. This article reviews the efficacy and safety profiles of COX-2-specific inhibitors, comparing them with conventional NSDAIDs.
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Gosepath, Jan, Juergen Brieger, and Wolf J. Mann. "New Immunohistologic Findings on the Differential Role of Cyclooxygenase 1 and Cyclooxygenase 2 in Nasal Polyposis." American Journal of Rhinology 19, no. 2 (March 2005): 111–17. http://dx.doi.org/10.1177/194589240501900201.
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Background Cyclooxygenase 1 (Cox-1) plays a key role in arachidonic acid metabolism and in the pathophysiology and immunology of nasal polyposis in patients suffering from aspirin intolerance. We hypothesize that Cox-2 also might be relevant in the etiology of nasal polyps of aspirin-tolerant patients by their effects on inflammatory mediators as well as on microvascular permeability. Methods Fifty-two surgical specimens were immunohistochemically labeled for Cox-1 and Cox-2. Specimens were taken from chronically inflamed mucosa (n = 19) and from nasal polyps (n = 19) during endonasal sinus surgery. Controls were obtained from healthy nasal respiratory mucosa (n = 14), harvested during turbinate surgery in patients with nasal obstruction without inflammatory disease. Staining intensities were semiquantitatively assessed and statistically analyzed. Results In chronically inflamed tissue the expression of Cox-1 and Cox-2 was strongly labeled. However, in nasal polyps the staining pattern of Cox-1 was similar, but Cox-2 expression in epithelial cells was significantly less than in inflamed, nonpolypous specimens. Conclusion These data suggest that while Cox-1 is strongly up-regulated, Cox-2 expression is significantly lower in epithelial cells of nasal polyps than in those of chronic sinusitis without polyps. The relevance of this finding has to be discussed with respect to the regulatory function of Cox on the inflammatory reaction in nasal respiratory mucosa and its hypothetical role in alterations of capillary permeability via vascular permeability factor/vascular endothelial growth factor.
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Mandic, Aljosa, Slavica Usaj-Knezevic, Tatjana Ivkovic-Kapicl, Dejan Nincic, and Goran Malenkovic. "Cyclooxygenase-2 expression in cervical cancer." Vojnosanitetski pregled 71, no. 11 (2014): 997–1005. http://dx.doi.org/10.2298/vsp1411997m.
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Background/Aim. Cyclooxygenase (COX) or prostaglandin H2 synthase is the first enzyme that catalyzes the first two steps in the biosynthesis of prostaglandins from arachidonic acid. The aim of the study was to determine the expression level of COX-2 in patients with cervical cancer and compare it with that in the control group with no cervical pathology. Methods. The study included 76 patients divided into two groups: the control group - 30 patients without histopathological changes and the group A - 46 patients with cervical cancer, FIGO stage IB-IIA. Histopathological and immunohistochemical analyses were performed in these two groups of patients. Results. In the control group, the expression of COX-2 was not confirmed compared to the group A of 26 (56.52%) patients. The expression of COX-2 showed a statistically significant difference in the presence of lymphocytic stromal infiltration (p = 0.0053). The expression of COX-2 was more pronounced in the stromal tissue without lymphocytic infiltration (80% vs 20%). Conclusion. A higher expression of COX-2 in cervical carcinoma without stromal lymphocytic infiltration suggests a possible paradoxical effect of COX-2 in immunosuppression. Frequent COX- 2 expression in the subgroup with poor prognostic histological parameters in the group A indicates the importance of COX-2 expression in the carcinogenesis of cervical cancer.
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Dickens, David S., Rafal Kozielski, Javed Khan, Anne Forus, and Timothy P. Cripe. "Cyclooxygenase-2 Expression in Pediatric Sarcomas." Pediatric and Developmental Pathology 5, no. 4 (July 2002): 356–64. http://dx.doi.org/10.1007/s10024-002-0005-1.
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Therapies for metastatic pediatric sarcomas have reached maximum tolerated doses, but continue to provide suboptimal cure rates. Additionally, these treatments are associated with numerous short- and long-term side effects. Therefore, the search for newer, less toxic therapeutic agents is warranted. Overexpression of the inducible enzyme, cyclooxygenase-2 (COX-2), has been discovered in a variety of adult solid tumors and numerous studies have shown COX-2 inhibitors to have significant antiproliferative effects. Therefore, we sought to determine the expression of COX-2 in pediatric sarcomas. We evaluated rhabdomyosarcoma (RMS), osteosarcoma (OS), and Ewing sarcoma (EWS) samples for COX-2 expression by immunohistochemical analysis as well as by cDNA microarray analysis. COX-2 expression was detected in 48/58 (82.8%) tumors by immunohistochemistry and in an additional 52/59 (88.1%) tumors tested by microarray gene analysis. There was a trend toward increased COX-2 expression in metastatic rhabdomyosarcoma and osteosarcoma, though it did not reach clinical significance. The degree of COX-2 immunoreactivity did not vary significantly with other clinicopathologic features such as age, gender, or histologic classification. We conclude that the majority of these pediatric sarcoma samples express COX-2 to varying degrees. Therefore, studies testing the efficacy of COX-2 inhibitors in the treatment of pediatric sarcomas are warranted.
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Thamm, D. H., E. J. Ehrhart, J. B. Charles, and Y. A. Elce. "Cyclooxygenase-2 Expression in Equine Tumors." Veterinary Pathology 45, no. 6 (November 2008): 825–28. http://dx.doi.org/10.1354/vp.45-6-825.
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The enzyme cyclooxygenase-2 (COX-2) is expressed in some tumor and stromal tissues, and catalyzes production of prostaglandins with growth stimulatory, antiapoptotic, proangiogenic, and immunosuppressive properties. Pharmacologic inhibition of COX-2 is associated with antitumor activity in various human and canine malignancies. The purpose of this study was to assess COX-2 expression in a series of equine sarcoids, melanomas, and squamous-cell carcinomas (SCC). COX-2 expression was assessed in formalin-fixed paraffin-embedded tissues from 14 sarcoids, 11 melanomas, and 37 SCC that represent various anatomic sites by using standard immunohistochemical methods. COX-2 was expressed in 2 of 14 sarcoids, 7 of 11 melanomas, and 32 of 37 SCC, 56% of which demonstrated moderate-to-strong immunoreactivity. There were no differences in expression between anatomic sites. In conclusion, most equine SCC and many melanomas appear to express COX-2 and thus could respond to COX-2 inhibitor therapy.
