鼠尾草酸通过诱导二相酶降低HepG2细胞氧化损伤的作用与PI3K/Akt-Nrf2转录途径之间的关系
|
摘要
目的：研究鼠尾草酸通过二相酶的诱导对HepG2细胞H202损伤的保护作用与PI3K/Akt-Nrf2转录途径之间的关系。
方法：
1.鼠尾草酸对HepG2细胞二相酶的诱导作用
HepG2细胞随机分为四组：对照组；低、中、高浓度鼠尾草酸组(5μM、10μM,20μM)。药物与细胞共同孵育不同时间后分别测定以下指标：采用化学分光光度法测定醌氧化还原酶(NQO 1)的活性和还原型谷胱甘肽(GSH)的活性；用免疫印迹法(Western blotting)测定转录因子Nrf2、NQO1和血红素氧合酶-1(HO-1)的蛋白表达。
2.鼠尾草酸对HepG2细胞二相酶诱导的信号转导通路研究
(1)HepG2细胞随机分为：对照组;20μM鼠尾草酸组；20μM鼠尾草酸+阻断剂组(P13K通路阻断剂LY294002组、NQO1抑制剂Dicoumarol组、HO-1抑制剂ZNPPIX组)。Western blotting法测定转录因子Nrf2、NQO1和HO-1的蛋白表达。
(2)HepG2细胞随机分为：对照组；PI3K阻断剂组；20μM鼠尾草酸组;20μM鼠尾草酸+PI3K阻断剂组Western blotting法测定Akt和P-Akt的蛋白表达。
3.鼠尾草酸对H202损伤的HepG2细胞保护作用研究
(1)HepG2细胞随机分为：对照组；H202损伤组(终浓度为2.4 mM)；低、中、高浓度鼠尾草酸治疗组(5μM、10μM、20μM)。采用MTT法测定细胞存活率；采用化学分光光度法测定细胞上清液中LDH活性。
(2)HepG2细胞随机分为：对照组；H202损伤组；20μM鼠尾草酸治疗组；20μM鼠尾草酸+阻断剂组。采用MTT法测定细胞存活率；采用化学分光光度法测定细胞中LDH活性。
结果：
1.鼠尾草酸与HepG2细胞共同孵育8h后,与对照组相比,药物组的细胞内二相酶GSH和NQO1活性均明显提高(P<0.01,P<0.01),在5-20μM呈浓度依赖性。16h时,上述两种酶的活性均有不同程度的降低,呈一定的时间相关性。
2.鼠尾草酸与HepG2细胞共同孵育8h后,与对照组相比,中、高浓度药物组细胞内Nrf2、NQO1和HO-1的蛋白表达显著提高(P<0.01,P<0.01,P<0.01),并呈一定的浓度依赖性。
3.PI3K通路的特异性阻断剂LY294002可以明显抑制鼠尾草酸诱导的HepG2细胞Nrf2、NQO1和HO-1的蛋白表达(P<0.01,P<0.01,P<0.01)。鼠尾草酸诱导的NQO1和HO-1的蛋白表达还可分别被特异的NQO1抑制剂Dicoumarol、HO-1抑制剂ZNPPIX所抑制(P<0.01,P<0.01)。
4.与对照组相比,鼠尾草酸不影响Akt的水平,但可明显增加P-Akt的蛋白表达水平。在鼠尾草酸同时存在或不存在时,PI3K通路的特异性阻断剂LY294002可明显减少P-Akt的蛋白表达。
5.H2O2刺激HepG2细胞后,与对照组相比,损伤组细胞生存率明显下降,LDH活性明显增高(P<0.01,P<0.01),而中、高浓度鼠尾草酸处理组细胞生存率显著提高,LDH活性显著下降(P<0.01,P<0.01),呈浓度依赖性。而且,特异性PI3K通路阻断剂LY294002、NQO1抑制剂Dicoumarol以及HO-1抑制剂ZNPPIX可以部分取消鼠尾草酸的细胞保护作用。
结论：
1.鼠尾草酸通过激活HepG2细胞的转录途径PI3K/Akt-Nrf2上调二相代谢酶HO-1、NQO1、GSH的活性和蛋白表达,并且呈浓度依赖性和时间相关性。
2.鼠尾草酸对H2O2损伤的HepG2细胞具有保护作用,其机制主要与鼠尾草酸激活PI3K/Akt-Nrf2通路,显著提高HepG2细胞二相代谢酶NQO1、HO-1等的表达有关。
Objective:To investigated whether Carnosic acid (CA) could induce antioxidant and phase 2 enzymes and confer protection against oxidative damage in HepG2 cells.
Methods:HepG2 cells were randomly divided into four groups (n=3): control group; carnosic acid (CA) group (5μM、10μM、20μM). The activity of NAD(P)H:quinone oxidore-ductase (NQO1) in HepG2 cells were measured by 2,6-dichloroindophenol reduction method. The activities of Glutathione Reductase (GSH) were determined with the method of chemical colorimetry. The protein expressions of nuclear factor E2-related factor2 (Nrf2), NQO1 and Heme oxygenase-1 (HO-1) in HepG2 cells were detected by Western blotting. HepG2 cells were randomly divided into five groups (n=3):control group; 20μM CA group; 20μM CA+inhibitor group (LY294002; Dicoumarol; ZNPPIX). The protein expressions of Nrf2, NQO1 and HO-1 in HepG2 cells were detected by Western blotting.HepG2 cells were randomly divided into four groups (n=3):control group; PI3K inhibitor group; 20μM CA group; 20μM CA group+PI3K inhibitor group. The protein expressions of Akt and P-Akt in HepG2 cells were detected by Western blotting. HepG2 cells were randomly divided into five groups and damaged by H2O2 (n=4):control group; H2O2 groups; CA treated group (5μM、10μM、20μM). MTT method was used to examine cell survival rate. The activities of lactate dehydrogenase (LDH) were determined with the method of chemical colorimetry. Then HepG2 cells were randomly divided into six groups (n=4):control group; 20μM CA treated group; 20μM CA group+inhibitor (LY294002, Dicoumarol, ZNPPIX) treated group. MTT method was used to examine cell survival rate. The activities of lactate dehydrogenase (LDH) were determined with the method of chemical colorimetry.
