title: Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin.
abstract: Apigenin (API) and luteolin (LUT) have been used as therapeutic agents in folk medicine for thousands of years. These compounds exert a variety of biological activities, including anticancer, antioxidant and antiinflammatory activities. This study investigated whether API and LUT could activate Nrf2-antioxidant response element (ARE)-mediated gene expression and induce antiinflammatory activities in human hepatoma HepG2 cells. The compounds did not exhibit any substantial toxicity at low doses (1.56-6.25 µm). The induction of ARE activity was assessed in HepG2-C8 cells after treatment with low doses of API and LUT for 6 and 12 h. It was found that the induction of ARE activity by these compounds at the higher doses was comparable to the effects of the positive control, SFN at a dose of 6.25 µm. Exposure to the PI3K inhibitor LY294002 abolished ARE activation by both API and LUT, whereas the ERK-1/2 inhibitor PD98059 only decreased ARE activity induced by API. Both compounds significantly increased the endogenous mRNA and protein levels of Nrf2 and Nrf2 target genes with important effects on heme oxygenase-1 (HO-1) expression. API and LUT significantly and dose-dependently decreased the production of nitric oxide (NO), nitric oxide synthase (iNOS) and cytosolic phospholipase A2 (cPLA2), which were induced by the treatment of HepG2 cells with 1 µg/ml of lipopolysaccharide (LPS) for 24 h. The results indicate that API and LUT significantly activate the PI3K/Nrf2/ARE system, and this activation may be responsible for their antiinflammatory effects, as demonstrated by the suppression of LPS-induced NO, iNOS and cPLA2.
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Ximena
authors.initials: X
authors.lastname: Paredes-Gonzalez
authors.affiliation: Facultad de Agronomía e Ingeniería Forestal, Facultad de Ingeniería y Facultad de Medicina, Pontificia Universidad Católica de Chile, Macul, Santiago, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: Fuentes
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Sundrina
authors.initials: S
authors.lastname: Jeffery
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Constance Lay-Lay
authors.initials: CL
authors.lastname: Saw
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Shu
authors.affiliation: Department of Bioscience Technology, Chung Yuan Christian University, Chung Li District, Taoyuan City, Taiwan.
authors.forename: Zheng-Yuan
authors.initials: ZY
authors.lastname: Su
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D047310:Apigenin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000494:pharmacology*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D047311:Luteolin / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D064209:Phytochemicals / Q000494:pharmacology*
chemical_list: D047309:Flavones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D064209:Phytochemicals; D047310:Apigenin; D047311:Luteolin
keywords: HepG2; LPS; Nrf2; apigenin; luteolin