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Bauer, A. K., L. D. Dwyer-Nield, and A. M. Malkinson. "High cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) contents in mouse lung tumors." Carcinogenesis 21, no. 4 (April 1, 2000): 543–50. http://dx.doi.org/10.1093/carcin/21.4.543.
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Loy, A. H. C., T. C. Putti, and L. K. S. Tan. "Cyclooxygenase-2 expression in Warthin's tumour." Journal of Laryngology & Otology 119, no. 7 (July 2005): 515–18. http://dx.doi.org/10.1258/0022215054352117.
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Objectives: To determine whether cyclooxygenase-2 (COX-2) is overexpressed in Warthin's tumours, and to characterize its pattern of expression.Methods: Twenty-one paraffin-embedded Warthin's tumour specimens were analysed by immunohistochemical staining for expression of human COX-2. Semi-quantitative analysis of the staining was performed.Results: In all of the specimens, we found that there was overexpression of COX-2 within the epithelial component of the tumours, with no expression in the lymphoid components. There was also overexpression of COX-2 in the salivary duct system of normal parotid tissue.Conclusions: Our results suggest that COX-2 is up-regulated in the epithelial component of Warthin's tumours. Our findings support the hypothesis that Warthin's tumours originate from heterotopic ductal epithelial cells of the parotid gland. The role of COX-2 expression in the pathogenesis of Warthin's tumours remains to be determined.
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Szweda, Marta, Andrzej Rychlik, Izabella Babińska, and Andrzej Pomianowski. "Significance of cyclooxygenase-2 in oncogenesis." Journal of Veterinary Research 63, no. 2 (June 1, 2019): 215–24. http://dx.doi.org/10.2478/jvetres-2019-0030.
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Abstract The cyclooxygenase-2 (COX-2) enzyme catalyses the first stage of biosynthesis of prostanoids, proteins that are implicated in various physiological and pathological processes in humans and animals. The expression of COX-2 increases significantly during pathological processes accompanied by inflammation, pain and fever. Overexpression of COX-2 was determined in tumour tissues, which suggests that this enzyme participates in oncogenesis. In this paper the topics discussed are mechanisms regulating COX-2 expression, COX isoforms, their role in the body and the oncogenic mechanisms triggered by the overexpression of COX-2, including inhibition of apoptosis, intensification of neoangiogenesis, increased metastatic capacity, and weakening of the immune system. The significance of and the mechanisms by which COX-2 participates in oncogenesis have been studied intensively in recent years. The results are highly promising, and they expand our understanding of the complex processes and changes at the molecular, cellular and tissue level that promote oncogenesis and cancer progression. Notwithstanding the knowledge already gleaned, many processes and mechanisms have not yet been elucidated in human medicine and, in particular, in veterinary medicine. Further research is required to develop effective tumour diagnostic methods and treatment procedures for humans and animals.
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Vernieri, Ermelinda, Isabel Gomez-Monterrey, Ciro Milite, Paolo Grieco, Simona Musella, Alessia Bertamino, Ilaria Scognamiglio, et al. "Design, Synthesis, and Evaluation of New Tripeptides as COX-2 Inhibitors." Journal of Amino Acids 2013 (February 26, 2013): 1–7. http://dx.doi.org/10.1155/2013/606282.
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Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 203 possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs.
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Iñiguez, Miguel A., Carmen Punzón, and Manuel Fresno. "Induction of Cyclooxygenase-2 on Activated T Lymphocytes: Regulation of T Cell Activation by Cyclooxygenase-2 Inhibitors." Journal of Immunology 163, no. 1 (July 1, 1999): 111–19. http://dx.doi.org/10.4049/jimmunol.163.1.111.
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Abstract Cyclooxygenase (COX), known to exist in two isoforms, COX-1 and COX-2, is a key enzyme in prostaglandin synthesis and the target for most nonsteroidal anti-inflammatory drugs. In this study, we show that human T lymphocytes express the COX-2 isoenzyme. COX-2 mRNA and protein were induced in both Jurkat and purified T cells stimulated by TCR/CD3 or PMA activation. COX-2 mRNA was induced very early after activation and superinduced by protein synthesis inhibitors, whereas it was inhibited by the immunosuppressive drug cyclosporin A, identifying it as an early T cell activation gene. Interestingly, treatment with COX-2-specific inhibitors such as NS398 or Celecoxib severely diminished early and late events of T cell activation, including CD25 and CD71 cell surface expression, IL-2, TNF-α, and IFN-γ production and cell proliferation, but not the expression of CD69, an immediate early gene. COX-2 inhibitors also abolished induced transcription of reporter genes driven by IL-2 and TNF-α promoters. Moreover, induced transcription from NF-κB- and NF-AT-dependent enhancers was also inhibited. These results may have important implications in anti-inflammatory therapy and open a new field on COX-2-selective nonsteroidal anti-inflammatory drugs as modulators of the immune activation.
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Chillingworth, Naomi L., Scott G. Morham, and Lucy F. Donaldson. "Sex differences in inflammation and inflammatory pain in cyclooxygenase-deficient mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 2 (August 2006): R327—R334. http://dx.doi.org/10.1152/ajpregu.00901.2005.
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There are two cyclooxygenase (COX) genes encoding characterized enzymes, COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs are commonly used as analgesics in inflammatory arthritis, and these often inhibit both cyclooxygenases. Recently, inhibitors of COX-2 have been used in the treatment of inflammatory arthritis, as this isoform is thought to be critical in inflammation and pain. The objective of this study was to determine the effect of COX-1 or COX-2 gene disruption on the development of chronic Freund’s adjuvant-induced arthritis and inflammatory pain in male and female mice. The effect of COX-1 or COX-2 gene disruption on inflammatory hyperalgesia, allodynia, inflammatory edema, and arthritic joint destruction was studied. COX-2 knockout mice (COX-2 −/−) showed reduced edema and joint destruction in female, but not male, animals. In addition, neither male nor female COX-2 −/− mice developed thermal hyperalgesia or mechanical allodynia, either ipsilateral or contralateral to the inflammation. COX-1 gene disruption also reduced inflammatory edema and joint destruction in female, but not male mice, although females of both COX −/− lines did show some bony destruction. There was no difference in ipsilateral allodynia between COX-1 knockout and wild-type animals, but female COX-1 −/− mice showed reduced contralateral allodynia compared with male COX-1 −/− or wild-type mice. These data show that the gene products of both COX genes contribute to pain and local inflammation in inflammatory arthritis. There are sex differences in some of these effects, and this suggests that the effects of COX inhibitors may be sex dependent.
