1,495 research outputs found

    Selective COX-2 inhibitors and risk of myocardial infarction

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    Selective inhibitors of cyclooxygenase- 2 ( COX- 2, ` coxibs') are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Recently some coxibs, which were designed to exploit the advantageous effects of non- steroidal anti-inflammatory drugs while evading their side effects, have been reported to increase the risk of myocardial infarction and atherothrombotic events. This has led to the withdrawal of rofecoxib from global markets, and warnings have been issued by drug authorities about similar events during the use of celecoxib or valdecoxib/ parecoxib, bringing about questions of an inherent atherothrombotic risk of all coxibs and consequences that should be drawn by health care professionals. These questions need to be addressed in light of the known effects of selective inhibition of COX- 2 on the cardiovascular system. Although COX- 2, in contrast to the cyclooxygenase-1 ( COX- 1) isoform, is regarded as an inducible enzyme that only has a role in pathophysiological processes like pain and inflammation, experimental and clinical studies have shown that COX- 2 is constitutively expressed in tissues like the kidney or vascular endothelium, where it executes important physiological functions. COX- 2- dependent formation of prostanoids not only results in the mediation of pain or inflammatory signals but also in the maintenance of vascular integrity. Especially prostacyclin ( PGI(2)), which exerts vasodilatory and antiplatelet properties, is formed to a significant extent by COX- 2, and its levels are reduced to less than half of normal when COX- 2 is inhibited. This review outlines the rationale for the development of selective COX- 2 inhibitors and the pathophysiological consequences of selective inhibition of COX- 2 with special regard to vasoactive prostaglandins. It describes coxibs that are currently available, evaluates the current knowledge on the risk of atherothrombotic events associated with their intake and critically discusses the consequences that should be drawn from these insights. Copyright (C) 2005 S. Karger AG, Basel

    Immunopresence and functional activity of prostaglandin-endoperoxide synthases and nitric oxide synthases in bovine corpora lutea during diestrus

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    The aim of this study was to evaluate the occurrence and the activity of prostaglandin-endoperoxide synthase 1 (PTGS1), PTGS2, and endothelial, neuronal, and inducible nitric oxide synthase (e-, n-, and iNOS) in early, mid, late, and regressive corpora lutea (CL) of bovines during diestrus. PTGS1 immunoreactivitywas localised mainly in the cytoplasm of small luteal cells, whereas PTGS2 was detected in the cytoplasm of large luteal cells during early, mid, and late stages. The immunoexpression of all NOS isoforms was observed in the nuclei of luteal cells in the CL stages examined. PTGS1 enzyme activity was higher in late CL and lower in regressive ones; PTGS2 increased from early to late CL andlowered in regressive ones. Constitutive NOS enzymatic activity (eNOS plus nNOS) was higher in late CL and lower in regressive ones; iNOS was lower in regressive CL. These results support the idea that PTGSs and NOSs regulate the bovine CL life span mainly during the transition from the luteotrophic to the luteolytic phase

    Immunopresence and functional activity of prostaglandin-endoperoxide synthases and nitric oxide synthases in bovine corpora lutea during diestrus.

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    The aim of this study was to evaluate the occurrence and the activity of prostaglandin- endoperoxide synthase 1 (PTGS1), PTGS2, and endothelial, neuronal, and inducible nitric oxide synthase (e-, n-, and iNOS) in early, mid, late, and regressive corpora lutea (CL) of bovines during diestrus. PTGS1 immunoreactivity was localised mainly in the cytoplasm of small luteal cells, whereas PTGS2 was detected in the cytoplasm of large luteal cells during early, mid, and late stages. The immunoexpression of all NOS isoforms was observed in the nuclei of luteal cells in the CL stages examined. PTGS1 enzyme activity was higher in late CL and lower in regressive ones; PTGS2 increased from early to late CL and lowered in regressive ones. Constitutive NOS enzymatic activity (eNOS plus nNOS) was higher in late CL and lower in regressive ones; iNOS was lower in regressive CL. These results support the idea that PTGSs and NOSs regulate the bovine CL life span mainly during the transition from the luteotrophic to the luteolytic phase

    Glomerulonephritis and Cellular Regulation of Prostaglandin Synthesis

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    Comparative Modeling and Functional Characterization of Two Enzymes of the Cyclooxygenase Pathway in Drosophila melanogaster