Results:The results showed that CA could induce Heme Oxygenasel (HO-1), quinone oxidoreductase 1 (NQO1) and glutathione reductase (GSH) expression in HepG2 cells in a time-and dose-dependent manner and protect them against hydrogen peroxide caused oxidative damage. The induction of HO-1 and NQO1 by CA was accompanied with the accumulation of nuclear factor-E2-related factor-2 (Nrf2) in nucleus and the activation of phosphatidylinositol 3-kinase PI3K/Akt signal pathway. Additionally, the specific inhibitor of PI3K/Akt could obviously decrease not only the induced expression of HO-1, NQO1 and GSH but also the antioxidant effect of CA. In conclusion, this study proved that CA exerts antioxidant effect by inducing HO-1, NQO1 and GSH expression mediated by PI3K/Akt and Nrf2.
Conclusion:The result indicated that CA increased the antioxidant and phase 2 enzymes through an activation of the PI3K-Akt/Nrf2 pathway. This may be a primary mechanism of antioxidative action of CA concerned with its therapeutic effectiveness in HepG2 cells.
方法：
1.鼠尾草酸对HepG2细胞二相酶的诱导作用
HepG2细胞随机分为四组：对照组；低、中、高浓度鼠尾草酸组(5μM、10μM,20μM)。药物与细胞共同孵育不同时间后分别测定以下指标：采用化学分光光度法测定醌氧化还原酶(NQO 1)的活性和还原型谷胱甘肽(GSH)的活性；用免疫印迹法(Western blotting)测定转录因子Nrf2、NQO1和血红素氧合酶-1(HO-1)的蛋白表达。
2.鼠尾草酸对HepG2细胞二相酶诱导的信号转导通路研究
(1)HepG2细胞随机分为：对照组;20μM鼠尾草酸组；20μM鼠尾草酸+阻断剂组(P13K通路阻断剂LY294002组、NQO1抑制剂Dicoumarol组、HO-1抑制剂ZNPPIX组)。Western blotting法测定转录因子Nrf2、NQO1和HO-1的蛋白表达。
(2)HepG2细胞随机分为：对照组；PI3K阻断剂组；20μM鼠尾草酸组;20μM鼠尾草酸+PI3K阻断剂组Western blotting法测定Akt和P-Akt的蛋白表达。
3.鼠尾草酸对H202损伤的HepG2细胞保护作用研究
(1)HepG2细胞随机分为：对照组；H202损伤组(终浓度为2.4 mM)；低、中、高浓度鼠尾草酸治疗组(5μM、10μM、20μM)。采用MTT法测定细胞存活率；采用化学分光光度法测定细胞上清液中LDH活性。
(2)HepG2细胞随机分为：对照组；H202损伤组；20μM鼠尾草酸治疗组；20μM鼠尾草酸+阻断剂组。采用MTT法测定细胞存活率；采用化学分光光度法测定细胞中LDH活性。
结果：
1.鼠尾草酸与HepG2细胞共同孵育8h后,与对照组相比,药物组的细胞内二相酶GSH和NQO1活性均明显提高(P<0.01,P<0.01),在5-20μM呈浓度依赖性。16h时,上述两种酶的活性均有不同程度的降低,呈一定的时间相关性。
2.鼠尾草酸与HepG2细胞共同孵育8h后,与对照组相比,中、高浓度药物组细胞内Nrf2、NQO1和HO-1的蛋白表达显著提高(P<0.01,P<0.01,P<0.01),并呈一定的浓度依赖性。
3.PI3K通路的特异性阻断剂LY294002可以明显抑制鼠尾草酸诱导的HepG2细胞Nrf2、NQO1和HO-1的蛋白表达(P<0.01,P<0.01,P<0.01)。鼠尾草酸诱导的NQO1和HO-1的蛋白表达还可分别被特异的NQO1抑制剂Dicoumarol、HO-1抑制剂ZNPPIX所抑制(P<0.01,P<0.01)。
4.与对照组相比,鼠尾草酸不影响Akt的水平,但可明显增加P-Akt的蛋白表达水平。在鼠尾草酸同时存在或不存在时,PI3K通路的特异性阻断剂LY294002可明显减少P-Akt的蛋白表达。
5.H2O2刺激HepG2细胞后,与对照组相比,损伤组细胞生存率明显下降,LDH活性明显增高(P<0.01,P<0.01),而中、高浓度鼠尾草酸处理组细胞生存率显著提高,LDH活性显著下降(P<0.01,P<0.01),呈浓度依赖性。而且,特异性PI3K通路阻断剂LY294002、NQO1抑制剂Dicoumarol以及HO-1抑制剂ZNPPIX可以部分取消鼠尾草酸的细胞保护作用。
结论：
1.鼠尾草酸通过激活HepG2细胞的转录途径PI3K/Akt-Nrf2上调二相代谢酶HO-1、NQO1、GSH的活性和蛋白表达,并且呈浓度依赖性和时间相关性。
2.鼠尾草酸对H2O2损伤的HepG2细胞具有保护作用,其机制主要与鼠尾草酸激活PI3K/Akt-Nrf2通路,显著提高HepG2细胞二相代谢酶NQO1、HO-1等的表达有关。
Objective:To investigated whether Carnosic acid (CA) could induce antioxidant and phase 2 enzymes and confer protection against oxidative damage in HepG2 cells.
