title: Anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway.
abstract: OBJECTIVE
  Products of Maillard reactions between aminoacids and reducing sugars are known to have anti-inflammatory properties. Here we have assessed the anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal and its possible mechanisms of action.
  
  
  METHODS
  We used cultures of LPS-activated macrophages (RAW264.7 cells) and human synoviocytes from patients with rheumatoid arthritis for in vitro assays and the collagen-induced arthritis model in mice. NO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities were measured in vitro and in joint tissues of arthritic mice, along with clinical scores and histopathological assessments. Binding of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal to STAT3 was evaluated by a pull-down assay and its binding site was predicted using molecular docking studies with Autodock VINA.
  
  
  RESULTS
  (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (2.5-10 μg·mL(-1) ) inhibited LPS-inducedNO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities in macrophage and human synoviocytes. This compound also suppressedcollagen-induced arthritic responses in mice by inhibiting expression of iNOS and COX2, and NF-κB/IKK and STAT3 activities; it also reduced bone destruction and fibrosis in joint tissues. A pull-down assay showed that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal interfered with binding of ATP to STAT3. Docking studies suggested that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal bound to the DNA-binding interface of STAT3 possibly inhibiting ATP binding to STAT3 in an allosteric manner.
  
  
  CONCLUSIONS
  (E)-2,4-bis(p-hydroxyphenyl)-2-butenal exerted anti-inflammatory and anti-arthritic effects through inhibition of the NF-κB/STAT3 pathway by direct binding to STAT3. This compound could be a useful agent for the treatment of arthritic disease.
authors: College of Pharmacy, Medical Research Center, Chungbuk National University, Cheongju, Chungbuk, Korea.
authors: Jung Ok
authors: JO
authors: Ban
authors: Dae Hwan
authors: DH
authors: Kim
authors: Hee Pom
authors: HP
authors: Lee
authors: Chul Ju
authors: CJ
authors: Hwang
authors: Jung-Hyun
authors: JH
authors: Shim
authors: Dae Joong
authors: DJ
authors: Kim
authors: Tae Myoung
authors: TM
authors: Kim
authors: Heon-Sang
authors: HS
authors: Jeong
authors: Seong Su
authors: SS
authors: Nah
authors: Hanyong
authors: H
authors: Chen
authors: Zigang
authors: Z
authors: Dong
authors: Young Wan
authors: YW
authors: Ham
authors: Youngsoo
authors: Y
authors: Kim
authors: Sang-Bae
authors: SB
authors: Han
authors: Jin Tae
authors: JT
authors: Hong
mesh_terms: D000328:Adult; D000368:Aged; D000447:Aldehydes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D033023:Foot Joints / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000166:cytology
chemical_list: C580808:2,4-bis(p-hydroxyphenyl)-2-butenal; D000447:Aldehydes; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010636:Phenols; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D015232:Dinoprostone
keywords: (E)-2; 4-bis(p-hydroxyphenyl)- 2-butenal; NF-κB; STAT3; arthritis; inflammation