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Doré, M., I. Lanthier, and J. Sirois. "Cyclooxygenase-2 Expression in Canine Mammary Tumors." Veterinary Pathology 40, no. 2 (March 2003): 207–12. http://dx.doi.org/10.1354/vp.40-2-207.
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Mammary tumors are the most common neoplasms in female dogs. Induction of cyclooxygenase-2 (COX-2) has been implicated in various cancers in humans. However, expression of COX-2 has not been investigated in canine mammary tumors. Normal mammary gland ( n = 4), simple or complex adenomas ( n = 63), and simple or complex adenocarcinomas ( n = 84) were studied by immunohistochemistry. Results showed that COX-2 was not expressed in the normal gland but was detected in 24% of adenomas and in 56% of adenocarcinomas ( P < 0.001). The incidence of COX-2 expression and the intensity of the COX-2 signal were higher in adenocarcinomas than in adenomas ( P < 0.001). These results demonstrate for the first time that COX-2 is induced in a proportion of canine mammary tumors and that COX-2 expression is more frequent and more intense in malignant than in benign tumors, suggesting a potential role for COX-2 in canine mammary tumorigenesis.
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Tong, Xin, Lei Yin, Shree Joshi, Daniel W. Rosenberg, and Charles Giardina. "Cyclooxygenase-2 Regulation in Colon Cancer Cells." Journal of Biological Chemistry 280, no. 16 (February 15, 2005): 15503–9. http://dx.doi.org/10.1074/jbc.m411978200.
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We are interested in the mechanism of cyclooxygenase-2 (Cox-2) regulation in colon cancer cells because this knowledge could provide insight into colon carcinogenesis and suggest ways to suppress Cox-2 expression in colon tumors. Studying the HT-29 colon cancer cell line as a model, we found that Cox-2 mRNA and protein levels were activated over 10-fold by the inflammatory cytokine tumor necrosis factor (TNF)-α. Moreover, we found that the histone deacetylase inhibitors butyrate and trichostatin A could block Cox-2 activation in a gene-specific manner. TNF-α and butyrate did not significantly affect Cox-2 promoter activity, mRNA stability, or negative regulation by the Cox-2 3′-untranslated RNA region. A nuclear run-on assay showed that TNF-α increased Cox-2 transcription, whereas butyrate was suppressive. Because butyrate has been reported to suppress polymerase elongation on the c-mycgene, we employed the chromatin immunoprecipitation assay to determine the influence of butyrate and trichostatin A on polymerase distribution on the Cox-2 gene. These data indicated that butyrate restricted polymerase elongation from exon 1 to 2 on both the c-mycand Cox-2 genes. We propose that histone deacetylases regulate a transcriptional block on the Cox-2 and c-mycgenes and that this block may be a potential target for pharmacological intervention.
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Kis, Bela, James A. Snipes, Toyohi Isse, Krisztina Nagy, and David W. Busija. "Putative Cyclooxygenase-3 Expression in Rat Brain Cells." Journal of Cerebral Blood Flow & Metabolism 23, no. 11 (November 2003): 1287–92. http://dx.doi.org/10.1097/01.wcb.0000090681.07515.81.
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Cyclooxygenase-3 (COX-3), a new acetaminophen-sensitive isoform of the COX family, has recently been cloned from canine tissues. Canine COX-3 apparently is identical to the full-length form of COX-1, with the exception that the COX-3 mRNA retains intron 1. Additionally, COX-3 mRNA expression is high in the brain. We investigated the expression of the putative rat COX-3 mRNA in primary cultures of neurons, astrocytes, endothelial cells, pericytes, and choroidal epithelial cells from the rat brain. Specific RT-PCR primers were designed to detect putative rat COX-3 mRNA, and the RT-PCR products were sequenced and compared to the known sequence of the rat COX-1 gene. Our results demonstrate that the mRNA of the putative COX-3 is expressed in all of the cell types except neurons. Cerebral endothelial cells showed the highest COX-3 expression. Whereas COX-2 expression increased several-fold after lipopolysaccharide (LPS) challenge, COX-1 and COX-3 expression did not change significantly, suggesting that cells constitutively express COX-3. In summary, we report, for the first time to our knowledge, that the putative COX-3 mRNA is detectable in rats and is differentially expressed in various cell types from rat brain, as well as that its expression is not stimulated by LPS.
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Zhang, Ming-Zhi, Jun-Ling Wang, H. F. Cheng, Raymond C. Harris, and James A. McKanna. "Cyclooxygenase-2 in rat nephron development." American Journal of Physiology-Renal Physiology 273, no. 6 (December 1, 1997): F994—F1002. http://dx.doi.org/10.1152/ajprenal.1997.273.6.f994.
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The inducible second isoform of cyclooxygenase (COX-2) that mediates inflammation also is expressed at low levels in normal adult rat kidneys and is upregulated in response to noninflammatory stimuli (R. C. Harris, J. A. McKanna, Y. Akai, H. R. Jacobson, R. N. DuBois, and M. D. Breyer. J. Clin. Invest. 94: 2504–2510, 1994). Roles in morphogenesis are indicated by reported teratogenicity of COX inhibitors and renal dysgenesis in COX-2 knockout mice (J. E. Dinchuk, B. D. Car, R. J. Focht, J. J. Johnston, B. D. Jaffee, M. B. Covington, N. R. Contel, V. M. Eng, R. J. Collins, P. M. Czerniak, A. G. Stewart, and J. M. Trzaskos. Nature 378: 406–409, 1995; S. G. Morham, R. Lagenbach, C. D. Loftin, H. F. Tiano, N. Vouloumanos, J. C. Jennette, J. F. Mahler, K. D. Kluckman, A. Ledford, C. A. Lee, and O. Smithies. Cell 83: 473–482, 1995). Blots from developing rat kidneys demonstrated that COX-2 mRNA and immunoreactive protein were present in neonates, peaked in the 2nd and 3rd postnatal weeks and declined to adult levels by the 3rd month. Immunolocalization and in situ hybridization detected intense COX-2 immunoreactivity and mRNA in a subset of thick ascending limb epithelial cells near the macula densa in each developing nephron; after 2 wk the COX-2 gradually waned. These data demonstrate that COX-2 expression is subject to normal developmental regulation and can be sustained over extended periods; they also support the conclusion that metabolites of COX-2 play important roles in the differentiation and early functions of mammalian nephrons.
