Journal of Physiology & Pathology in Korean Medicine (동의생리병리학회지)

The Physiological Society of Korean Medicine and The Society of Pathology in Korean Medicine (대한동의생리학회·한의병리학회)
권호 표지

Identification of the Plant Part of Gleditsia sinensis that Activates Nrf2, an Anti-oxidative Transcription Factor

조협의 부위에 따른 항산화 전사인자 Nrf2 활성 효과

  • Choi, Jiyeon (Division of Applied Medicine, School of Korean Medicine, Pusan National University) ;
  • Kim, Kyun Ha (Division of Applied Medicine, School of Korean Medicine, Pusan National University) ;
  • Choi, Jun Yong (Department of Oriental Internal Medicine, Korean Medicine Hospital, Pusan National University) ;
  • Han, Chang Woo (Department of Oriental Internal Medicine, Korean Medicine Hospital, Pusan National University) ;
  • Ha, Ki Tae (Division of Applied Medicine, School of Korean Medicine, Pusan National University) ;
  • Jeong, Han-Sol (Division of Applied Medicine, School of Korean Medicine, Pusan National University) ;
  • Joo, Myungsoo (Division of Applied Medicine, School of Korean Medicine, Pusan National University)
  • 최지연 (부산대학교 한의학전문대학원 응용의학부) ;
  • 김균하 (부산대학교 한의학전문대학원 응용의학부) ;
  • 최준용 (부산대학교 한방병원 내과학교실) ;
  • 한창우 (부산대학교 한방병원 내과학교실) ;
  • 하기태 (부산대학교 한의학전문대학원 응용의학부) ;
  • 정한솔 (부산대학교 한의학전문대학원 응용의학부) ;
  • 주명수 (부산대학교 한의학전문대학원 응용의학부)
  • Received : 2014.03.31
  • Accepted : 2014.06.09
  • Published : 2014.06.25
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Abstract

The fruit of Gleditsia sinensis has been extensively used as a key ingredient of an herbal remedy for the treatment of various inflammatory diseases in traditional Korean Medicine. However, the reason of using the fruit of G. sinensis for the remedy is unclear. Since Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key anti-inflammatory transcription factor, which is activated by the fruit of G. sinesis, we examined whether other plant parts of G. sinensis are also capable of suppressing inflammatory responses by activating Nrf2. Water extracts of various parts of G. sinensis were prepared and tested for Nrf2 activation by reporter assay and western blot analysis. Our results show that the hull of G. sinensis is the most potent in activating Nrf2. Sequential organic solvent extraction of the hull show that all the fractions had a higher potency in activating Nrf2 than the water extract, albeit differential degrees. The hull originated from Korea in general activated Nrf2 strongly compared to that of China. Chloroform fraction of the hull was further examined, showing that the fraction induced nuclear localization of Nrf2, indicative of activated Nrf2, and Nrf2-dependent gene expression including NAD(P)H dehydrogenase quinone 1 (NQO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and heme oxygenase - 1 (HO-1). Therefore, our results show that, among other plant parts examined in this study, the hull of G. sinensis is the most potent, providing the experimental basis for the use of the hull of G. sinensis as an active ingredient for an anti-inflammatory remedy.

