title: Anti-inflammatory and vascularprotective properties of 8-prenylapigenin.
abstract: Flavonoids display several biological activities, but exhibit poor oral absorption and rapid metabolism. To improve their pharmacological profile four C8-prenyl flavonoids, structurally related to the anti-inflammatory lead apigenin, were synthesized, and the two least cytotoxic (IC(50)>30 microM) compounds [8-prenylnaringenin (8-PN) and 8-prenylapigenin (8-PA)] in RAW 264.7 murine macrophages were assayed against a panel of biological targets. The anti-inflammatory properties of these compounds were evaluated in an in vitro model of inflammation [cells exposed to 0.1 microg/ml lipopolysaccharide (LPS) for 24h]. Both 8-PN and 8-PA were equally effective and potent in inhibiting the LPS-induced gene expression [tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2] (RT-PCR) and release (ELISA) of pro-inflammatory mediators [TNF-alpha, NO, prostaglandin (PG)E(2)], through mechanisms involving the inhibition of nuclear factor-kappaB (NF-kappaB) activation (EMSA) and reactive oxygen species accumulation [2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) determination]. One-digit nM concentrations of 8-PN or 8-PA induced a significant increase in the basal production of the atheroprotective prostacyclin (PGI(2)) by human umbilical vein endothelial cells (HUVEC), with maximal effects at 10 nM. Both NS-398, a specific COX-2 inhibitor, and ICI 182 780, a non-selective estrogen receptor antagonist, abolished the activity of these compounds, suggesting a COX- and estrogen receptor-dependent mechanism of activity. 8-PA, a weaker estrogenic compound than 8-PN, resulted only 2-fold less potent than 8-PN in potentiating PGI(2) production by HUVEC, qualifying this C8-prenyl flavonoid as a lead for the rational design of new anti-inflammatory and vascularprotective compounds.
authors.affiliation: DISCAFF Department, University of Piemonte Orientale Amedeo Avogadro, Novara, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Paoletti
authors.forename: Silvia
authors.initials: S
authors.lastname: Fallarini
authors.forename: Francesca
authors.initials: F
authors.lastname: Gugliesi
authors.forename: Alberto
authors.initials: A
authors.lastname: Minassi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Grazia
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis; D044950:Flavanones / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D054876:Prenylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C546004:8-prenylapigenin; C119737:8-prenylnaringenin; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D044950:Flavanones; D047309:Flavones; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D011464:Epoprostenol; D052247:Nitric Oxide Synthase Type II; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone