title: Pro-oxidant activity of indicaxanthin from Opuntia ficus indica modulates arachidonate metabolism and prostaglandin synthesis through lipid peroxide production in LPS-stimulated RAW 264.7 macrophages.
abstract: Macrophages come across active prostaglandin (PG) metabolism during inflammation, shunting early production of pro-inflammatory towards anti-inflammatory mediators terminating the process. This work for the first time provides evidence that a phytochemical may modulate the arachidonate (AA) metabolism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, promoting the ultimate formation of anti-inflammatory cyclopentenone 15deoxy-PGJ2. Added 1 h before LPS, indicaxanthin from Opuntia Ficus Indica prevented activation of nuclear factor-κB (NF-κB) and over-expression of PGE2 synthase-1 (mPGES-1), but up-regulated cyclo-oxygenase-2 (COX-2) and PGD2 synthase (H-PGDS), with final production of the anti-inflammatory cyclopentenone. The effects were positively related with concentration between 50 and 100 µM. Indicaxanthin did not have any effect in the absence of LPS. A kinetic study investigating the redox status of LPS-stimulated macrophages between 0.5 and 12 h, either in the absence or in the presence of 50-100 µM indicaxanthin, revealed a differential control of ROS production, with early (0.5-3 h) modest inhibition, followed by a progressive (3-12 h) concentration-dependent enhancement over the level induced by LPS alone. In addition, indicaxanthin caused early (0.5-3 h) concentration-dependent elevation of conjugated diene lipid hydroperoxides, and production of hydroxynonenal-protein adducts, over the amount induced by LPS. In LPS-stimulated macrophages indicaxanthin did not affect PG metabolism when co-incubated with either an inhibitor of NADPH oxidase or vitamin E. It is concluded that LPS-induced pro-oxidant activity of indicaxanthin at the membrane level allows formation of signaling intermediates whose accumulation modulates PG biosynthetic pathway in inflamed macrophages.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via M. Cipolla 74, Palermo 90123, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Allegra
authors.affiliation: Centre for Biochemical Pharmacology, William Harvey Research Institute, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, United Kingdom.
authors.forename: F
authors.initials: F
authors.lastname: D'Acquisto
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via M. Cipolla 74, Palermo 90123, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Tesoriere
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via M. Cipolla 74, Palermo 90123, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Attanzio
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo, Via M. Cipolla 74, Palermo 90123, Italy.
authors.forename: M A
authors.initials: MA
authors.lastname: Livrea
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D050860:Betaxanthins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005638:Fruit / Q000737:chemistry; D008054:Lipid Peroxides / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D029747:Opuntia / Q000737:chemistry; D016877:Oxidants / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011453:Prostaglandins / Q000096:biosynthesis*; D011725:Pyridines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D050860:Betaxanthins; D008054:Lipid Peroxides; D008070:Lipopolysaccharides; D016877:Oxidants; D011453:Prostaglandins; D011725:Pyridines; C469628:indicaxanthin; D016718:Arachidonic Acid
keywords: Eicosanoids; Indicaxanthin; Inflammation; Oxidative stress; Phytochemicals