PDF(Pubmed)
Abstract：
Non-steroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, cause gastric mucosal damage, including ulcers, directly or indirectly, by which the development of GI-safer (-sparing) NSAIDs relates to unmet medical needs. This study aimed to document the preventive effects of walnut polyphenol extracts (WPEs) against NSAID-induced gastric damage along with the molecular mechanisms. RGM-1 gastric mucosal cells were administered with indomethacin, and the expressions of the inflammatory mediators between indomethacin alone or a combination with WPEs were compared. The expressions of the inflammatory mediators, including COX-1 and COX-2, prostaglandin E2, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and antioxidant capacity, were analyzed by Western blot analysis, RT-PCR, and ELISA, respectively. HO-1, Nrf-2, and keap1 were investigated. The in vivo animal models were followed with in vitro investigations. The NSAIDs increased the expression of COX-2 and decreased COX-1 and 15-PGDH, but the WPEs significantly attenuated the NSAID-induced COX-2 expression. Interestingly, the WPEs induced the expression of 15-PGDH. By using the deletion constructs of the 15-PGDH promoter, we found that c-Jun is the most essential determinant of the WPE-induced up-regulation of 15-PGDH expression. We confirmed that the knockdown of c-Jun abolished the ability of the WPEs to up-regulate the 15-PGDH expression. In addition, the WPEs significantly increased the HO-1 expression. The WPEs increased the nuclear translocation of Nrf2 by Keap-1 degradation, and silencing Nrf2 markedly reduced the WPE-induced HO-1 expression. We found that the WPE-induced HO-1 up-regulation was attenuated in the cells harboring the mutant Keap1, in which the cysteine 151 residue was replaced by serine. These in vitro findings were exactly validated in indomethacin-induced gastric rat models. Daily walnut intake can be a promising nutritional supplement providing potent anti-inflammatory, antioxidative, and mucosa-protective effects against NSAID-induced GI damage.
摘要：
非甾体抗炎药（NSAIDs）世界上治疗疼痛的最高处方药物，炎症,发烧，导致胃粘膜损伤，包括溃疡,直接或间接,由此，GI-更安全（-节省）NSAIDs的开发与未满足的医疗需求有关。本研究旨在记录核桃多酚提取物（WPEs）对NSAID诱导的胃损伤的预防作用及其分子机制。RGM-1胃粘膜细胞与吲哚美辛一起施用，并比较了消炎痛单独或与WPE联合使用的炎症介质的表达。炎症介质的表达，包括COX-1和COX-2，前列腺素E2，15-羟基前列腺素脱氢酶（15-PGDH），和抗氧化能力，通过蛋白质印迹分析进行分析，RT-PCR,和ELISA，分别。研究了HO-1、Nrf-2和keap1。对体内动物模型进行体外研究。NSAIDs增加COX-2的表达，降低COX-1和15-PGDH，但WPE显著减弱了NSAID诱导的COX-2表达。有趣的是,WPE诱导15-PGDH的表达。通过使用15-PGDH启动子的缺失构建体，我们发现c-Jun是WPE诱导的15-PGDH表达上调的最重要决定因素。我们证实了c-Jun的敲低消除了WPE上调15-PGDH表达的能力。此外,WPE显著增加HO-1表达。WPE通过Keap-1降解增加了Nrf2的核易位，沉默Nrf2显著降低WPE诱导的HO-1表达。我们发现WPE诱导的HO-1上调在含有突变体Keap1的细胞中减弱，其中半胱氨酸151残基被丝氨酸取代。这些体外发现在吲哚美辛诱导的胃大鼠模型中得到了精确验证。每天摄入核桃可以是一种有前途的营养补充剂，提供有效的抗炎，抗氧化，和对NSAID诱导的胃肠道损伤的粘膜保护作用。
