title: Ginsenoside Rc modulates Akt/FoxO1 pathways and suppresses oxidative stress.
abstract: Ginsenoside Rc (Rc), a protopanaxadiol type ginsenoside, is the active component mainly responsible for the therapeutic and pharmacologic properties of ginseng, which are derived from its suppression of superoxide-induced free radicals. Forkhead box O (FoxO1) regulates various genes involved in cellular metabolism related to cell death and response to oxidative stress, and Rc is known to prevent FoxO1 phosphorylation by activation of PI3K/Akt and subsequent inhibition of AMP-activated protein kinase (AMPK) in cells exposed to tert-butylhydroperoxide (t-BHP). In the current study, we attempted the mechanism of increased catalase expression by Rc through inhibition of FoxO1 activation resulting from t-BHP-induced production of reactive species (RS). We found that overexpression of catalase induced by Rc resulted in suppression of RS production in kidney human embryo kidney 293T cells (HEK293T) cells, and that oxidative stress induced activation of PI3K/Akt and inhibition of the AMPK pathway and FoxO1 phosphorylation, leading to down-regulation of catalase, a FoxO1-targeting gene. In addition, treatment of HEK293T cells with Rc resulted in cAMP-response element-binding protein (CREB)-binding protein (CBP) regulated FoxO1 acetylation. Our results suggest that Rc modulates FoxO1 phosphorylation through activation of PI3K/Akt and inhibition of AMPK and FoxO1 acetylation through interaction with CBP and SIRT1, and that this leads to upregulation of catalase under conditions of oxidative stress.
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Chan Hum
authors.initials: CH
authors.lastname: Park
authors.forename: Daeui
authors.initials: D
authors.lastname: Park
authors.forename: Yeon Ja
authors.initials: YJ
authors.lastname: Choi
authors.forename: Min Hi
authors.initials: MH
authors.lastname: Park
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.forename: So Ra
authors.initials: SR
authors.lastname: Kim
authors.forename: Jun Sik
authors.initials: JS
authors.lastname: Lee
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D004305:Dose-Response Relationship, Drug; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D036145:Ginsenosides / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D005894:Panax; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D036145:Ginsenosides; C044462:ginsenoside Rc; D051057:Proto-Oncogene Proteins c-akt