Methods:HepG2 cells were randomly divided into four groups (n=3): control group; carnosic acid (CA) group (5μM、10μM、20μM). The activity of NAD(P)H:quinone oxidore-ductase (NQO1) in HepG2 cells were measured by 2,6-dichloroindophenol reduction method. The activities of Glutathione Reductase (GSH) were determined with the method of chemical colorimetry. The protein expressions of nuclear factor E2-related factor2 (Nrf2), NQO1 and Heme oxygenase-1 (HO-1) in HepG2 cells were detected by Western blotting. HepG2 cells were randomly divided into five groups (n=3):control group; 20μM CA group; 20μM CA+inhibitor group (LY294002; Dicoumarol; ZNPPIX). The protein expressions of Nrf2, NQO1 and HO-1 in HepG2 cells were detected by Western blotting.HepG2 cells were randomly divided into four groups (n=3):control group; PI3K inhibitor group; 20μM CA group; 20μM CA group+PI3K inhibitor group. The protein expressions of Akt and P-Akt in HepG2 cells were detected by Western blotting. HepG2 cells were randomly divided into five groups and damaged by H2O2 (n=4):control group; H2O2 groups; CA treated group (5μM、10μM、20μM). MTT method was used to examine cell survival rate. The activities of lactate dehydrogenase (LDH) were determined with the method of chemical colorimetry. Then HepG2 cells were randomly divided into six groups (n=4):control group; 20μM CA treated group; 20μM CA group+inhibitor (LY294002, Dicoumarol, ZNPPIX) treated group. MTT method was used to examine cell survival rate. The activities of lactate dehydrogenase (LDH) were determined with the method of chemical colorimetry.
Results:The results showed that CA could induce Heme Oxygenasel (HO-1), quinone oxidoreductase 1 (NQO1) and glutathione reductase (GSH) expression in HepG2 cells in a time-and dose-dependent manner and protect them against hydrogen peroxide caused oxidative damage. The induction of HO-1 and NQO1 by CA was accompanied with the accumulation of nuclear factor-E2-related factor-2 (Nrf2) in nucleus and the activation of phosphatidylinositol 3-kinase PI3K/Akt signal pathway. Additionally, the specific inhibitor of PI3K/Akt could obviously decrease not only the induced expression of HO-1, NQO1 and GSH but also the antioxidant effect of CA. In conclusion, this study proved that CA exerts antioxidant effect by inducing HO-1, NQO1 and GSH expression mediated by PI3K/Akt and Nrf2.
Conclusion:The result indicated that CA increased the antioxidant and phase 2 enzymes through an activation of the PI3K-Akt/Nrf2 pathway. This may be a primary mechanism of antioxidative action of CA concerned with its therapeutic effectiveness in HepG2 cells.
引文
1. Osaki M, Oshimura M, Ito H. PI3K-Akt pathway:its functions and alterations in human cancer. Apoptosis 2004 Nov;9(6):667-76
2. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA. Involvement of PI3K/Akt pathway in cell cycle progression, apoptoais and neoplastic transformation:a target for cancer chemotherapy. Leukemia 2003 Mar;17(3):590-603
3. Edwards LA, Thiessen B, Dragowska WH. Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activa-tion, induces apoptosis, and delays tumor growth. NATURE 2005;24(22):3596-3605
4. Song G, Ouyang G, Ban S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005;9(1):59-71
5. Sale EM, Hodgkinson CP, Jones NP, Sale GJ. Role of protein kinase B in phosphorylating glycogen synthase kinase-3, tuberin, WNK1, and ATP citrate lyase. Biochemistry 2006 Jan;45(1):213-223
6. Sakai A, Thieblemont C, Wellmann A, Jaffe ES, Raffeld M. PTEN Gene Aheralions in Lymphoid Neoplasms. Blood 1998 Nov;92(9):3410-15
7. Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, Gewirtz AM, Perussia B, Calabretta B. Phosphatidylinositol 3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome positive cells. Blood 1995 Jul;86(2):726-36
8. Skorski T, Bellacosa A, Nieborowska Skorska M. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI3k/Akt-dependent pathway. EMBO J 1997; 16(20):6151-61
9. Ly C, Arechiga AF, Melo JV, Walsh CM, Ong ST. Bcr Ab1 kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 2003 Sep; 63(18):5716-22
10. Picinato MC, Hirata AE, Cipolla-Neto J, Curi R, Carvalho CR, Anhe GF, Carpinelli AR. Activation of insulin and IGF-1 signaling pathways by melatonin through MT1 receptor in isolated rat pancreatic islets. J Pin Res 2008 Jan; 44(1):88-94
11. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA.Involvement of PI3K/Akt pathway in'cell cycle progression, Apoptoais, and neoplastic transformation:a target for cancer chemotherapy. Leukemia 2003 Mar;17(3):590-603
12. Scheijen B, Ngo HT, Kang H. FIT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins. Oneogene 2004;23(19):3338-49
13. Chian R, Young S, Danilkovitch-Miagkova A, Ronnstrand L, Leonard E, Ferrao P, Ashman L, Linnekin D. Phosphatidylinositol 3 kinase contributes to the transfor-mation of hematopoietic cells by the D816V c Kit mutant. Blood 2001 Sep;98(5):1365-73
14. Hashimoto K, Matsumura I, Tsujimura T, Kim DK, Ogihara H, Ikeda H, Ueda S, Mizuki M, Sugahara H, Shibayama H, Kitamura Y, Kanakura Y. Necessity of tyrosine 719 and phosphatidyIinositoI 3'kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation. Blood 2003 Feb;101(3):1094-1102
15. Tang Y, Zhang D, Fallavollita L, Brodt P. Vascular endothelial grow-factor C expression and lymph node metastasis are regulated by the type 1 insulin-like growth factor receptor. Cancer Res 2003 Mar;63:1 166-71
16. Niquet J, Wasterlain CG. Bim, Bad, and Bax:a deadly combination in epileptic seizures. J Clin Invest 2004 Apr;113(7):960-62