Keywords

References

  1. Itoh, K., Ishii, T., Wakabayashi, N., Yamamoto, M. Regulatory mechanisms of cellular response to oxidative stress. Free Radic Res 31: 319-324, 1999. https://doi.org/10.1080/10715769900300881
  2. Rahman, I., Biswas, S.K., Kirkham, P.A. Regulation of inflammation and redox signaling by dietary polyphenols. Biochem Pharmacol 72: 1439-1452, 2006. https://doi.org/10.1016/j.bcp.2006.07.004
  3. 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 236: 313-322, 1997. https://doi.org/10.1006/bbrc.1997.6943
  4. Ishii, T., Itoh, K., Takahashi, S., Sato, H., Yanagawa, T., Katoh, Y., Bannai, S., Yamamoto, M. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275: 16023-16029, 2000. https://doi.org/10.1074/jbc.275.21.16023
  5. Cho, H.Y., Jedlicka, A.E., Reddy, S.P., Kensler, T.W., Yamamoto, M., Zhang, L.Y., Kleeberger, S.R. Role of Nrf2 in protection against hyperoxic lung injury in mice. Am J Resp Cell Mol 26: 175-182, 2002. https://doi.org/10.1165/ajrcmb.26.2.4501
  6. Lugade, A.A., Vethanayagam, R.R., Nasirikenari, M., Bogner, P.N., Segal, B.H., Thanavala, Y. Nrf2 Regulates Chronic Lung Inflammation and B-Cell Responses to Nontypeable Haemophilus influenzae. Am J Respir Cell Mol Biol 45(3):557-565, 2011. https://doi.org/10.1165/rcmb.2010-0321OC
  7. Satoh, T., Lipton, S.A. Redox regulation of neuronal survival by electrophilic compounds. Trends Neurosci 30: 38-45, 2007.
  8. Vargas, M.R., Johnson, J.A. The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev Mol Med 11: e17, 2009. https://doi.org/10.1017/S1462399409001094
  9. Surh, Y.J., Na, H.K. NF-kappaB and Nrf2 as prime molecular targets for chemoprevention and cytoprotection with anti-inflammatory and antioxidant phytochemicals. Genes & Nutrition 2(4):313-317, 2008. https://doi.org/10.1007/s12263-007-0063-0
  10. Zhang, D.D. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38: 769-789, 2006. https://doi.org/10.1080/03602530600971974
  11. Herbology textbook compilation committee. Herbology. Seoul. Younglimsa. p 491, 2008.
  12. Ju, Y.S. Ungok Herbology. Jeonju. Woosuk Press. p 1035, 2013.
  13. Literature research institute of Eastern Medicine. Korean version of Donguibogam. Seoul. Bubin. p 724, 2007.
  14. Shin, T.Y., Kim, D.K. Inhibitory effect of mast cell-dependent anaphylaxis by Gleditsia sinensis. Arch Pharm Res 23: 401-406, 2000. https://doi.org/10.1007/BF02975455
  15. Dai, Y., Chan, Y.P., Chu, L.M., Bu, P.P. Antiallergic and anti-inflammatory properties of the ethanolic extract from Gleditsia sinensis. Biol Pharm Bull 25: 1179-1182, 2002. https://doi.org/10.1248/bpb.25.1179
  16. Chow, L.M.C., Chui, C.H., Tang, J.C.O., Teo, I.T.N., Lau, F.Y., Cheng, G.Y.M., Wong, R.S.M., Leung, T.W.T., Lai, K.B., Yau, M.Y.C., Gou, D., Chan, A.S.C. Gleditsia sinensis fruit extract is a potential chemotherapeutic agent in chronic and acute myelogenous leukemia. Oncol Rep 10: 1601-1607, 2003.
  17. Fu, L.J., Dai, Y., Wang, Z.T., Zhang, M. Inhibition of experimental allergic rhinitis by the n-butanol fraction from the anomalous fruits of Gleditsia sinensis. Biol Pharm Bull 26: 974-977, 2003. https://doi.org/10.1248/bpb.26.974
  18. Dai, Y., Chan, Y.P., Chu, L.M., Bu, P.P. Antiallergic and anti-inflammatory properties of the ethanolic extract from gleditsia sinensis. Biol Pharm Bull 25: 1179-1182, 2002. https://doi.org/10.1248/bpb.25.1179
  19. Hou, L.F., Dai, Y., Xia, Y.F., Gong, Z.N. Alleviation of Picryl Chloride-Induced Delayed Type Hypersensitivity Reaction by Saponin Fraction of Gleditsia sinensis. Biol Pharm Bull 29: 1056-1059, 2006. https://doi.org/10.1248/bpb.29.1056
  20. Choi, J.Y., Kwun, M.J., Kim, K.H., Lyu, J.H., Han, C.W., Jeong, H.S., Ha, K.T., Jung, H.J., Lee, B.J., Sadikot, R.T., Christman, J.W., Jung, S.K., Joo, M. Protective Effect of the Fruit Hull of Gleditsia sinensis on LPS-Induced Acute Lung Injury Is Associated with Nrf2 Activation. Evid-Based Compl Alt: eCAM, 974713, 2012.
