삼릉(三稜) 추출물의 간세포 보호 및 미토콘드리아 보호 효과 = Mitochondria protection of Sparganii Rhizoma against oxidative stress in heptocytes

다국어 초록 (Multilingual Abstract)

Objectives : Sparganii Rhizoma is frequently used in traditional herbal medicine for treatment of blood stasis, amenorrhea and functional dyspepsia and has been reported to exhibit anti-oxidant, anti-proliferation and anti-angiogenesis peoperties. In this study, we investigated the cytoprotective effect and underlying mechanism of Sparganii Rhizoma water extract (SRE) against oxidative stress-induced mitochondrial dysfunction and apoptosis in hepatocyte. Methods : To determine the effects of SRE on oxidative stress, we induced synergistic cytotoxicity by co-treatment of arachidonic acid (AA) and iron in the HepG2 cell, a human derived hepatocyte cell line. Results : Treatment of SRE increased relative cell viability and altered the expression levels of apoptosis-related proteins such as Bcl-xL, Bcl-2 and procaspase-3. And SRE also inhibited the mitochondrial dysfunction and excessive reactive oxygen species production induced by AA+iron. In addition, SRE activated of AMP-activated protein kinase (AMPK), a potential target for cytoprotection, by increasing the phosphorylation of AMPKα at Thr-172. Morever, SRE increased phosphorylation of acetyl-CoA carboxylase, a direct downstream target of AMPK. Conclusion : These results indicated that SRE has the ability to protect against oxidative stress-induced hepatocyte damage, which may be mediated with AMPK pathway.

참고문헌 (Reference)

1 강용경, "활성산소 소거활성에 따른 꾸지뽕잎 추출물의 신경세포 보호 효과" 한국식품조리과학회 28 (28): 820-828, 2012

2 신숙정, "삼릉, 황금, 살송편버섯 혼합추출물의 항종양 작용" 한국생약학회 35 (35): 324-329, 2004

3 Tewari M, "Yama/CPP32beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase" 81 (81): 801-809, 1995

4 Shaw RJ, "The tumor suppressor LKB1 kinase directly activates AMP-actkvated kinase and regulates apoptosis in response to energy stress" 101 : 3329-3335, 2000

5 Green DR, "The pathophysiology of mitochondrial cell death" 305 (305): 626-629, 2004

6 Grimes CA, "The multifaceted roles of glycogen synthase kinase 3 beta in cellular signaling" 65 : 391-426, 2001

7 Lee BC, "The inhibitory effects of the Sparganii Rhizoma on melanogenesis" 31 (31): 305-310, 2005

8 Carling, D., "The AMP-activated protein kinase cascade—a unifying system for energy control" 29 (29): 18-24, 2004

9 Huh SJ, "Study on the analgesic and anticoagulative effects of Sparganii rhizoma aqua acupuncture" 8 : 98-, 2000

10 Lan F, "SIRT1 modulation of the acetylation status, cytosolic localization, andactivity of LKB1. Possible role in AMP-activted protein kinase activation" 283 : 27628-27635, 2008

11 Lan F, "SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation" 283 : 27628-27635, 2008

12 Nakanishi, M., "Roles of cPLA2a and arachidonic acid in cancer" 1761 : 1335-, 2006

13 Shin SM, "Resveratrol protects mitochondria against oxidative stress through AMPK-mediated GSK3βinhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway" 76 : 884-895, 2009

14 Shin SM, "Resveratrol protects mitochondria against oxidative stress through AMPK-mediated GSK3βinhibition downstream of poly(ADP-ribose)polymerase-LKB1 pathway" 76 : 884-895, 2009

15 Claria, J., "Regulation of cell proliferation and apoptosis by bioactive lipid mediators" 1 : 369-, 2006

16 Cryns V, "Proteases to die for" 12 (12): 1551-1570, 1998

17 McLaren CE, "Prevalence of heterozygotes for hemochromatosis in the white population of the United States" 86 : 2021-2027, 1995