17. Hinz M, Krappmann D, Eichten A, Heder A, Scheidereit C, Strauss M. NF-kappaB function in growth control:regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol 1999;19(4):2690-98
18. Madrid LV, Mayo MW, Reuther JY. Akt stimulates the trans-activation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the kappa B kinase and activation of the mitogen-activated protein kinase p38 J Biol Chem.2001; 276(22):18934-40
19. Shew JP. NFAT is responsible for tissue-specific expression. Science 1988;241-202
20. Huang H, Tindall DJ. Dynamic FoxO transcription factors. J Cell Sci 2007; 120(15):2479-87
21. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinesitol 3-kinase/AKT-mediated activation of estrogen receptor alpha:a new model for anti-estrogen resistance. J Biol Chem 2001 Mar;276 (13):9817-24
22. Mimi TA, Kentaro H, Kiyoshi N. Down-rogulation of P27 KIP1 promotes cell proliferation of rat neonatal eardiomyocytes induced by nuclear of cyclinDl and CDK4. J Biol Chem 2004;279(48):50429-36
23. Cardone MH, Roy N, Stennicke HR. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998;282 (5392):1318-21
24. Michael S C, Cynthis A A, Barrett J C. Regulation of p53 stabili-ty and actability in response to genotoxie stress. Muta Res 2000;352:1-17
25. Cheng SW, Fryer LG, Carling D, Shepherd PR. Thr2446 is a novel mammlian target of rapamyein (mTOR) phesphorylation site regnlated by nutrient status. J Biol Chem 2004 Apr;279(16):15719-22
26. Chiu M1, Katz H, Berlin V. RAPT1, a mannnalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci U S A 1994 Dec; 91(26):12574-8
27. Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossman R, Reid K, Moelling K, Yancopoulos GD, Glass DJ. Diferentiation stage-specific inhibition of the Raf-MEK-EBK pathway by Akt. Science 1999 Nov;286(5445):1738-41
1. 何水祥,舒昌杰.自由基在病理性肝炎中的作用及其防治.中国实用内科杂志,1994；14(11)：679-80
2. 邵惠训.自由基和自由基清除剂.生物工程进展,1994；14(4)：49-5
3. Hori M, Gotoh K, Kitakaze M, Iwai K, Iwakura K, Sato H, Koretsune Y, Inoue M, Kitabatake A, Kamada T. Role of oxygen-derived free radicals in myocalodial edema and ischemia in coronary microvascular embolization. Circulation 1991 Aug;84(2):951-4
4. Nieto G, Diaz P, Ban'on S, Garrido MD. Dietary administration of ewe diets with a distillate from rosemary leaves (Rosmarinus officinalis L.):influence on lamb meat quality.2010 Jan;84(1):23-9
5. Pintore G, Marchetti M, Chessa M, Sechi B,Scanu N, Mangano G, Tirillini B.Rosmarinus officinalis L.:chemical modifications of the essential oil and evaluation of antioxidant and antimicrobial activity. Nat Prod Commun 2009 Dec;4(12):1685-90
6. Harach T, Aprikian O, Monnard I, Moulin J, Membrez M, Beolor JC, Raab T, Mace K, Darimont C.Rosemary (Rosmarinus officinalis L.) leaf extract limits weight gain and liver steatosis in mice fed a high-fat diet. Planta Med 2010 Apr;76(6):566-71
7. Perez-Fons L, Garzon MT, Micol V. Relationship between the antioxidant capacity and effect of rosemary (Rosmarinus officinalis L.) polyphenols on membrane phospholipid order. J Agric Food Chem 2010 Jan 13;58(1):161-71
8. Takaki I, Bersani-Amado LE, Vendruscolo A, Sartoretto SM, Diniz SP, Bersani-Amado CA, Cuman RK.Anti-inflammatory and antinociceptive effects of Rosmarinus officinalis L. essential oil in experimental animal models. J Med Food 2008 Dec;11(4):741-6
9. LoAH, Liang YC, LinShiau SY, Ho CT, Lin JK.Carnosol, an antioxidant in rosemary, suppresses inducible nitre oxide synthase through down-regulating nuclear factor-kappaB in mouse maerophages. Carcinogenesis 2002 Jun;23(6): 983-91
10. DanilenkoM, Wang X, Studzinski GP.Carnosic Acid and Promotion of Monoeytic Differentiation of HL60-G Cells Initiated by Other Agents. Cancer Res 2003 Mar;63(6):1325-32
11. Kuzmenko AI, Morozova RP, Nikolenko IA, Donchenko GV, Richheimer SL, Bailey DT.Chemilmuinescence determination of the in vivo and in vitro antioxidant activity of Rose OX and carnosic acid. J Photochem Photobiol B 1999 Jan;48(1):63-7
12. Satoh T, Izumi M, Inukai Y, Tsutsumi Y, Nakayama N, Kosaka K, Shimojo Y, Kitajima C, Itoh K, Yokoi T, Shirasawa T. Carnosic acid protects neuronal HT22 Cells through activation of the antioxidant-responsive element in free carboxylic acid-and catechol hydroxyl moieties-dependent manners. Neuroscience Letters 2008 Apr;434(3):260-5
13. Takahashi T, Tabuchi T, Tamaki Y, Kosaka K, Takikawa Y, Satoh T. Carnosic acid and carnosol inhibit adipocyte differentiation in mouse 3T3-L1 cells through induction of phase2 enzymes and activation of glutathione metabolism. Biochemical and Biophysical Research Communications 2009 May;382(3): 549-54
14. Lim JH, Kim KM, Kim SW, Hwang O, Choi HJ. Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling:Novel cytoprotective mechanism against oxidative damage. Pharmacol Res 2008 May;57(5):325-31
15. Chiang CW, Huang Y, Leong KW, Chen LC, Chen HC, Chen SJ, Chou CK. PKCalpha mediated induction of miR-101 in human hepatoma HepG2 cells. J Biomed Sci 2010 May;17(1):35
16. Bayet-Robert M, Loiseau D, Rio P, Demidem A, Barthomeuf C, Stepien G, Morvan D. Quantitative two-dimensional HRMAS 1H-NMR spectroscopy-based metabolite profiling of human cancer cell lines and response to chemotherapy. Magn Reson Med 2010 May;63(5):I172-83
17. Calabrese V, Cornelius C, Trovato A, Cavallaro M, Mancuso C, Di Rienzo L, Condorelli D, De Lorenzo A, Calabrese EJ. The hormetic role of dietary antioxidants in free radical-related diseases.Curr Pharm 2010 Des;16(7):877-83.
