DOI QR코드

DOI QR Code

Four active monomers from Moutan Cortex exert inhibitory effects against oxidative stress by activating Nrf2/Keap1 signaling pathway

  • Zhang, Baoshun (College of Pharmaceutical Sciences, Southwest University) ;
  • Yu, Deqing (College of Pharmaceutical Sciences, Southwest University) ;
  • Luo, Nanxuan (College of Pharmaceutical Sciences, Southwest University) ;
  • Yang, Changqing (College of Pharmaceutical Sciences, Southwest University) ;
  • Zhu, Yurong (College of Pharmaceutical Sciences, Southwest University)
  • 투고 : 2020.01.02
  • 심사 : 2020.07.21
  • 발행 : 2020.09.01

초록

Paeonol, quercetin, β-sitosterol, and gallic acid extracted from Moutan Cortex had been reported to possess anti-oxidative, anti-inflammatory, and anti-tumor activities. This work aimed to illustrate the potential anti-oxidative mechanism of monomers in human liver hepatocellular carcinoma (HepG2) cells-induced by hydrogen peroxide (H2O2) and to evaluate whether the hepatoprotective effect of monomers was independence or synergy in mice stimulated by carbon tetrachloride (CCl4). Monomers protected against oxidative stress in HepG2 cells in a dose-response manner by inhibiting the generation of reactive oxygen species, increasing total antioxidant capacity, catalase and superoxide dismutase (SOD) activities, and activating the antioxidative pathway of nuclear factor E2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/Keap1) signaling pathway. We found that the in vitro antioxidant capacities of paeonol and quercetin were better than those of β-sitosterol and gallic acid. Furthermore, paeonol apparently diminished the levels of alanine transaminase and aspartate aminotransferase, augmented the contents of glutathione and SOD, promoted the expressions of Nrf2 and heme oxygenase-1 proteins in mice stimulated by CCl4. In HepG2 cells, paeonol, quercetin, β-sitosterol, and gallic acid play a defensive role against H2O2-induced oxidative stress through activating Nrf2/Keap1 pathway, indicating that these monomers have anti-oxidative properties. Totally, paeonol and quercetin exerted anti-oxidative and hepatoprotective effects, which is independent rather than synergy.

