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First published November 27, 2007; doi:10.1152/ajpendo.00495.2007.-Endocannabinoids have been implicated in the mechanisms of implantation, maintenance of pregnancy, and parturition in women. Intrauterine prostaglandin production ...
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First published November 27, 2007; doi:10.1152/ajpendo.00495.2007.-Endocannabinoids have been implicated in the mechanisms of implantation, maintenance of pregnancy, and parturition in women. Intrauterine prostaglandin production and actions are also critical in each of these mechanisms. Hence, we have evaluated the effects of cannabinoids on prostaglandin biosynthesis by human gestational membranes. Explants of term amnion and choriodecidua were established and treated with the endogenous endocannabinoids 2-arachi-donoyl glycerol and anandamide, as well as the synthetic cannabinoid CP55,940, to determine their ability to modulate PGE2 production. The explants were also treated with CP55,940 in the presence of either SR141716A (a potent and selective antagonist of the cannabinoid receptor CB1) or NS398 [a cyclooxygenase (COX)-2 inhibitor] to determine whether any observed stimulation of PGE2 production was mediated through the CBl-receptor and/or COX-2 activity. All three cannabinoids caused a significant increase in PGE2 production in the amnion but not in the choriodecidua. However, separated fetal (chorion) explants responded to cannabinoid treatment in a similar manner to amnion, whereas maternal (decidual) explants did not. The enhanced PGE2 production caused by CP55,940 was abrogated by cotreatment with either SR141716A or NS398, illustrating that the cannabinoid action on prostaglandin production in fetal membranes is mediated by CB1 agonism and COX-2. Data from Western blotting show that cannabinoid treatment results in the upregulation of COX-2 expression. This study demonstrates a potential role for endocannabinoids in the modulation of prostaglandin production in late human pregnancy, with potentially important implications for the timing and progression of term and preterm labor and membrane rupture.
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Some drugs used to treat noncardiovascular conditions may adversely impact the cardiovascular status of individuals both with and without known cardiovascular disease. When the US Food and Drug Administration judges the potential ...
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Some drugs used to treat noncardiovascular conditions may adversely impact the cardiovascular status of individuals both with and without known cardiovascular disease. When the US Food and Drug Administration judges the potential cardiovascular safety signal to be of sufficient concern, it may require the pharmaceutical manufacturer of the drug in question to conduct a postmarketing (phase 4) randomized controlled trial (RCT). Although historically many phase 4 RCTs focused on efficacy (using a superiority design), contemporary phase 4 RCTs often are focused on safety and use a noninferiority design. The choices made by investigators during the planning stage of a postmarketing phase 4 RCT dedicated to the evaluation of cardiovascular safety can influence the ability to compare the standard and test agents. Multiple factors reflecting the conduct of a phase 4 RCT for a general medical condition may influence interpretation of a cardiovascular safety signal. The higher the rates of failure to adhere to the protocol and dropout from the study, the greater the risk of bias. Trials evaluating the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs) when used for arthritis are difficult to conduct and even more challenging to interpret. Concerns include the comparison of drug regimens that do not provide comparable analgesic efficacy and problems with adherence to the protocol and retention in the study. On the basis of phase 4 RCTs of NSAIDs to date, it appears that a comparatively low dose of celecoxib administered to low-risk subjects is associated with approximately the same cardiovascular risk as NSAIDs with less cyclooxygenase-2 inhibitory activity, but at the cost of not controlling arthritic pain as effectively.
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Cydooxygenase (COX)-2 is involved in many biological functions such as inflammation, fibrosis and carcino-. genesis. Arachidonic acid is freed by phospholipase A2 from phospholipids (e.g. phosphatidylethanolamine, phosphatidylchol...
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Cydooxygenase (COX)-2 is involved in many biological functions such as inflammation, fibrosis and carcino-. genesis. Arachidonic acid is freed by phospholipase A2 from phospholipids (e.g. phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositides) in plasma membrane, and further metabolized by COX or lipoxygenase to eicosanoids acting as second messengers. COX is responsible for the conversion of arachidonic acid to prostaglandin (PG) H2, which is the precursor of other prostaglandins and thromboxane (IX). Currently three isoforms of COX (COX-1, COX-2 and COX-3) are reported. COX-3 is a splice variant of COX-1.
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Increasing evidence suggests that inflammation may be involved in the loss of dopaminergic neurons in Parkinson's disease (PD). Among inflammatory molecules, COX-2, a key kinase for the inflammatory response, has been suggested to...
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Increasing evidence suggests that inflammation may be involved in the loss of dopaminergic neurons in Parkinson's disease (PD). Among inflammatory molecules, COX-2, a key kinase for the inflammatory response, has been suggested to play an important role in dopaminergic neuron loss in PD. However, the upstream molecular pathways of COX-2 expression remain uncertain. In the present study, we investigated the role of c-Jun [1] N-terminal kinase (JNK) in the process of COX-2 expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of subacute PD. Our data showed that MPTP induced a transient JNK activation of dopaminergic neurons, upregulated COX-2 expression in dopaminergic neurons, and caused the loss of dopaminergic neurons. We found that inhibiting JNK with SP600125, a special inhibitor of JNK, reduced the levels of c-Jun phosphorylation, blocked p-c-Jun translocation from the cytoplasm to the nucleus in dopaminergic neurons of substantia nigra, mitigated the loss of dopaminergic neurons, and improved motor function in MPTP-induced PD in C57BL/6N mice. These results indicate that JNK signaling pathway may be the major upstream mediator of regulation of COX-2 expression induced by MPTP in vivo and inhibiting JNK activity may represent a new and effective strategy to PD.
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Increasing evidence suggests that inflammation may be involved in the loss of dopaminergic neurons in Parkinson's disease (PD). Among inflammatory molecules, COX-2, a key kinase for the inflammatory response, has been suggested to...
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Increasing evidence suggests that inflammation may be involved in the loss of dopaminergic neurons in Parkinson's disease (PD). Among inflammatory molecules, COX-2, a key kinase for the inflammatory response, has been suggested to play an important role in dopaminergic neuron loss in PD. However, the upstream molecular pathways of COX-2 expression remain uncertain. In the present study, we investigated the role of c-Jun [1] N-terminal kinase (JNK) in the process of COX-2 expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of subacute PD. Our data showed that MPTP induced a transient JNK activation of dopaminergic neurons, upregulated COX-2 expression in dopaminergic neurons, and caused the loss of dopaminergic neurons. We found that inhibiting JNK with SP600125, a special inhibitor of JNK, reduced the levels of c-Jun phosphorylation, blocked p-c-Jun translocation from the cytoplasm to the nucleus in dopaminergic neurons of substantia nigra, mitigated the loss of dopaminergic neurons, and improved motor function in MPTP-induced PD in C57BL/6N mice. These results indicate that JNK signaling pathway may be the major upstream mediator of regulation of COX-2 expression induced by MPTP in vivo and inhibiting JNK activity may represent a new and effective strategy to PD.
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Intraperitoneal administration of urate crystals to mice reduced subsequent macrophage conversion of arachidonic acid (AA) to prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid for up to 6 h. In contrast, levels of 12-hydrox...
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Intraperitoneal administration of urate crystals to mice reduced subsequent macrophage conversion of arachidonic acid (AA) to prostaglandins (PGs) and 12-hydroxyeicosatetraenoic acid for up to 6 h. In contrast, levels of 12-hydroxyheptadecatrienoic acid (12-HHT) were markedly elevated. This metabolic profile was previously observed in vitro when recombinant cyclooxygenase (COX) enzymes were incubated with reduced glutathione (GSH). Analysis of peritoneal GSH levels revealed a fivefold elevation after urate crystal administration. The GSH synthesis inhibitor L-buthionine-[S,R]-sulfoximine partially reversed the urate crystal effect on both GSH elevation and PG synthesis. Moreover, addition of exogenous GSH to isolated peritoneal macrophages shifted AA metabolism from PGs to 12-HHT. Urate crystal administration reduced COX-1, but induced COX-2 expression in peritoneal cells. The reduction of COX-1 may contribute to the attenuation of PG synthesis after 1 and 2 h, but PG synthesis remained inhibited up to 6 h, when COX-2 levels were high. Overall, our results indicate that elevated GSH levels inhibit PG production in this model and provide in vivo evidence for the role of GSH in the regulation of PG biosynthesis.
