Anti-arthritis effects of ( E)-2,4-bis(p-hydroxyphenyl)2-butenal are mediated by inhibition of the STAT3 pathway
- Authors
- Ban, Jung Ok; Kim, Dae Hwan; Lee, Hee Pom; Hwang, Chul Ju; Shim, Jung-Hyun; Kim, Dae Joong; Kim, Tae Myoung; Jeong, Heon-Sang; Nah, Seong Su; Chen, Hanyong; Dong, Zigang; Ham, Young Wan; Kim, Youngsoo; Han, Sang-Bae; Hong, Jin Tae
- Issue Date
- Jun-2014
- Publisher
- Wiley-Blackwell
- Keywords
- (E)-2; 4-bis(p-hydroxyphenyl)-2-butenal; STAT3; NF-B; arthritis; inflammation
- Citation
- British Journal of Pharmacology, v.171, no.11, pp 2900 - 2912
- Pages
- 13
- Journal Title
- British Journal of Pharmacology
- Volume
- 171
- Number
- 11
- Start Page
- 2900
- End Page
- 2912
- URI
- https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/12186
- DOI
- 10.1111/bph.12619
- ISSN
- 0007-1188
1476-5381
- Abstract
- Background and PurposeProducts 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. Experimental ApproachWe 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-B/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. Key Results(E)-2,4-bis(p-hydroxyphenyl)-2-butenal (2.5-10 gmL(-1)) inhibited LPS-inducedNO generation, iNOS and COX2 expression, and NF-B/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-B/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 and Implications(E)-2,4-bis(p-hydroxyphenyl)-2-butenal exerted anti-inflammatory and anti-arthritic effects through inhibition of the NF-B/STAT3 pathway by direct binding to STAT3. This compound could be a useful agent for the treatment of arthritic disease.
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