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Prasojo, Stefanus Layli, Fajar Agung Dwi Hartanto, Nunung Yuniarti, Zullies Ikawati, and Enade Perdana Istyastono. "DOCKING OF 1-PHENYLSULFONAMIDE-3-TRIFLUOROMETHYL-5-PARABROMOPHENYL-PYRAZOLE TO CYCLOOXYGENASE-2 USING PLANTS." Indonesian Journal of Chemistry 10, no. 3 (December 14, 2010): 348–51. http://dx.doi.org/10.22146/ijc.21441.
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The docking protocols to virtually screen selective cyclooxygenase-2 (COX-2) ligands using PLANTS docking software were developed and validated. The crystal structure of 1-phenylsulfonamide-3-trifluoromethyl-5-parabromophenyl-pyrazole (S58) binds to cyclooxygenase-2 (COX-2) was used as the reference structure. The developed protocols could predict the binding pose of S58 to COX-2 accurately (RMSD is 1.2 Ǻ).
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Reese, Jeff, Xuemei Zhao, Wen-Ge Ma, Naoko Brown, Timothy J. Maziasz, and S. K. Dey. "Comparative Analysis of Pharmacologic and/or Genetic Disruption of Cyclooxygenase-1 and Cyclooxygenase-2 Function in Female Reproduction in Mice*." Endocrinology 142, no. 7 (July 1, 2001): 3198–206. http://dx.doi.org/10.1210/endo.142.7.8307.
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Abstract Cyclooxygenase (COX)-derived prostaglandins are critical in female reproduction. Gene targeting studies show that ovulation, fertilization, implantation, and decidualization are defective in COX-2 deficient mice. We used genetic and pharmacologic approaches to perturb COX function and examine the differential and synergistic effects of inhibition of COX-1, COX-2, or of both isoforms on reproductive outcomes during early pregnancy in mice. The results demonstrate that simultaneous inhibition of COX-1 and COX-2 produces more severe effects on early pregnancy events than inhibition of either isoform alone. The effects of pharmacological inhibition of COX-2 on female reproductive functions were less severe than the null mutation of the COX-2 gene. A combined approach showed that COX-2 inhibition in COX-1−/− mice induced complete reproductive failure, suggesting a lack of alternative sources of prostaglandin synthesis. This investigation raises caution regarding the indiscriminate use of COX inhibitors and shows for the first time the distinct and overlapping pathways of the cyclooxygenase systems in female reproduction.
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Rubin, Bernard R. "Specific cyclooxygenase-2 (COX-2) inhibitors." Journal of the American Osteopathic Association 99, no. 6 (June 1, 1999): 322. http://dx.doi.org/10.7556/jaoa.1999.99.6.322.
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Little, Dianne, Samuel L. Jones, and Anthony T. Blikslager. "Cyclooxygenase (COX) Inhibitors and the Intestine." Journal of Veterinary Internal Medicine 21, no. 3 (May 2007): 367–77. http://dx.doi.org/10.1111/j.1939-1676.2007.tb02978.x.
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Reuss-Borst, M. "Selektive Cyclooxygenase-2 (COX-2)-Hemmer." Der Internist 38, no. 3 (March 12, 1997): 266–71. http://dx.doi.org/10.1007/s001080050040.
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Schmassmann, Adrian, Georg Zoidl, Brigitta M. Peskar, Bea Waser, Diana Schmassmann-Suhijar, Jan-Olaf Gebbers, and Jean Claude Reubi. "Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 4 (April 2006): G747—G756. http://dx.doi.org/10.1152/ajpgi.00416.2005.
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Traditional NSAIDs, selective cyclooxygenase (COX)-2 inhibitors, and inhibitors of nitric oxide synthase (NOS) impair the healing of preexisting gastric ulcers. However, the role of COX-1 (with or without impairment of COX-2) and the interaction between COX and NOS isoforms during healing are less clear. Thus we investigated healing and regulation of COX and NOS isoforms during ulcer healing in COX-1 and COX-2 deficiency and inhibition mouse models. In this study, female wild-type COX-1−/− and COX-2−/− mice with gastric ulcers induced by cryoprobe were treated intragastrically with vehicle, selective COX-1 (SC-560), COX-2 (celecoxib, rofecoxib, and valdedoxib), and unselective COX (piroxicam) inhibitors. Ulcer healing parameters, mRNA expression, and activity of COX and NOS were quantified. Gene disruption or inhibition of COX-1 did not impair ulcer healing. In contrast, COX-2 gene disruption and COX-2 inhibitors moderately impaired wound healing. More severe healing impairment was found in dual (SC-560 + rofecoxib) and unselective (piroxicam) COX inhibition and combined COX impairment (in COX-1−/− mice with COX-2 inhibition and COX-2−/− mice with COX-1 inhibition). In the ulcerated repair tissue, COX-2 mRNA in COX-1−/− mice, COX-1 mRNA in COX-2−/− mice, and, remarkably, NOS-2 and NOS-3 mRNA in COX-impaired mice were more upregulated than in wild-type mice. This study demonstrates that COX-2 is a key mediator in gastric wound healing. In contrast, COX-1 has no significant role in healing when COX-2 is unimpaired but becomes important when COX-2 is impaired. As counterregulatory mechanisms, mRNA of COX and NOS isoforms were increased during healing in COX-impaired mice.
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Ferreri, Nicholas R., Shao-Jian An, and John C. McGiff. "Cyclooxygenase-2 expression and function in the medullary thick ascending limb." American Journal of Physiology-Renal Physiology 277, no. 3 (September 1, 1999): F360—F368. http://dx.doi.org/10.1152/ajprenal.1999.277.3.f360.
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The medullary thick ascending limb (MTAL) metabolizes arachidonic acid (AA) via cytochrome P-450 (CyP450)- and cyclooxygenase (COX)-dependent pathways. In the present study, we demonstrated that the COX-2-selective inhibitor, NS-398, prevented tumor necrosis factor-α (TNF)- and phorbol myristate acetate (PMA)-mediated increases in PGE2 production by cultured MTAL cells. Accumulation of COX-2, but not COX-1, mRNA increased when cells were challenged with TNF (1 nM) or PMA (1 μM). Pretreatment of cells for 30 min with actinomycin D (AcD, 1 μM) had little effect on COX-2 mRNA accumulation in unstimulated cells or in cells challenged with either TNF or PMA. Moreover, a posttranscriptional mechanism(s) appears to contribute significantly to COX-2 mRNA accumulation as pretreatment for 15 min with cycloheximide (CHX, 1 μM) caused a superinduction of COX-2 mRNA accumulation in unstimulated cells as well as in cells challenged with either TNF or PMA. Expression of COX-2 protein in unstimulated MTAL cells was attenuated by preincubation for 2 h with dexamethasone (Dex, 2 μM); however, Dex had little or no effect on COX-2 expression in cells challenged with either PMA or TNF. The time-dependent inhibition of86Rb uptake by MTAL cells challenged with TNF was diminished by pretreating cells with NS-398. These data suggest that TNF-mediated induction of COX-2 protein expression accounted for the lag-time required for this cytokine to inhibit 86Rb uptake in MTAL cells.
