PDF(Pubmed)
Abstract：
Introduction: Although sinapic acid is found in various edible plants and has been shown to have anti-inflammatory properties including colitis, its underlying mechanism and effects on the composition of the gut microbiota are largely unknown. We aimed to identify an early response kinase that regulates the localization of tight junction proteins, act at the onset of the inflammatory response, and is regulated by sinapic acid. Additionally, we analyzed the effects of sinapic acid on the homeostasis of the intestinal microbiome. Methods: We examined the aberrant alterations of early response genes such as nuclear factor-kappa B (NF-κB) and activating transcription factor (ATF)-2 within 2 h of sinapic acid treatment in fully differentiated Caco-2 cells with or without lipopolysaccharide and tumor necrosis factor (TNF)-α stimulation. To confirm the effect of sinapic acid on stimulus-induced delocalization of tight junction proteins, including zonula occludens (ZO)-1, occludin, and claudin-2, all tight junction proteins were investigated by analyzing a fraction of membrane and cytosol proteins extracted from Caco-2 cells and mice intestines. Colitis was induced in C57BL/6 mice using 2% dextran sulfate sodium and sinapic acid (2 or 10 mg/kg/day) was administrated for 15 days. Furthermore, the nutraceutical and pharmaceutical activities of sinapic acid for treating inflammatory bowel disease (IBD) evaluated. Results: We confirmed that sinapic acid significantly suppressed the stimulus-induced delocalization of tight junction proteins from the intestinal cell membrane and abnormal intestinal permeability as well as the expression of inflammatory cytokines such as interleukin (IL)-1β and TNF-α in vitro and in vivo. Sinapic acid was found to bind directly to transforming growth factor beta-activated kinase 1 (TAK1) and inhibit the stimulus-induced activation of NF-κB as well as MAPK/ATF-2 pathways, which in turn regulated the expression of mitogen-activated protein kinase (MLCK). Dietary sinapic acid also alleviated the imbalanced of gut microbiota and symptoms of IBD, evidenced by improvements in the length and morphology of the intestine in mice with colitis. Discussion: These findings indicate that sinapic acid may be an effective nutraceutical and pharmaceutical agent for IBD treatment as it targets TAK1 and inhibits subsequent NF-κB and ATF-2 signaling.
摘要：
简介：虽然芥子酸存在于各种食用植物中，并已被证明具有抗炎特性，包括结肠炎，其潜在的机制和对肠道菌群组成的影响在很大程度上是未知的。我们的目的是确定调节紧密连接蛋白定位的早期反应激酶，在炎症反应开始时发挥作用，受芥子酸调节。此外,我们分析了芥子酸对肠道微生物组稳态的影响。方法：我们检查了在有或没有脂多糖和肿瘤坏死因子（TNF）-α刺激的完全分化的Caco-2细胞中芥子酸处理2小时内早期反应基因的异常变化，例如核因子-κB（NF-κB）和激活转录因子（ATF）-2。为了证实芥子酸对刺激诱导的紧密连接蛋白离域的影响，包括小带闭塞(ZO)-1，闭塞蛋白，和claudin-2，通过分析从Caco-2细胞和小鼠肠道中提取的一部分膜蛋白和胞质溶胶蛋白来研究所有紧密连接蛋白。使用2%葡聚糖硫酸钠在C57BL/6小鼠中诱导结肠炎,并施用芥子酸(2或10mg/kg/天)15天。此外，评估芥子酸治疗炎症性肠病（IBD）的营养和药物活性。结果：我们证实了芥子酸在体外和体内显着抑制了刺激诱导的肠细胞膜紧密连接蛋白的离域和异常的肠通透性以及炎性细胞因子如白细胞介素（IL）-1β和TNF-α的表达。发现芥子酸直接与转化生长因子β激活激酶1（TAK1）结合，并抑制刺激诱导的NF-κB激活以及MAPK/ATF-2途径，进而调节丝裂原活化蛋白激酶（MLCK）的表达。膳食芥子酸还缓解了肠道微生物群的不平衡和IBD的症状，结肠炎小鼠肠道长度和形态的改善证明了这一点。讨论：这些发现表明芥子酸可能是IBD治疗的有效营养和药物，因为它靶向TAK1并抑制随后的NF-κB和ATF-2信号传导。
