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P049 Dietary walnus to prevent indomethacin-induced intestinal damages

K. B. Hahm*1, Y. W. Shin2

1CHA University, Gastroenterology, Seongnam, South Korea, 2Inha University Hospital, Incheon, South Korea

Background

Non-steroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, caused gastric mucosal damages including ulcer directly or indirectly, by which development of GI safer NSAIDs is unmet medical needs. This study was aimed to document the preventive effects of walnut phenolic extract (WPE) against NSAIDs-induced gastric damages along with molecular mechanisms for future clinical implications.

Methods

RGM-1 gastric mucosal cells were administered with NSAIDs and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and WPE. The expressions of inflammatory mediators, including COX-1 and COX-2, prostaglandin E2, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and anti-oxidant capacity, were analysed by western blot analysis, RT-PCR, and ELISA,, respectively. HO-1, Nrf-2, keap1 of Phase 2 enzymes were investigated. In vivo animal models were followed with in vitro investigations.

Results

NSAID increased the expression of COX-2 and decreased COX-1 and 15-PGDH, but WPE significantly attenuated NSAID-induced COX-2 expression. Interestingly, WPE-induced expression of 15-PGDH. By using deletion constructs of the 15-PGDH promoter, we have found that c-Jun is the most essential determinant for WPE-induced up-regulation of 15-PGDH expression. We confirmed that knockdown of c-Jun abolished the ability of WPE to up-regulate 15-PGDH expression. In addition, WPE significantly increased HO-1 expression. WPE increased nuclear translocation of Nrf2 by Keap-1 degradation and silencing Nrf2 markedly reduced the WPE-induced HO-1 expression. We have found that WPE-induced HO-1 up-regulation was attenuated in cells harbouring 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.

Conclusion

Daily walnut intake can be promising nutritional supplement providing potent anti-inflammatory, anti-oxidative, and mucosa protective effects against NSAID-induced GI damages.