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Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the m...
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Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs. However, recent data indicate that COX-2 can mediate neuroprotection and that COX-1 is a major player in the neuroinflammatory process. We discuss the specific contributions of COX-1 and COX-2 in various neurodegenerative diseases and in models of neuroinflammation. We suggest that, owing to its predominant localization in microglia, COX-1 might be the major player in neuroinflammation, whereas COX-2, which is localized in neurons, might have a major role in models in which the neurons are directly challenged. Overall, the benefit of using COX-2 inhibitors should be carefully evaluated and COX-1 preferential inhibitors should be further investigated as a potential therapeutic approach in neurodegenerative diseases with an inflammatory component.
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A series of 3-unsubstituted/substituted-4,5-diphenyl-2-oxo-3H-1,3-oxazole derivatives were prepared as selective cyclooxygenase-2 (COX-2) inhibitors. Among the synthesized compounds, 4-(4-phenyl-3-methyl-2-oxo-3H-1,3-oxazol-5-yl)b...
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A series of 3-unsubstituted/substituted-4,5-diphenyl-2-oxo-3H-1,3-oxazole derivatives were prepared as selective cyclooxygenase-2 (COX-2) inhibitors. Among the synthesized compounds, 4-(4-phenyl-3-methyl-2-oxo-3H-1,3-oxazol-5-yl)benzensulfonamide (compound 6) showed selective COX-2 inhibition with a selectivity index of >50 (IC(50)COX-1=>100 microm, IC(50)COX-2=2 microm) in purified enzyme (PE) assay. Compound 6 also exhibited selective COX-2 inhibition in human whole blood assay. Molecular docking studies showed that 6 can be docked into the COX-2 binding site thus providing the molecular basis for its activity.
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AIM: To determine the expression of PGH synthase-1 and the sensitivity of vascular smooth muscle to PGH_2 in the aorta form the SHR at an age when no endothelium-dependent contractions to acetylcholine are observed under control c...
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AIM: To determine the expression of PGH synthase-1 and the sensitivity of vascular smooth muscle to PGH_2 in the aorta form the SHR at an age when no endothelium-dependent contractions to acetylcholine are observed under control conditions. CONCLUSION: In the aorta of 20-wk-old SHR, endothelium- Dependent contractions to acetylcholine are observed Only when the production of nitric oxide is prevented. They are associated with an augmented sensitivity of the Smooth muscle to PGH_2, but not with an increased Expression of PGH synthase-1.
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Prostaglandin G/H synthases (PGHS), commonly referred to as cyclooxygenases (COX-1 and COX-2), catalyze a key step in the synthesis of biologically active prostaglandins (PGs), the conversion of arachidonic acid (AA) into prostagl...
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Prostaglandin G/H synthases (PGHS), commonly referred to as cyclooxygenases (COX-1 and COX-2), catalyze a key step in the synthesis of biologically active prostaglandins (PGs), the conversion of arachidonic acid (AA) into prostaglandin H(2) (PGH(2)). PGs have important functions in a variety of physiologic and pathologic settings, including inflammation, cardiovascular homeostasis, reproduction, and carcinogenesis. However, an evaluation of prostaglandin function in early development has been difficult due to the maternal contribution of prostaglandins from the uterus. The emergence of zebrafish as a model system has begun to provide some insights into the roles of this signaling cascade during vertebrate development. In zebrafish, COX-1 derived prostaglandins are required for two distinct stages of development, namely during gastrulation and segmentation. During gastrulation, PGE(2) signaling promotes cell motility, without altering the cell shape or directional migration of gastrulating cells. Duringsegmentation, COX-1 signaling is also required for posterior mesoderm development, including the formation of vascular tube structures, angiogenesis of intersomitic vessels, and pronephros morphogenesis. We propose that deciphering the role for prostaglandin signaling in zebrafish development could yield insight and ultimately address the mechanistic details underlying various disease processes that result from perturbation of this pathway.
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