Meloxicam Inhibits Prostaglandin E<sub>2</sub> Generation via Cyclooxygenase 2 in the Inflammatory Site but Not That via Cyclooxygenase 1 in the Stomach

ABSTRACT We sought to determine if infection of the colon withEntamoeba histolytica induces the expression of cyclooxygenase-2 and, if it does, to determine the contribution of prostaglandins produced through cyclooxygenase-2 to the host response to amebic infection. Human fetal intestinal xenografts were implanted subcutaneously in mice with severe combined immunodeficiency and allowed to grow; the xenografts were then infected with E. histolytica trophozoites. Infection with E. histolytica resulted in the expression of cyclooxygenase-2 in epithelial cells and lamina propria macrophages. Infection with E. histolytica increased prostaglandin E2(PGE2) levels 10-fold in the xenografts and resulted in neutrophil infiltration, as manifested by an 18-fold increase in myeloperoxidase activity. Amebic infection also induced an 18-fold increase in interleukin 8 (IL-8) production and a >100-fold increase in epithelial permeability. Treatment of the host mouse with indomethacin, an inhibitor of cyclooxygenase-1 and cyclooxygenase-2, or with NS-398, a selective inhibitor of cyclooxygenase-2, resulted in (i) decreased PGE2 levels, (ii) a decrease in neutrophil infiltration, (iii) a decrease in IL-8 production, and (iv) a decrease in the enhanced epithelial permeability seen with amebic infection. These results indicate that amebic infection in the colon induces the expression of cyclooxygenase-2 in epithelial cells and macrophages. Moreover, prostaglandins produced through cyclooxygenase-2 participate in the mediation of the neutrophil response to infection and enhance epithelial permeability.

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gem-Difluorobisarylic derivatives: design, synthesis and anti-inflammatory effect

BMC Chemistry ◽

10.1186/s13065-019-0640-5 ◽

2019 ◽

Vol 13 (1) ◽

Author(s):

Abeer J. Ayoub ◽

Layal Hariss ◽

Nehme El-Hachem ◽

Ghewa A. El-Achkar ◽

Sandra E. Ghayad ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Protein Expression ◽

Interleukin 6 ◽

Cyclooxygenase 2 ◽

Prostaglandin E ◽

Diaryl Ethers ◽

Cyclooxygenase 1 ◽

Anti Inflammatory ◽

Oxide Synthase

Abstract Introduction New fluorinated diaryl ethers and bisarylic ketones were designed and evaluated for their anti-inflammatory effects in primary macrophages. Methods The synthesis of the designed molecules started from easily accessible and versatile gem-difluoro propargylic derivatives. The desired aromatic systems were obtained using Diels–Alder/aromatization sequences and this was followed by Pd-catalyzed coupling reactions and, when required, final functionalization steps. Both direct inhibitory effects on cyclooxygenase-1 or -2 activities, protein expression of cyclooxygenase-2 and nitric oxide synthase-II and the production of prostaglandin E2, the pro-inflammatory nitric oxide and interleukin-6 were evaluated in primary murine bone marrow-derived macrophages in response to lipopolysaccharide. Docking of the designed molecules in cyclooxygenase-1 or -2 was performed. Results Only fluorinated compounds exerted anti-inflammatory activities by lowering the secretion of interleukin-6, nitric oxide, and prostaglandin E2, and decreasing the protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in mouse primary macrophages exposed to lipopolysaccharide, as well as cyclooxygenase activity for some inhibitors with different efficiencies depending on the R-groups. Docking observation suggested an inhibitory role of cyclooxygenase-1 or -2 for compounds A3, A4 and A5 in addition to their capacity to inhibit nitrite, interleukin-6, and nitric oxide synthase-II and cyclooxygenase-2 expression. Conclusion The new fluorinated diaryl ethers and bisarylic ketones have anti-inflammatory effects in macrophages. These fluorinated compounds have improved potential anti-inflammatory properties due to the fluorine residues in the bioactive molecules.

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Relative contribution of cyclooxygenases, epoxyeicosatrienoic acids, and pH to the cerebral blood flow response to vibrissal stimulation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00794.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. H1075-H1085 ◽

Cited By ~ 16

Author(s):

Xiaoguang Liu ◽

Chunyuan Li ◽

John R. Falck ◽

David R. Harder ◽

Raymond C. Koehler

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Metabotropic Glutamate Receptors ◽

