title: Induction of Nrf2-mediated phase II detoxifying/antioxidant enzymes in vitro by chitosan-caffeic acid against hydrogen peroxide-induced hepatotoxicity through JNK/ERK pathway.
abstract: Chemical modification of chitosan is a promising method for the improvement of biological activity. In this study, chitosan-caffeic acid (CCA) was prepared and its in vitro hepatoprotective ability against hydrogen peroxide-induced hepatic damage in liver cells was evaluated. Treatment with CCA (50-400 µg/mL) did not show cytotoxicity and also significantly (p < 0.05) recovered cell viability against 650 µM hydrogen peroxide-induced hepatotoxicity. CCA treatment attenuated reactive oxygen species generation and lipid peroxidation in addition to increasing cellular glutathione level in cultured hepatocytes. To validate the underlying mechanism, antioxidant and phase II detoxifying enzyme expressions, which are mediated by NF-E2-related factor 2 (Nrf2) activation, were analyzed and CCA treatment was found to increase the expression of superoxide dismutase-1 (SOD-1), glutathione reductase (GR), heme oxygenase-1 (HO-1), and NAD(P)H:quinine oxidoreductase 1 (NQO1). CCA treatment resulted in increased Nrf2 nuclear translocation. The phosphorylation of extracellular regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) by CCA treatment contributed to Nrf2 activation. Pharmacological blockade of ERK, JNK, and p38 MAPK revealed that SP600125 (JNK inhibitor) and PD98059 (ERK inhibitor) treatment reduced Nrf2 translocation into the nucleus while SB203580 (p38 inhibitor) exhibited weak inhibition. Collectively, CCA protects liver cells against hydrogen peroxide-induced injury and this ability is attributed to the induction of antioxidants and phase II detoxifying enzymes that are mediated by Nrf2 translocation via JNK/ERK signaling.
authors.affiliation: Division of Food and Nutrition, Chonnam National University, Gwangju, 61186, Republic of Korea.
authors.forename: Chang-Bum
authors.initials: CB
authors.lastname: Ahn
authors.affiliation: Department of Marine-Bio Convergence Science, Pukyong National University, Busan, 48547, Republic of Korea. jjy1915@pknu.ac.kr.
authors.forename: Jae-Young
authors.identifier: http://orcid.org/0000-0002-4800-0566
authors.initials: JY
authors.lastname: Je
authors.affiliation: Department of Chemistry, Pukyong National University, Busan, 48513, Republic of Korea.
authors.forename: Young-Sang
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Pukyong National University, Busan, 48513, Republic of Korea.
authors.forename: Sun-Joo
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Specialized Graduate School of Science & Technology Convergence, Pukyong National University, Busan, 48547, Republic of Korea.
authors.forename: Boo Il
authors.initials: BI
authors.lastname: Kim
mesh_terms: D002109:Caffeic Acids / Q000494:pharmacology*; D002460:Cell Line; D048271:Chitosan / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010088:Oxidoreductases / Q000096:biosynthesis*
chemical_list: D002109:Caffeic Acids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D048271:Chitosan; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D048049:Extracellular Signal-Regulated MAP Kinases; C040048:caffeic acid
keywords: Chitosan; HO-1; Hepatocyte; NQO1; Nrf2; Oxidative stress