Browse > Article
http://dx.doi.org/10.6116/kjh.2015.30.4.57.

Gleditsia Spina Extract Protects Hepatocytes from Oxidative Stress through Nrf2 Activation  

Kim, Jae Kwang (Department of Herbal Formula, College of Korean Medicine, Daegu Haany University)
Park, Sang Mi (Department of Herbal Formula, College of Korean Medicine, Daegu Haany University)
Jegal, Kyung Hwan (Department of Herbal Formula, College of Korean Medicine, Daegu Haany University)
Kim, Young Woo (Department of Herbal Formula, College of Korean Medicine, Daegu Haany University)
Byun, Sung Hui (Department of Herbal Formula, College of Korean Medicine, Daegu Haany University)
Kim, Sang Chan (Department of Herbal Formula, College of Korean Medicine, Daegu Haany University)
Cho, Il Je (Department of Herbal Formula, College of Korean Medicine, Daegu Haany University)
Publication Information
The Korea Journal of Herbology / v.30, no.4, 2015 , pp. 57-64 More about this Journal
Abstract
Objectives : Oxidative stress is one of the most causes of hepatocyte injury. Gleditsia spina, the thorns ofGleditsia sinensisLam., has been known for its anti-cancer and anti-inflammatory effects in Korean medicine. The present study investigated hepatoprotective effect of Gleditsia spina water extract (GSE) against oxidative stress induced by arachidonic acid (AA) + iron in HepG2 cells.Methods : To investigate cytoprotective effect of GSE, cells were pretreated with GSE and then subsequently exposed to 10 μM AA for 12 h, followed by 5 μM iron. Cell viability was monitored by MTT assay, and expression of apoptosis-related proteins was examined by immunoblot analysis. To identify responsible molecular mechanisms, reactive oxygen species (ROS) production, GSH contents, and mitochondrial membrane potential were measured. In addition, effect of GSE on nuclear factor erythroid 2-related factor 2 (Nrf2) activation was determined by immunoblot and antioxidant response element (ARE)-driven reporter gene assays.Results : GSE pretreatment prevented AA + iron-mediated cytotoxicity in concentration dependent manner. In addition, ROS production, glutathione depletion, and mitochondrial impairment by AA + iron were significantly inhibited by GSE. Furthermore, GSE promoted translocation of Nrf2 to nucleus, which acts as essential transcription factor for induction of antioxidant genes. Increased nuclear Nrf2 that caused by GSE treatment promoted transcriptional activity of ARE. Finally, GSE up-regulated sestrin-2 which was widely recognized as target gene of Nrf2.Conclusions : This study demonstrates that GSE protects hepatocytes from oxidative stress via activation of Nrf2 signaling pathway.
Keywords
Gleditsia spina; Gleditsia sinensis Lam.; Hepatoprotection; Oxidative stress; Nrf2; Antioxidant gene;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Zipper LM, Mulcahy RT. Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells. Toxicol Sci. 2003 ; 73(1) : 124–34.   DOI   ScienceOn
2 Kang KW, Lee SJ, Park JW, Kim SG. Phosphatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress. Mol Pharmacol. 2002 ; 62(5) : 1001–10.   DOI   ScienceOn
3 Galaris D, Pantopoulos K. Oxidative stress and iron homeostasis: mechanistic and health aspects. Crit Rev Clin Lab Sci. 2008 ; 45(1) : 1–23.   DOI   ScienceOn
4 Siddiqui MA, Ahmad J, Farshori NN, Saquib Q, Jahan S, Kashyap MP, Ahamed M, Musarrat J, Al-Khedhairy AA. Rotenone-induced oxidative stress and apoptosis in human liver HepG2 cells. Mol Cell Biochem. 2013 ; 384(1-2) : 59-69.   DOI   ScienceOn
5 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) : 242–53.   DOI   ScienceOn
6 Balboa MA, Balsinde J. Oxidative stress and arachidonic acid mobilization. Biochim Biophys Acta. 2006 ; 1761(4) : 385–91.   DOI   ScienceOn
7 Chen Y, Dong H, Thompson DC, Shertzer HG, Nebert DW, Vasiliou V. Glutathione defense mechanism in liver injury: insights from animal models. Food Chem Toxicol. 2013 ; 60 : 38–44.   DOI   ScienceOn
8 Ribas V, García-Ruiz C, Fernández-Checa JC. Glutathione and mitochondria. Front Pharmacol. 2014 ; 5 : 151.   DOI   ScienceOn
9 Yang JH, Kim KM, Kim MG, Seo KH, Han JY, Ka SO, Park BH, Shin SM, Ku SK, Cho IJ, Ki SH. Role of sestrin2 in the regulation of proinflammatory signaling in macrophages. Free Radic Biol Med. 2015 ; 78 : 156–67.   DOI   ScienceOn
10 Jin SH, Yang JH, Shin BY, Seo K, Shin SM, Cho IJ, Ki SH. Resveratrol inhibits LXRα-dependent hepatic lipogenesis through novel antioxidant Sestrin2 gene induction. Toxicol Appl Pharmacol. 2013 ; 271(1) : 95–105.   DOI   ScienceOn
11 Huang HC, Nguyen T, Pickett CB. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem. 2002 ; 277(45) : 42769–74.   DOI   ScienceOn
12 Yi JM, Park JS, Oh SM, Lee J, Kim J, Oh DS, Bang OS, Kim NS. Ethanol extract of Gleditsia sinensis thorn suppresses angiogenesis in vitro and in vivo. BMC Complement Altern Med. 2012 ; 12 : 243.   DOI
13 Jung EH, Kim SC, Cho IJ, Kim YW. Akebiae Caulis Inhibits Oxidative Stress through AMPK Activation. J Physiol Pathol Korean Med. 2015 ; 29(1) : 18–26.   DOI
