Dissertations / Theses: 'Cyclooxygenase'

1

Gilroy, Derek William. "Cyclooxygenase 2 inflammation." Thesis, Queen Mary, University of London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265077.

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2

Chen, Suzi Su-Hsin, and suzi chen@med monash edu au. "Cyclooxygenase Expression in Human Diabetes." RMIT University. Medical Sciences, 2007. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080206.121439.

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Cyclooxygenase (COX) is the rate limiting enzyme that catalyses the production of prostanoids, which are crucial to vascular homeostasis. Evidence suggests that endothelial dysfunction and inflammation play a role in vascular complications in aging and diabetes. Previous animal studies by our laboratory at RMIT University reported enhanced COX expression with aging in rat aortas, platelets and monocytes. Potentially, alteration in COX expression may result in an imbalanced prostanoid production favoring the synthesis of vasoconstrictors and hence increase the risk of cardiovascular events in the aging population. The regulation of altered COX expression in aging, however, is not clear. It has been suggested that histone hyperacetylation may be an important mechanism that regulates COX levels during the aging process as increased histone acetylation has been shown to occur with aging. Thus, we hypothesized that COX expression is modulated by histone hyperacetylati on. This was investigated by measuring COX expression in histone hyperacetylated cultured endothelial cells. In the case of diabetes, studies have reported that the development of diabetes and its complications is associated with persistent inflammatory activity, evident with increased inflammatory markers in the circulation. COX-mediated pathways may be involved in this inflammatory process in diabetes. Furthermore, the formation of advanced glycation end products (AGEs) is accelerated in diabetes. AGEs can bind to receptors for AGEs (RAGE), which has also been suggested to play a role in inflammation in diabetes. We hypothesized that COX- and RAGE-mediated pathways contribute to increased inflammation in diabetes and potentiate the development of diabetic vascular complications. This was investigated by measuring changes in COX-mediated pathways in both rat and human diabetic models. The current thesis reports: 1) in cultured endothelial cells, histone hyperacetylation was associated with increased COX expression; 2) an overall increase in inflammation was observed in diabetes involving COX- and RAGE-mediated pathways. This was supported by increased platelet COX-1 and monocyte COX-2 levels in Zucker rats, increased monocyte COX-2 in human Type 1 diabetes and elevated plasma TXB2 and PGE2 levels in both human Type 1 and Type 2 diabetic subjects. Up-regulation of RAGE expression was further found in platelets and monocytes in both human diabetes types. When treated with NSAIDs, plasma prostanoid levels, COX and RAGE expression were reduced significantly in both platelets and monocytes in human diabetic subjects. 3) It is unclear how COX and RAGE expression was regulated, but histone modifications may be one of the mechanisms. Data from cultured cells indicated that increased COX expression was associated with increased histone acetylation levels induced by TSA. Concurrent increases in histone acetylation and COX-2 levels were also observed in human Type 1 diabetes, but similar findings were not observed in human Type 2 diabetes. In addition, we failed to find an age-dependent increase in monocyte histone H4 acetylation in human Type 2 diabetes despite an age-dependent increase in monocyte COX-2 expression. Thus, whether histone hyperacetylation modulates COX expression and in what conditions require further investigation.

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3

Cahlin, Christian. "Cyclooxygenase activity and tumor progression /." Göteborg : Departments of Surgery and Transplantation, Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, 2008. http://hdl.handle.net/2077/18198.

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4

Xu, Yibing. "Studies on Cyclooxygenase-1, its Structure and Splice Variants, and Modulation of Cyclooxygenase-2 by Inducible Nitric Oxide Synthase and Novel Phytochemicals." BYU ScholarsArchive, 2006. https://scholarsarchive.byu.edu/etd/6208.

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Cyclooxygenases (COXs) are of important therapeutic value as they are the target site of aspirin-like drugs. Here I report nine new COX-1 splice variants in chapter 1, which I characterized with regard to heme-binding and other properties. Inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) are co-inducible in many tissues following mitogenic and proinflammatory stimulation. In chapter 2, I investigate the physical and enzymatic properties of human COX-2 and iNOS and demonstrate that, despite reports to the contrary by another laboratory, they do not interact. The only reported COX-1 splice variant to exhibit cyclooxygenase activity has been isolated from dog brain and is termed COX-3. It contains an in-frame insertion of intron 1. However the existence of human COX-3 remains questionable since intron 1 is out of frame. Two putative in-frame human COX-3 isozymes, COX-1b2 and COX-1b3, (herein designated as COX-3-72 and COX-3-50) have been reported in the literature, but only one of them, COX-3-72, has been characterized. In chapter 3, COX-3-50 and COX-3-72 are reported to be over-expressed and determined to be active cyclooxygenases. COX-3-72 and, to a greater extent, COX-3-50, were stimulated by rofecoxib at physiological concentrations. A similar rofecoxib-stimulated COX activity is observed in quiescent A549 cells. Immunoblot and immunoprecipitation analysis suggest that human platelet and potentially A549 cells, contain a COX-3-50 like protein. Lonicera japonica is used as an anti-inflammatory treatment in traditional Chinese medicine. Its working mechanism is not well known. In chapter 4, I report that extracts from this herb inhibit COX-2 by three mechanisms: direct inhibition, transcriptional and post-transcriptional down regulation. COX-1 and COX-2 are similar to each other in their crystallographic structures. One of the most striking differences is that there are eight amino acids immediately following the signal peptide in COX-1 which are not found in COX-2. The function of this sequence is unknown. In chapter 5, I found that deletion of these amino acids decreased COX-1 Vmax by approximately 4-fold, but had little effect on other properties of the enzyme. Selecting bacteria transformed with recombinant plasmids is a laborious step in gene cloning experiments. This selection process is even more tedious when large numbers of clones need to be screened. In appendix I, I describe an ultra fast plasmid screening method. This new method was frequently used in the experiments performed in chapters 2-6.

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5

Müller, Berit Maria. "Expression der Cyclooxygenase-2 im Mammakarzinom." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=974951161.

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6

Faluyi, Olusola Olusesan. "Cyclooxygenase 2 expression in intestinal tumorigenesis." Thesis, University of Leeds, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275680.

