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 (TNF)-α, and prostaglandin E2 (PGE2), as well as the mRNA expression of inducible NO synthase (iNOS), TNF-α, 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, EtOH/HCl-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 anti-inflammatory activities in vitro and in vivo and may potentially be developed for use as a novel anti-inflammatory drug.

中文翻译：

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白藜芦醇衍生物2,4-二羟基-N-（4-羟基苯基）苯甲酰胺的JAK2靶向抗炎作用

白藜芦醇的化学衍生化已被广泛进行，以克服其化学不稳定性和治疗潜力。在本研究中，我们使用受Toll样受体（TLR）配体刺激的体外巨噬细胞模型和几种动物炎症性疾病模型，研究了含有酰胺功能的白藜芦醇衍生物的抗炎作用。在测试的白藜芦醇衍生物中，化合物8（2,4-二羟基-N-（4-羟基苯基）苯甲酰胺）最强烈地抑制一氧化氮（NO），肿瘤坏死因子（TNF）-α和前列腺素E2（PGE2）的产生），以及脂多糖（LPS）激活的RAW264.7细胞，分化的U937细胞和腹膜巨噬细胞中诱导型NO合酶（iNOS），TNF-α和环氧合酶（COX）-2的mRNA表达。化合物8的抑制活性显然是通过抑制信号转导子和转录激活子（STAT）-1，STAT-3，STAT-5和干扰素调节因子（IRF）-3的磷酸化介导的。使用直接激酶测定法和分析与这些分子形成复合物的方法，发现化合物8的直接靶标是Janus激酶2（JAK2），而不是TANK结合激酶（TBK）1。此外，TBK1的上游激酶似乎也被化合物8抑制。该化合物还强烈改善了花生四烯酸诱导的耳水肿，右旋糖酐硫酸钠（DSS）治疗的结肠炎，EtOH / HCl引起的胃炎，胶原蛋白中所见的小鼠炎症症状。 II型触发的关节炎和乙酸引起的扭体。因此，在我们测试的白藜芦醇衍生物中，