14 Professors of herbology in colleges of Korean medicine. Herbology. Seoul : Yeonglimsa. 2004 : 481-2.
15 Kim CM, Shin MG, An DG, Lee KS. Unabridged Dictionary of Chinese Medication. Seoul : Jungdam. 1998 : 4940-42.
16 Ha HH, Park SY, Ko WS, Kim Y. Gleditsia sinensis thorns inhibit the production of NO through NF-kappaB suppression in LPS-stimulated macrophages. J Ethnopharmacol. 2008 ; 118(3) : 429–34.   DOI   ScienceOn
17 Lee SJ, Cho YH, Kim H, Park K, Park SK, Ha SD, Kim WJ, Moon SK. Inhibitory effects of the ethanol extract of Gleditsia sinensis thorns on human colon cancer HCT116 cells in vitro and in vivo. Oncol Rep. 2009 ; 22(6) : 1505-12.
18 Lee SJ, Park K, Ha SD, Kim WJ, Moon SK. Gleditsia sinensis thorn extract inhibits human colon cancer cells: the role of ERK1/2, G2/M‐ phase cell cycle arrest and p53 expression. Phytother Res. 2010 ; 24(12) : 1870–6.   DOI   ScienceOn
19 Lee SJ, Ryu DH, Jang LC, Cho SC, Kim WJ, Moon SK. Suppressive effects of an ethanol extract of Gleditsia sinensis thorns on human SNU-5 gastric cancer cells. Oncol Rep. 2013 ; 29(4) : 1609–16.   DOI
20 Hwang YJ, Wi HR, Kim HR, Park KW, Hwang KA. Pinus densiflora Sieb. et Zucc. alleviates lipogenesis and oxidative stress during oleic acid-induced steatosis in HepG2 cells. Nutrients. 2014 ; 6(7) : 2956-72.   DOI   ScienceOn
21 Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009 ; 47(9) : 1304–9.   DOI   ScienceOn
22 Dong GZ, Jang EJ, Kang SH, Cho IJ, Park SD, Kim SC, Kim YW. Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway. BMC Complement Altern Med. 2013 ; 13 : 64.   DOI   ScienceOn
23 Reuland DJ, Khademi S, Castle CJ, Irwin DC, McCord JM, Miller BF, Hamilton KL. Upregulation of phase II enzymes through phytochemical activation of Nrf2 protects cardiomyocytes against oxidant stress. Free Radic Biol Med. 2013 ; 56 : 102–11.   DOI   ScienceOn
24 Tang W, Jiang YF, Ponnusamy M, Diallo M. Role of Nrf2 in chronic liver disease. World J Gastroenterol. 2014 ; 20(36) : 13079–87.   DOI   ScienceOn
25 Scapagnini G, Vasto S, Abraham NG, Caruso C, Zella D, Galvano F. Modulation of Nrf2/ARE Pathway by Food Polyphenols: A Nutritional Neuroprotective Strategy for Cognitive and Neurodegenerative Disorders. Mol Neurobiol. 2011 ; 44(2) : 192–201.   DOI   ScienceOn
26 Meakin PJ, Chowdhry S, Sharma RS, Ashford FB, Walsh SV, McCrimmon RJ, Dinkova-Kostova AT, Dillon JF, Hayes JD, Ashford ML. Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance. Mol Cell Biol. 2014 ; 34(17) : 3305–20.   DOI   ScienceOn
27 Dong GZ, Lee JH, Ki SH, Yang JH, Cho IJ, Kang SH, Zhao RJ, Kim SC, Kim YW. AMPK activation by isorhamnetin protects hepatocytes against oxidative stress and mitochondrial dysfunction. Eur J Pharmacol. 2014 ; 740 : 634–40.   DOI   ScienceOn
28 Shin BY, Jin SH, Cho IJ, Ki SH. Nrf2-ARE pathway regulates induction of Sestrin-2 expression. Free Radic Biol Med. 2012 ; 53(4) : 834–41.   DOI   ScienceOn
29 Statistics Korea. Annual report on the cause of death statistics. Korean Statistical Information Service. 2013[cited 2015 Jun 17]. Available from : URL : http://kosis.kr/
30 Park SH, Jeon WK, Kim SH, Kim HJ, Park DI, Cho YK, Sung IK, Sohn CI, Keum DK, Kim BI. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol. 2006 ; 21(1 Pt 1) : 138–43.   DOI   ScienceOn
31 Raymond JMN, John de V, Mannfred AH. Toxicology: Principle and Application. 1st ed. Boca Raton, Florida : CRC press Inc. 1996 : 702-23.
32 Arias I, Wolkoff A, Boyer J, Shafritz D, Fausto N, Alter H, Cohen D. The Liver: Biology and Pathobiology. 5th ed. Chichester : John Wiley & Sons Ltd. 2009 : 3-15.
33 Cichoż-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol. 2014 ; 20(25) : 8082–91.   DOI   ScienceOn
34 Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked?. Free Radic Biol Med. 2010 ; 49(11) : 1603–16.   DOI   ScienceOn