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Rand, Amy A., Bogdan Barnych, Christophe Morisseau, Tomas Cajka, Kin Sing Stephen Lee, Dipak Panigrahy, and Bruce D. Hammock. "Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids." Proceedings of the National Academy of Sciences 114, no. 17 (April 10, 2017): 4370–75. http://dx.doi.org/10.1073/pnas.1616893114.
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Arachidonic acid (ARA) is metabolized by cyclooxygenase (COX) and cytochrome P450 to produce proangiogenic metabolites. Specifically, epoxyeicosatrienoic acids (EETs) produced from the P450 pathway are angiogenic, inducing cancer tumor growth. A previous study showed that inhibiting soluble epoxide hydrolase (sEH) increased EET concentration and mildly promoted tumor growth. However, inhibiting both sEH and COX led to a dramatic decrease in tumor growth, suggesting that the contribution of EETs to angiogenesis and subsequent tumor growth may be attributed to downstream metabolites formed by COX. This study explores the fate of EETs with COX, the angiogenic activity of the primary metabolites formed, and their subsequent hydrolysis by sEH and microsomal EH. Three EET regioisomers were found to be substrates for COX, based on oxygen consumption and product formation. EET substrate preference for both COX-1 and COX-2 were estimated as 8,9-EET > 5,6-EET > 11,12-EET, whereas 14,15-EET was inactive. The structure of two major products formed from 8,9-EET in this COX pathway were confirmed by chemical synthesis: ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) and ct-8,9-epoxy-15-hydroxy-eicosatrienoic acid (ct-8,9-E-15-HET). ct-8,9-E-11-HET and ct-8,9-E-15-HET are further metabolized by sEH, with ct-8,9-E-11-HET being hydrolyzed much more slowly. Using an s.c. Matrigel assay, we showed that ct-8,9-E-11-HET is proangiogenic, whereas ct-8,9-E-15-HET is not active. This study identifies a functional link between EETs and COX and identifies ct-8,9-E-11-HET as an angiogenic lipid, suggesting a physiological role for COX metabolites of EETs.
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Krzyżak, Edward, Dominika Szkatuła, Benita Wiatrak, Tomasz Gębarowski, and Aleksandra Marciniak. "Synthesis, Cyclooxygenases Inhibition Activities and Interactions with BSA of N-substituted 1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones Derivatives." Molecules 25, no. 12 (June 25, 2020): 2934. http://dx.doi.org/10.3390/molecules25122934.
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Inhibition of cyclooxygenase is the way of therapeutic activities for anti-inflammatory pharmaceuticals. Serum albumins are the major soluble protein able to bind and transport a variety of exogenous and endogenous ligands, including hydrophobic pharmaceuticals. In this study, a novel N-substituted 1H-pyrrolo[3–c]pyridine-1,3(2H)-diones derivatives were synthesized and biologically evaluated for their inhibitory activity against cyclooxygenases and interactions with BSA. In vitro, COX-1 and COX-2 inhibition assays were performed. Interaction with BSA was studied by fluorescence spectroscopy and circular dichroism measurement. The molecular docking study was conducted to understand the binding interaction of compounds in the active site of cyclooxygenases and BSA. The result of the COX-1 and COX-2 inhibitory studies revealed that all the compounds potentially inhibited COX-1 and COX-2. The IC50 value was found similar to meloxicam. The intrinsic fluorescence of BSA was quenched by tested compounds due to the formation of A/E–BSA complex. The results of the experiment and molecular docking confirmed the main interaction forces between studied compounds and BSA were hydrogen bonding and van der Waals force.
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Bronger, H., S. Kraeft, A. Stöckel, A. Welk, M. Kiechle, M. Schmitt, and U. R. M. Schwarz-Boeger. "Effect of cyclooxygenase inhibition on CXCR3 ligand secretion in breast cancer." Journal of Clinical Oncology 29, no. 27_suppl (September 20, 2011): 45. http://dx.doi.org/10.1200/jco.2011.29.27_suppl.45.
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45 Background: In murine cancer models, the two IFN-γ inducible chemokines CXCL9 and CXCL10, those bind to the common receptor CXCR3, recruit NK cells and tumor-suppressive lymphocytes into the tumor site and impair tumor growth and metastatic spread. In human breast cancer (BC), we and others have shown that high levels of CXCL9 mRNA correlate with favorable prognosis and the number of infiltrating lymphocytes. Raising the intratumoral level of CXCR3 ligands might therefore be a feasible way to enhance the infiltration by tumor-suppressive immune cells and to improve immune intervention in breast cancer. Inhibition of cyclooxygenases (COX) has been shown to inhibit tumor growth and metastases formation in a lymphocytic and IFN-γ dependent manner. We therefore tested whether COX inhibition induces CXCR3 ligand secretion from breast cancer cells. Methods: Human MCF-7 and MDA-MB 231 BC cells were stimulated with IFN-γ with or without prostaglandin E2 (PGE2) or COX inhibitors (indomethacin, aspirin, celecoxib). CXCL9 and CXCL10 release was measured by ELISA. COX-1 and COX-2 expression was measured in 45 BC samples and correlated with intratumoral CXCR3 ligand concentration. Results: Prostaglandin E2 inhibits CXCL10 and CXCL9 release from breast cancer cells. Aspirin and indomethacin enhance the INF-γ mediated secretion of these CXCR3 ligands by inhibition of endogenous cyclooxygenases. Celecoxib has this effect only at low concentrations, at higher concentrations is shows PGE2 agonistic effects. In human breast cancer samples, COX-2 overexpression inversely correlates with CXCR3 ligand concentration, which shows that the mechanism of PGE2 induced CXCL9/CXCL10 suppression might also be relevant in vivo. Conclusions: Suppressing endogenous PGE2 by cyclooxygenase inhibition increases CXCL9 and CXCL10 release from breast cancer cells and is therefore a feasible way to enhance the infiltration of breast tumors by tumor-suppressive lymphocytes. However, our results show that unselective COX inhibitors might be more suitable than the COX-2 specific celecoxib. Clinical trials are now warranted to clarify the mechanisms and therapeutic efficacy of COX inhibition in breast cancer.
