DJ-1 plays an important role in caffeic acid-mediated protection of the gastrointestinal mucosa against ketoprofen-induced oxidative damage

J Nutr Biochem. 2014 Oct;25(10):1045-57. doi: 10.1016/j.jnutbio.2014.05.007. Epub 2014 Jun 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Antioxidants / pharmacology
  • Caffeic Acids / pharmacology*
  • Cell Line
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gastrointestinal Tract / cytology
  • Gastrointestinal Tract / drug effects*
  • Gastrointestinal Tract / metabolism
  • Glutathione Peroxidase / metabolism
  • Glutathione Reductase / metabolism
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Inflammation / drug therapy
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Ketoprofen / administration & dosage
  • Ketoprofen / adverse effects*
  • Male
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mucous Membrane / drug effects
  • Mucous Membrane / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Oxidative Stress / drug effects*
  • Phytochemicals / pharmacology
  • Protein Deglycase DJ-1
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Translocation, Genetic

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antioxidants
  • Caffeic Acids
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nfe2l2 protein, rat
  • Oncogene Proteins
  • Phytochemicals
  • RNA, Messenger
  • Reactive Oxygen Species
  • Ketoprofen
  • Glutathione Peroxidase
  • Heme Oxygenase-1
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Glutathione Reductase
  • PARK7 protein, human
  • PARK7 protein, rat
  • Protein Deglycase DJ-1
  • caffeic acid