Abstract
Ketoprofen is widely used to alleviate pain and inflammation in clinical medicine; however, this drug may cause oxidative stress and lead to gastrointestinal (GI) ulcers. We previously reported that nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in protecting cells against reactive oxygen species, and it facilitates the prevention of ketoprofen-induced GI mucosal ulcers. Recent reports suggested that Nrf2 becomes unstable in the absence of DJ-1/PARK7, attenuating the activity of Nrf2-regulated downstream antioxidant enzymes. Thus, increasing Nrf2 translocation by DJ-1 may represent a novel means for GI protection. In vitro, caffeic acid increases the nuclear/cytosolic Nrf2 ratio and the mRNA expression of the downstream antioxidant enzymes, ϒ-glutamyl cysteine synthetase, glutathione peroxidase, glutathione reductase, and heme oxygenase-1, by activating the JNK/p38 pathway in Int-407 cells. Moreover, knockdown of DJ-1 also reversed caffeic acid-induced nuclear Nrf2 protein expression in a JNK/p38-dependent manner. Our results also indicated that treatment of Sprague-Dawley rats with caffeic acid prior to the administration of ketoprofen inhibited oxidative damage and reversed the inhibitory effects of ketoprofen on the antioxidant system and DJ-1 protein expression in the GI mucosa. Our observations suggest that DJ-1 plays an important role in caffeic acid-mediated protection against ketoprofen-induced oxidative damage in the GI mucosa.
Keywords:
Caffeic acid; DJ-1; Gastrointestinal ulcer; HO-1; Ketoprofen; NSAIDs; Nrf2.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
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Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
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Antioxidants / pharmacology
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Caffeic Acids / pharmacology*
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Cell Line
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Gastrointestinal Tract / cytology
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Gastrointestinal Tract / drug effects*
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Gastrointestinal Tract / metabolism
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Glutathione Peroxidase / metabolism
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Glutathione Reductase / metabolism
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Heme Oxygenase-1 / metabolism
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Humans
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Inflammation / drug therapy
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Ketoprofen / administration & dosage
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Ketoprofen / adverse effects*
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Male
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Mucous Membrane / drug effects
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Mucous Membrane / metabolism
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NF-E2-Related Factor 2 / genetics
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NF-E2-Related Factor 2 / metabolism
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Oxidative Stress / drug effects*
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Phytochemicals / pharmacology
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Protein Deglycase DJ-1
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism
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Translocation, Genetic
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Antioxidants
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Caffeic Acids
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Intracellular Signaling Peptides and Proteins
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Microtubule-Associated Proteins
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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Nfe2l2 protein, rat
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Oncogene Proteins
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Phytochemicals
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RNA, Messenger
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Reactive Oxygen Species
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Ketoprofen
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Glutathione Peroxidase
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Heme Oxygenase-1
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Cyclooxygenase 2
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Ptgs2 protein, rat
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Glutathione Reductase
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PARK7 protein, human
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PARK7 protein, rat
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Protein Deglycase DJ-1
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caffeic acid