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Legan, Mateja, Boštjan Luzar, Vera Ferlan-Marolt, and Andrej Cör. "Cyclooxygenase-2 Expression Determines Neoangiogenesis in Gallbladder Carcinomas." Bosnian Journal of Basic Medical Sciences 6, no. 4 (October 20, 2006): 58–63. http://dx.doi.org/10.17305/bjbms.2006.3122.
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Neo-angiogenesis may have an important role in the poor prognosis of gallbladder carcinoma. An enhanced expression of COX-2 was found in precancerous lesions and in gallbladder carcinoma, likely to be involved in carcinogenesis as well as in angiogenesis. To study the relationships between the COX-2 expression and degree of vascularization, as well as to evaluate their role in the prognosis of patients with gallbladder carcinoma. 27 cases of gallbladder adenocarcinoma were included, classified grading I-III according the WHO classification. The COX-2 and endothelial antigen CD105 expressions were assessed immunohistochemically. COX-2 expression was evaluated according to the percentage and staining intensity of positive cells into "COX-2 positive" and "COX-2 negative" groups. In order to assess tumor microvessel density (MVD), CD105 positively stained microvessels were counted for each specimen in predominantly vascular areas (hot spots) at 200 x magnification. The MVD ranged from 9 to 46 microvessels/field. 15 tumors belonged to the hypervascular group (MVD > or = 25) and 12 to the hypovascular group. There were 16 (59.2%) COX-2 positive cases. There was difference in the degree of angiogenesis between COX-2 positive vs. COX-2 negative group: 11 (68.8%) out of 16 "COX-2 positive" tumors were hypervascular, in comparison with just 4 (36.4%) of "COX-2 negative" tumors. Our data show that the MVD corresponds to the COX-2 overexpression in gallbladder carcinomas. Augmented tumor neovascularization induced by COX-2 might be responsible for the poor prognosis in gallbladder carcinoma patients.
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Harris, Raymond C., and Matthew D. Breyer. "Physiological regulation of cyclooxygenase-2 in the kidney." American Journal of Physiology-Renal Physiology 281, no. 1 (July 1, 2001): F1—F11. http://dx.doi.org/10.1152/ajprenal.2001.281.1.f1.
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In adult mammalian kidney, cyclooxygenase-2 (COX-2) expression is found in a restricted subpopulation of cells. The two sites of renal COX-2 localization detected in all species to date are the macula densa (MD) and associated cortical thick ascending limb (cTALH) and medullary interstitial cells (MICs). Physiological regulation of COX-2 in these cellular compartments suggests functional roles for eicosanoid products of the enzyme. COX-2 expression increases in high-renin states (salt restriction, angiotensin-converting enzyme inhibition, renovascular hypertension), and selective COX-2 inhibitors significantly decrease plasma renin levels, renal renin activity, and mRNA expression. There is evidence for negative regulation of MD/cTALH COX-2 by angiotensin II and by glucocorticoids and mineralocorticoids. Conversely, nitric oxide generated by neuronal nitric oxide synthase is a positive modulator of COX-2 expression. Decreased extracellular chloride increases COX-2 expression in cultured cTALH, an effect mediated by increased p38 mitogen-activated protein kinase activity, and, in vivo, a sodium-deficient diet increases expression of activated p38 in MD/cTALH. In contrast to COX-2 in MD/cTALH, COX-2 expression increases in MICs in response to a high-salt diet as well as water deprivation. Studies in cultured MICs have confirmed that expression is increased in response to hypertonicity and is mediated, at least in part, by nuclear factor-κB activation. COX-2 inhibition leads to apoptosis of MICs in response to hypertonicity in vitro and after water deprivation in vivo. In addition, COX-2 metabolites appear to be important mediators of medullary blood flow and renal salt handling. Therefore, there is increasing evidence that COX-2 is an important physiological mediator of kidney function.
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Saadi, Esraa, Rapita Sood, Ido Dromi, Ranin Srouji, Ossama Abu Hatoum, Sharon Tal, and Liza Barki-Harrington. "Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation." International Journal of Molecular Sciences 21, no. 9 (April 30, 2020): 3195. http://dx.doi.org/10.3390/ijms21093195.
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Accumulating evidence suggests that the cyclooxygenase-2 (COX-2) enzyme has additional catalytic-independent functions. Here we show that COX-2 appears to be cleaved in mouse and human tumors, which led us to hypothesize that COX-2 proteolysis may play a role in cell proliferation. The data presented herein show that a K598R point mutation at the carboxyl-terminus of COX-2 causes the appearance of several COX-2 immunoreactive fragments in nuclear compartments, and significantly enhances cell proliferation. In contrast, insertion of additional mutations at the border of the membrane-binding and catalytic domains of K598R COX-2 blocks fragment formation and prevents the increase in proliferation. Transcriptomic analyses show that K598R COX-2 significantly affects the expression of genes involved in RNA metabolism, and subsequent proteomics suggest that it is associated with proteins that regulate mRNA processing. We observe a similar increase in proliferation by expressing just that catalytic domain of COX-2 (ΔNT- COX-2), which is completely devoid of catalytic activity in the absence of its other domains. Moreover, we show that the ΔNT- COX-2 protein also interacts in the nucleus with β-catenin, a central regulator of gene transcription. Together these data suggest that the cleavage products of COX-2 can affect cell proliferation by mechanisms that are independent of prostaglandin synthesis.
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Pannunzio, Alessandra, and Mauro Coluccia. "Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature." Pharmaceuticals 11, no. 4 (October 11, 2018): 101. http://dx.doi.org/10.3390/ph11040101.
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Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE2) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway and to the effects of prostaglandins already known for their ability of affecting the tumor phenotype. A knowledge-based choice of the most appropriate tumor cell models, and a major effort in investigating the COX-1 issue in the more general context of arachidonic acid metabolic network by using the systems biology approaches, should be strongly encouraged.
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Rassnick, Kenneth M., and Bradley L. Njaa. "Cyclooxygenase-2 Immunoreactivity in Equine Ocular Squamous-Cell Carcinoma." Journal of Veterinary Diagnostic Investigation 19, no. 4 (July 2007): 436–39. http://dx.doi.org/10.1177/104063870701900419.