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7

Acton, Stephen Justin. "Post-transcriptional control of cyclooxygenase-2." Thesis, University of Leicester, 2007. http://hdl.handle.net/2381/29531.

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Cyclooxygenase-2 is an early response gene that is rapidly and transiently induced by a variety of extracellular ligands in many cell types, including macrophages and mesangial cells. The 3' untranslated region (UTR) of cox-2 mRNA plays a vital role in its post-transcriptional control by regulating mRNA stability and translation. The proximal 60-nucleotides of the 3' UTR contain highly conserved Adenosine-uridine Rich Elements (AREs)---AUUUA, which are known to regulate mRNA stability and translation.;Insertion of the 1--60 sequence was sufficient to cause a marked decrease (>65%) in expression of a luciferase reporter-gene, in both rat mesangial and RAW 264.7 cells. Although reporter-gene constructs proved unresponsive to stimulation with IL1beta in the rat mesangial cells, a response was seen with LPS in the RAW 264.7 cells, which was dependent on the proximal 20 nucleotides of the 1--60 sequence.;Electromobility shift assays revealed that multiple RNA binding proteins, including HuR, TIA-1, TIAR, hnRNP U and AUF1, interacted with this region of the cyclooxygenaase-2 3' TR, with some noticeable differences occurring following removal of the LPS responsive sequence.;These studies provide further evidence of the role played by the 3 ' UTR in the post-transcriptional control of cyclooxygenase-2, as well as identifying several RNA binding proteins likely to be involved in this process.

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8

Müller, Berit Maria. "Expression der Cyclooxygenase-2 im Mammakarzinom." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2005. http://dx.doi.org/10.18452/15245.

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Cyclooxygenasen regulieren die Produktion von Prostaglandinen und spielen eine Rolle bei der Entstehung und Progression maligner Tumore. Versuche mit COX Inhibitoren (NSAIDs) zeigten im Tiermodell eine deutliche Reduktion von Inzidenz und Größe der Tumoren in einer dosisabhängigen Weise. Das Ziel der vorliegenden Arbeit war, das Expressionsmuster der induzierbaren Isoform COX-2 und der konstitutiven Isoform COX-1 im Mammakarzinom zu untersuchen. Die Grundlage der Untersuchung bildeten Tumorproben von 221 Patientinnen mit primärem Mammakarzinom. Diese wurden mittels immunhistochemischer Methoden auf beide COX-Isoenzyme untersucht. Eine erhöhte COX-2 Expression wurde in 36% der untersuchten Mammakarzinome festgestellt. Sie korrelierte signifikant mit verschiedenen klinisch-pathologischen Parametern, insbesondere mit einem positiven Lymphknotenstatus, einer geringen Differenzierung und einer Tumorgröße >20 mm. Eine erhöhte COX-1 Expression wurde in 45% der untersuchten Tumoren gefunden und korrelierte signifikant mit kleineren und nicht in regionäre Lymphknoten metastasierten Karzinomen. In der univariaten Überlebensanalyse stellte sich eine positive COX-2 Expression im Gegensatz zur COX-1 sowohl im rezidivfreien Überleben als auch im Gesamtüberleben als prognostisch relevant heraus. In der multivariaten Analyse erreichte eine erhöhte COX-2 Expression eine grenzwertige statistische Signifikanz als unabhängiger Parameter innerhalb des rezidivfreien Überlebens. Eine erhöhte COX-1 Expression erreichte keinen statistisch signifikanten Einfluß auf die Prognose. Aufgrund dieser Ergebnisse ist somit eine erhöhte COX-2 Expression im Mammakarzinom mit prognostisch ungünstigen Faktoren assoziiert. Inwieweit selektive COX-2 Inhibitoren als Therapeutika geeignet sind, werden die Ergebnisse weiterer Studien zeigen.
Cyclooxygenases regulate the production of prostaglandins and play a role in tumor development and progression. COX-inhibitors (NSAIDs) showed a significant reduction of tumor incidence and tumor size in rodent models. In this study, we investigated the prognostic impact of expression of both COX-isoforms as well as the association of COX expression and other clinicopathological parameters in primary breast cancer. The expression of COX-1 and –2 was determined by immunohistochemistry retrospectivly in a cohort of 221 women. An elevated expression of COX-2 as the inducible form of the cyclooxygenases was detected in 36% of tumors and was significantly associated with several clinicopathological parameters, for example positive nodal status, poor differentiation and larger tumor size. In contrast, an increased expression of COX-1 was detected in 45% of breast carcinomas and was associated with smaller tumor size and negative nodal status. In univariate survival analysis a significant association between an increased expression of COX-2 and a decreased disease-free survival as well as decreased overall survival was found. An elevated expression of COX-1 had no significant influence on patient prognosis. The data of this study show a prognostic role of COX-2 expression. Further studies on selective COX-2 inhibitors will investigate their role in treatment of patients with breast cancer.

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9

Tarantino, E. "THE ROLE OF CYCLOOXYGENASE-1 (COX-1) AND CYCLOOXYGENASE-2 (COX-2) IN A VENOUS THROMBOSIS MOUSE MODEL." Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/353697.