18 Tong H, "Posphrylation of glycogen synthase kinase-3β during preconditioning through a phosphatidylinositol-3-kinase-dependent pathway is cardioprotective" 90 : 377-379, 2002

19 Muralikrishna Adibhatla R, "Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerevral ischemia" 40 : 376-387, 2006

20 Wang ZQ, "PARP is important for genomic stability but dispensable in apoptosis" 11 (11): 2347-2358, 1997

21 Galaris, D., "Oxidative stress and iron homeostasis: mechanistic and health aspects" 45 (45): 1-23, 2008

22 Browning JD, "Molecular mediators of hepatic steatosis and liver injury" 114 : 147-152, 2004

23 Stowe DF, "Mitochondrial reactive oxygen species production in excitable cells:Modulators of mitochondrial and cell function" 11 (11): 1373-1414, 2009

24 Yeom, J. B., "Mitochondrial Physiology" 15 (15): 25-33, 2008

25 Scorrano, L., "Mitochondria are direct targets of the lipoxygenase inhibitor MK886. A strategy for cell killing by combined treatment with MK886 and cyclooxygenase inhibitors" 276 : 12035-, 2001

26 Swanson CA, "Iron intake and regulation:implications for iron deficiency and iron overload" 30 (30): 99-102, 2003

27 Shin SM, "Inhibition of arachidonic acid and iron-induced mitochondrial dysfunction and apoptosis by oltipraz and nove 1,2-dithiole-3thione congeners" 75 : 242-253, 2009

28 Korea professors of Herbal medicine, "Herbal medicine" Youngrimsa korea 418-419, 1991

29 Hawley, S. A., "Haracterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172as the major site at which it phosphorylates AMP-activated protein kinase" 271 (271): 27879-27887, 1996

30 Juhaszova M, "Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore" 113 : 1535-1549, 2004

31 Kockeritz L, "Glycogen synthase kinase-3-an overview of an over-achieving protein kinase" 7 : 1377-1388, 2006

32 Das S, "Glycogen synthase kinase 3inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation" 103 : 983-991, 2008

33 Foretz M, "Foufelle F : AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes" 273 : 14767-11771, 1988

34 Shindo, Y., "Enzymic and non-enzymic antioxidants in epidermis and dermis of human skin" 102 (102): 112-128, 1944

35 Ashkenazi A, "Death receptors :signaling and modulation" 281 (281): 1305-1308, 1998

36 Lee SM, "Cytosolic NADP+-dependent isocitrate dehydrogenase status modulates oxidative damage to cells" 32 : 1185-1196, 2002

37 Murgia M, "Controlling metabolism and cell death: At the heart of mitochondrial calcium signalling" 46 (46): 781-788, 2009

38 Jang WD., "Compound of Sparganii Rhizoma" 20 (20): 486-487, 1995

39 Aisen P, "Chemistry and biology of eukaryotic iron metabolism" 33 (33): 940-959, 2001

40 Shin SY, "Chemical constituents of the Rhizomes of Sparganium stoloniferum" 44 (44): 334-339, 2000

41 Wood A, "Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constiutively active and dominant negative forms of the kinase" 20 : 6704-6711, 2000

42 Henderson LM, "Article NADPH oxidase of neutrophils" 1273 : 87-107, 1996

43 Cocco T, "Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation" 27 : 51-59, 1999

44 Cocco, T., "Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation" 27 (27): 51-59, 1999

45 Scorrano L, "Arachidonic acid caused cell death through the mitochondrial permeability transition. Implications for tumor necrosis factor-alha apoptotic signaling" 276 : 12035-12040, 2001

46 Kim JG, "Antioxidative activity and antimicrobial activity of extracts from medicinal plants" 37 (37): 69-75, 2003

47 Choi SH, "AMPK-mediated GSK-3beta inhibition by isoliquiritigenine contributes to protecting mitochondria against iron-catalyzed oxidative stress" 79 (79): 1352-1362, 2010

48 Towler, M.C., "AMP-activated protein kinase in metabolic control and insulin signaling" 100 (100): 328-341, 2007

49 Assifi MM, "AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats" 289 : 794-800, 2005