title: Genipin Inhibits the Induction of Inducible Nitric Oxide Synthase Through the Inhibition of NF-κB Activation in Rat Hepatocytes.
abstract: Genipin is a component of Japanese traditional herbal medicine (Kampo), inchinkoto, and is used for the treatment of various liver injuries. However, there are few scientific evidence for its anti-inflammatory effects and mechanisms. In inflamed liver, proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β stimulate liver cells, followed by the expression of inducible nitric oxide synthase (iNOS). Excessive levels of NO produced by iNOS have been implicated as one of the factors in liver injury. Thus it is essential to inhibit iNOS induction for the prevention of liver injury. In this study, we examined IL-1β-stimulated hepatocytes as a simple "in vitro liver injury model" to investigate liver protective effects of genipin.
  
  
  
  Primary cultured rat hepatocytes were treated with IL-1β in the presence or absence of genipin. The induction of NO production and iNOS, and its signaling pathway were analyzed.
  
  
  
  In IL-1β-stimulated hepatocytes, genipin inhibited the production of NO dose- and timedependently, and reduced the levels of iNOS protein and its mRNA expression. Genipin also reduced mRNA expressions of TNF-α and IL-6. Genipin inhibited two essential signaling pathways for iNOS induction, IκB degradation/NF-κB activation and type I IL-1 receptor upregulation. Transfection experiments revealed that genipin decreased the expression of iNOS mRNA through both inhibitions of the promoter activation and mRNA stabilization. Delayed administration of genipin after IL-1β addition also inhibited iNOS induction.
  
  
  
  Genipin influenced the induction of inflammatory mediators, iNOS and TNF-α, in part through the inhibition of NF-κB activation in hepatocytes. Genipin may have therapeutic potential for organ injuries including liver.
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Richi
authors: R
authors: Nakatake
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Takumi
authors: T
authors: Tsuda
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Takashi
authors: T
authors: Matsuura
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Hirokazu
authors: H
authors: Miki
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Hidehiko
authors: H
authors: Hishikawa
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Hideyuki
authors: H
authors: Matsushima
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Morihiko
authors: M
authors: Ishizaki
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Kosuke
authors: K
authors: Matsui
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Masaki
authors: M
authors: Kaibori
authors: Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan. 0.
authors: Mikio
authors: M
authors: Nishizawa
authors: Department of Surgery, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka 573-1010. Japan.
authors: Tadayoshi
authors: T
authors: Okumura
authors: Department of Surgery, Kansai Medical University, Hirakata, Osaka. Japan.
authors: Masanori
authors: M
authors: Kon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D022781:Hepatocytes; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D039823:Iridoids / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017114:Liver Failure, Acute / Q000188:drug therapy*; D020835:Medicine, Kampo / Q000379:methods; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000633:toxicity; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D061251:Primary Cell Culture; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: D004365:Drugs, Chinese Herbal; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D039823:Iridoids; D016328:NF-kappa B; D010936:Plant Extracts; D020011:Protective Agents; D012333:RNA, Messenger; C078038:inchinko-to; D009569:Nitric Oxide; C007834:genipin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat
keywords: Genipin; inducible nitric oxide synthase; nuclear factor- κB; primary cultured hepatocytes; tumor necrosis factor-α; type I interleukin-1 receptor