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Background: Deep vein thrombosis (DVT) is a serious national health problem, and pulmonary thromboembolism (PE) represents the life-threatening most common complication. Venous thromboembolism (VTE), including both these conditions, is traditionally treated with anticoagulant drugs. In particular, vitamin K antagonists and heparins are usually used in the reduction of thrombus development and in secondary prevention. However, the use of these drugs has several limitations: wide variability dose/response relationship between patients and in the same patient, multiple interactions with other drugs/foods, variability of daily doses, need of periodic withdrawals of blood during therapy, problems of overdosing. Then, the discovery of new drugs for VTE needs. The cyclooxygenase isoenzymes, COX-1 and COX-2, catalyse the formation of prostaglandins and, thromboxane from arachidonic acid, and play a critical role in thrombosis. Recent meta-analysis suggests that low-dose aspirin (ASA) reduces the rate of VTE recurrence. In contrast, the clinical use of COX-2 inhibitors seems associated with increased risk of venous thrombosis. However, the role of COX-1 and COX-2 in venous thrombosis remain unclear. Aim: We investigated the impact of COX-1 and COX-2 enzymes in venous thrombosis in order to identify the molecular mechanisms responsible for this effect and develop new therapeutic strategies to prevent venous thrombosis. In particular, we focused on the impact of inhibition of COX-pathway on leukocyte activation, important regulators of formation and propagation of venous thrombus. Methods and Results: Using in vivo and in vitro approaches, we provide evidence that: a) thromboxane, produced by platelets, triggers activation of leukocytes, with consequent development and propagation of venous thrombus induced by inferior vena cava ligation. In particular, we showed that ASA, by inhibiting irreversibly platelet COX-1, prevents platelet thromboxane production resulting in decreased venous thrombosis. b) COX-2 deletion induces platelet hyper-activity and hyper-coagulation state, associated with a reduced fibrinolysis and formation of bigger thrombi. In this scenario, the high levels of tissue factor observed in leukocytes of COX-2KO mouse may explain the positive association observed between administration of COX-2 inhibitors and VTE. Thanking advantage of an accurate, and clinically relevant, technique such as ultrasonography, we are setting a method helpful to monitor thrombus growing and to better understand the pathophysiology of venous thromboembolism. Conclusion: In conclusion, data obtained show that the inhibition of COX-1 and COX-2 in a venous thrombosis mouse model could lead to opposite effect on the thrombus development, stabilization and resolution. In particular, COX-1 inhibition is responsible of an impairment development and growth of venous thrombus, with a mechanism most likely dependent of TXA2/TP pathway. In contrast, COX-2 inhibition caused an increased in thrombus development, growing accompanied with reduction in the thrombus resolution. All data obtained support evidences that both COX-1 and COX-2 play a key role in DVT, opening the way to novel therapeutic approaches.

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10

Bräutigam, Lutz. "Analytik und pharmakologische Effekte selektiver Cyclooxygenase-Inhibitoren." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=970822464.

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11

Meunier, Andreas. "Cyclooxygenase-2 inhibitors and knee prosthesis surgery." Doctoral thesis, Linköping : Department of Clinical and Experimental Medicine, Linköping University, 2008. http://www.bibl.liu.se/liupubl/disp/disp2008/med1077s.pdf.

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12

Buckley, Lisa Rebecca. "Monocyte cyclooxygenase in non-obese diabetic mice." Thesis, Queen Mary, University of London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408136.

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13

Phillips, James Benjamin. "Cyclooxygenase expression and regulation in cultured glia." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393688.

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14

Kunz, Tina. "The Role of Cyclooxygenase-2 in Models of Epilepsy and Traumatic Brain Injury : Effects of Selective Cyclooxygenase-2 Inhibitors." Doctoral thesis, Uppsala University, Department of Pharmaceutical Biosciences, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2543.

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Cyclooxygenase-2 (COX-2) catalyses prostaglandin synthesis from arachidonic acid during inflammation. COX-2 is expressed in the normal brain and is induced in neurological disorders. There is evidence that COX-2 is involved in secondary events leading to cell death in the brain. The first objective was to study the expression of COX-2 in the brain after kainate (KA)-induced limbic seizures and brain trauma caused by controlled cortical contusion (CCC) and fluid percussion injury (FPI). COX-2 mRNA and protein were strongly induced by limbic seizures in the hippocampus, amygdala and piriform cortex. CCC and FPI resulted in an upregulation of COX-2 mainly in the dentate gyrus and cortex, with differences in expression levels in these regions between the models. The second objective was to evaluate the effects of selective COX-2 inhibitors on delayed cell death. Limbic seizures induced cell death in parts of the hippocampus, amygdala and functionally connected regions. Treatment with the selective COX-2 inhibitor rofecoxib 8 h after KA injection significantly reduced hippocampal cell death. Pre-treatment with the COX-2 inhibitor nimesulide augmented acute seizures with increased mortality and thus the effect of nimesulide on delayed cell death could not be evaluated. Effects of rofecoxib on trauma-induced cell death were studied in the FPI model. FPI induced delayed cell death mainly in the ipsilateral cortex and bilaterally in the dentate gyrus. Rofecoxib treatment, starting directly after injury was caused, had no protective effect against cell death.

The results suggest that COX-2 inhibition may be both detrimental and beneficial and largely dependent on the time schedule of treatment. COX-2 inhibitors might thus be of value as a neuroprotective treatment approach, provided that the role of COX-2 and the time course of effects of its metabolites in the brain are elucidated.

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Ringbom, Therese. "Bioassay Development for Identification of Cyclooxygenase-2 Inhibitors of Natural Origin." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5276-0/.

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16

Perchick, Gabrielle Beth. "Cyclooxygenase-2 and prostaglandins in human endometrial function." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/29319.

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The initial aim of the research presented in this thesis was to investigate the temporal expression and signalling of the prostaglandin E₂ pathway in the normal human endometrium across the menstrual cycle. During the course of my PhD, numerous reports were published implicating cyclooxygenase-2 and its products in angiogenesis through the expression of angiogenic factors such as vascular endothelial growth factor, basic fibroblast growth factor and angiopoietins. To investigate the potential role of cyclooxygenase-2 in regulation of endometrial angiogenesis, cDNA array technology was employed to identify differentially expressed genes that may be involved in vascular function. Using this technique, a total of 81 genes were differentially regulated including cathepsin D. Cathepsin D mRNA and protein expression were elevated in the cyclooxygenase-2 antisense cells compared with the sense and wild type cells. Cathepsin D is known to proteolytically cleave plasminogen to the antiangiogenic factor angiostatin. Hence, we investigated the generation of angiostatin from plasminogen in conditioned media collected from cyclooxygenase-2 sense, cyclooxygenase-2 antisense and wild type cells. The cleavage of angiostatin from plasminogen was markedly enhanced in conditioned media from cyclooxygenase-2 antisense cells compared with cyclooxygenase-2 sense and wild type cells. Co-incubation of plasminogen with pepstatin A, a selective cathepsin D inhibitor, markedly reduced the cleavage of angiostatin from plasminogen thus further implicating cathepsin D in the differential angiostatin production by the cyclooxygenase-2 sense and antisense cell lines.