18. Farah MH, Edwards R, Lindquist M, Leon C, Shaw D. International monitoring of adverse health effects associated with herbal medicines. Pharm Drug Safety 2000 Mar;9(2):105-112
19. Kaplowitz N. Biochemical and eelular mechanisms of toxic liver injury. Semin Liver Dis 2002;22(2):137-14
20. Zhang J, Yin L, Liang G, Liu R, Pu Y. Detection of quinone oxidoreductase 1 (NQO1) single-nucleotide polymorphisms (SNP) related to Benzenemetabolism in immortalized B lymphocytes from A Chinese Han population. J Toxicol Environ Health A 2010 Jan;73(7):490-8
21. Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D. Rapid poly-ubiquitination and proteasomal de gradation of a mutant form of NAD(P)H: quinine oxidoreductase 1. Mol Pharmacol 2001;59(2):263-8
22. Kuehl BL, Paterson JW, Peacock JW, Paterson MC, Rauth AM. Presence of a heterozygous substitution and its relationship to DT-diaphorase activity. Br J Cancer 1995 Sep;72(3):555-61
23. Zeng-Chun MA,Qian HONG, Yu-Guang WANG, Hong-Ling TAN. Radiation Induced Oxidative Stress by Phosphatidylinositol 3-Kinase and Extracellular Signal-Regulated Kinase Pathways.Biol Pharm Bull 2010;33(1) 29-34
24. D. J. Long II, R. L. Waikel, X.-J. Wang, D. R. Roop, and A. K. Jaiswal. NAD (P)H:quinone Oxidoreductase 1 Deficiency and Increased Susceptibility to 7, 12-Dimethylbenz-anthracene-Induced Carcinogenesis in Mouse Skin.J Natl Cancer Ins 2001 Aug; 93(15):1166-70
25. V. Radjendirane, P. Joseph, Y. H. Lee, S. Kimura, F. J. Gonzalez, and A. K. Jaiswal. Disruption of the DT Diaphorase (NQO1) Gene in Mice Leads to Increased Menadione Toxicity. J Biol Chem 1998 Mar; 273(13):7382-89
26. Ge ZJ, Jiang GJ, Zhao YP, Wang GX, Tan YF. Systemic perfluorohexane attenuates lung injury induced by lipopolysaccharide in rats:the role of heme oxygenase-1. Pharmacol Rep 2010 Jan-Feb;62(1):170-7
27. Genc K, Egrilmez MY, Genc S. Erythropoietin induces nuclear translocation of Nrf2 and heme oxygenase-1 expression in SH-SY5Y cells. Cell Biochem Funct 2010 Apr;28(3):197-201
28. Furukawa Y, Urano T, Minamimura M, Nakajima M, Okuyama S, Furukawa S. 4-Methylcatechol-induced heme oxygenase-1 exerts a protective effect against oxidative stress in cultured neural stem/progenitor cells via PI3 kinase/Akt pathway. Biomed Res 2010;31(1):45-52
29. Ping Yao, Andreas Nussler,Liegang Liu2, Liping Hao.Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. Journal of Hepatology 2007 Mar;47(2):253-261
30. Poss K D, Tonegawa S. Reduced stress defense in heme oxy-genase 1-deficient cells. P f Natl Acad Sci USA 1997;94(20):10925-30
31. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell unjury in human heme oxygenase-1 deficiency. J Clin Invest 1999 Jan; 103(1):129-135
32. Karaman M, Ozen H, Tuzcu M, Cigremis Y, Onder F, Ozcan K. Pathological, biochemical and haematological investigations on the protective effect of alpha-lipoic acid in experimental aflatoxin toxicosis in chicks. Br Poult Sci 2010 Feb;51(1):132-41
33. Wang CY, Chau LY. Heme oxygenase-1 in cardiovascular diseases:molecular mechanisms and clinical perspectives. Chang Gung Med J 2010 Jan-Feb; 33 (1): 13-24
34. Shimizu E, Hashimoto K, Komatsu N, Iyo M. Roles of endogenous glutathi-one levels on 6-hydroxydopamine-induced apoptotie neuronal cell death in human neuroblastonra sK-N-SH cells. Neurophannacology 2002 Sep;43 (9):434-36
35. Fraternale A, Tonelli A, Casabianca A, Vallanti G, Chiarantini L, Schiavano GF, Benatti U, De Flora A, Magnani M. Role of macrophage protection in the development of murine AIDS. J Acquir Immune Defic Syndr 1999 Jun;21(2):81-9
36. Kang KW, Lee SJ, Park JW. Phos pllatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress. Mol Pharmacol 2002;62(5):100-10
37. Arlsawa K. Evaluation of adult T-cell leukemia/ymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan. Int J Cancer 2003,85:319-24
38. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003 Apr;11(4):895-904
39. Chen J, Zheng XF, Brown EJ, Schreiber SL. Identification ofanll-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin associated protein and characterization of a critical serine residue. Proc NatlAcad Sci 1995 May;92(11):4947-51
40. Kobayashi A, Ohta T, Yamamoto M. Unique function of the Nrf2-keapl pathway in the inducible expression of antioxidant and detoxifying enzynmes. Methods Enzymol 2004;378:273-86
41. Papaiahgari S, Zhang Q, Kleeberger SR. Hyperoxia stimu-lates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK kinase signaling in pulmonary epithelial cells. Antioxid Redox Signal 2006;8(1-2):1 43-52
