title: Potent anti-inflammatory effect of a novel furan-2,5-dione derivative, BPD, mediated by dual suppression of COX-2 activity and LPS-induced inflammatory gene expression via NF-κB inactivation.
abstract: OBJECTIVE
  We previously reported that 3-(benzo[d]-1,3-dioxol-5-yl)-4-phenylfuran-2,5-dione (BPD) showed strong inhibitory effects on PGE(2) production. However, the exact mechanism for the anti-inflammatory effect of BPD is not completely understood. In this study, we investigated the molecular mechanism involved in the effects of BPD on inflammatory mediators in LPS-stimulated macrophages and animal models of inflammation.
  
  
  METHODS
  The expressions of COX-2, inducible NOS (iNOS), TNF-α, IL-6 and IL-1β, in LPS-stimulated RAW 264.7 cells and murine peritoneal macrophages, were determined by Western blot and/or qRT-PCR, respectively. NF-κB activation was investigated by EMSA, reporter gene assay and Western blotting. Anti-inflammatory effects of BPD were evaluated in vivo in carrageenan-induced paw oedema in rats and LPS-induced septic shock in mice.
  
  
  RESULTS
  BPD not only inhibited COX-2 activity but also reduced the expression of COX-2. In addition, BPD inhibited the expression of iNOS, TNF-α, IL-6 and IL-1β at the transcriptional level. BPD attenuated LPS-induced DNA-binding activity and the transcription activity of NF-κB; this was associated with a decrease in the phosphorylation level of inhibitory κB-α (IκB-α) and reduced nuclear translocation of NF-κB. Furthermore, BPD suppressed the formation of TGF-β-activated kinase-1 (TAK1)/TAK-binding protein1 (TAB1), which was accompanied by a parallel reduction of phosphorylation of TAK1 and IκB kinase (IKK). Pretreatment with BPD inhibited carrageenan-induced paw oedema and LPS-induced septic death.
  
  
  CONCLUSIONS
  Taken together, our data indicate that BPD is involved in the dual inhibition of COX-2 activity and TAK1-NF-κB pathway, providing a molecular basis for the anti-inflammatory properties of BPD.
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Biomedical Science, College of Medical Science, Kyung Hee University, Seoul, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, KoreaDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Biomedical Science, College of Medical Science, Kyung Hee University, Seoul, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, KoreaDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Biomedical Science, College of Medical Science, Kyung Hee University, Seoul, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, KoreaDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Suran
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Biomedical Science, College of Medical Science, Kyung Hee University, Seoul, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, KoreaDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Han Byul
authors.initials: HB
authors.lastname: Kang
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Biomedical Science, College of Medical Science, Kyung Hee University, Seoul, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, KoreaDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Biomedical Science, College of Medical Science, Kyung Hee University, Seoul, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, KoreaDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Biomedical Science, College of Medical Science, Kyung Hee University, Seoul, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, KoreaDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Jae-Yeol
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Biomedical Science, College of Medical Science, Kyung Hee University, Seoul, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, KoreaDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Young-Wuk
authors.initials: YW
authors.lastname: Cho
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, KoreaDepartment of Biomedical Science, College of Medical Science, Kyung Hee University, Seoul, KoreaResearch Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, KoreaDepartment of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
mesh_terms: D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D002351:Carrageenan; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008299:Maleic Anhydrides / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy; D018808:Transcription Factor AP-1 / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D052117:Benzodioxoles; D002351:Carrageenan; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D015232:Dinoprostone; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D008299:Maleic Anhydrides; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D009195:Peroxidase; D018808:Transcription Factor AP-1; D000099151:MAP Kinase Kinase Kinase 7; C573320:3-(benzo(d)-1,3-dioxol-5-yl)-4-phenylfuran-2,5-dione; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; C077623:Ptgs2 protein, mouse