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17

Barrios-Rodiles, Miriam. "Regulation of cyclooxygenase-2 expression in human macrophages." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0033/NQ64507.pdf.

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18

Roberts, Tomos Huw. "Synthetic approaches towards novel cyclooxygenase and lipoxygenase inhibitors." Thesis, Bangor University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265240.

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19

Trivedi, Darshini. "CYCLOOXYGENASE-2-DEPENDENT REMODELING OF THE DUCTUS ARTERIOSUS." UKnowledge, 2007. http://uknowledge.uky.edu/gradschool_diss/537.

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Transition of the cardiopulmonary circulation at birth requires functional closure of the ductus arteriosus (DA). The DA is an arterial shunt that is vital in the fetus for diverting the pulmonary circulation away from the uninflated lungs. Failure of the vessel to functionally close after birth is known as patent DA, which is the second most common congenital heart disease. Patent DA may seriously compromise neonatal health and current pharmacological treatments are often limited by serious complications or a significant failure rate, thereby increasing the necessity for surgical intervention. Recently, we were the first to show that genetic or pharmacological inactivation of cyclooxygenase (COX) -2 produces postnatal patent DA in mice. We also demonstrated that the DA expresses high levels of COX-2 during normal closure after birth, suggesting novel contractile actions of COX-2-dependent prostanoids in the DA. In humans, patent DA is more common in preterm infants than those born at full-term, however, mechanism(s) responsible for the reduced DA closure have not been identified. In the current studies, we examined COX-1 and COX-2 expression in the DA at multiple stages of gestation to determine whether alterations in the expression of these enzymes contribute to patent DA in preterm mice. Using real-time PCR, analysis of the time-course of COX-2 mRNA in the fetal mouse DA indicated that COX-2 expression significantly increased with advancing gestational age. The preterm (day 17.5) neonatal mouse DA showed attenuated COX-2 expression, as compared to the full-term (day 19.5) neonatal DA at 3 hours after birth. Furthermore, the DA of preterm neonatal mice showed incomplete closure after 3 hours of birth, a time-point when the DA of full-term neonates was completely remodeled. These data indicate a correlation between reduced DA closure and attenuated COX-2 expression. Additionally, COX-2 expression was significantly attenuated in the DA of mice deficient in the prostanoid receptor EP4, which also show a patent DA phenotype, suggesting the importance of this receptor for the induction of COX-2 required for DA closure. Overall, these studies suggest that attenuated expression of COX-2 may contribute to increased patent DA at preterm gestation.

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Lau, Kam-shing, and 劉錦成. "The role of cyclooxygenase-1 in liver injury." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31970655.

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Minter, Helena Anne. "The role of cyclooxygenase-2 in oral carcinogenesis." Thesis, University of Bristol, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268830.

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Lau, Kam-shing. "The role of cyclooxygenase-1 in liver injury." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25176547f.

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Hunter, John Cameron. "Multiple Recoding Mechanisms Produce Cyclooxygenase and Cyclooxygenase-Related Proteins from Frameshift-Containing COX-3/COX-1b Transcripts in Rat and Human." BYU ScholarsArchive, 2012. https://scholarsarchive.byu.edu/etd/6149.

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To increase diversity of enzymes and proteins, cells mix and match exonic and intronic regions retained in mature mRNAs by alternative splicing. An estimated 94% of all multi-exon genes express one or more alternatively spliced transcripts generating proteins with similar or modified functions. Cyclooxygenase is a signaling enzyme that catalyzes the rate-limiting step in the synthesis of diverse bioactive lipids termed prostaglandins. Prostaglandins are involved in myriad physiological and pathopysiological processes including vasoregulation, stomach mucosal maintenance, parturition, pain, fever, inflammation, neoplasia and angiogenesis and are inhibited by aspirin-like drugs known as NSAIDs. In 2002 an alternatively spliced, intron-1 retaining variant of COX-1 was cloned from canine brain tissue. This new variant, termed COX-3 or COX-1b, is an enzymatically active prostaglandin synthase expressed at relatively high levels in a tissue and cell type dependant manner in all species examined. In humans and most rodent species intron-1 is 94 and 98 nucleotides long respectively. Retention of the intron in these species introduces a frameshift and is predicted to result in translation of a very small 8-16kD protein with little similarity to either 72kD COX-1 or COX-2, calling into question the role of this variant. In this dissertation, I present my results from cloning and ectopically expressing a complete and accurate COX-3 cDNA from both rat and human. I confirmed that COX-3 mRNA encodes multiple large molecular weight cyclooxygenase-like proteins in the same reading frame as COX-1. Translation of these proteins relies on several recoding mechanisms including cap-independent translation initiation, alternative start site selection, and ribosomal frameshifting. Using siRNA and Western blotting I have identified some of these proteins in tissues and cells. Two COX-3 encoded proteins are active prostaglandin synthase enzymes with activities similar to COX-1 and represent novel targets of NSAIDs. Other COX-3 proteins have unknown function, but their size and cellular location suggest potential roles as diverse as cytosolic enzymes and nuclear factors.

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Tang, Chi-man Terence. "The effect of celecoxib on hepatocellular carcinoma." Click to view the E-thesis via HKUTO, 2005. http://sunzi.lib.hku.hk/hkuto/record/B35774393.

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Kim, Janet Heejung. "Cyclooxygenase-2 Expression in Post-Mastectomy Chest Wall Relapse." Yale University, 2006. http://ymtdl.med.yale.edu/theses/available/etd-06282006-104942/.

