Caffeic acid phenethyl ester activation of Nrf2 pathway is enhanced under oxidative state: Structural analysis and potential as a pathologically targeted therapeutic agent in treatment of colonic inflammation |
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| Affiliation: | 1. College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea;2. Department of Civil and Environmental Engineering, Pusan National University, Busan 609-735, Republic of Korea;3. College of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 420–743, Republic of Korea;4. College of Pharmacy, Kyungpook National University, Daegu, 702-701, Republic of Korea;1. College of Pharmacy, Pusan National University, Busan 609-735, South Korea;2. KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea;1. Department of Life Sciences and Biotechnology, University of Ferrara, Via L. Borsari 46, 44100 Ferrara, Italy;2. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK;3. Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Jena, Philosophenweg 14, 07743 Jena, Germany;4. Department of Medical Sciences, University of Ferrara, Via Fossato di Mortara 74, 44100, Ferrara, Italy;1. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;2. Department of Pharmacology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran;3. CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal;4. Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, Italy |
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| Abstract: | Caffeic acid phenethyl ester (CAPE) is a polyphenolic natural product that possesses numerous biological activities including anti-inflammatory effects. CAPE-mediated nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2) activation is likely responsible for some of its biological effects. CAPE was chemically modified to yield CAPE analogues that were subjected to experiments examining cellular Nrf2 activity. CAPE and the CAPE analogue with a catechol moiety, but not the other analogues, activated the Nrf2 pathway. In addition, only biotin-labeled CAPE analogues with the catechol moiety precipitated Kelch-like ECH associated protein 1 (Keap1) when incubated with cell lysates and streptavidin agarose beads. Sodium hypochlorite (NaOCl) oxidation of the catechol moiety in CAPE produced an oxidized, electrophilic form of CAPE (Oxi-CAPE) and greatly enhanced the ability of CAPE to activate Nrf2 and to bind to Keap1. Rectal administration of CAPE ameliorated 2,4,6-trinitrobenzene sulfonic acid-induced rat colitis and activated the Nrf2 pathway in the inflamed colon, and incubation of CAPE in the lumen of the inflamed distal colon generated Oxi-CAPE. However, these biological effects and chemical change of CAPE were not observed in the normal colon. Our data suggest that CAPE requires the catechol moiety for the oxidation-enhanced activation of the Nrf2 pathway and has potential as a pathologically targeted Nrf2-activating agent that is exclusively activated in pathological states with oxidative stress such as colonic inflammation. |
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| Keywords: | Caffeic acid phenethyl ester Oxidation of catechol Electrophile Nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 Kelch-like ECH associated protein 1 Pathologically targeted therapeutic agent Structural analysis |
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