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Squamous-cell carcinoma (SCC) is the second most common tumor in horses, and 40%-50% may occur in ocular and adnexal structures. Cyclooxygenase (COX)-2 is an inducible enzyme responsible for the production of prostaglandins that control cell growth and the development and progression of cancer. Mechanisms responsible for the initial upregulation of COX-2 in neoplasia are unclear; prolonged sunlight exposure and mutations in the p53 gene may be possibilities. Because the etiopathogenesis of ocular SCC in horses may involve ultraviolet sunlight and p53 mutations, the purpose of this study was to characterize the immunoreactivity of COX-2 in these tumors. Cyclooxygenase-2 expression was found in 6 of 22 (27%) paraffin-embedded equine SCCs. Cyclooxygenase-2 immunoreactivity was associated with the mitotic index ( P < 0.001). Strategies to inhibit COX-2 by the use of topical or systemic COX-2 inhibitors might prove to be a safe and economical treatment in some horses with SCC.
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Joo, Sun Hyung, Bum Soo Kim, Sung Il Choi, Jeong Yoon Song, Kil Yeon Lee, Yun Wha Kim, Gyo Young Kim, Suk Hwan Lee, Sang Mok Lee, and Sung Wha Hong. "Cyclooxygenase (COX)-1, Cyclooxygenase (COX)-2 and E-cadherin Expression in Colorectal Cancer Patients with Hepatic Metastasis." Journal of the Korean Surgical Society 78, no. 3 (2010): 177. http://dx.doi.org/10.4174/jkss.2010.78.3.177.
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Griswold, Don E., and Jerry L. Adams. "Constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2): Rationale for selective inhibition and progress to date." Medicinal Research Reviews 16, no. 2 (March 1996): 181–206. http://dx.doi.org/10.1002/(sici)1098-1128(199603)16:2<181::aid-med3>3.0.co;2-x.
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Abdelwahab, Siddig Ibrahim, Mohammed Al-Mamary, Khaled Hassanein, Manal Mohamed Elhassan Taha, Abdullah Farasani, and Hassan Alhazmi. "Effects of anti-cyclooxygenases (COX-1 and COX-2), structure activity relationship, molecular docking and in silico ADMET of some synthesized chalcones." Tropical Journal of Pharmaceutical Research 21, no. 11 (February 16, 2023): 2419–27. http://dx.doi.org/10.4314/tjpr.v21i11.22.
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Purpose: To develop effective cancer chemopreventive and anti-inflammatory agents, a series of chalcones were prepared by reacting suitable aromatic aldehyde with appropriate acetophenones.
Methods: Twenty-four synthesized chalcones (namely, 1 - 24) were assessed for their in vitro anti-cyclooxygenase-1 (COX-1) and anti-cyclooxygenase-2 (COX-2) activity in a COX catalyzed prostaglandin synthesis bioassay. Molecular docking was done to investigate the ligand-protein interactions, and selectivity on both enzymes. ADMET (absorption, distribution, metabolism, excretion, toxicity) modeling and software were also used.
Results: The compounds inhibited both COX-1 and COX-2. Two compounds (3 and 19) demonstrated more marked COX-2 inhibition than compound 1. Indomethacin as a standard anti-cyclooxygenase shows unselective inhibition of 81.44 ± 6.5 and 91 ± 9.5, respectively. The in silico data revealed that a chalcone skeleton with C=O at 4-position, C2–C3 double bond and OH at 5-position are necessary properties for anti-cyclooxygenase effects. It was also revealed that the propenone moiety comprises of an appropriate scaffold which proposes a new acyclic 1,3-diphenylprop-2-en-1-ones with selective anti-COX effects. A molecular modeling investigations where these chalcones 1, 3 and 19 were docked in the active site of COX-2 depicted that the p-CH3 substituent on the C-4- phenyl ring A are oriented in the vicinity of the COX-2 secondary pocket Phe381, Gly526, Tyr385 and Val349.
Conclusion: Based on the screening for oral bioavailability, in silico ADMET, and toxicity risk assessment, this study shows that these compounds could be a cornerstone for the development of new pharmaceuticals in the battle against COX-associated inflammatory disorders.
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Naruse, Takahiro, Yukihiro Matsuyama, and Naoki Ishiguro. "Cyclooxygenase-2 expression in ependymoma of the spinal cord." Journal of Neurosurgery: Spine 6, no. 3 (March 2007): 240–46. http://dx.doi.org/10.3171/spi.2007.6.3.240.
Full textAbstract:
Object Cyclooxygenase-2 (COX-2), also known as prostaglandin endoperoxide synthase, has been reported to play an important role in the tumorigenicity of many types of tumors. The expression of COX-2 in spinal ependymomas, however, has not been studied. The authors evaluated COX-2 expression in ependymoma of the spinal cord. Methods Sixteen ependymoma samples obtained in patients undergoing surgery between 1995 and 2004 were utilized for immunohistochemical studies to evaluate COX-2 and vascular endothelial growth factor (VEGF) expression. Intratumoral microvessels were also stained immunohistochemically using anti–human von Willebrand factor antibody and were quantified to determine the microvessel density (MVD). The clinical features were reviewed and recorded and the association with COX-2 expression was assessed. Seven (43.8%) of the 16 ependymoma specimens expressed COX-2. All three of the myxopapillary-type ependymomas exhibited COX-2–positive staining. Excluding the three myxopapillary-type cases, COX-2 expression was identified in four (30.8%) of 13 cellular-type ependymomas. The COX-2–positive samples exhibited a significant increase in VEGF-positive staining cells and MVD compared with COX-2-negative samples. The clinical features were not associated with COX-2 expression. Conclusions The results of the present study indicate that COX-2 expression may promote angiogenesis through VEGF expression in ependymomas of the spinal cord. It is suggested that the use of selective COX-2 inhibitors may provide a new therapeutic strategy for spinal cord ependymomas due to their inhibition of the COX-2-mediated angiogenesis.
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Rachmania, Rizky Arcinthya, Hariyanti Hariyanti, Ririh Zikriah, and Aditya Sultan. "Studi In Silico Senyawa Alkaloid Herba Bakung Putih (Crinum Asiaticum L.) pada Penghambatan Enzim Siklooksigenase (COX)." Jurnal Kimia VALENSI 4, no. 2 (November 30, 2018): 124–36. http://dx.doi.org/10.15408/jkv.v4i2.7686.
