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Anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway.

ABSTRACT: BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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-?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 ?g·mL(-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.

SUBMITTER: Ban JO

PROVIDER: S-EPMC4243863 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway.

Ban Jung Ok JO Kim Dae Hwan DH Lee Hee Pom HP Hwang Chul Ju CJ Shim Jung-Hyun JH Kim Dae Joong DJ Kim Tae Myoung TM Jeong Heon-Sang HS Nah Seong Su SS Chen Hanyong H Dong Zigang Z Ham Young Wan YW Kim Youngsoo Y Han Sang-Bae SB Hong Jin Tae JT

British journal of pharmacology 20140601 11

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>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 mi ...[more]

PMID: 24520814

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Anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway.

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Anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal are mediated by inhibition of the STAT3 pathway.

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