title: Cultivated sea lettuce is a multiorgan protector from oxidative and inflammatory stress by enhancing the endogenous antioxidant defense system.
abstract: The health-promoting effects of seaweeds have been linked to antioxidant activity that may counteract cancer-causing oxidative stress-induced damage and inflammation. Although antioxidant activity is commonly associated with direct radical scavenging activity, an alternative way to increase the antioxidant status of a cell is to enhance the endogenous (phase II) defense system consisting of cytoprotective antioxidant enzymes, including NAD(P)H:quinone oxidoreductase 1 (NQO1). These enzymes are transcriptionally regulated by the antioxidant response element (ARE) via the transcription factor Nrf2. Extracts derived from cultivated Ulva sp., a green alga regarded as a marine vegetable (sea lettuce), potently activated the Nrf2-ARE pathway in IMR-32 neuroblastoma and LNCaP prostate cancer cells. RNA interference studies showed that Nrf2 and phosphoinositide 3-kinase (PI3K) are essential for the phase II response in IMR-32 cells. Activity-enriched fractions induced Nrf2 nuclear translocation and target gene transcription, and boosted the cellular glutathione level and therefore antioxidant status. A single-dose gavage feeding of Ulva-derived fractions increased Nqo1 transcript levels in various organs. Nqo1 induction spiked in different tissues, depending on the specific chemical composition of each administered fraction. We purified and characterized four ARE inducers in this extract, including loliolide (1), isololiolide (2), a megastigmen (3), and a novel chlorinated unsaturated aldehyde (4). The ARE-active fractions attenuated lipopolysaccharide-induced iNOS and Cox2 gene expression in macrophagic RAW264.7 cells, decreasing nitric oxide (NO) and prostaglandin E2 (PGE2) production, respectively. Nqo1 activity and NO production were abrogated in nrf2(-/-) mouse embryonic fibroblasts, providing a direct link between the induction of phase II response and anti-inflammatory activity.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Ranjala
authors.initials: R
authors.lastname: Ratnayake
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Paul
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017747:Seafood; D044445:Ulva / Q000737:chemistry*
chemical_list: D000975:Antioxidants; D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human