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Lipoxygenase Pathways (lipoxygenase + pathway)

Distribution by Scientific Domains

Medical Sciences	66%

Selected Abstracts

Photoactivation of an Inhibitor of the 12/15-Lipoxygenase Pathway

CHEMBIOCHEM, Issue 7 2006
Stephan Herre
Abstract Lipoxygenases are lipid-peroxidizing enzymes that have been implicated in the pathogenesis of inflammatory diseases and lipoxygenase inhibitors may be developed as anti-inflammatory drugs. Structure comparison with known lipoxygenase inhibitors has suggested that (2Z)-2-(3-benzylidene)-3-oxo-2,3-dihydrobenzo[b]thiophene-7-carboxylic acid methyl ester might inhibit the lipoxygenase pathway but we found that it exhibited only a low inhibitory potency for the pure 12/15-lipoxygenase (IC50=0.7 mM). However, photoactivation, which induces a Z -to- E isomerization of the double bond, strongly augmented the inhibitory potency and an IC50 value of 0.021 mM was determined for the pure E isomer. Similar isomer-specific differences were observed with the recombinant enzyme and its 12-lipoxygenating Ile418Ala mutant, as well as in intracellular lipoxygenase activity. Structure modeling of the enzyme/inhibitor complex suggested the molecular reasons for this isomer specificity. Since light-induced isomerization may proceed in the skin, such photoreactive compounds might be developed as potential drugs for inflammatory skin diseases. [source]

Inhibition of platelet phospholipase A2 activity by catuaba extract suggests antiin,ammatory properties

PHYTOTHERAPY RESEARCH, Issue 11 2004
Nádia R. Barbosa
Abstract In the in,ammation process, phospholipase A2 (PLA2) catalyses the cleavage of the sn -2 ester-linked fatty acids from phospholipids, being the enzyme responsible for arachidonic acid (AA) release by cells for the biosynthesis of the prostaglandins and thromboxanes via the cyclooxygenase system, and the leukotrienes and eicosatetraenoids via the lipoxygenase pathway. AA mobilization by PLA2 and subsequent prostaglandins synthesis is considered to be a pivotal event in in,ammation. Therefore, drugs that inhibit PLA2, thus blocking the COX and LOX pathways in the AA cascade, may be effective in the treatment of in,ammatory processes. New strategies for the treatment of in,ammatory processes could be detected by a search for active principles of vegetal origin that control the lipid mediator production by inhibition of PLA2. The present data are part of a wide explorative investigation on the effects of Trichilia catigua (catuaba), which found that PLA2 activity was totally inhibited by catuaba at a concentration of 120 µg/mL, suggesting that this natural substance may have antiin,ammatory properties. Copyright © 2004 John Wiley & Sons, Ltd. [source]

Photoactivation of an Inhibitor of the 12/15-Lipoxygenase Pathway

Local application of n,3 or n,6 polyunsaturated fatty acids in the treatment of human experimental gingivitis

