PMID- 30326282 OWN - NLM STAT- MEDLINE DCOM- 20200217 LR - 20211204 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 130 DP - 2019 Jan TI - Protocatechuic acid-mediated DJ-1/PARK7 activation followed by PI3K/mTOR signaling pathway activation as a novel mechanism for protection against ketoprofen-induced oxidative damage in the gastrointestinal mucosa. PG - 35-47 LID - S0891-5849(18)32181-6 [pii] LID - 10.1016/j.freeradbiomed.2018.10.415 [doi] AB - Oxidative stress contributes to the progression of non-steroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) cell apoptosis. In our previous study, we reported that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a protective role against ketoprofen-induced GI mucosal oxidative injury. Recent reports suggest that Nrf2 could exhibit antioxidative and antiapoptosis responses through up-regulation of DJ-1 (PARK7). In the current study, we proposed that induction of DJ-1 expression by protocatechuic acid (PCA) might provide a potential therapeutic approach for treating oxidative stress-associated GI ulcer diseases. The results indicated that PCA increased mRNA expression of glutathione peroxidase and heme oxygenase-1 through up-regulation of DJ-1 followed by Nrf2 translocation. Furthermore, PCA protected Int-407 cells against ketoprofen-induced oxidative stress by regulating the DJ-1, PI3K, and mTOR pathways. Pretreatment with PCA inhibited mitochondrial ROS generation, up-regulated the mitochondrial membrane potential, and down-regulated pro-apoptotic Bax as well as downstream caspase-8, caspase-9, and caspase-3 activity, and reversed impaired DJ-1 and anti-apoptotic Bcl-2 protein expression in Int-407 cells induced by ketoprofen. Similar to the in vitro results, SD rats treated with PCA before administration of ketoprofen exhibited decreased caspase-3 protein expression as well as oxidative damage, and impairment of the antioxidant system and DJ-1 protein expression in the GI mucosa were reversed. The administration of lansoprazole, a type of proton pump inhibitor (PPI), strongly inhibited ketoprofen-induced GI mucosal injuries via up-regulation of DJ-1, indicating that DJ-1 is essential for the dietary antioxidant- and PPI drug-mediated mechanism of ulcer therapy. These results suggest that DJ-1 could be a novel target for protection against ketoprofen-induced GI ulcers due to its antioxidant and anti-apoptosis characteristics. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Cheng, Yu-Ting AU - Cheng YT AD - Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. FAU - Lin, Jer-An AU - Lin JA AD - Graduate Institute of Food Safety, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. FAU - Jhang, Jhih-Jia AU - Jhang JJ AD - Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. FAU - Yen, Gow-Chin AU - Yen GC AD - Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan; Graduate Institute of Food Safety, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan. Electronic address: gcyen@nchu.edu.tw. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181013 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Anti-Inflammatory Agents, Non-Steroidal) RN - 0 (Hydroxybenzoates) RN - 0 (RNA, Small Interfering) RN - 36R5QJ8L4B (protocatechuic acid) RN - 90Y4QC304K (Ketoprofen) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.2.- (PARK7 protein, human) RN - EC 3.1.2.- (Protein Deglycase DJ-1) SB - IM MH - Animals MH - Anti-Inflammatory Agents, Non-Steroidal/*adverse effects MH - Cell Line MH - Cytoprotection MH - Drug-Related Side Effects and Adverse Reactions/*prevention & control MH - Epithelial Cells/*immunology MH - Gastric Mucosa/*physiology MH - Humans MH - Hydroxybenzoates/*metabolism MH - Ketoprofen/*adverse effects MH - Male MH - Oxidative Stress MH - Phosphatidylinositol 3-Kinases/metabolism MH - Protein Deglycase DJ-1/genetics/*metabolism MH - RNA, Small Interfering/genetics MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction MH - TOR Serine-Threonine Kinases/metabolism OTO - NOTNLM OT - DJ-1 OT - Gastrointestinal ulcer OT - Ketoprofen OT - NSAIDs OT - Nrf2 OT - Protocatechuic acid EDAT- 2018/10/17 06:00 MHDA- 2020/02/18 06:00 CRDT- 2018/10/17 06:00 PHST- 2018/05/03 00:00 [received] PHST- 2018/09/30 00:00 [revised] PHST- 2018/10/08 00:00 [accepted] PHST- 2018/10/17 06:00 [pubmed] PHST- 2020/02/18 06:00 [medline] PHST- 2018/10/17 06:00 [entrez] AID - S0891-5849(18)32181-6 [pii] AID - 10.1016/j.freeradbiomed.2018.10.415 [doi] PST - ppublish SO - Free Radic Biol Med. 2019 Jan;130:35-47. doi: 10.1016/j.freeradbiomed.2018.10.415. Epub 2018 Oct 13.