42. Joung EJ, Li MH, Lee HG, Somparn N, Jung YS, Na HK, Kim SH, Cha YN, Surh YJ. Capsaicin induces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling:NAD(P)H:quinone oxidoreductase as a potential target. Antioxid Redox Signal 2007 Dec;9(12):2087-98
43. Zhang Y, Guan L, Wang X, Wen T, Xing J, Zhao J. Protection of chlorophyllin against oxidative damage by inducing HO-1 and NQO1 expression mediated by PI3K/Akt and Nrf2 2008 Apr;42(4):362-71
2. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA. Involvement of PI3K/Akt pathway in cell cycle progression, apoptoais and neoplastic transformation:a target for cancer chemotherapy. Leukemia 2003 Mar;17(3):590-603
3. Edwards LA, Thiessen B, Dragowska WH. Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activa-tion, induces apoptosis, and delays tumor growth. NATURE 2005;24(22):3596-3605
4. Song G, Ouyang G, Ban S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005;9(1):59-71
5. Sale EM, Hodgkinson CP, Jones NP, Sale GJ. Role of protein kinase B in phosphorylating glycogen synthase kinase-3, tuberin, WNK1, and ATP citrate lyase. Biochemistry 2006 Jan;45(1):213-223
6. Sakai A, Thieblemont C, Wellmann A, Jaffe ES, Raffeld M. PTEN Gene Aheralions in Lymphoid Neoplasms. Blood 1998 Nov;92(9):3410-15
7. Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, Gewirtz AM, Perussia B, Calabretta B. Phosphatidylinositol 3 kinase activity is regulated by BCR/ABL and is required for the growth of Philadelphia chromosome positive cells. Blood 1995 Jul;86(2):726-36
8. Skorski T, Bellacosa A, Nieborowska Skorska M. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI3k/Akt-dependent pathway. EMBO J 1997; 16(20):6151-61
9. Ly C, Arechiga AF, Melo JV, Walsh CM, Ong ST. Bcr Ab1 kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 2003 Sep; 63(18):5716-22
10. Picinato MC, Hirata AE, Cipolla-Neto J, Curi R, Carvalho CR, Anhe GF, Carpinelli AR. Activation of insulin and IGF-1 signaling pathways by melatonin through MT1 receptor in isolated rat pancreatic islets. J Pin Res 2008 Jan; 44(1):88-94
11. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, Franklin RA, McCubrey JA.Involvement of PI3K/Akt pathway in'cell cycle progression, Apoptoais, and neoplastic transformation:a target for cancer chemotherapy. Leukemia 2003 Mar;17(3):590-603
12. Scheijen B, Ngo HT, Kang H. FIT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins. Oneogene 2004;23(19):3338-49
13. Chian R, Young S, Danilkovitch-Miagkova A, Ronnstrand L, Leonard E, Ferrao P, Ashman L, Linnekin D. Phosphatidylinositol 3 kinase contributes to the transfor-mation of hematopoietic cells by the D816V c Kit mutant. Blood 2001 Sep;98(5):1365-73
14. Hashimoto K, Matsumura I, Tsujimura T, Kim DK, Ogihara H, Ikeda H, Ueda S, Mizuki M, Sugahara H, Shibayama H, Kitamura Y, Kanakura Y. Necessity of tyrosine 719 and phosphatidyIinositoI 3'kinase-mediated signal pathway in constitutive activation and oncogenic potential of c-kit receptor tyrosine kinase with the Asp814Val mutation. Blood 2003 Feb;101(3):1094-1102
15. Tang Y, Zhang D, Fallavollita L, Brodt P. Vascular endothelial grow-factor C expression and lymph node metastasis are regulated by the type 1 insulin-like growth factor receptor. Cancer Res 2003 Mar;63:1 166-71
16. Niquet J, Wasterlain CG. Bim, Bad, and Bax:a deadly combination in epileptic seizures. J Clin Invest 2004 Apr;113(7):960-62
17. Hinz M, Krappmann D, Eichten A, Heder A, Scheidereit C, Strauss M. NF-kappaB function in growth control:regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol 1999;19(4):2690-98
18. Madrid LV, Mayo MW, Reuther JY. Akt stimulates the trans-activation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the kappa B kinase and activation of the mitogen-activated protein kinase p38 J Biol Chem.2001; 276(22):18934-40
19. Shew JP. NFAT is responsible for tissue-specific expression. Science 1988;241-202
20. Huang H, Tindall DJ. Dynamic FoxO transcription factors. J Cell Sci 2007; 120(15):2479-87
21. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinesitol 3-kinase/AKT-mediated activation of estrogen receptor alpha:a new model for anti-estrogen resistance. J Biol Chem 2001 Mar;276 (13):9817-24
22. Mimi TA, Kentaro H, Kiyoshi N. Down-rogulation of P27 KIP1 promotes cell proliferation of rat neonatal eardiomyocytes induced by nuclear of cyclinDl and CDK4. J Biol Chem 2004;279(48):50429-36