Cyclooxygenase 2 ◽

Model Systems ◽

Epoxyeicosatrienoic Acids ◽

Prostaglandin E ◽

Cyclooxygenase 1 ◽

Group I ◽

Whisker Stimulation

The increase in cerebral blood flow (CBF) during neuronal activation can be only partially attenuated by individual inhibitors of epoxyeicosatrienoic acids (EETs), cyclooxgenase-2, group I metabotropic glutamate receptors (mGluR), neuronal nitric oxide synthase (nNOS), N-methyl-D-aspartate receptors, or adenosine receptors. Some studies that used a high concentration (500 μM) of the cyclooxygenase-1 inhibitor SC-560 have implicated cyclooxygenase-1 in gliovascular coupling in certain model systems in the mouse. Here, we found that increasing the concentration of SC-560 from 25 μM to 500 μM over whisker barrel cortex in anesthetized rats attenuated the CBF response to whisker stimulation. However, exogenous prostaglandin E2 restored the response in the presence of 500 μM SC-560 but not in the presence of a cyclooxygenase-2 inhibitor, thereby suggesting a limited permissive role for cyclooxygenase-1. Furthermore, inhibition of the CBF response to whisker stimulation by an EET antagonist persisted in the presence of SC-560 or a cyclooxygenase-2 inhibitor, thereby indicating that the EET-dependent component of vasodilation did not require cyclooxygenase-1 or -2 activity. With combined inhibition of cyclooxygenase-1 and -2, mGluR, nNOS, EETs, N-methyl-D-aspartate receptors, and adenosine 2B receptors, the CBF response was reduced by 60%. We postulated that the inability to completely block the CBF response was due to tissue acidosis resulting from impaired clearance of metabolically produced CO2. We tested this idea by increasing the concentration of superfused bicarbonate from 25 to 60 mM and found a markedly reduced CBF response to hypercapnia. However, increasing bicarbonate had no effect on the initial or steady-state CBF response to whisker stimulation with or without combined inhibition. We conclude that the residual response after inhibition of several known vasodilatory mechanisms is not due to acidosis arising from impaired CO2 clearance when the CBF response is reduced. An unidentified mechanism apparently is responsible for the rapid, residual cortical vasodilation during vibrissal stimulation.

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The role of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide and interleukin-1 stimulated enterocyte prostanoid formation

Mediators of Inflammation ◽

10.1080/09629359891225 ◽

1998 ◽

Vol 7 (2) ◽

pp. 85-91 ◽

Cited By ~ 13

Author(s):

W. E. Longo ◽

L. J. Damore ◽

J. E. Mazuski ◽

G. S. Smith ◽

N. Panesar ◽

...

Keyword(s):

Interleukin 1 ◽

Immunoblot Analysis ◽

Cyclooxygenase 2 ◽

Interleukin 1Β ◽

Cyclooxygenase Inhibitors ◽

Prostaglandin E ◽

Cyclooxygenase 1 ◽

Low Concentrations ◽

Prostaglandin F

Lipopolysaccharide is an inflammatory agent and interleukin-1 is a cytokine. Their pro-inflammatory effects may be mediated by prostanoids produced by inducible cyclooxygenase-2. The aim of this study was to determine the prostanoids produced by lipopolysaccharide and interleukin-1 stimulated enterocytes through the cyclooxygenase-1 and 2 pathways. Cultured enterocytes were stimulated with lipopolysaccharide or interleukin-1 β with and without cyclooxygenase inhibitors. Low concentrations of indomethacin and valerylsalicylic acid (VSA) were evaluated as cyclooxygenase-1 inhibitors and their effects compared with the effects of a specific cyclooxygenase-2 inhibitor, SC-58125. Prostaglandin E2, 6-keto prostaglandin F1α, prostaglandin D2and leukotriene B4levels were determined by radio immunoassay. Immunoblot analysis using isoformspecific antibodies showed that the inducible cyclooxygenase enzyme (COX-2) was expressed by 4 h in LPS and IL-1β treated cells while the constitutive COX-1 remained unaltered in its expression. Interleukin-1β and lipopolysaccharide stimulated the formation of all prostanoids compared with untreated cells, but failed to stimulate leukotriene B4. Indomethacin at 20 μ M concentration, and VSA inhibited lipopolysaccharide and interleukin 1β stimulated prostaglandin E2, but not 6-keto prostaglandin F1αformation. SC-58125 inhibited lipopolysaccharide and interleukin-1β stimulated 6-keto prostaglandin F1αbut not prostaglandin E2release. The specific cyclooxygenase-2 inhibitor also inhibited lipopolysaccharide produced prostaglandin D2but not interleukin-1β stimulated prostaglandin D2While SC-58125 inhibited basal 6-keto prostaglandin-F1αformation it significantly increased basal prostaglandin E2and prostaglandin D2formation. As SC-58125 inhibited lipopolysaccharide and interleukin-1β induced 6-keto prostaglandin F1αproduction but not prostaglandin E2production, it suggests that these agents stimulate prostacyclin production through a cyclooxygenase-2 mediated mechanism and prostaglandin E2production occurs through a cyclooxygenase-1 mediated mechanism. Prostaglandin D2production appeared to be variably produced by cyclooxygenase-1 or cyclooxygenase-2, depending on the stimulus.

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