Full textAbstract:
Inflammation is a response to tissue injury involving the physiological process of cyclooxygenase enzyme activation which has two isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. The use of anti-inflammatory drugs of Non Steroidal Anti Inflammatory (AINS) and steroid groups has side effects in long-term use. The objective of this study was to find out eight active white herbic alkaloid compounds (Crinum asiaticum L.) to be used as anti-inflammatory by inhibiting COX-1 and COX-2 enzymes. Molecular docking method for the prediction of complex structures of proteins called ligand-protein docking using the PLANTS 1.2 software. where the lowest ChemPLP score which is free energy is the molecular tethering parameter. The herbaceous white herbaceae compound obtained the lowest CHEMPLP score of hippadine -83.3684 Kcal / mol and pratorimin -83.2661 Kcal / mol and aspirin comparator -67.3292 Kcal / mol and paracetamol -66.3535 Kcal / mol. Molecular docking in COX-2 shows lycobetaine -87.3991 Kcal / mol is lower than that of the celecoxib -85.3729 Kcal / mol comparator against the cyclooxygenase-2 receptor (COX-2). These results show that the white lycopene alkaloid compounds hyppadine, pratorimin and lycobetaine have better affinity and stability than the comparative compounds. The results of drug scans, hippadin, pratorimin and lycobetaine have the criteria for oral preparations. It can be concluded that herbaceous white herbaceae are predicted to have potential as anti-inflammatory compounds.
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Chida, M., and N. F. Voelkel. "Effects of acute and chronic hypoxia on rat lung cyclooxygenase." American Journal of Physiology-Lung Cellular and Molecular Physiology 270, no. 5 (May 1, 1996): L872—L878. http://dx.doi.org/10.1152/ajplung.1996.270.5.l872.
Full textAbstract:
Cyclooxygenase-2 (COX-2) is an inducible cyclooxygenase enzyme and may play an important role in the pathogenesis of lung injury and in pulmonary vascular remodeling. In this study we determined the effects of acute or chronic hypoxia on COX-2 induction and its modulation by .NO and adenosine 3'-5'-cyclic monophosphate (cAMP). Isolated perfused rat lungs were exposed to a normoxic gas mixture or a hypoxic gas mixture for 3 h. Northern blot analysis showed that 3 h of acute hypoxia were sufficient to increase COX-2 but not COX-1 transcripts in the lung. COX-2 expression induced by acute hypoxia was enhanced by an inhibitor of nitric oxide synthase, N(G)-nitro-L-arginine methyl ester, and was suppressed by sodium nitroprusside, meclofenamate, and H-7 (an inhibitor of protein kinase A and C). COX-2 expression was also enhanced by dibutyryl cAMP and iloprost, a prostacyclin analogue. In contrast, 2 wk of chronic hypobaric hypoxia did not enhance COX-2 expression in the lung, but increased COX-2 protein levels, as assessed by Western blots. We conclude that acute hypoxia induces COX-2 gene expression in rat lung and that COX-2 induction by acute hypoxia is modulated by .NO, cAMP, and cyclooxygenase products. In particular, prostacyclin produced by the lung during hypoxia or shear stress induces lung COX-2 expression via a positive feedback mechanism.
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Wang, Hongbo, Yan Wen, Stephen Mooney, Barry Behr, and Mary Lake Polan. "Phospholipase A2 and Cyclooxygenase Gene Expression in Human Preimplantation Embryos." Journal of Clinical Endocrinology & Metabolism 87, no. 6 (June 1, 2002): 2629–34. http://dx.doi.org/10.1210/jcem.87.6.8532.
Full textAbstract:
Phospholipase A2 (PLA2) and cyclooxygenase (COX) are two key enzymes in PG synthesis; the latter has two forms, COX-1 and COX-2. mRNA was extracted from single preimplantation embryos and examined for PLA2, COX-1, and COX-2 gene expression by RT-PCR to investigate whether PLA2 and COX genes are expressed in human preimplantation conceptuses from zygote to blastocyst stage and to compare COX-1 and COX-2 gene expression within the same stage of embryonic development. Expression of PLA2, COX-1, and COX-2 was detected in 48, 37, and 45%, respectively, of total embryos examined. COX-1 was expressed in approximately 66% of early human preimplantation embryos from zygote to two-cell stage, whereas COX-2 was expressed in about 58% of later stage embryos from eight-cell to blastocyst stage (P < 0.05). Furthermore, COX-2 mRNA and protein were localized to trophectoderm in blastocyst stage embryos. In conclusion, PLA2, COX-1, and COX-2 are expressed during early human embryonic development and may contribute to the production of PGs such as PGE2 in human embryogenesis. COX-1 and COX-2 are differentially expressed, with COX-2 being primarily expressed by trophectoderm in late-stage human preimplantation embryos, which may promote embryonic differentiation and implantation.
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Brust, Anja-Kristina, Holger K. Ulbrich, Gail M. Seigel, Norbert Pfeiffer, and Franz H. Grus. "Effects of Cyclooxygenase Inhibitors on Apoptotic Neuroretinal Cells." Biomarker Insights 3 (January 2008): BMI.S692. http://dx.doi.org/10.4137/bmi.s692.
Full textAbstract:
Glaucoma is characterized by a loss of retinal ganglion cells (RGC) which is associated with a decrease of visual function. Neuroprotective agents as a new therapeutic strategy could prevent the remaining neurons from apoptotic cell death. Previous studies have shown the involvement of the Cyclooxygenase (COX)-2 signalling in the apoptotic death of neurons. Herein we investigated the neuroprotective effect of COX-1/COX-2- and selective COX-2- inhibitors on apoptotic. R28, a neuroretinal cell line and determined the PGE2 levels by ELISA. Furthermore we investigated differences in protein expression in the cells after exposure to elevated pressure compared to untreated cells by ProteinChip analysis. In addition, a protein profiling study of the cells after exposure to elevated pressure was performed. The protein expression profiles were measured by SELDI-TOF (Surface Enhanced Laser Desorption/Ionization-time of flight) Protein Chips. The protein identification was performed by mass spectrometry (MS). It could be shown that COX-2 inhibition significantly prevented the cells from apoptosis and reduced the PGE2 concentrations. Selective COX-2 inhibitors were significant more potent than non-selective inhibitors or COX-1 inhibitors. We found differently expressed protein patterns in neuroretinal cells cultured at atmospheric pressure compared to those cells exposed to elevated pressure with or without celecoxib respectively. We identified three biomarkers, ubiquitin, HSP10 and NDKB, which were differently expressed in the groups. However, our data indicates a distinct neuroprotective effect of COX-2 inhibition. The local treatment with selective COX-2 inhibitors might provide an innovative strategy of therapeutic intervention for glaucoma.