23. Cardone MH, Roy N, Stennicke HR. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998;282 (5392):1318-21
24. Michael S C, Cynthis A A, Barrett J C. Regulation of p53 stabili-ty and actability in response to genotoxie stress. Muta Res 2000;352:1-17
25. Cheng SW, Fryer LG, Carling D, Shepherd PR. Thr2446 is a novel mammlian target of rapamyein (mTOR) phesphorylation site regnlated by nutrient status. J Biol Chem 2004 Apr;279(16):15719-22
26. Chiu M1, Katz H, Berlin V. RAPT1, a mannnalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci U S A 1994 Dec; 91(26):12574-8
27. Rommel C, Clarke BA, Zimmermann S, Nunez L, Rossman R, Reid K, Moelling K, Yancopoulos GD, Glass DJ. Diferentiation stage-specific inhibition of the Raf-MEK-EBK pathway by Akt. Science 1999 Nov;286(5445):1738-41
1. 何水祥,舒昌杰.自由基在病理性肝炎中的作用及其防治.中国实用内科杂志,1994；14(11)：679-80
2. 邵惠训.自由基和自由基清除剂.生物工程进展,1994；14(4)：49-5
3. Hori M, Gotoh K, Kitakaze M, Iwai K, Iwakura K, Sato H, Koretsune Y, Inoue M, Kitabatake A, Kamada T. Role of oxygen-derived free radicals in myocalodial edema and ischemia in coronary microvascular embolization. Circulation 1991 Aug;84(2):951-4
4. Nieto G, Diaz P, Ban'on S, Garrido MD. Dietary administration of ewe diets with a distillate from rosemary leaves (Rosmarinus officinalis L.):influence on lamb meat quality.2010 Jan;84(1):23-9
5. Pintore G, Marchetti M, Chessa M, Sechi B,Scanu N, Mangano G, Tirillini B.Rosmarinus officinalis L.:chemical modifications of the essential oil and evaluation of antioxidant and antimicrobial activity. Nat Prod Commun 2009 Dec;4(12):1685-90
6. Harach T, Aprikian O, Monnard I, Moulin J, Membrez M, Beolor JC, Raab T, Mace K, Darimont C.Rosemary (Rosmarinus officinalis L.) leaf extract limits weight gain and liver steatosis in mice fed a high-fat diet. Planta Med 2010 Apr;76(6):566-71
7. Perez-Fons L, Garzon MT, Micol V. Relationship between the antioxidant capacity and effect of rosemary (Rosmarinus officinalis L.) polyphenols on membrane phospholipid order. J Agric Food Chem 2010 Jan 13;58(1):161-71
8. Takaki I, Bersani-Amado LE, Vendruscolo A, Sartoretto SM, Diniz SP, Bersani-Amado CA, Cuman RK.Anti-inflammatory and antinociceptive effects of Rosmarinus officinalis L. essential oil in experimental animal models. J Med Food 2008 Dec;11(4):741-6
9. LoAH, Liang YC, LinShiau SY, Ho CT, Lin JK.Carnosol, an antioxidant in rosemary, suppresses inducible nitre oxide synthase through down-regulating nuclear factor-kappaB in mouse maerophages. Carcinogenesis 2002 Jun;23(6): 983-91
10. DanilenkoM, Wang X, Studzinski GP.Carnosic Acid and Promotion of Monoeytic Differentiation of HL60-G Cells Initiated by Other Agents. Cancer Res 2003 Mar;63(6):1325-32
11. Kuzmenko AI, Morozova RP, Nikolenko IA, Donchenko GV, Richheimer SL, Bailey DT.Chemilmuinescence determination of the in vivo and in vitro antioxidant activity of Rose OX and carnosic acid. J Photochem Photobiol B 1999 Jan;48(1):63-7
12. Satoh T, Izumi M, Inukai Y, Tsutsumi Y, Nakayama N, Kosaka K, Shimojo Y, Kitajima C, Itoh K, Yokoi T, Shirasawa T. Carnosic acid protects neuronal HT22 Cells through activation of the antioxidant-responsive element in free carboxylic acid-and catechol hydroxyl moieties-dependent manners. Neuroscience Letters 2008 Apr;434(3):260-5
13. Takahashi T, Tabuchi T, Tamaki Y, Kosaka K, Takikawa Y, Satoh T. Carnosic acid and carnosol inhibit adipocyte differentiation in mouse 3T3-L1 cells through induction of phase2 enzymes and activation of glutathione metabolism. Biochemical and Biophysical Research Communications 2009 May;382(3): 549-54
14. Lim JH, Kim KM, Kim SW, Hwang O, Choi HJ. Bromocriptine activates NQO1 via Nrf2-PI3K/Akt signaling:Novel cytoprotective mechanism against oxidative damage. Pharmacol Res 2008 May;57(5):325-31
15. Chiang CW, Huang Y, Leong KW, Chen LC, Chen HC, Chen SJ, Chou CK. PKCalpha mediated induction of miR-101 in human hepatoma HepG2 cells. J Biomed Sci 2010 May;17(1):35
16. Bayet-Robert M, Loiseau D, Rio P, Demidem A, Barthomeuf C, Stepien G, Morvan D. Quantitative two-dimensional HRMAS 1H-NMR spectroscopy-based metabolite profiling of human cancer cell lines and response to chemotherapy. Magn Reson Med 2010 May;63(5):I172-83
17. Calabrese V, Cornelius C, Trovato A, Cavallaro M, Mancuso C, Di Rienzo L, Condorelli D, De Lorenzo A, Calabrese EJ. The hormetic role of dietary antioxidants in free radical-related diseases.Curr Pharm 2010 Des;16(7):877-83.
