JAK2-targeted anti-inflammatory effect of a resveratrol derivative 2,4-dihydroxy-N-(4-hydroxyphenyl)benzamide

被引：38

作者：

Kim, Min Ho ^{[2
,3
]}

Son, Young-Jin ^{[4
]}

Lee, Sang Yeol ^{[5
]}

Yang, Woo Seok ^{[1
]}

Yi, Young-Su ^{[1
]}

Yoon, Deok Hyo ^{[6
]}

Yang, Yanyan ^{[1
]}

Kim, Shi Hyoung ^{[1
]}

Lee, Duckhee ^{[7
]}

Rhee, Man Hee ^{[8
]}

Kang, Hyojeung ^{[9
,10
]}

Kim, Tae Woong ^{[6
]}

Sung, Gi-Ho ^{[11
]}

Cho, Jae Youl ^{[1
]}

机构：

[1] Sungkyunkwan Univ, Dept Genet Engn, Suwon 440746, South Korea

[2] Kangwon Natl Univ, Coll Biomed Sci, Chunchon 200701, South Korea

[3] Kangwon Natl Univ, Inst Biosci & Biotechnol, Chunchon 200701, South Korea

[4] Sunchon Natl Univ, Dept Pharm, Sunchon 540742, South Korea

[5] Gachon Univ, Dept Life Sci, Songnam 461701, South Korea

[6] Kangwon Natl Univ, Dept Biochem, Chunchon 200701, South Korea

[7] Wonkwang Univ, Coll Nat Sci, Div Bionanochem, Iksan, South Korea

[8] Kyungpook Natl Univ, Coll Vet Med, Taegu 702701, South Korea

[9] Kyungpook Natl Univ, Coll Pharm, Taegu 702701, South Korea

[10] Kyungpook Natl Univ, Pharmaceut Sci Res Inst, Taegu 702701, South Korea

[11] Rural Dev Adm, Natl Inst Hort & Herbal Sci, Dept Herbal Crop Res, Suwon 441707, South Korea

来源：

BIOCHEMICAL PHARMACOLOGY | 2013年 / 86卷 / 12期

关键词：

Resveratrol derivatives; Amide functionality; JAK2; Anti-inflammatory effects; Inflammatory mediators; NF-KAPPA-B; STIMULATED RAW264.7 CELLS; JAK2 INHIBITOR THERAPY; TOLL-LIKE RECEPTORS; IN-VITRO; SIGNAL-TRANSDUCTION; ACTIVATION; PATHWAY; KINASE; CANCER;

D O I：

10.1016/j.bcp.2013.10.006

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

Chemical derivatization of resveratrol has been widely conducted in an effort to overcome its chemical instability and therapeutic potential. In the present study, we examined the anti-inflammatory effects of resveratrol derivatives containing an amide functionality using in vitro macrophage models that were stimulated by Toll-like receptor (TLR) ligands, and using several animal inflammatory disease models. Of the resveratrol derivatives tested, compound 8 (2,4-dihydroxy-N-(4-hydroxyphenyl)benzamide) most strongly inhibited the production of nitric oxide (NO), tumor necrosis factor (TNE)-a, and prostaglandin E2 (PGE2), as well as the mRNA expression of inducible NO synthase (iNOS), TNE-ce, and cyclooxygenase (COX)-2 in lipopolysaccharide (LPS)-activated RAW264.7 cells, differentiated U937 cells, and peritoneal macrophages. The inhibitory activity of compound 8 was apparently mediated by suppressing the phosphorylation of signal transducer and activator of transcription (STAT)-1, STAT-3, STAT-5, and interferon regulatory factor (IRF)-3. The direct target of compound 8 was revealed to be Janus kinase 2 (JAK2) but not TANK-binding kinase (TBK) 1 using the direct kinase assay and analyses of complex formation with these molecules. Additionally, upstream kinase of TBK1 seems to be also inhibited by compound 8. This compound also strongly ameliorated mouse inflammatory symptoms seen in arachidonic acid-induced ear edema, dextran sodium sulfate (DSS)-treated colitis, Et0H/HCI-induced gastritis, collagen type II-triggered arthritis, and acetic acid-induced writhing. Therefore, of the resveratrol derivatives that we tested, compound 8 was determined to have the strongest antiinflammatory activities in vitro and in vivo and may potentially be developed for use as a novel antiinflammatory drug. (C) 2013 Elsevier Inc. All rights reserved.

引用

页码：1747 / 1761

页数：15

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