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    Eicosanoids are biologically active molecules oxygenated from twenty carbon polyunsaturated fatty acids. Natural eicosanoids exert potent biological effects in humans, and a great deal of pharmaceutical research has led to the discovery of compounds for selective inhibition of specific enzymes in eicosanoid biosynthesis. Coupled with different receptors, eicosanoids mediate various physiological and pathophysiological processes, including fever generation, pain response, vasoconstriction, vasodilation, platelet aggregation, platelet declumping, body temperature maintenance and sleep-wake cycle regulation. In mammals, the eicosanoid biosynthesis has three pathways: the cyclooxygenase (COX) pathway, the lipoxygenase (LOX) pathway and the epoxygenase pathway. The COX pathway synthesizes prostanoids, which are important signaling molecules in inflammation. Because of their central role in inflammatory disease and human health, COX enzymes continue to be a focus of intense research as new details emerge about their mechanism of action and their interactions with NSAIDs. To date, the majority of studies dealing with the COX pathway are centered on mammalian systems. Although the literature is rich in speculations that prostaglandins are central signaling molecules for mediating and coordinating insect cellular immunity, genes responsible for encoding COX or COX-like enzymes and other enzymes in the COX pathway have not been reported in insects. The value of Drosophila melanogaster as a model organism is well established, and the fundamental regulatory signaling mechanisms that regulate immunity at the cellular level in human and flies are conserved. Given the importance of eicosanoids in mammalian and insect immunity, this study was designed to identify and characterize the enzymes that mediate eicosanoid biosynthesis in D. melanogaster computationally. After a preliminary extensive search for putative D. melanogaster homologues for all enzymes in the COX pathway, we conducted a systematic, comprehensive, and detailed computational investigation for two enzymes, COX and prostaglandin E synthase (PGES) in an endeavor to model and characterize the possible candidates and identify those that possess all the requisite sequence and structural motifs to qualify as valid COX(s)/PGE synthase proteins. In this study, we report the presence of qualified D. melanogaster COX(s)/PGE synthase proteins, characterize their biophysical properties, and compare them with their mammalian counterparts. This study lays the groundwork for further exploration of these proteins and establishing their role in D. melanogaster inflammation and immunity, opening up avenues for addressing the use of this model organism in COX signaling and its crosstalk with other signaling pathways

    Ascorbic acid enhances the inhibitory effect of aspirin on neuronal cyclooxygenase-2-mediated prostaglandin E2 production.

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    Inhibition of neuronal cyclooxygenase-2 (COX-2) and hence prostaglandin E2 (PGE2) synthesis by non-steroidal anti-inflammatory drugs has been suggested to protect neuronal cells in a variety of pathophysiological situations including Alzheimer's disease and ischemic stroke. Ascorbic acid (vitamin C) has also been shown to protect cerebral tissue in a variety of experimental conditions, which has been attributed to its antioxidant capacity. In the present study, we show that ascorbic acid dose-dependently inhibited interleukin-1beta (IL-1beta)-mediated PGE2 synthesis in the human neuronal cell line, SK-N-SH. Furthermore, in combination with aspirin, ascorbic acid augmented the inhibitory effect of aspirin on PGE2 synthesis. However, ascorbic acid had no synergistic effect along with other COX inhibitors (SC-58125 and indomethacin). The inhibition of IL-1beta-mediated PGE2 synthesis by ascorbic acid was not due to the inhibition of the expression of COX-2 or microsomal prostaglandin E synthase (mPGES-1). Rather, ascorbic acid dose-dependently (0.1-100 microM) produced a significant reduction in IL-1beta-mediated production of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a reliable indicator of free radical formation, suggesting that the effects of ascorbic acid on COX-2-mediated PGE2 biosynthesis may be the result of the maintenance of the neuronal redox status since COX activity is known to be enhanced by oxidative stress. Our results provide in vitro evidence that the neuroprotective effects of ascorbic acid may depend, at least in part, on its ability to reduce neuronal COX-2 activity and PGE2 synthesis, owing to its antioxidant properties. Further, these experiments suggest that a combination of aspirin with ascorbic acid constitutes a novel approach to render COX-2 more sensitive to inhibition by aspirin, allowing an anti-inflammatory therapy with lower doses of aspirin, thereby avoiding the side effects of the usually high dose aspirin treatment

    N-glycosylation site occupancy in human prostaglandin H synthases expressed in Pichia pastoris

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    Cyclooxygenase-2 and its regulation in inflammation

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    Vasoconstrictor prostanoids

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    In cardiovascular diseases and during aging, endothelial dysfunction is due in part to the release of endothelium-derived contracting factors that counteract the vasodilator effect of the nitric oxide. Endotheliumdependent contractions involve the activation of endothelial cyclooxygenases and the release of various prostanoids, which activate thromboxane prostanoid (TP) receptors of the underlying vascular smooth muscle. The stimulation of TP receptors elicits not only the contraction and the proliferation of vascular smooth muscle cells but also diverse physiological/pathophysiological reactions, including platelet aggregation and activation of endothelial inflammatory responses. TP receptor antagonists curtail endothelial dysfunction in diseases such as hypertension and diabetes, are potent antithrombotic agents, and prevent vascular inflammation. © Springer-Verlag 2009.postprin
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