키워드

참고문헌

  1. Yu BP. Cellular defenses against damage from reactive oxygen species. Physiol Rev. 1994;74:139-162. https://doi.org/10.1152/physrev.1994.74.1.139
  2. Berndt C, Lillig CH, Flohe L. Redox regulation by glutathione needs enzymes. Front Pharmacol. 2014;5:168. https://doi.org/10.3389/fphar.2014.00168
  3. Wang P, Gao YM, Sun X, Guo N, Li J, Wang W, Yao LP, Fu YJ. Hepatoprotective effect of 2'-O-galloylhyperin against oxidative stressinduced liver damage through induction of Nrf2/ARE-mediated antioxidant pathway. Food Chem Toxicol. 2017;102:129-142. https://doi.org/10.1016/j.fct.2017.02.016
  4. Zitka O, Skalickova S, Gumulec J, Masarik M, Adam V, Hubalek J, Trnkova L, Kruseova J, Eckschlager T, Kizek R. Redox status expressed as GSH:GSSG ratio as a marker for oxidative stress in paediatric tumour patients. Oncol Lett. 2012;4:1247-1253. https://doi.org/10.3892/ol.2012.931
  5. Lin TA, Ke BJ, Cheng CS, Wang JJ, Wei BL, Lee CL. Red quinoa bran extracts protects against carbon tetrachloride-induced liver injury and fibrosis in mice via activation of antioxidative enzyme systems and blocking TGF-${\beta}1$ pathway. Nutrients. 2019;11:395. https://doi.org/10.3390/nu11020395
  6. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011;16:123-140. https://doi.org/10.1111/j.1365-2443.2010.01473.x
  7. Su C, Xia X, Shi Q, Song X, Fu J, Xiao C, Chen H, Lu B, Sun Z, Wu S, Yang S, Li X, Ye X, Song E, Song Y. Neohesperidin dihydrochalcone versus CCl4-induced hepatic injury through different mechanisms: the implication of free radical scavenging and Nrf2 activation. J Agric Food Chem. 2015;63:5468-5475. https://doi.org/10.1021/acs.jafc.5b01750
  8. Liu J, Sun H, Zhang A, Yan G, Han Y, Xue C, Zhou X, Shi H, Wang X. Serum pharmacochemistry combined with multiple data processing approach to screen the bioactive components and their metabolites in Mutan Cortex by ultra-performance liquid chromatography tandem mass spectrometry. Biomed Chromatogr. 2014;28:500-510. https://doi.org/10.1002/bmc.3060
  9. Lin MY, Lee YR, Chiang SY, Li YZ, Chen YS, Hsu CD, Liu YW. Cortex Moutan induces bladder cancer cell death via apoptosis and retards tumor growth in mouse bladders. Evid Based Complement Alternat Med. 2013;2013:207279.
  10. Oh GS, Pae HO, Oh H, Hong SG, Kim IK, Chai KY, Yun YG, Kwon TO, Chung HT. In vitro anti-proliferative effect of 1,2,3,4,6-penta-O-galloyl-beta-D-glucose on human hepatocellular carcinoma cell line, SK-HEP-1 cells. Cancer Lett. 2001;174:17-24. https://doi.org/10.1016/S0304-3835(01)00680-2
  11. Chen G, Zhang L, Zhu Y. Determination of glycosides and sugars in Moutan Cortex by capillary electrophoresis with electrochemical detection. J Pharm Biomed Anal. 2006;41:129-134. https://doi.org/10.1016/j.jpba.2005.11.001
  12. Li J, Li Y, Pan S, Zhang L, He L, Niu Y. Paeonol attenuates ligationinduced periodontitis in rats by inhibiting osteoclastogenesis via regulating Nrf2/$NF-{\kappa}B$/NFATc1 signaling pathway. Biochimie. 2019;156:129-137. https://doi.org/10.1016/j.biochi.2018.09.004
  13. Li XY, Xu JD, Zhou SS, Kong M, Xu YY, Zou YT, Tang Y, Zhou L, Xu MZ, Xu J, Li SL. Time segment scanning-based quasi-multiple reaction monitoring mode by ultra-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry for quantitative determination of herbal medicines: Moutan Cortex, a case study. J Chromatogr A. 2018;1581-1582:33-42. https://doi.org/10.1016/j.chroma.2018.10.047
  14. Feng RB, Wang Y, He C, Yang Y, Wan JB. Gallic acid, a natural polyphenol, protects against tert-butyl hydroperoxide- induced hepatotoxicity by activating ERK-Nrf2-Keap1-mediated antioxidative response. Food Chem Toxicol. 2018;119:479-488. https://doi.org/10.1016/j.fct.2017.10.033
  15. Peng Z, Gong X, Yang Y, Huang L, Zhang Q, Zhang P, Wan R, Zhang B. Hepatoprotective effect of quercetin against LPS/d-GalN induced acute liver injury in mice by inhibiting the IKK/$NF-{\kappa}B$ and MAPK signal pathways. Int Immunopharmacol. 2017;52:281-289. https://doi.org/10.1016/j.intimp.2017.09.022
  16. Chen F, Mo K, Zhang Q, Fei S, Zu Y, Yang L. A novel approach for distillation of paeonol and simultaneous extraction of paeoniflorin by microwave irradiation using an ionic liquid solution as the reaction medium. Sep Purif Technol. 2017;183:73-82. https://doi.org/10.1016/j.seppur.2017.03.069
  17. Li YL, Li J, Wang NL, Yao XS. Flavonoids and a new polyacetylene from Bidens parviflora Willd. Molecules. 2008;13:1931-1941. https://doi.org/10.3390/molecules13081931
  18. Li WH, Chang ST, Chang SC, Chang HT. Isolation of antibacterial diterpenoids from Cryptomeria japonica bark. Nat Prod Res. 2008;22:1085-1093. https://doi.org/10.1080/14786410802267510
  19. He L, She Z. Molecular structure identification and properties of gallic acid from galla chinensis. Chem Fiber Text Techol. 2017;46:5-9.
  20. Sun X, Wang P, Yao LP, Wang W, Gao YM, Zhang J, Fu YJ. Paeonol alleviated acute alcohol-induced liver injury via SIRT1/Nrf2/$NF-{\kappa}B$ signaling pathway. Environ Toxicol Pharmacol. 2018;60:110-117. https://doi.org/10.1016/j.etap.2018.04.016
