Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA; Physical Chemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina; IBIMOL, University of Buenos Aires-CONICET, Buenos Aires, Argentina.
Departments of Nutrition and Environmental Toxicology, University of California, Davis, CA, USA.
Free Radic Biol Med. 2020 May 20;152:776-786. doi: 10.1016/j.freeradbiomed.2020.01.022. Epub 2020 Jan 23.
Chronic intestinal inflammation involves a cycle of oxidative stress, activation of redox sensitive transcription factors, and barrier permeabilization. The latter can lead to systemic inflammation and its associated co-morbidities. Diet can play a major role in the modulation of intestinal inflammation. Among plant bioactives, ellagic acid (EA) was reported to inhibit inflammatory bowel disease in animal models. This work investigated the mechanisms by which EA inhibits tumor necrosis factor alpha (TNFα)-induced inflammation, oxidative stress, and loss of barrier integrity. Caco-2 cells differentiated into an intestinal epithelial cell monolayer were incubated with TNFα (10 ng/ml), in the presence of different EA concentrations. TNFα triggered interleukin (IL) 6 and 8 release into the medium, which was inhibited by EA in a dose-dependent manner (IC = 17.3 μM for IL-6). TNFα also led to: i) increased ICAM-1 and NLRP3 expression; ii) loss of epithelial barrier function; iii) increased oxidant production from NOX and mitochondrial origin; iv) NF-κB and ERK1/2 activation; and v) increased MLCK gene expression and MLC phosphorylation. EA (10-40 μM) inhibited all these adverse effects of TNFα. EA mainly acted through NF-κB and ERK1/2 inhibition, breaking the cycle of inflammation, oxidative stress, redox-sensitive pathway (e.g. NF-κB, ERK1/2) activation and intestinal permeabilization. This suggests that consumption of EA, via foods or supplements, may afford a strategy to mitigate intestinal inflammation and its associated co-morbidities.
慢性肠道炎症涉及氧化应激、氧化还原敏感转录因子激活和屏障通透性增加的循环。后者可导致全身炎症及其相关合并症。饮食可以在调节肠道炎症中发挥重要作用。在植物生物活性物质中，鞣花酸 (EA) 被报道可抑制动物模型中的炎症性肠病。这项工作研究了 EA 抑制肿瘤坏死因子-α (TNFα) 诱导的炎症、氧化应激和屏障完整性丧失的机制。将分化为肠上皮细胞单层的 Caco-2 细胞与 TNFα（10ng/ml）一起孵育，同时存在不同浓度的 EA。TNFα 触发白细胞介素 (IL) 6 和 8 释放到培养基中，EA 以剂量依赖的方式抑制其释放（IL-6 的 IC = 17.3μM）。TNFα 还导致：i）增加细胞间黏附分子 1 (ICAM-1) 和 NLRP3 的表达；ii）上皮屏障功能丧失；iii）来自 NOX 和线粒体的氧化产物增加；iv）NF-κB 和 ERK1/2 激活；和 v）增加肌球蛋白轻链激酶 (MLCK) 基因表达和肌球蛋白轻链磷酸化。EA（10-40μM）抑制了 TNFα 的所有这些不利影响。EA 主要通过 NF-κB 和 ERK1/2 抑制起作用，打破了炎症、氧化应激、氧化还原敏感途径（如 NF-κB、ERK1/2）激活和肠道通透性增加的循环。这表明通过食物或补充剂摄入 EA 可能提供一种减轻肠道炎症及其相关合并症的策略。