18. Farah MH, Edwards R, Lindquist M, Leon C, Shaw D. International monitoring of adverse health effects associated with herbal medicines. Pharm Drug Safety 2000 Mar;9(2):105-112
19. Kaplowitz N. Biochemical and eelular mechanisms of toxic liver injury. Semin Liver Dis 2002;22(2):137-14
20. Zhang J, Yin L, Liang G, Liu R, Pu Y. Detection of quinone oxidoreductase 1 (NQO1) single-nucleotide polymorphisms (SNP) related to Benzenemetabolism in immortalized B lymphocytes from A Chinese Han population. J Toxicol Environ Health A 2010 Jan;73(7):490-8
21. Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D. Rapid poly-ubiquitination and proteasomal de gradation of a mutant form of NAD(P)H: quinine oxidoreductase 1. Mol Pharmacol 2001;59(2):263-8
22. Kuehl BL, Paterson JW, Peacock JW, Paterson MC, Rauth AM. Presence of a heterozygous substitution and its relationship to DT-diaphorase activity. Br J Cancer 1995 Sep;72(3):555-61
23. Zeng-Chun MA,Qian HONG, Yu-Guang WANG, Hong-Ling TAN. Radiation Induced Oxidative Stress by Phosphatidylinositol 3-Kinase and Extracellular Signal-Regulated Kinase Pathways.Biol Pharm Bull 2010;33(1) 29-34
24. D. J. Long II, R. L. Waikel, X.-J. Wang, D. R. Roop, and A. K. Jaiswal. NAD (P)H:quinone Oxidoreductase 1 Deficiency and Increased Susceptibility to 7, 12-Dimethylbenz-anthracene-Induced Carcinogenesis in Mouse Skin.J Natl Cancer Ins 2001 Aug; 93(15):1166-70
25. V. Radjendirane, P. Joseph, Y. H. Lee, S. Kimura, F. J. Gonzalez, and A. K. Jaiswal. Disruption of the DT Diaphorase (NQO1) Gene in Mice Leads to Increased Menadione Toxicity. J Biol Chem 1998 Mar; 273(13):7382-89
26. Ge ZJ, Jiang GJ, Zhao YP, Wang GX, Tan YF. Systemic perfluorohexane attenuates lung injury induced by lipopolysaccharide in rats:the role of heme oxygenase-1. Pharmacol Rep 2010 Jan-Feb;62(1):170-7
27. Genc K, Egrilmez MY, Genc S. Erythropoietin induces nuclear translocation of Nrf2 and heme oxygenase-1 expression in SH-SY5Y cells. Cell Biochem Funct 2010 Apr;28(3):197-201
28. Furukawa Y, Urano T, Minamimura M, Nakajima M, Okuyama S, Furukawa S. 4-Methylcatechol-induced heme oxygenase-1 exerts a protective effect against oxidative stress in cultured neural stem/progenitor cells via PI3 kinase/Akt pathway. Biomed Res 2010;31(1):45-52
29. Ping Yao, Andreas Nussler,Liegang Liu2, Liping Hao.Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. Journal of Hepatology 2007 Mar;47(2):253-261
30. Poss K D, Tonegawa S. Reduced stress defense in heme oxy-genase 1-deficient cells. P f Natl Acad Sci USA 1997;94(20):10925-30
31. Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S. Oxidative stress causes enhanced endothelial cell unjury in human heme oxygenase-1 deficiency. J Clin Invest 1999 Jan; 103(1):129-135
32. Karaman M, Ozen H, Tuzcu M, Cigremis Y, Onder F, Ozcan K. Pathological, biochemical and haematological investigations on the protective effect of alpha-lipoic acid in experimental aflatoxin toxicosis in chicks. Br Poult Sci 2010 Feb;51(1):132-41
33. Wang CY, Chau LY. Heme oxygenase-1 in cardiovascular diseases:molecular mechanisms and clinical perspectives. Chang Gung Med J 2010 Jan-Feb; 33 (1): 13-24
34. Shimizu E, Hashimoto K, Komatsu N, Iyo M. Roles of endogenous glutathi-one levels on 6-hydroxydopamine-induced apoptotie neuronal cell death in human neuroblastonra sK-N-SH cells. Neurophannacology 2002 Sep;43 (9):434-36
35. Fraternale A, Tonelli A, Casabianca A, Vallanti G, Chiarantini L, Schiavano GF, Benatti U, De Flora A, Magnani M. Role of macrophage protection in the development of murine AIDS. J Acquir Immune Defic Syndr 1999 Jun;21(2):81-9
36. Kang KW, Lee SJ, Park JW. Phos pllatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress. Mol Pharmacol 2002;62(5):100-10
37. Arlsawa K. Evaluation of adult T-cell leukemia/ymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan. Int J Cancer 2003,85:319-24
38. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003 Apr;11(4):895-904
39. Chen J, Zheng XF, Brown EJ, Schreiber SL. Identification ofanll-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin associated protein and characterization of a critical serine residue. Proc NatlAcad Sci 1995 May;92(11):4947-51
40. Kobayashi A, Ohta T, Yamamoto M. Unique function of the Nrf2-keapl pathway in the inducible expression of antioxidant and detoxifying enzynmes. Methods Enzymol 2004;378:273-86
41. Papaiahgari S, Zhang Q, Kleeberger SR. Hyperoxia stimu-lates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK kinase signaling in pulmonary epithelial cells. Antioxid Redox Signal 2006;8(1-2):1 43-52
42. Joung EJ, Li MH, Lee HG, Somparn N, Jung YS, Na HK, Kim SH, Cha YN, Surh YJ. Capsaicin induces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling:NAD(P)H:quinone oxidoreductase as a potential target. Antioxid Redox Signal 2007 Dec;9(12):2087-98
43. Zhang Y, Guan L, Wang X, Wen T, Xing J, Zhao J. Protection of chlorophyllin against oxidative damage by inducing HO-1 and NQO1 expression mediated by PI3K/Akt and Nrf2 2008 Apr;42(4):362-71