title: Cardamonin suppresses nitric oxide production via blocking the IFN-γ/STAT pathway in endotoxin-challenged peritoneal macrophages of ICR mice.
abstract: OBJECTIVE
  Overproduction of nitric oxide (NO) from inducible NO synthase (iNOS) plays many pivotal roles in various inflammatory diseases. In this study, we examined the effects of 6 flavonoids on lipopolysaccharide (LPS)-induced NO generation in macrophage (Mφ), and addressed molecular mechanisms of cardamonin.
  
  
  METHODS
  Suppressive effects on NO generation in vitro were assayed in LPS-stimulated macrophages (Mφ). In vivo anti-inflammatory activity was evaluated with LPS-challenged ICR mice. Mechanistic analyses were done by ELISA, Western blot, RT-PCR, etc.
  
  
  RESULTS
  Cardamonin, a chalcone, exhibited pronounced suppressive activity, while pinocembrin, a counterpart flavanone, was much less active. Administration of cardamonin (0.02-2 mg/kg body weight) significantly decreased NOx concentrations in the sera from LPS-challenged ICR mice. This efficacy was superior to that of curcumin, a well-known anti-inflammatory agent present in turmeric. Cardamonin down-regulated iNOS mRNA expression and suppressed activation of STAT-1, but not nuclear factor kappaB, both of which are transcription factors for the iNOS gene in peritoneal Mφ of ICR mice. Interferon (IFN)-γ was identified as the major cytokine which mediates LPS-induced STAT-1 activation and resultant iNOS expression. Intriguingly, cardamonin suppressed the activation of not only STAT-1 but also STATs-2, 3 and 4. The involvement of the JAK/STATs pathway in NO generation was suggested because its specific inhibitor, AG490, decreased NO generation.
  
  
  CONCLUSIONS
  Cardamonin was identified to be a unique phytochemical that targets the production of IFN- and thereby suppresses the STAT pathway for mitigating inflammation.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Amane
authors.initials: A
authors.lastname: Takahashi
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D009573:Nitrites / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047188:Chalcones; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C436747:cardamonin