Kim Dae Hyun, Park Chan Hum, Park Daeui, Choi Yeon Ja, Park Min Hi, Chung Ki Wung, Kim So Ra, Lee Jun Sik, Chung Hae Young
Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
Arch Pharm Res. 2014 Jun;37(6):813-20. doi: 10.1007/s12272-013-0223-2. Epub 2013 Aug 6.
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.
人参皂苷Rc（Rc）是一种原人参二醇型人参皂苷，是人参具有治疗和药理特性的主要活性成分，这些特性源于其对超氧化物诱导的自由基的抑制作用。叉头框O（FoxO1）调节与细胞死亡和氧化应激反应相关的各种细胞代谢基因，已知Rc通过激活PI3K/Akt并随后抑制暴露于叔丁基过氧化氢（t-BHP）的细胞中的AMP激活蛋白激酶（AMPK）来阻止FoxO1磷酸化。在本研究中，我们试图探究Rc通过抑制t-BHP诱导的活性物质（RS）产生导致的FoxO1激活来增加过氧化氢酶表达的机制。我们发现，Rc诱导的过氧化氢酶过表达导致人胚肾293T细胞（HEK293T）中RS产生的抑制，并且氧化应激诱导PI3K/Akt激活、AMPK途径抑制和FoxO1磷酸化，导致FoxO1靶向基因过氧化氢酶的下调。此外，用Rc处理HEK293T细胞导致cAMP反应元件结合蛋白（CREB）结合蛋白（CBP）调节FoxO1乙酰化。我们的结果表明，Rc通过激活PI3K/Akt和抑制AMPK来调节FoxO1磷酸化，并通过与CBP和SIRT1相互作用抑制FoxO1乙酰化，这导致在氧化应激条件下过氧化氢酶上调。