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The purpose of this study was to assess the prognostic significance and clinical correlations of cyclooxgenase-2 expression (COX) in a cohort of patients treated with radiation (RT) for post-mastectomy chest wall relapse (PMCWR). Between 1975 and 1999, 113 patients were treated for isolated PMCWR. All patients were treated with biopsy and/or excision of the CWR followed by RT. Median follow-up was 10 years. All clinical data including demographics, pathology, staging, receptor status, HER-2/neu status, and adjuvant therapy were entered into a computerized database. Paraffin-embedded CWR specimens were retrieved from 42 patients, of which 38 were evaluated, created into a tissue microarray, stained by immunohistochemical methods for COX, and graded 0-3+. A score of 2-3+ was considered positive. Overall survival from original diagnosis for the entire cohort was 44% at 10 years. Survival rate after chest wall recurrence was 28% at 10 years. The distant metastasis-free survival rate after CWR was 40% at 10 years. Local-regional control of disease was achieved in 79% at 10 years after CWR. COX was considered positive in 13 of 38 cases. COX was inversely correlated with ER (p= .045) and PR (p = .028), and positively correlated with HER-2/neu (p =.003). COX was also associated with a shorter time to PMCWR. The distant metastasis-free rate for COX negative patients was 70% at 10 years, compared with 31% at 10 years for COX-2 positive patients (p = 0.029). COX positive had a poorer local-regional progression-free rate of 19% at 10 years, compared with 81% at 10 years for COX negative (p = 0.003). Outcome following RT for PMCWR is relatively poor. Positive COX correlated with other markers of poor outcome including a shorter time to local relapse, negative ER/PR and positive Her-2/neu status. Positive COX correlated with higher distant metastasis and lower local-regional control of disease. If confirmed with larger studies, these data have implications with respect to the concurrent use of COX-2 inhibitors and radiation for PMCWR.

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Panter, Katerine Ruth. "Cyclooxygenase expression and inhibition and tocolysis in preterm labour." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391614.

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27

Leung, Edmund. "Cyclooxygenase-2 and its role in colorectal cancer metastasis." Thesis, University of Warwick, 2009. http://wrap.warwick.ac.uk/3160/.

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Studies have shown that elevated COX2 expression in colorectal cancer is associated with enhanced metastasis, although the mechanism is unclear. Cancer cells are characterised by the ability of invasive cells detaching from the primary site by downregulation of adhesion molecules such as E-Cadherins. Subsequently, these cells invade through basement membrane onto extracellular matrix by metalloproteinases (MMP). Interaction of cells and extracellular matrix involves cell adhesion molecules such as CD44 and b1-integrins. Finally, intravasation requires cancer cells adhering onto endothelium, an interaction between epithelial Sialyl-Lewis Antigens (SLAs) and endothelial (E)-Selectins. Colorectal cancer cell lines (HT29, CaCO2 and Colo205) and human dermal microvascular endothelial cells (HDMECs) were subjected to different agents (LPS, butyrate, dexamethasone, PGE2 and NS398) in order to determine their COX2, MMP2, E-Cadherins, b1-integrins, CD44, SLAs and E-selectins expression. An index of cells’ invasive potential was assayed using Matrigel chamber simulating extracellular matrix and coculture with HDMECs. HT29 expressed more COX2 than CaCO2. Colo205 was COX2-negative. LPS induced COX2 expression in HT29 but had no significant effects on CaCO2 and Colo205, whereas dexamethasone was inhibitory to the same effect. Butyrate did not demonstrate any significant changes to COX2 expression in all cell lines. NS398 caused a dose and time-dependent inhibition of COX2 activity, as demonstrated by PGE2 assay.

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Wilson, Jeremy Ian. "Cyclooxygenase and lipoxygenase as factors in colorectal cancer progression." Thesis, University of York, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441045.

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Edwards, John G. "Angiogenesis, cyclooxygenase-2 and matrix metalloproteinases in malignant mesothelioma." Thesis, University of Leicester, 2003. http://hdl.handle.net/2381/29871.

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Malignant Mesothelioma (MM) is a fatal tumour, related to prior asbestos exposure, of increasing incidence. Current treatment modalities may provide symptom palliation but survival benefits remain unclear. Angiogenesis is essential for tumour growth of greater than 1-2mm in diameter and is stimulated by hypoxia, which is reflected by tumour necrosis (TN). Angiogenesis can be assessed by the intratumoural microvessel density (MVD). Cyclooxygenase(COX)-2 plays a central role in the upregulation of angiogeneic growth factors, such as vascular endothelial growth factor and matrix metalloproteinases (MMPs). Epidermal Growth Factor Receptor (EGFR) is overexpressed in many solid tumours and participates both in COX-2 and MMP upregulation. These factors may be prognostic in solid tumours. A database of MM cases in Leicester from 1987 to 2001 was created. Clinical and pathological prognostic factors were derived. Angiogenesis, TN and EGFR were assessed in 171 MM cases by immunohistochemistry and/or microscopy. COX-2 and MMP expression were analysed prospectively by semi-quantitative Western blotting and gelatin zymography, respectively, in up to 47 snap-frozen samples. TN, COX-2 and MMPs were identified for the first time in MM. MVD, COX-2, and EGFR correlated with TN but not with each other. The prognostic significance of MVD and EGFR were confirmed in the largest series of MM studied. TN, COX-2 and MMP-2 were novel prognostic factors. MVD, TN, EGFR, COX-2 and MMP-2 each contributed both the CALGB and EORTC prognostic scoring systems in multivariate analyses. In addition to establishing new laboratory methods and the prognostic importance of these factors, this work has identified novel targeted therapies for MM. These include anti-angiogenic therapies, such as thalidomide, and COX-2, EGFR and MMP inhibition, all of which are now either under current or future investigation in clinical trials in Leicester and other international centres.

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Kellogg, Aaron. "Effect of Cyclooxygenase (COX)-2 Activation on Diabetic Neuropathy." University of Toledo Health Science Campus / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=mco1211909697.

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Sun, Haipeng. "Regulation of Cyclooxygenase Gene Expression by Glucocorticoids in Cardiomyocytes." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/194896.

