title: Protective effect of rutaecarpine against t-BHP-induced hepatotoxicity by upregulating antioxidant enzymes via the CaMKII-Akt and Nrf2/ARE pathways.
abstract: Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, has been shown to have cytoprotective potential, but the molecular mechanism underlying this activity remains unclear. Our study was designed to investigate the cytoprotective effect of rutaecarpine against tert-butyl hydroperoxide (t-BHP) and to elucidate its action mechanism of action of rutaecarpine in a cultured HepG2 cell line and in mouse liver. Rutaecarpine decreased t-BHP-induced reactive oxygen species (ROS) production, cytotoxicity, and apoptosis in HepG2 cells. Pretreatment with rutaecarpine prior to the injection of t-BHP significantly prevented the increase in serum levels of AST, ALT, and lipid peroxidation in mice liver. It increased the transcriptional activity of NF-E2-related factor 2 (Nrf2) as well as the products of the Nrf2 target genes hemeoxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutamate cysteine ligase (GCL). Moreover, rutaecarpine also enhanced the phosphorylation of Akt and Ca2+/calmodulin-dependent protein kinase-II (CaMKII). The pharmaceutical inhibitors, such as KN-93 (CaMKII inhibitor) and LY294002 (Akt inhibitor) suppressed rutaecarpine-induced HO-1 expression and cytoprotection. Our findings identify the CaMKII-PI3K/Akt-Nrf2 cascade as an antioxidant pathway mediating rutaecarpine signaling and leading to HO-1 expression in hepatocytes.
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Jin
authors.affiliation: Department of Pharmaceutical Engineering, International University of Korea, Jinju, Republic of Korea.
authors.forename: Yong Pil
authors.initials: YP
authors.lastname: Hwang
authors.affiliation: Jeollanamdo Institute of Natural Resources Research, Jeollanamdo, Republic of Korea.
authors.forename: Chul Yung
authors.initials: CY
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Se Jong
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Yongan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Food Science, International University of Korea, Jinju, Republic of Korea.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Chung
authors.affiliation: Department of Convergence Medicine, ASAN Medical Center, University of Ulsan College of Medicine, Republic of Korea.
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
authors.forename: Tae Cheon
authors.initials: TC
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea. Electronic address: hgjeong@cnu.ac.kr.
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D056945:Hep G2 Cells; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation; D014665:Vasodilator Agents / Q000494:pharmacology; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D020122:tert-Butylhydroperoxide / Q000633:toxicity*; D052999:Quinazolinones
chemical_list: D000975:Antioxidants; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D026121:Indole Alkaloids; D051267:NF-E2-Related Factor 2; D020011:Protective Agents; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D033921:Vesicular Transport Proteins; D020122:tert-Butylhydroperoxide; C495635:NFE2L2 protein, human; C115740:VPS52 protein, human; C028632:rutecarpine; D052999:Quinazolinones
keywords: Akt; CaMKII; HO-1; Nrf2; Oxidative stress; Rutaecarpine