Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway

BMC Complementary and Alternative Medicine

Young Woo Kim¹  Sang Chan Kim¹  Sun-Dong Park¹  Il Je Cho¹  Seung Ho Kang²  Eun Jeong Jang¹  Guang-Zhi Dong¹ 

[1] Medical research center for Globalization of Herbal Formulation, College of Oriental Medicine, Daegu Haany University, Daegu 706-828, Korea;Sunlin University, Pohang, Kyungsangbuk-do 791-712, Korea

关键词: Mitochondria;    Oxidative stress;    AMPK;    Red ginseng;    Arachidonic acid;   

Others  :  1230159
DOI  :  10.1186/1472-6882-13-64

 received in 2012-09-13, accepted in 2013-02-26,  发布年份 2013

【 摘 要 】

Background

Korean ginseng (Panax ginseng C.A. Meyer) has been used as a botanical medicine throughout the history of Asian traditional Oriental medicine. Formulated red ginseng (one form of Korean ginseng) has been shown to have antioxidant and chemopreventive effects.

Methods

This study investigated the cytoprotective effects and mechanism of action of Korean red ginseng extract (RGE) against severe ROS production and mitochondrial impairment in a cytotoxic cell model induced by AA + iron.

Results

RGE protected HepG2 cells from AA + iron-induced cytotoxicity by preventing the induction of mitochondrial dysfunction and apoptosis. Moreover, AA + iron-induced production of ROS and reduction of cellular GSH content (an important cellular defense mechanism) were remarkably attenuated by treatment with RGE. At the molecular level, treatment with RGE activated LKB1-dependent AMP-activated protein kinase (AMPK), which in turn led to increased cell survival. The AMPK pathway was confirmed to play an essential role as the effects of RGE on mitochondrial membrane potential were reversed upon treatment with compound C, an AMPK inhibitor.

Conclusions

Our results demonstrate that RGE has the ability to protect cells from AA + iron-induced ROS production and mitochondrial impairment through AMPK activation.