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Glucocorticoids (GCs) are endogenous steroid hormones that regulate a number of critical physiological processes. Psychological stress increases the level of GCs in the circulating system. The biological effect of elevated GCs on the heart is not well understood. We found that GCs induced Cyclooxygenase-1 (COX-1) and COX-2 gene expression in cardiomyocytes. COX-1 or COX-2 encodes the rate-limiting enzyme in the biosynthesis of prostanoids, which modulate crucial physiological and pathophysiological responses. The present studies aim to elucidate the signaling transduction pathway and the mechanism underlying GC induced COX expression.Our data demonstrate that GCs activate COX-1 gene expression through transcriptional regulation. COX-1 gene promoter studies support a role of Sp binding site in CT induced COX-1 gene expression. The nuclear protein binding to this site appears to be Sp3 transcription factor. Co-immunoprecipitation assays indicated a physical interaction between GR and Sp3 protein. Silencing of Sp3 transcription factor with small interfering RNA suppressed CT-induced COX-1 promoter activation. These data suggest that the activated GR interacts with Sp3 transcription factor that binds to COX-1 promoter to up-regulate COX-1 gene expression in cardiomyocytes.We also found that administration of GC in adult mice increased the level of COX-2 in the ventricles. With isolated neonatal cardiomyocytes, corticosterone (CT) induces the transcription of COX-2 gene. This response appears to be cardiomyocyte cell type specific and GC receptor (GR)-dependent. CT causes activation of p38 MAPK and subsequently CREB phosphorylation that mediates COX-2 gene expression. Mifepristone, a GR antagonist, failed to inhibit p38 and CREB activation and p38 inhibition failed to prevent activation of GR. These data suggest that two parallel signaling pathways, GR and p38 MAPK, act in concert to regulate the expression of COX-2 gene in cardiomyocytes.In addition to the investigation of mechanism and signaling transduction pathway, I have explored pharmacological agents that modulate COX expression. LY294002, a commonly used PI3K inhibitor, inhibited COX-2 gene expression via a PI3K-independent mechanism. Whereas GSK-3 inhibitors, such as lithium chloride, upregulated COX-2 gene expression, but suppressed GC-induced COX-1 expression. These data have paved the foundation for pharmacological manipulation of COX-1 and COX-2 gene expression in the heart.

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Degner, Stephanie C. "Regulation of Cyclooxygenase-2 by Environmental and Dietary Factors." Diss., The University of Arizona, 2007. http://hdl.handle.net/10150/195632.

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Each year over 260,000 new cases of breast cancer will be diagnosed in the U.S. and approximately 40,000 women will die of metastatic breast cancer. The etiology of breast cancer is poorly understood and only 5 -10% of cases can be attributed to genetic factors. This suggests that the development of breast cancer may involve environmental factors including diet, lifestyle, and exposure to chemicals. Several lines of experimental and epidemiological evidence have highlighted COX-2 as a potential target for breast cancer prevention. The central hypothesis of this proposal is that activation of COX-2 transcription by epigenetic effectors can be prevented by dietary agents that target the activator protein-1 (AP-1) transcription factor and the aromatic hydrocarbon receptor (AhR). The first specific aim was to determine the mechanism through which conjugated linoleic acid (CLA) and rosmarinic acid (RA) inhibit TPA-induced COX-2 trancription. These studies documented that CLA and RA repressed COX-2 transcription by antagonizing the AP-1 transcription factor. The second specific aim was to investigate whether or not the AhR plays a role in TCDD-induced COX-2 transcription and effects of chemopreventive agents. Results indicated that AhR agonists induced the binding of the AhR to COX-2 and was prevented by CLA and the AhR antagonist, resveratrol (RES) and 3-methoxy-4-nitroflavone (3M4NF). The third specific aim was to examine the effects of AhR agonists and dietary selective AhR modulators on chromatin modifications associated with the COX-2 promoter. Chromatin immunoprecipitation (ChIP) assays revealed that the AhR is recruited to the region of the COX-2 promoter containing a xenobiotic response element and accompanied by recruitment of p300 and acetylation of histone H4. Transcriptional regulation of COX-2 by AhR agonists and dietary antagonists may also involve other post-transcriptional modifications of histones, which along with chromatin remodeling factors modulate the structure of chromatin and recruitment of RNA polymerase II. Overall, the results demonstrated that COX-2 transcription can be targeted by a variety of dietary agents that act through different mechanisms. Therefore, inhibition of transcriptional regulation of COX-2 by selected dietary factors may be a breast cancer preventive strategy that bypasses the side effects of drugs that target COX-2.

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Bühler, Nico Martin. "Selektive COX-2 Inhibitoren und Nierenschädigung bei salzsensitiver Hypertonie /." [S.l.] : [s.n.], 2009. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000297941.

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Guo, Xiaoxi. "The function of cyclooxygenase 1 and 2 in fracture repair." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/b4020327x.

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Guo, Xiaoxi, and 郭晓曦. "The function of cyclooxygenase 1 and 2 in fracture repair." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B4020327X.

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Leung, Pui-hong, and 梁沛康. "Structural activity relationship of flavonoids on the expression and activity of cyclooxygenase." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42712129.

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Leung, Pui-hong. "Structural activity relationship of flavonoids on the expression and activity of cyclooxygenase." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B42712129.

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Prosperi, Jenifer Robyn. "In vitro and in vivo characterization of the estrogen dependent human breast cancer cell line, MCF-7, over-expressing cyclooxygenase-2." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1164814953.

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McArthur, David. "Cyclooxygenase-2 and its role in angiogenesis in colorectal cancer." Thesis, University of Warwick, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487970.