JOURNAL OF CLINICAL PERIODONTOLOGY, Issue 4 2002
Jörg Eberhard
Abstract Background: Polyunsaturated fatty acids have the potential to attenuate inflammation by the synthesis of mediators of the 15-lipoxygenase pathways, which show opposite effects to the pro-inflammatory arachidonic acid metabolites such as leukotriene B4 (LTB4). Aims: The aim of this clinical study was to evaluate the effects of topical application of n,6 or n,6 polyunsaturated fatty acids in patients with experimental gingivitis. Methods: In each subject, similar teeth served as experimental and control over a 21-day non-hygiene phase and a 9-day resolving phase. Efficacy assessment was based on the bleeding on probing frequency (BOP) and the gingivocrevicular fluid volume (GCF). GCF was determined by inserting a filter paper strip for 30 s and measurements were performed on a Periotron 8000. The LTB4 concentration was analyzed by reversed-phase high-pressure liquid chromatography. Results: After 21 days of plaque growth, the BOP, GCF and LTB4 levels were significantly increased in all groups, with no differences between the control and experimental side. Rinsing of an area with established gingivitis for a 9-day period significantly reduced the GCF in the n,6 group (71.9 (18.7) versus 47.4 (11.4) Periotron Units, median (inter quartile range)). Conclusion: The topical application of n,6 or n,6 fatty acids failed to inhibit the development of experimental gingivitis. Rinsing with n,6 fatty acids could reduce the level of GCF in established experimental gingivitis. Zusammenfassung Hintergrund: Vielfach ungesättigte Fettsäuren haben das Potential, die Entzündung durch die Synthese von Mediatoren des 15-Lipoxygenaseweges zu behindern. Dies zeigt Gegeneffekte zu den pro-inflammatorischen Arachnoidonsäuremetaboliten wie Leukotrien B4 (LTB4). Ziele: Das Ziel dieser klinischen Studie war die Überprüfung des Effektes einer topischen Applikation von n,3 oder n,6 vielfach ungesättigten Fettsäuren bie Patienten mit experimenteller Gingivitis. Methoden: Bei jeder Person dienten ähnliche Zähne als Experiment und Kontrollen über eine 21tägige Nichthygiene-Phase und einer 9tägigen Erholungsphase. Wirksamkeitsmessungen basierten auf der Häufigkeit von Provokationsblutung (BOP) und dem Volumen der gingivalen krevikulären Flüssigkeit (GCF). GCF wurde durch Einbringen von Filterpapierstreifen für 30 Sekunden bestimmt. Die Messungen wurden mit einen Periotron 8000 durchgeführt. Die LTB4 Konzentration wurde mit der Umkehrphasen-Hochdruck-Flüssigkeitschromatographie analysiert. Ergebnisse: Nach 21 Tagen des Plaquewachstums waren die Level für BOP, GCF und LTB4 in allen Gruppen signifikant erhöht, ohne Differenzen zwischen den Kontrollen und den experimentellen Flächen. Die Spülung eines Gebietes mit etablierter Gingivitis für eine 9tägige Periode reduzierte die GCF in der n,6 Gruppe signifikant (71.9 (18.7) versus 47.4 (11.4) Peritron-Einheiten, Median (Zwischenquartilstreuung)). Zusammenfassung: Die topische Applikation von n,3 oder n,6 Fettsäuren verhindert die Entwicklung einer experimentellen Gingivitis nicht. Die Spülung mit n,6 Fettsäure konnte den Level der GCF bei einer bestehenden experimentellen Gingivitis reduzieren. Résumé Origine: Les acides gras poly-insaturés ont le potentiel d'atténuer l'inflammation en synthétisant des médiateurs des voies de la lipoxygénase 15 qui montrent des effets opposés aux métabolites de l'acide arachidonique pro-inflammatoire comme la leucotriène B4 (LTB4). But: Le but de cette étude clinique a été d'évaluer les effets de l'application topique d'acide gras poly-insaturés n,3 ou n,6 chez des patients effectuant d'une gingivite expérimentale. Méthodes: Chez chaque sujet, des dents semblables ont servi de sites tests et contrôles durant une phase sans hygiène buccale de 21 jours et une phase de retour à la normale de 9 jours. L'efficacité a été mesurée sur base de la fréquence du saignement au sondage (BOP) et le volume de fluide gingivale (GCF). Le GCF a été déterminé en insérant des papiers filtres pendant 30 s et les mesures ont été lues à l'aide du Périotron 8000. La concentration de LTB4 a été analysée par chromotographie liquide à haute pression à phrase arrière. Résultats: Après 21 jours d'accumulation de plaque dentaire les niveaux de BOP, GCF et LTB4 ont augmenté significativement dans tous les groupes sans aucune différence entre les sites tests et contrôles. Le rinçage d'une zone avec gingivite établie durant une période de 9 journées diminuait les GCF dans le groupe n,6 (unités du Péritron 72 (médian 19) versus 47 (11)). Conclusion: L'application topique d'acide gras n,3 ou n,6 ne permettait pas d'inhiber le développement de la gingivite expérimentale. Le rinçage avec des acides gras n,6 pouvait réduire le niveau de GCF dans la gingivite expérimentale établie. [source]

Effects of furocoumarins from Cachrys trifida on some macrophage functions

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2001
M. J. Abad
Phytochemical and biological studies aimed at the discovery and development of novel antiinflammatory agents from natural sources have been conducted in our laboratory for a number of years. In this communication, three naturally occurring furocoumarins (imperatorin, isoimperatorin and prantschimgin) were evaluated as potential inhibitors of some macrophage functions involved in the inflammatory process. These furocoumarins have been tested in two experimental systems: ionophore-stimulated mouse peritoneal macrophages serve as a source of cyclooxygenase-1 and 5-lipoxygenase, and mouse peritoneal macrophages stimulated with E. coli lipopolysaccharide are the means of testing for anti-cyclooxygenase-2 and nitric-oxide-synthase activity. All above-mentioned furocoumarins showed significant effect on 5-lipoxygenase (leukotriene C4) with IC50 values of < 15 ,M. Imperatorin and isoimperatorin exhibited strong-to-medium inhibition on cyclooxygenase-1- and cyclooxygenase-2-catalysed prostaglandin E2 release, with inhibition percentages similar to those of the reference drugs, indometacin and nimesulide, respectively. Of the three furocoumarins, only imperatorin caused a significant reduction of nitric oxide generation. Imperatorin and isoimperatorin can be classified as dual inhibitors, since it was evident that both cyclooxygenase and lipoxygenase pathways of arachidonate metabolism were inhibited by these compounds. However, selective inhibition of the 5-lipoxygenase pathway is suggested to be the primary target of action of prantschimgin. [source]

19 Cytosolic phospholipase A2 increases proliferation, inhibits apoptosis and facilitates angiogenesis in prostate cancer: a potential new therapeutic target

BJU INTERNATIONAL, Issue 2006
M.I. PATEL
The end-products from the arachadonic acid (AA) pathway have been shown to be tumourigenic in prostate cancer (CaP). Cytosolic phospholipase A2 (cPLA2) is the enzyme that liberates AA from plasma membranes and feeds it to the cycloxygenase and lipoxygenase pathways. In this study we aim to determine the importance of cPLA2 in prostate cancer by examining human prostate cancer specimens and in vitro cell line models. Immunohistochemistry of human prostate specimens revealed that activated cPLA2 levels were significantly higher in prostate cancer compared to benign glands.. Next to determine if inhibition of cPLA2 would lead to decreases in prostate cancer growth, we treated three CaPcell lines (PC3, DU145 and LNCaP) with pyrrolidine 2 (P2), a specific cPLA2 inhibitor and showed it significantly inhibited the growth of all three cell lines at concentrations between 1,10,M by MTS assay. P2 treatment induced a cell cycle block at G0/G1 and a corresponding reduction in BrdU incoprporation by flow cytometry and 3H-Thymidine incorporation. In addition cPLA2 knock by siRNA also showed a similar inhibition in proliferation, confirming the importance of cPLA2 in CaP proliferation. P2 also induced apoptosis in CaP cell lines by Caspase 3/7 assay. Treatment of Endothelial cell (HUVECs) cells with P2 had a very significant inhibitory effect on capillary tube formation in matrigel. We conclude that cytosolic phospholipase A2 is overactive in human prostate cancer. It leads to CaP proliferation as well as apoptosis. cPLA2 also is required in endothelial angiogenesis. Inhitibion of cPLA2 by P2 will reduce cancer growth, induce apoptosis and inhibit angiogeneisis in an in vitro model. Together, these findings suggest that cPLA2 could be a potential target in CaP treatment and warrants further validation in animal and human trials. [source]