Herbal Formula Science (대한한의학방제학회지)

The Korean Medicine Society for the Herbal Formula Study (대한한의학방제학회)
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Regulation of Hippo-YAP AXIS and CYP450 enzymes by herbal pharmaceuticals, Ojeok-san

Human Hippo-YAP AXIS 및 CYP450에 미치는 오적산의 영향

  • Bae, Su Jin (School of Korean Medicine, Dongguk University) ;
  • Yun, Un-Jung (School of Korean Medicine, Dongguk University) ;
  • Bak, Seon-Been (School of Korean Medicine, Dongguk University) ;
  • Song, Yu-Rim (School of Korean Medicine, Dongguk University) ;
  • Kim, Choon-Ok (Department of clinical pharmacology, Severance hospital, Yonsei university health system) ;
  • Kang, Hyung Won (Department of Neuropsychiatry of Korean Medicine, College of Korean Medicine, Wonkwang University) ;
  • Kim, Young Woo (School of Korean Medicine, Dongguk University)
  • 배수진 (동국대학교 한의학과 방제학교실) ;
  • 윤언정 (동국대학교 한의학과 방제학교실) ;
  • 박선빈 (동국대학교 한의학과 방제학교실) ;
  • 송유림 (동국대학교 한의학과 방제학교실) ;
  • 김춘옥 (연세대학교의료원 세브란스병원 임상약리학과) ;
  • 강형원 (원광대학교 한의과대학 한방신경정신과) ;
  • 김영우 (동국대학교 한의학과 방제학교실)
  • Received : 2021.11.15
  • Accepted : 2021.12.01
  • Published : 2022.02.28
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Abstract

Objectives : This study investigated the protective effect of Ojeok-san (OJS) on cellular damage induced by oxidative stress and whether it induces changes in CYP450 expression. Methods : To investigate the protective effect, we used cells stimulated by oxidative stress caused by the combination treatment of AA+iron. Changes in CYP450 expression were detected by immunoblotting analysis using Huh7 cells. Results : We observed that OJS altered the expression of CYP1A2, CYP3A4, CYP2C19, CYP2D6, and CYP2E1. OJS increased cell viability against AA+iron-induced oxidative stress and inhibited mitochondrial dysfunction. OJS increased phosphorylation of LKB1, phosphorylation of AMPK, and phosphorylation of ACC, which are related to the LKB1-AMPK pathway. In addition, phosphorylation of LATS1 and phosphorylation of YAP, which are related to the Hippo-YAP pathway, were increased. Conclusions : Our results show that OJS has 1) the ability to protect hepatocytes against oxidative stress, and 2) the potential to induce changes in CYP450.

Keywords

Acknowledgement

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (number: HF20C0212) and (HF21C0061).

