1,720,974 research outputs found
Leukotrienes: lipid bioeffectors of inflammatory reactions
No full textThe leukotrienes arise from oxidative metabolism of arachidonic acid through the action of the 5-lipoxy- genase enzyme, leading to the unstable allylic epoxide leukotriene A4. This intermediate represents the substrate for two different specific enzymes, namely leukotriene A4-hydrolase and leukotriene C4-synthase, generating LTB4 and cysteinyl leukotrienes, respectively. The name "leukotriene" is referring to the cellular source (leukocytes are one of the major sources) as well as the conjugated triene that characterizes their structure. LTC4 and LTD4 are potent contracting agents of smooth muscle in airways and blood vessels; in addition, they induce mucus secretion and promote plasmatic exudation with direct action on endothelial cells. On the other side, LTB4 is known as a potent chemokinetic and chemotactic agent. A number of evidences reported in the literature underline the potential role of leukotrienes in the inflammatory responses that characterize asthma and other pathological conditions. These potent lipid bioeffectors are synthesized during the course of inflammatory reactions and their pharmacological modulation is able to significantly attenuate the clinical manifestations associated with different inflammatory pathologies
CYTOCHROME P 450-DEPENDENT METABOLISM OF ESSENTIAL FATTY ACIDS IN STURGEON ACIPENSER NACCARII
No full textEffect of the organomercury compound thimerosal on the synthesis of 5-LO metabolites by human neutrophils stimulated with GM-CSF and fMLP
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Differential metabolism of exogenous and endogenous arachidonic acid in human neutrophils
No full textLeukotrienes can be produced by cooperative interactions between cells in which, for example, arachidonate derived from one cell is oxidized to leukotriene A4 (LTA4) by another and this can then be exported for conversion to LTB4 or cysteinyl leukotrienes (cys-LTs) by yet another. Neutrophils do not contain LTC4 synthase but are known to cooperate with endothelial cells or platelets (which do have this enzyme) to generate cys- LTs. Stimulation of human neutrophils perfusing isolated rabbit hearts resulted in production of cys-LTs, whereas these were not seen with perfused hearts alone or isolated neutrophils. In addition, the stimulated, neutrophil-perfused hearts generated much greater amounts of total LTA4 products, suggesting that the hearts were supplying arachidonate to the neutrophils and, in addition, that this externally derived arachidonate was preferentially used for exported LTA4 that could be metabolized to cys-LTs by the coronary endothelium. Stable isotope-labeled arachidonate and electrospray tandem mass spectrometry were used to differentially follow metabolism of exogenous and endogenous arachidonate. Isolated, adherent neutrophils at low concentrations (to minimize transcellular metabolism between them) were shown to generate higher proportions of nonenzymatic LTA4 products from exogenous arachidonate (deuterium-labeled) than from endogenous (unlabeled) sources. The endogenous arachidonate, on the other hand, was preferentially used for conversion to LTB4 by the LTA4 hydrolase. This result was not because of saturation of the LTA4 hydrolase, because it occurred at widely differing concentrations of exogenous arachidonate. Finally, in the presence of platelets (which contain LTC4 synthase), the LTA4 synthesized from exogenous deuterium-labeled arachidonate was converted to cys-LTs to a greater degree than that from endogenous sources. These experiments suggest that exogenous arachidonate is preferentially converted to LTA4 for export (not intracellular conversion) and raises the likelihood that there are different intracellular pathways for arachidonate metabolism
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Effect of arachidonic acid reacylation on leukotriene biosynthesis in human neutrophils stimulated with granulocyte-macrophage colony-stimulating factor and formyl-methionyl-leucyl-phenylalanine
No full textPriming of human neutrophils with granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by treatment with formyl-methionyl-leucyl-phenylalanine (fMLP) stimulates cells in a physiologically relevant manner with modest 5-lipoxygenase activation and formation of leukotrienes. However, pretreatment of neutrophils with thimerosal, an organomercury thiosalicylic acid derivative, led to a dramatic increase (>50-fold) in the production of leukotriene B(4) and 5-hydroxyeicosatetraenoic acid, significantly higher than that observed after stimulation with calcium ionophore A23187. Little or no effect was observed with thimerosal alone or in combination with either GM-CSF or fMLP. Elevation of [Ca(2+)](i) induced by thimerosal in neutrophils stimulated with GM-CSF/fMLP was similar but more sustained compared with samples where thimerosal was absent. However, [Ca(2+)](i) was significantly lower compared with calcium ionophore-treated cells, suggesting that a sustained calcium rise was necessary but not sufficient to explain the effects of this compound on the GM-CSF/fMLP-stimulated neutrophil. Thimerosal was found to directly inhibit neutrophil lysophospholipid:acyl-CoA acyltransferase activity at the doses that stimulate leukotriene production, and analysis of lysates from neutrophil preparations stimulated in the presence of thimerosal showed a marked increase in free arachidonic acid, supporting the inhibition of the reincorporation of this fatty acid into the membrane phospholipids as a mechanism of action for this compound. The dramatic increase in production of leukotrienes by neutrophils when a physiological stimulus such as GM-CSF/fMLP is employed in the presence of thimerosal suggests a critical regulatory role of arachidonate reacylation that limits leukotriene biosynthesis in concert with 5-lipoxygenase and cytosolic phospholipase A(2)alpha activation
The potential role of tocopherol in asthma and allergies: modification of the leukotriene pathway
No full textMetabolism of arachidonic acid via the 5-lipoxygenase (5-LO) pathway leads to the formation of hydroperoxyeicosatetraenoic acids (HPETEs) and leukotriene (LT) A4. This unstable allylic epoxide can be further converted by secondary enzymes into LTB4 and cysteinyl LTs. LTs represent a family of potent biologically active compounds synthesised by specific cell types and by transcellular biosynthetic mechanisms. Cysteinyl LTs are involved in the pathogenesis of asthma, and recent data indicate that individuals with asthma may have enhanced basal excretion of urinary LTE4 compared with normal individuals. Tocopherol (vitamin E) and tocopherol acetate strongly inhibit potato 5-LO in an irreversible and noncompetitive way, and, by affecting the redox state of cells possessing 5-LO, they may influence the production of biologically active LTs. It has been reported that normal plasma levels of tocopherol may enhance the lipoxygenation of arachidonic acid, whereas higher tocopherol levels exert a suppressive effect that is consistent with its role as a hydroperoxide scavenger. Receptor-mediated activation of neutrophils in individuals with asthma results in the synthesis of LTs. This activation is inhibited by tocopherol in a concentration- dependent manner. Additional controlled studies are needed to assess the effect of tocopherol on leukotriene production in asthmatic individuals. The results of these studies may be useful in developing new therapeutic approaches in asthmatic/allergic patients
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