【 授权许可】

   
2013 Dong et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Balboa MA, Balsinde J: Oxidative stress and arachidonic acid mobilization. Biochim Biophys Acta 2006, 1761(4):385-391.
• [2]Gijon MA, Leslie CC: Regulation of arachidonic acid release and cytosolic phospholipase A2 activation. J Leukoc Biol 1999, 65(3):330-336.
• [3]Fleming RE, Bacon BR: Orchestration of iron homeostasis. N Engl J Med 2005, 352(17):1741-1744.
• [4]Galaris D, Pantopoulos K: Oxidative stress and iron homeostasis: mechanistic and health aspects. Crit Rev Clin Lab Sci 2008, 45(1):1-23.
• [5]Halliday JW, Searle J: Hepatic iron deposition in human disease and animal models. Biometals 1996, 9(2):205-209.
• [6]Neufeld EJ: Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood 2006, 107(9):3436-3441.
• [7]Kim YW, Lee SM, Shin SM, Hwang SJ, Brooks JS, Kang HE, Lee MG, Kim SC, Kim SG: Efficacy of sauchinone as a novel AMPK-activating lignan for preventing iron-induced oxidative stress and liver injury. Free Radic Biol Med 2009, 47(7):1082-1092.
• [8]Terai K, Hiramoto Y, Masaki M, Sugiyama S, Kuroda T, Hori M, Kawase I, Hirota H: AMP-activated protein kinase protects cardiomyocytes against hypoxic injury through attenuation of endoplasmic reticulum stress. Mol Cell Biol 2005, 25(21):9554-9575.
• [9]Detaille D, Guigas B, Chauvin C, Batandier C, Fontaine E, Wiernsperger N, Leverve X: Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. Diabetes 2005, 54(7):2179-2187.
• [10]Ido Y, Carling D, Ruderman N: Hyperglycemia-induced apoptosis in human umbilical vein endothelial cells: inhibition by the AMP-activated protein kinase activation. Diabetes 2002, 51(1):159-167.
• [11]Yang YM, Han CY, Kim YJ, Kim SG: AMPK-associated signaling to bridge the gap between fuel metabolism and hepatocyte viability. World J Gastroenterol 2010, 16(30):3731-3742.
• [12]Shin SM, Kim SG: Inhibition of arachidonic acid and iron-induced mitochondrial dysfunction and apoptosis by oltipraz and novel 1,2-dithiole-3-thione congeners. Mol Pharmacol 2009, 75(1):242-253.
• [13]Kim CS, Park JB, Kim KJ, Chang SJ, Ryoo SW, Jeon BH: Effect of Korea red ginseng on cerebral blood flow and superoxide production. Acta Pharmacol Sin 2002, 23(12):1152-1156.
• [14]Kim YH, Kim GH, Shin JH, Kim KS, Lim JS: Effect of korean red ginseng on testicular tissue injury after torsion and detorsion. Korean J urol 2010, 51(11):794-799.
• [15]Yun TK, Kim SH, Lee YS: Trial of a new medium-term model using benzo(a)pyrene induced lung tumor in newborn mice. Anticancer Res 1995, 15(3):839-845.
• [16]Attele AS, Wu JA, Yuan CS: Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999, 58(11):1685-1693.
• [17]Shin HR, Kim JY, Yun TK, Morgan G, Vainio H: The cancer-preventive potential of Panax ginseng: a review of human and experimental evidence. Cancer Causes Control 2000, 11(6):565-576.
• [18]Kubo M, Chun-Ning T, Matsuda H: Influence of the 70% methanolic extract from red ginseng on the lysosome of tumor cells and on the cytocidal effect of mitomycin c1. Planta Med 1992, 58(5):424-428.
• [19]Chen X: Cardiovascular protection by ginsenosides and their nitric oxide releasing action. Clin Exp Pharmacol Physiol 1996, 23(8):728-732.
• [20]Lee BM, Lee SK, Kim HS: Inhibition of oxidative DNA damage, 8-OHdG, and carbonyl contents in smokers treated with antioxidants (vitamin E, vitamin C, beta-carotene and red ginseng). Cancer Lett 1998, 132(1–2):219-227.
• [21]Gum SI, Jo SJ, Ahn SH, Kim SG, Kim JT, Shin HM, Cho MK: The potent protective effect of wild ginseng (Panax ginseng C.A. Meyer) against benzo[alpha]pyrene-induced toxicity through metabolic regulation of CYP1A1 and GSTs. J Ethnopharmacol 2007, 112(3):568-576.
• [22]Park SH, Jang JH, Chen CY, Na HK, Surh YJ: A formulated red ginseng extract rescues PC12 cells from PCB-induced oxidative cell death through Nrf2-mediated upregulation of heme oxygenase-1 and glutamate cysteine ligase. Toxicology 2010, 278(1):131-139.
• [23]Choi SH, Kim YW, Kim SG: AMPK-mediated GSK3beta inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress. Biochem Pharmacol 2010, 79(9):1352-1362.
• [24]Shin SM, Cho IJ, Kim SG: Resveratrol protects mitochondria against oxidative stress through AMP-activated protein kinase-mediated glycogen synthase kinase-3beta inhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway. Mol Pharmacol 2009, 76(4):884-95.
• [25]Naito Y, Yoshikawa T: Molecular and cellular mechanisms involved in Helicobacter pylori-induced inflammation and oxidative stress. Free Radic Biol Med 2002, 33(3):323-336.
• [26]Cocco T, Di Paola M, Papa S, Lorusso M: Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation. Free Radic Biol Med 1999, 27(1–2):51-59.
• [27]Maia RC, Culver CA, Laster SM: Evidence against calcium as a mediator of mitochondrial dysfunction during apoptosis induced by arachidonic acid and other free fatty acids. J Immunol 2006, 177(9):6398-6404.
• [28]Kobayashi K, Arakawa T: Arachidonic acid cascade and gastric mucosal injury, protection, and healing: topics of this decade. J Clin Gastroenterol 1995, 21(Suppl 1):S12-17.
• [29]Zhu A, Kaunitz J: Gastroduodenal mucosal defense. Curr Gastroenterol Rep 2008, 10(6):548-554.
• [30]McLaren CE, Gordeuk VR, Looker AC, Hasselblad V, Edwards CQ, Griffen LM, Kushner JP, Brittenham GM: Prevalence of heterozygotes for hemochromatosis in the white population of the United States. Blood 1995, 86(5):2021-2027.
• [31]Caro AA, Cederbaum AI: Synergistic toxicity of iron and arachidonic acid in HepG2 cells overexpressing CYP2E1. Mol Pharmacol 2001, 60(4):742-752.
• [32]Kwon YN, Shin SM, Cho IJ, Kim SG: Oxidized metabolites of oltipraz exert cytoprotective effects against arachidonic acid through AMP-activated protein kinase-dependent cellular antioxidant effect and mitochondrial protection. Drug Metab Dispos 2009, 37(6):1187-1197.
• [33]Hayashi T, Hirshman MF, Fujii N, Habinowski SA, Witters LA, Goodyear LJ: Metabolic stress and altered glucose transport: activation of AMP-activated protein kinase as a unifying coupling mechanism. Diabetes 2000, 49(4):527-531.
• [34]Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA: The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem 2005, 280(32):29060-29066.
• [35]Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG: Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab 2005, 2(1):9-19.
• [36]Xie Z, Dong Y, Scholz R, Neumann D, Zou MH: Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation 2008, 117(7):952-962.