  21. Durackova, Z. Some current insights into oxidative stress. Physiol Res 59: 459-469, 2010.
  22. Schraufstatter, I., Hyslop, P.A., Jackson J.H, Cochrane, C.G. Oxidant-induced DNA damage of target cells. J Clin Invest, 82: 1040-1050, 1988. https://doi.org/10.1172/JCI113660
  23. Lee, J.M., Johnson, J.A. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol 37: 139-143, 2004. https://doi.org/10.5483/BMBRep.2004.37.2.139
  24. Kang, M.I., Kobayashi, A., Wakabayashi, N., Kim, S.G., Yamamoto, M. Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci 101: 2046-2051, 2004. https://doi.org/10.1073/pnas.0308347100
  25. Padmanabhan, B., Tong, K.I., Ohta, T., Nakamur, Y., Scharlock, M., Ohtsuji, M., Kang, M.I., Kobayash,i A., Yokoyama, S., Yamamoto, M. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell 21: 689-700, 2006. https://doi.org/10.1016/j.molcel.2006.01.013
  26. Itoh, K., Tong, K.I., Yamamoto, M. Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 36: 1208-1213, 2004. https://doi.org/10.1016/j.freeradbiomed.2004.02.075
  27. Vodovotz, Y., Constantine, G., Faeder, J., Mi, Q., Rubin, J., Bartels, J., Sarkar, J., Squires, R.H., Okonkwo, D.O., Gerlach, J., Zamora, R., Luckhart, S., Ermentrout, B., An, G. Translational systems approaches to the biology of inflammation and healing. Immunopharmacol Immunotoxicol 32: 181-195, 2010. https://doi.org/10.3109/08923970903369867
  28. Kobayashi, A., Kang, M.I., Watai, Y., Tong, K.I., Shibata, T., Uchida, K., Yamamoto, M. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 26: 221-229, 2006. https://doi.org/10.1128/MCB.26.1.221-229.2006
  29. Tong, K.I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., Yamamoto, M. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol 26: 2887-2900, 2006. https://doi.org/10.1128/MCB.26.8.2887-2900.2006
  30. Yamahara, J., Shintani, Y., Konoshima, T., Swada, T., Fugimura, H. Biological active principles of the crude drugs. II. Antiulcerogenic and anti-inflammatory actions of the crude drugs containing saponin. Yakugaku Zasshi 95: 1179-1182, 1975. https://doi.org/10.1248/yakushi1947.95.10_1179
  31. Dhakshinamoorthy, S., Long, D.J. 2nd. Jaiswal, A.K. Antioxidant regulation of genes encoding enzymes that detoxify xenobiotics and carcinogens. Curr Top Cell Regul 36: 201-216, 2000.
  32. Dalton, T.P., Dieter, M.Z., Yan,g Y., Shertze,r H.G., Neber,t D.W. Knockout of the mouse glutamate cysteine ligase catalytic subunit (Gclc) gene: Embryonic lethal when homozygous, and proposed model for moderate glutathione deficiency when heterozygous. Biochem Biophys Res Commun 279: 324-329, 2000. https://doi.org/10.1006/bbrc.2000.3930
  33. Pompella, A., Visviki,s A., Paolicch,i A., De Tata, V., Casini, A.F. The changing faces of glutathione, a cellular protagonist. Biochem Pharmacol 66(8):1499-1503, 2003. https://doi.org/10.1016/S0006-2952(03)00504-5
  34. Okinaga, S., Takahashi, .K, Takeda, K., Yoshizawa, M., Fujita, H., Sasaki, H., Shibahara, S. Regulation of human heme oxygenase-1 gene expression under thermal stress. Blood 87: 5074-5084, 1996.
  35. Willis, D., Moore, A.R., Frederick, R., Willoughby, D.A. Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med 2: 87-90, 1996. https://doi.org/10.1038/nm0196-87
  36. Zhang, D.D., Hannink, M. Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23: 8137-8151, 2003. https://doi.org/10.1128/MCB.23.22.8137-8151.2003
  37. Kobayashi, A., Kang, M.I., Watai, Y., Tong, K.I., Shibata, T., Uchida, K., Yamamoto, M. Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity of Keap1. Mol Cell Biol 26: 221-229, 2006. https://doi.org/10.1128/MCB.26.1.221-229.2006