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Colorectal cancer (CRC) pathogenesis is multi-factorial and complex. Gaining insight into mechanisms involved in the malignant process opens potential therapeutic and preventative interventions. This thesis details work undertaken to investigate one area ofCRC formation, namely the role that cyclooxygenase-2 (COX-2) has in its development, focussing especially on effects COX-2 has on tumour angiogenesis. COX-2 has been shown to be over-expressed in up to 85% ofCR~s and 50% of adenomas. This discovery caused excitement that COX-2 inhibitors might have roles in the prevention and treatment ofCRC. Further studies have shown that COX-2 influences malignant transformation at numerous levels, including causing reduced apoptosis, increased invasiveness and promoting angiogenesis. However, questions exist including which cells are responsible for COX-2 production, what causes COX2 expression by these cells, and how COX-2 influences cellular interactions in malignancy. Investigations, predominantly employing flow cytometry, were undertaken on CRC cell lines and disaggregated ex vivo CRC specimens. COX-2 expression by cell lines was increased by cytokines. The overall rate ofCOX-2 expression by ex vivo tumour cells was in keeping with that previously reported. However, COX-2 expression was lost when these cells were cultured for 24 hours, an effect not reversed by previously efficacious cytokines, suggesting expression in vivo is dependent on another form of cellular stimulation, possibly from neighbouring cells. High levels ofCOX-2 were discovered in paired normal colonic tissue, opening up the potential that certain individuals express COX-2 prior to cancer development, predisposing to a malignant state; these persons might benefit from COX-2 inhibitors to prevent metachronous lesions. CRC cell lines were co-cultured with human umbilical vein endothelial cells (HUVECs) to investigate COX-2 dependent effects on angiogenesis. Endothelial cell derived COX-2 increased cancer cell invasiveness by increasing ICAM-l, an effect reversed by COX-2 inhibition. COX-2 inhibition also reduced VEGF production by endothelial cells. Additionally, COX-2 levels by the two cell types were maintained at steady state, whereby an increase by HUVECs brought about a reciprocal reduction by cancer cells or vice versa.

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Gardiner, Natalie Jane. "The involvement of the cyclooxygenase pathway in spinal nociceptive processing." Thesis, University of Leicester, 1998. http://hdl.handle.net/2381/29968.

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In recent years evidence has accumulated which suggests that prostaglandins are involved in spinal nociceptive processing. Several studies have shown that spinally-administered prostaglandins evoke characteristic pain behaviour in rats. Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, inhibit the enzyme cyclooxygenase (COX) and thus prevent the formation of prostaglandins. It has been hypothesised that a component of the analgesic properties of NSAIDs may be due to an action in the spinal cord, a theory which is supported by behavioural and electrophysiological studies. The current study shows by Western blotting that the two isoforms of COX, COX-1 and COX-2, are present in rat spinal cord tissue. Furthermore, using immunocytochemical techniques, we have localised COX-2-like immunoreactivity to regions of the spinal cord associated with nociceptive processing, namely the superficial and deep dorsal horn and around the central canal. Spinal COX-2, but not COX-1 is bilaterally upregulated in a time-dependent manner (< 3 days) following the induction of a unilateral inflammation around the ankle joint. An increase in spinal PGE2 levels occurs over the same time course. The basal release of 4 species of prostaglandins was assessed by superfusing the spinal cord with artificial cerebrospinal fluid and analysing the superfusate by radioimmunoassay (PGD2> PGE2> 6-keto-PGF1> PGF2). Using this superfusion technique and an antibody-microprobe technique we detected increases in the spinal release of PGE2 within 30 minutes following acute inflammation. The increased release of PGE2 was maintained for at least 12 hours. Noxious mechanical stimulation also evoked the spinal release of PGE2. In conclusion, we have shown that COX-2 is present in the spinal cord in locations commensurate with an involvement in nociceptive processing. The increase in spinal COX-2 and PGE2 following inflammation suggests that prostaglandins (possibly synthesised by COX-2) may play an active role in modulating spinal nociceptive processing.

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Richards, John Brent. "The effect of cyclooxygenase-2 inhibitors on bone mineral density /." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=99200.

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Objective. The use of cyclooxygenase-2 (COX-2) inhibitors may impair load-induced bone formation but also prevent menopause-associated bone loss. We hypothesized that COX-2 inhibitor use would be associated with an increased bone mineral density (BMD) in postmenopausal women not using estrogen therapy and conversely, a decreased BMD in men.
Methods. We used data from the Canadian Multicenter Osteoporosis Study, a longitudinal, randomly selected, population-based community cohort study. The outcome measure was percent difference in bone mineral density (g/cm2). Using linear regression, we estimated the effect of COX-2 inhibitors on this outcome, while adjusting for important potential confounders.
Results. There were 4780 subjects available for study, of which 394 subjects reported daily COX-2 inhibitor use. In males, daily use of COX-2 inhibitors was associated with a lower BMD at all hip sites (percent difference between users and non-users at total hip: -3.1% [95% confidence interval (CI), -6.0, -0.3]. In post-menopausal women not using estrogen replacement therapy, daily COX-2 inhibitor use was associated with higher BMD at most sites (percent difference at total hip: +3.0% [95% Cl, 0.3, 5.8]).
Conclusions. COX-2 inhibitor use was associated with a lower BMD in men and, on the other hand, a higher BMD in post-menopausal women not using estrogen replacement therapy. Men who have used COX-2 inhibitors may wish to seek a BMD measurement to assess their fracture risk. However, COX-2 inhibitors may have utility in post-menopausal women if bone-selective analogues can be developed.

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Suemanotham, Namphung. "The role of cyclooxygenase enzymes in feline chronic kidney disease." Thesis, Royal Veterinary College (University of London), 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559010.

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Betambeau, Nadine. "Biological effects of cyclooxygenase-2 inhibition in human breast cancer." Thesis, University of London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.536233.

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Mukherjee, Kamalika. "ROLE OF CYCLOOXYGENASE-2 IN ABDOMINAL AORTIC ANEURYSMS IN MICE." UKnowledge, 2012. http://uknowledge.uky.edu/pharmacy_etds/29.

