title: Citrus nobiletin suppresses inducible nitric oxide synthase gene expression in interleukin-1β-treated hepatocytes.
abstract: BACKGROUND
  Nobiletin is a polymethoxylated flavone that is abundant in the peels of citrus fruits, such as Citrus unshiu (Satsuma mandarin) and Citrus sinensis. The dried peels of C. unshiu (chinpi) have been included in several formulae of Japanese Kampo medicines. Nobiletin may suppress the induction of inducible nitric oxide synthase (iNOS), which synthesizes the inflammatory mediator nitric oxide (NO) in hepatocytes.
  
  
  METHODS
  A C. unshiu peel (CUP) extract was prepared. Primary cultured rat hepatocytes were treated with the CUP extract or nobiletin in the presence of interleukin 1β (IL-1β), which induces iNOS expression. NO production and iNOS gene expression were analyzed.
  
  
  RESULTS
  High-performance liquid chromatography analyses revealed that the nobiletin content in the CUP extract was 0.14%. Nobiletin dose-dependently reduced the NO levels and decreased iNOS expression at the protein, mRNA and antisense transcript levels. Flavone, which does not contain any methoxy groups, also suppressed iNOS induction. Nobiletin reduced the transcriptional activity of iNOS promoter-luciferase constructs and the DNA-binding activity of nuclear factor κB (NF-κB) in the nuclei.
  
  
  CONCLUSIONS
  The suppression of iNOS induction by nobiletin suggests that nobiletin may be responsible for the anti-inflammatory effects of citrus peels and have a therapeutic potential for liver diseases.
authors: Department of Biomedical Sciences, College of Life Sciences, Kusatsu, Shiga, Japan; Ritsumeikan Global Innovation Research Organization (R-GIRO), Kusatsu, Shiga, Japan.
authors: Emi
authors: E
authors: Yoshigai
authors: Toru
authors: T
authors: Machida
authors: Tetsuya
authors: T
authors: Okuyama
authors: Masatoshi
authors: M
authors: Mori
authors: Hiromitsu
authors: H
authors: Murase
authors: Ryota
authors: R
authors: Yamanishi
authors: Tadayoshi
authors: T
authors: Okumura
authors: Yukinobu
authors: Y
authors: Ikeya
authors: Hoyoku
authors: H
authors: Nishino
authors: Mikio
authors: M
authors: Nishizawa
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002957:Citrus / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D000893:Anti-Inflammatory Agents; D047309:Flavones; D053583:Interleukin-1beta; D016328:NF-kappa B; D009569:Nitric Oxide; C008661:nobiletin; D007770:L-Lactate Dehydrogenase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: Chinpi; Flavone; Flavonoid; Inflammation; Nitric oxide; Plant polyphenol