title: Reduced scytonemin isolated from Nostoc commune suppresses LPS/IFNγ-induced NO production in murine macrophage RAW264 cells by inducing hemeoxygenase-1 expression via the Nrf2/ARE pathway.
abstract: Reduced scytonemin (R-scy) and scytonemin (Scy) isolated from Nostoc commune exhibit anti-tumor and ultraviolet-absorbing properties. In this study, we examined the effects of R-scy and Scy on the induction of nitric oxide (NO) production by lipopolysaccharide (LPS) and interferon-γ (IFNγ) in murine macrophage RAW264 cells. While both R-scy and Scy suppressed LPS/IFNγ-induced NO production, R-scy exhibited a stronger inhibitory effect compared with Scy. To further elucidate the mechanisms underlying the anti-inflammatory effects of R-scy, we examined the changes in the intracellular signaling cascade after LPS/IFNγ stimulation in cells. In addition to the attenuation of LPS/IFNγ-induced upregulation of the inducible isoform of NO synthase, R-scy decreased the activity of nuclear factor-κB, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs) after LPS/IFNγ stimulation. R-scy treatment increased heme oxygenase-1 (HO-1) expression by increasing the intracellular levels of reactive oxygen species and thereby activating nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element signaling. The induction of HO-1 by R-scy was inhibited by pretreatment with an antioxidant, N-acetyl-cysteine (NAC), as well as SB203580 and LY294002, inhibitors for p38 MAPK and PI3K/Akt, respectively. Our findings suggest that the anti-inflammatory effects of R-scy could involve both the ROS/PI3K/Akt and the p38 MAPK/Nrf2 signaling pathways.
authors.affiliation: Laboratory of Aquatic Food Science, Department of Fisheries, Faculty of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan. Electronic address: titoh@nara.kindai.ac.jp.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Koketsu
authors.affiliation: Laboratory of Aquatic Food Science, Department of Fisheries, Faculty of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yokota
authors.affiliation: Laboratory of Aquatic Food Science, Department of Fisheries, Faculty of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Touho
authors.affiliation: Laboratory of Aquatic Food Science, Department of Fisheries, Faculty of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ando
authors.affiliation: Laboratory of Aquatic Food Science, Department of Fisheries, Faculty of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Tsukamasa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects*; D002460:Cell Line / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007211:Indoles / Q000302:isolation & purification* / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D050501:Nostoc commune / Q000737:chemistry*; D010636:Phenols / Q000302:isolation & purification* / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D007211:Indoles; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010636:Phenols; D017382:Reactive Oxygen Species; C083368:scytonemin; D009569:Nitric Oxide; D007371:Interferon-gamma; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Heme oxygenase-1; Intracellular ROS; Nitric oxide; Nrf2/ARE signaling; Reduced scytonemin