title: Asiatic acid enhances Nrf2 signaling to protect HepG2 cells from oxidative damage through Akt and ERK activation.
abstract: Asiatic acid (AA), a natural triterpene isolated from the plant Centella asiatica, have antioxidative potential, but the molecular mechanism of AA against oxidative stress remains unclear. Our study was performed to investigate the antioxidative effect of AA against oxidative stress and the antioxidative mechanism in tert-butyl hydroperoxide (t-BHP) -stimulated the HepG2 cells. The results showed that AA suppressed t-BHP-induced cytotoxicity, apoptosis, and reactive oxygen species (ROS) generation. Additionally, AA activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signal, which was closely related to induction Nrf2 nuclear translocation, reduction the expression of Keap1 and up-regulation the activity of the antioxidant response element (ARE). Meanwhile, activation of Nrf2 signal upregulated the protein expressions of antioxidant genes, including heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidase (NQO-1), and glutamyl cysteine ligase catalytic subunit (GCLC). Excitingly, Knockout of Nrf2 almost abolished AA-mediated antioxidant activity and cytoprotection against t-BHP. Further studies showed the mechanism underlying that AA induced Nrf2 activation in HepG2 cells via Akt and ERK signal activation. We found Akt and ERK inhibitors treatment attenuated AA-mediated Nrf2 nuclear translocation. Furthermore, treatment with either Akt or ERK inhibitor also decreased AA-mediated cytoprotection against t-BHP-induced cellular damage. Collectively, these results presented in this study indicate that AA has the protective effect against t-BHP-induced cellular damage and oxidative stress by modulating Nrf2 signaling through activating the signals of Akt and ERK.
authors.affiliation: Institute of Translational Medicine, The First Hospital of Jilin University, College of Veterinary Medicine, Jilin University, Changchun, 130061, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Institute of Translational Medicine, The First Hospital of Jilin University, College of Veterinary Medicine, Jilin University, Changchun, 130061, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ci
authors.affiliation: Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun, 130061, China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Huang
authors.affiliation: Institute of Translational Medicine, The First Hospital of Jilin University, College of Veterinary Medicine, Jilin University, Changchun, 130061, China.
authors.forename: Qinmei
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Institute of Translational Medicine, The First Hospital of Jilin University, College of Veterinary Medicine, Jilin University, Changchun, 130061, China.
authors.forename: Qinlei
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Dermatology and Venereology, The First Hospital of Jilin University, Changchun, 130061, China. Electronic address: 646603407@qq.com.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute of Translational Medicine, The First Hospital of Jilin University, College of Veterinary Medicine, Jilin University, Changchun, 130061, China. Electronic address: dengxm@jlu.edu.cn.
authors.forename: Xuming
authors.initials: X
authors.lastname: Deng
mesh_terms: D061745:Antioxidant Response Elements / Q000235:genetics; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055786:Gene Knockout Techniques; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects* / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D053978:Pentacyclic Triterpenes / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020122:tert-Butylhydroperoxide / Q000037:antagonists & inhibitors / Q000633:toxicity
chemical_list: D000975:Antioxidants; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D020122:tert-Butylhydroperoxide; C017032:asiatic acid; D051058:Oncogene Protein v-akt
keywords: Asiatic acid; HepG2 cells; Nrf2; Oxidative stress