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Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease with no available pharmacological treatment. AAA formation reduces the structural integrity of the vessel and increases the susceptibility to rupture. The inflammatory response within human aneurysmal tissue is characterized by increased expression of cyclooxygenase-2 (COX-2). Similarly, in a mouse model of the disease induced by chronic Angiotensin II (AngII) infusion, we have shown that COX-2 expression in the abdominal aortic smooth muscle layer increases early in the development of the disease. Furthermore, genetic or pharmacological inactivation of COX-2 prior to disease initiation reduces AAA incidence. The current study utilized nonhyperlipidemic mice to determine the effectiveness of COX-2 inhibition initiated after AAA formation. COX-2 inhibitor treatment was initiated 5 days after beginning the AngII infusion, a time-point where significant aneurysmal pathology is observed. COX-2 inhibition with celecoxib significantly reduced the incidence as well as severity of AAAs as compared to the control group. Celecoxib treatment also protected the mice from aortic rupture and death. AAA development is characterized by degradation of the aortic smooth muscle layer with loss of the contractile phenotype. We found that the effectiveness of celecoxib was associated with significantly increased mRNA expression of alpha-actin, SM22alpha and desmin, all of which are markers of a differentiated smooth muscle cell phenotype. Celecoxib treatment also decreased mRNA expression of a marker of dedifferentiated smooth muscle (hyaluronic acid synthase 2). We also examined the role of altered expression of COX-2 in the increased susceptibility of the abdominal segment to AAA formation. We found a prolonged and greater induction of COX-2 in the abdominal aortic smooth muscle layer in contrast to a transient induction of COX-2 in the other regions of the aorta throughout disease progression. Overall, these findings suggest that COX-2 plays an important role in AAA development in mice, and COX-2 inhibition with celecoxib attenuates progression of aneurysm development by maintaining a differentiated phenotype in abdominal aortic smooth muscle cells.

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Ko, Chi Wai Stanley. "Cyclooxygenase-2-mediated macrophage-epithelial cell signalling in intestinal tumorigenesis." Thesis, University of Leeds, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403028.

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Weaver, Sean Anthony. "Expression and regulation of cyclooxygenase 2 in colonic epithelial cells." Thesis, University of Bath, 2001. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760756.

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Sales, Kurt Jason. "Expression and functional role of cyclooxygenase enzymes in cervical carcinoma." Doctoral thesis, University of Cape Town, 2001. http://hdl.handle.net/11427/3149.

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Bibliography: leaves 133-156.
Cervical cancer is considered an important clinical problem in sub-Saharan Africa. Recent studies have suggested that epithelial tumors may be regulated by cyclooxygenase enzyme products. The purpose of this thesis was to determine the expression, localisation and possible functional role of cyclooxygenase enzymes in cervical carcinomas. The initial aim of the study was to determine whether cyclooxygenase-1 and cyclooxygenase-2 expession and prostglandin E₂ synthesis are up-regulated in cervical cancers. Real-time quantitative reverse-transcriptase polymerase chain reaction and Western blot analysis confirmed cyclooxygenase-1 and cyclooxygenase-2 ribonucleic acid and protein expression in all cases of squamous cell carcinoma and adenocarcinoma investigated. In contrast, minimal expression of cyclooxygenase-1 or cyclooxygenase-2 was detected in histologically normal cervix. Immunohistochemical analyses localised the site of cyclooxygenase-1 and cyclooxygenase-2 expression and prostaglandin E₂ synthesis to neoplastic epithelial cells of all squamous cell carcinomas and adenocarcinomas studied.

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Britt, Rodney Deon Jr. "The Role of Cyclooxygenase-2 in Newborn Hyperoxic Lung Injury." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1350400061.

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Saukkonen, Kirsi. "Cyclooxygenase-2 in neoplasias of the lung and the stomach." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/saukkonen/.

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Comer, Brian S. "Cyclooxygenase-2 expression in asthmatic human airway smooth muscle cells." Thesis, University of South Alabama, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3608829.

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Asthmatic human airway smooth muscle cells (hASMCs) exhibit enhanced expression of numerous cytokine-responsive genes but this trend has not been observed for cyclooxygenase-2 (COX-2) expression despite knowledge that conserved regulatory mechanisms exist for cytokine-responsive gene expression. Enhanced expression of cytokine-responsive genes in asthmatic hASMCs has been attributed to differences in histone post-translational modifications and microRNA (miR or miRNA) expression. COX-2 expression is of interest because it serves as a model cytokine-responsive gene and is regulated by epigenetic mechanisms. In other cell types, miR-146a represses COX-2 and Interleukin (IL)-1β expression, directly and indirectly, respectively. Due to sequence homology, miR-146b is predicted to repress the expression of COX-2 and IL-1β. I investigated COX-2 expression in asthmatic and non-asthmatic hASMCS treated with cytomix (IL-1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ). Also, I chose to compare histone acetylation, transcription factor binding, and miR-146a/b expression in asthmatic and non-asthmatic hASMCs to identify any correlations with COX-2 expression. A major goal of this project was to help identify new treatment targets for asthma therapeutics . I hypothesized that asthmatic hASMCs treated with cytomix express more COX-2 and secrete more prostaglandinE2 (PGE2) than non-asthmatic hASMCs due to differences in COX-2 epigenetic regulation. It is reported here that asthmatic hASMCs treated with cytomix expressed more COX-2 (mRNA/protein), and secreted more PGE2 than non-asthmatic hASMCs. Histone H3/H4 pan-acetylation at the COX-2 promoter did not increase with cytomix treatment and was not different in asthmatic and non-asthmatic hASMCs. Treatment of hASMCs with cytomix increased RNA Polymerase II and nuclear factor-κB binding at the COX-2 promoter with no difference between asthmatic and non-asthmatic hASMCs. Treatment of hASMCs with cytomix increased miR-146a and miR-146b expression with greater miR-146a expression in asthmatic. MiR-146a/b expression in asthmatic hASMCs treated with cytomix did not negatively correlate with COX-2 expression. These results led me to investigate whether miR-146a/b were capable of negatively regulating COX-2 and IL-1β expression in hASMCs. MiR-146a and miR-146b mimics reduced COX-2 and IL-1β mRNA/protein, and PGE2 secretion in hASMCs. MiR-146a and miR-146a/b combination inhibition increased COX-2 and pro-IL-1β protein in hASMCs but not miR-146b inhibition alone. In conclusion, elevated miR-146a expression and histone acetylation are not responsible for increased COX-2 expression in asthmatic hASMCs. MiR-146a is a minor negative regulator of COX-2 and IL-1β expression in hASMCs at physiological expression levels but mimics are capable of antagonizing cytokine-responsive gene expression profoundly. These results coupled with other evidence from the literature indicate that miR-146a/b should be investigated in animal models of asthma to determine if they are relevant asthma drug target in patients that do not respond to current anti-inflammatory therapies.

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Dissertations / Theses on the topic 'Cyclooxygenase'

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