  21. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer. 2003;3:768-780. https://doi.org/10.1038/nrc1189
  22. Pinheiro-Sant'ana HM, Guinazi M, Oliveira Dda S, Della Lucia CM, Reis Bde L, Brandao SC. Method for simultaneous analysis of eight vitamin E isomers in various foods by high performance liquid chromatography and fluorescence detection. J Chromatogr A. 2011;1218:8496-8502. https://doi.org/10.1016/j.chroma.2011.09.067
  23. Yen GC, Duh PD, Tsai HL. Antioxidant and pro-oxidant properties of ascorbic acid and gallic acid. Food Chem. 2002;79:307-313. https://doi.org/10.1016/S0308-8146(02)00145-0
  24. Ho HH, Chang CS, Ho WC, Liao SY, Wu CH, Wang CJ. Anti-metastasis effects of gallic acid on gastric cancer cells involves inhibition of NF-kappaB activity and downregulation of PI3K/AKT/small GTPase signals. Food Chem Toxicol. 2010;48:2508-2516. https://doi.org/10.1016/j.fct.2010.06.024
  25. Hsiang CY, Hseu YC, Chang YC, Kumar KJ, Ho TY, Yang HL. Toona sinensis and its major bioactive compound gallic acid inhibit LPS-induced inflammation in nuclear $factor-{\kappa}B$ transgenic mice as evaluated by in vivo bioluminescence imaging. Food Chem. 2013;136:426-434. https://doi.org/10.1016/j.foodchem.2012.08.009
  26. Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem. 2017;86:715-748. https://doi.org/10.1146/annurev-biochem-061516-045037
  27. Wei S, Chi J, Zhou M, Li R, Li Y, Luo J, Kong L. Anti-inflammatory lindenane sesquiterpeniods and dimers from Sarcandra glabra and its upregulating AKT/Nrf2/HO-1 signaling mechanism. Ind Crops Prod. 2019;137:367-376. https://doi.org/10.1016/j.indcrop.2019.05.041
  28. Chen B, Lu Y, Chen Y, Cheng J. The role of Nrf2 in oxidative stressinduced endothelial injuries. J Endocrinol. 2015;225:R83-R99.
  29. Zhuang Y, Ma Q, Guo Y, Sun L. Protective effects of rambutan (Nephelium lappaceum) peel phenolics on $H_{2}O_{2}$-induced oxidative damages in HepG2 cells and D-galactose-induced aging mice. Food Chem Toxicol. 2017;108(Pt B):554-562. https://doi.org/10.1016/j.fct.2017.01.022
  30. Lyu Z, Ji X, Chen G, An B. Atractylodin ameliorates lipopolysaccharide and D-galactosamine-induced acute liver failure via the suppression of inflammation and oxidative stress. Int Immunopharmacol. 2019;72:348-357. https://doi.org/10.1016/j.intimp.2019.04.005
  31. Auten RL, Davis JM. Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr Res. 2009;66:121-127. https://doi.org/10.1203/PDR.0b013e3181a9eafb
  32. Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003;33:105-136. https://doi.org/10.1080/713611034
  33. Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci. 2008;4:89-96.
  34. Johnston DE, Kroening C. Mechanism of early carbon tetrachloride toxicity in cultured rat hepatocytes. Pharmacol Toxicol. 1998;83:231-239. https://doi.org/10.1111/j.1600-0773.1998.tb01474.x
  35. Vuda M, D'Souza R, Upadhya S, Kumar V, Rao N, Kumar V, Boillat C, Mungli P. Hepatoprotective and antioxidant activity of aqueous extract of Hybanthus enneaspermus against CCl4-induced liver injury in rats. Exp Toxicol Pathol. 2012;64:855-859. https://doi.org/10.1016/j.etp.2011.03.006
  36. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997;236:313-322. https://doi.org/10.1006/bbrc.1997.6943
  37. Chun KS, Kundu J, Kundu JK, Surh YJ. Targeting Nrf2-Keap1 signaling for chemoprevention of skin carcinogenesis with bioactive phytochemicals. Toxicol Lett. 2014;229:73-84. https://doi.org/10.1016/j.toxlet.2014.05.018
  38. Keum YS. Regulation of the Keap1/Nrf2 system by chemopreventive sulforaphane: implications of posttranslational modifications. Ann N Y Acad Sci. 2011;1229:184-189. https://doi.org/10.1111/j.1749-6632.2011.06092.x
  39. Lou Y, Guo Z, Zhu Y, Kong M, Zhang R, Lu L, Wu F, Liu Z, Wu J. Houttuynia cordata Thunb. and its bioactive compound 2-undecanone significantly suppress benzo(a)pyrene-induced lung tumorigenesis by activating the Nrf2-HO-1/NQO-1 signaling pathway. J Exp Clin Cancer Res. 2019;38:242. https://doi.org/10.1186/s13046-019-1255-3
  40. Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284:13291-13295. https://doi.org/10.1074/jbc.R900010200
  41. Calabrese V, Cornelius C, Dinkova-Kostova AT, Calabrese EJ, Mattson MP. Cellular stress responses, the hormesis paradigm, and vitagenes: novel targets for therapeutic intervention in neurodegenerative disorders. Antioxid Redox Signal. 2010;13:1763-1811. https://doi.org/10.1089/ars.2009.3074
  42. Bucolo C, Drago F, Maisto R, Romano GL, D'Agata V, Maugeri G, Giunta S. Curcumin prevents high glucose damage in retinal pigment epithelial cells through ERK1/2-mediated activation of the Nrf2/HO-1 pathway. J Cell Physiol. 2019;234:17295-17304. https://doi.org/10.1002/jcp.28347
  43. Sharath Babu GR, Anand T, Ilaiyaraja N, Khanum F, Gopalan N. Pelargonidin modulates Keap1/Nrf2 pathway gene expression and ameliorates citrinin-induced oxidative stress in HepG2 cells. Front Pharmacol. 2017;8:868. https://doi.org/10.3389/fphar.2017.00868
  44. Dinkova-Kostova AT, Talalay P. NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys. 2010;501:116-123. https://doi.org/10.1016/j.abb.2010.03.019

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