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AB0601 Anti-arthritis effects of (E)-2,4-bis(P-hydroxyphenyl)-2-butenal through inhibition of IKK-beta activity
  1. J.-H. Shim1,
  2. S.-S. Nah2,
  3. J.O. Ban3,
  4. J.T. Hong3,
  5. S.J. Lee2,
  6. H.-J. Kim4
  1. 1Department of Biochemistry
  2. 2Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University, College of Medicine, Choenan
  3. 3College of Pharmacy, Medical Research Center, Chungbuk National University, Cheongju
  4. 4Medical Research center, Soonchunhyang University, College of Medicine, Choenan, Korea, Republic Of

Abstract

Background Maillard reaction products (MRPs) are known to have antioxidant, antimutagenic and anticardiogenic activities. The antioxidant capacity of MRPs is comparable to those of commonly used food antioxidants; butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and a-tocopherol. Maillard reaction (MR) could produce non-enzymatically colored or colorless products such as glucose-tyrosine, glucose-lysine, fructose-lysine, ribose-lysine, xylose-arginine, xylose-glycine and xylose-tryptophanRecently, we synthesized (E)-2,4-bis(p-hydroxyphenyl)-2-butenal using tyrosine and fructose under a typical MR condition of high temperature and pressure.

Objectives Objective of this study was to assess anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal and its action mechanisms.In the present study, we investigated whether (E)-2,4-bis(p-hydroxyphenyl)-2-butenal can have anti-inflammatory activity and anti-arthritic activities through inhibition of NF-kB/IKK and STAT3 pathways in cultured macrophage and synoviocytes, and collagen-induced arthritis (CIA) animal model.

Methods Nitric oxide (NO) and prostaglandin E2 assay, electrophoretic mobility shift assay, luciferase assay, Western blot, real-time PCR and pull-down assay were used for mechanism studies. Anti-inflammatory effect was done in cultured RAW 264.7 cells and synoviocytes, and collagen-induced arthritis model was used for evaluation of anti-inflammation and anti-arthritis effects in vivo. Binding target of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal was identified using pull-down assay and sol-gel biochip assay, and its binding site was proposed through a docking experiment.

Results (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (2.5-10 mg/ml) inhibited lipopolysaccharides (1 mg/ml)-induced pro-inflammatory responses through downregulating IkB kinase b (IKKb)/nuclear factor-kapaB (NF-kB) and signal transducer and activator of transcription 3 (STAT3) pathways in RAW 264.7 cells and synoviocytes. (E)-2,4-bis(p-hydroxyphenyl)-2-butenal not only suppressed the collagen (100 mg/0.1ml)-induced arthritic responses through inhibition of IKKb/NF-kB and STAT3 activities but also reduced the extent of bone destruction and fibrosis in joint tissue. The population of white blood cells in blood and NO generation in murine splenic T cells of collagen-induced arthritic mice were significantly reduced by (E)-2,4-bis(p-hydroxyphenyl)-2-butenal. Sol-gel biochip analysis proved that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal directly binds to IKKb, and thus inhibit its activity. A docking experiment and pull-down assay indicate that IKKb might be a potential target of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal.

Conclusions These findings indicated that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal exerted its anti-inflammatory and anti-arthritic effects through inhibition of IKKb/NF-kB activity via direct binding to IKKb, and that it could be a useful agent for the treatment of arthritic diseases.

  1. Hwang IG, Kim HY, Woo KS, Hong JT, Hwang BY, Jung JK, et al. Isolation and characterisation of an a-glucosidase inhibitory substance from fructose–tyrosine Maillard reaction products. Food Chemistry 2011;127:122–6.

Disclosure of Interest None Declared

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