References

  1. Park HM, Shin HT, Lee SD. Herbal Toxicological Effects on Rats' Fetus-Focusing on Ojeoksan-. Journal of Society of Preventive Korean Medicine. 2008;12(2):27-35.
  2. Lee MS, Jeong SM, Oh SH, Lee HY, Leem HG, Ahn YM, Ahn SY, Lee BC. A Retrospective Study on the Effect of the Co-Administration of Ojeok-san and Hypoglycemic Agents on Blood Glucose Levels in Type 2 Diabetes Mellitus. J. Int. Korean Med. 2021; 42(1):40-52.
  3. Lee NH, Ha HK, Lee HY, Jung DY, Choi JY, Lee JK, Shin HK. Analysis of Studies on Ojeok-san for Establishment of Evidence Based Medicine. Herbal Formula Science. 2008;16(2):1-9.
  4. Rani V, Deep G, Singh RK, Palle K, Yadav U. Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies. Life Sciences. 2016;148: 183-193. https://doi.org/10.1016/j.lfs.2016.02.002
  5. Ha HL, Shin HJ, Feitelson MA, Yu DY. Oxidative stress and antioxidants in hepatic pathogenesis. World J Gastroenterol. 2010;16(48): 6035-6043. https://doi.org/10.3748/wjg.v16.i48.6035
  6. Cichoz-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol. 2014;20(25):8082-8091. https://doi.org/10.3748/wjg.v20.i25.8082
  7. Adwas AA, Elsayed A, Azab AE, Quwaydir FA. Oxidative stress and antioxidant mechanisms in human body. Journal of Applied Biotechnology & Bioengineering. 2019;6(1):43-47. https://doi.org/10.15406/jabb.2019.06.00173
  8. Hardie DG. AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Current opinion in cell biology. 2015;33:1-7. https://doi.org/10.1016/j.ceb.2014.09.004
  9. Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metabolism. 2006; 3(6):403-416. https://doi.org/10.1016/j.cmet.2006.05.005
  10. 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. https://doi.org/10.3748/wjg.v16.i30.3731
  11. 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 Radical Biology and Medicine. 2009;47(7):1082-1092. https://doi.org/10.1016/j.freeradbiomed.2009.07.018
  12. 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 Complementary and Alternative Medicine. 2013; 13(64):doi:10.1186/1472-6882-13-64.
  13. Shao D, Zhai P, Del Re DP, Sciarretta S, Yabuta N, Nojima H, Lim DS, Pan D, Sadoshima J. 2014. A functional interaction between Hippo-YAP signaling and FoxO1 mediates the oxidative stress response. Nature Communications. 2014; 5:3315. https://doi.org/10.1038/ncomms4315
  14. R Bhadra, K Ravakhah, RK Ghosh. Herb- drug interaction: The importance of communicating with primary care physicians. Australas Med J. 2015; 8(10):315-319. https://doi.org/10.4066/AMJ.2015.2479
  15. Vohora D, Singh G. Pharmaceutical Medicine and Translational Clinical Research, 1st ed. Academic Press, Cambridge, 2017, p.81-106.
  16. Sharma AK, Kapoor VK, Kaur G. Herb-drug interactions: A mechanistic approach. Drug and Chemical Toxicology. 2020;doi.org/10.1080/01480545. 2020.1738454.
  17. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, Ang C. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clinical Pharmacology & Therapeutics. 2002; 72(3):276-287. https://doi.org/10.1067/mcp.2002.126913
  18. Xu LL, Tang XL, Ma ZC, Wang YG, Liang QD, Tan HL, Xiao CR, Li H, Yuan M, Gao Y. Effects of aqueous extract of Cassiae Semen on activity hepatic microsomal CYP450 isozymes in rats. China Journal of Chinese Materia Medica. 2016;41(8):1504-1510.
  19. Rocejanasaroj A, Tencomnao T, Sangkitikomol W. Thunbergia laurifolia extract minimizes the adverse effects of toxicants by regulating P-glycoprotein activity, CYP450, and lipid metabolism gene expression in HepG2 cells. Genetics and Molecular Research. 2014;13(1): 205-219. https://doi.org/10.4238/2014.January.10.12
  20. Kim JH, Lee DH, Jung SE, Yang WM, Kwon BI. Anti-inflammatory Effects of Ojeok-san in LPS-induced Inflammatory Rat Model. The Society of Korean Medicine. 2021;42(2):21-30. https://doi.org/10.13048/jkm.21012
  21. Han BH, Kim HY, Hong MH, Na SW, Gang DG. Inhibitory Effects of Ojeoksan on TNF-α-induced Vascular Inflammation in Human Umbilical Vein Endothelial Cells. The Korea Journal of Herbology. 2018;33(4):59-67. https://doi.org/10.6116/KJH.2018.33.4.59
  22. Choi HM, Moon SO, Lee HH. Inhibitory effect of by Ojeok-san lipid accumulation in high fat diet-induced obesity mice and 3T3-L1 adipocytes. The Korea Association of Herbology. 2015;30(4): 121-128. https://doi.org/10.6116/kjh.2015.30.4.121.
  23. Spector A. Oxidative Stress and Disease. Journal of Ocular Pharmacology and Therapeutics. 2000;16(2): 193-201. https://doi.org/10.1089/jop.2000.16.193
  24. West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nature Reviews Immunology. 2011;11(6):389-402. https://doi.org/10.1038/nri2975
  25. 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. Molecular Pharmacology. 2009;75(1): 242-253. https://doi.org/10.1124/mol.108.051128
  26. Hasenjaeger A, Gillissen B, Mueller A, Normand G, Hemmati PG, Schuler M, Doerken B, Daniel PT. Smac induces cytochrome c release and apoptosis independently from Bax/Bcl-xL in a strictly caspase-3-dependent manner in human carcinoma cells. Oncogene. 2004;23:4523-4535. https://doi.org/10.1038/sj.onc.1207594
  27. Price L, Kowdley KV. The Role of Iron in the Pathophysiology and Treatment of Chronic Hepatitis C. Can J Gastroenterol. 2009;23(12): 822-828. https://doi.org/10.1155/2009/290383
  28. Caro AA, Cederbaum AI. Synergistic toxicity of iron and arachidonic acid in HepG2 cells overexpressing CYP2E1. Molecular Pharmacology. 2001;60(4):742-752.
  29. Lee EH, Baek SY, Park JY, Kim YW. Emodin in Rheum undulatum inhibits oxidative stress in the liver via AMPK with Hippo/Yap signalling pathway. Pharm Biol. 2020;58(1):333-341. https://doi.org/10.1080/13880209.2020.1750658