Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Anti-Inflammatory Effect of Quercetagetin, an Active Component of Immature Citrus unshiu, in HaCaT Human Keratinocytes

  • Kang, Gyeoung-Jin (Department of Pharmacology, School of Medicine, Jeju National University) ;
  • Han, Sang-Chul (Department of Pharmacology, School of Medicine, Jeju National University) ;
  • Ock, Jong-Woo (School of Medicine, Jeju National University) ;
  • Kang, Hee-Kyoung (Department of Pharmacology, School of Medicine, Jeju National University) ;
  • Yoo, Eun-Sook (Department of Pharmacology, School of Medicine, Jeju National University)
  • Received : 2013.01.02
  • Accepted : 2013.01.21
  • Published : 2013.03.31
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Abstract

Citrus fruit contain various flavonoids that have multiple biological activities. However, the content of these flavonoids are changed during maturation and immature Citrus is known to contain larger amounts than mature. Chemokines are significant mediators for cell migration, while thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well known as the typical inflammatory chemokines in atopic dermatitis (AD), a pruritic and chronic inflammatory skin disease. We reported recently that the EtOH extract of immature Citrus unshiu inhibits TARC and MDC production. Therefore, we investigated the activity of flavonoids contained in immature Citrus on TARC and MDC levels. As a result, among the various flavonoids, quercetagetin has stronger inhibitory effects on the protein and mRNA expression of TARC and MDC than other flavonoids. Quercetagetin particularly has better activity on TARC and MDC level than quercetin. In HPLC analysis, the standard peak of quercetagetin matches the peaks of extract of immature C. unshiu. This suggests that quercetagetin is an anti-inflammatory component in immature C. unshiu.

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References

  1. Arafa, el-SA., Zhu, Q., Barakat, B. M., Wani, G., Zhao, Q., El-Mahdy, M. A. and Wani, A. A. (2009) Tangeretin sensitizes cisplatin-resistant human ovarian cancer cells through downregulation of phosphoinositide 3-kinase/Akt signaling pathway. Cancer Res. 69, 8910-8917. https://doi.org/10.1158/0008-5472.CAN-09-1543
  2. Baek, S., Kang, N. J., Popowicz, G. M., Arciniega, M., Jung, S. K., Byun, S., Song, N. R., Heo, Y. S., Kim, B. Y., Lee, H. J., Holak, T. A., Augustin, M., Bode, A. M., Huber, R., Dong, Z. and Lee, K. W. (2013) Structural and functional analysis of the natural JNK1 inhibitor quercetagetin. J. Mol. Biol. 452, 411-423.
  3. Cavia-Saiz, M., Busto, M. D., Pilar-Izquierdo, M. C., Ortega, N., Perez-Mateos, M. and Muniz, P. (2010) Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study. J. Sci. Food Agric. 90, 1238-1244. https://doi.org/10.1002/jsfa.3959
  4. Cespedes, C. L., Avila, J. G., Martinez, A., Serrato, B., Cal-deron-Mugica, J. C. and Salgado-Garciglia, R. (2006) Antifungal and antibacterial activities of Mexican tarragon (Tagetes lucida). J. Agric. Food Chem. 54, 3521-3527. https://doi.org/10.1021/jf053071w
  5. Choi, I. Y., Kim, S. J., Jeong, H. J., Park, S. H., Song, Y. S., Lee, J. H., Kang, T. H., Park, J. H., Hwang, G. S., Lee, E. J., Hong, S. H., Kim, H. M. and Um, J. Y. (2007) Hesperidin inhibits expression of hypoxia inducible factor-1 alpha and inflammatory cytokine production from mast cells. Mol. Cell. Biochem. 305, 153-161. https://doi.org/10.1007/s11010-007-9539-x
  6. Gough, D. J., Levy, D. E., Johnstone, R. W. and Clarke, C. J. (2008) IFNgamma signaling-does it mean JAK-STAT? Cytokine Growth Factor Rev. 19, 383-394. https://doi.org/10.1016/j.cytogfr.2008.08.004
  7. Hijnen, D., De Bruin-Weller, M., Oosting, B., Lebre, C., De Jong, E., Bruijnzeel-Koomen, C. and Knol, E. (2004) Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell- attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis. J. Allergy Clin. Immunol. 113, 334-340. https://doi.org/10.1016/j.jaci.2003.12.007
  8. Holvoet, S., Vincent, C., Schmitt, D. and Serres, M. (2003) The inhibition of MAPK pathway is correlated with down-regulation of MMP-9 secretion induced by TNF-alpha in human keratinocytes. Exp. Cell Res. 290, 108-119. https://doi.org/10.1016/S0014-4827(03)00293-3
  9. Huang, R. Y., Yu, Y. L., Cheng, W. C., OuYang, C. N., Fu, E. and Chu, C. L. (2010) Immunosuppressive effect of quercetin on dendritic cell activation and function. J. Immunol. 184, 6815-6821. https://doi.org/10.4049/jimmunol.0903991
  10. Kakinuma, T., Nakamura, K., Wakugawa, M., Mitsui, H., Tada, Y., Saeki, H., Torii, H., Asahina, A., Onai, N., Matsushima, K. and Tamaki, K. (2001) Thymus and activation-regulated chemokine in atopic dermatitis: Serum thymus and activation-regulated chemokine level is closely related with disease activity. J. Allergy Clin. Immunol. 107, 535-541. https://doi.org/10.1067/mai.2001.113237
  11. Kang, G. J., Han, S. C., Yi, E. J., Kang, H. K. and Yoo, E. S. (2011) The inhibitory effect of premature Citrus unshiu extract on atopic dermatitis in vitro and in vivo. Toxicol. Res. 27, 173-180. https://doi.org/10.5487/TR.2011.27.3.173
  12. Kim, Y. D., Ko, W. J., Koh, K. S., Jeon, Y. J. and Kim, S. H. (2009) Composition of flavonoids and antioxidative activity from juice of Jeju native citrus fruits during maturation. Korean J. Nutr. 42, 278-290. https://doi.org/10.4163/kjn.2009.42.3.278
  13. Lee, C. H., Jeong, T. S., Choi, Y. K., Hyun, B. H., Oh, G. T., Kim, E. H., Kim, J. R., Han, J. I. and Bok, S. H. (2001) Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits. Biochem. Biophys. Res. Commun. 284, 681-688. https://doi.org/10.1006/bbrc.2001.5001
  14. Lee, E. J., Ji, G. E. and Sung, M. K. (2010) Quercetin and kaempferol suppress immunoglobulin E-mediated allergic inflammation in RBL-2H3 and Caco-2 cells. Inflamm. Res. 59, 847-854. https://doi.org/10.1007/s00011-010-0196-2
  15. Leung, T. F., Ma, K. C., Hon, K. L., Lam, C. W., Wan, H., Li, C. Y. and Chan, I. H. (2003) Serum concentration of macrophage-derived chemokine may be a useful inflammatory marker for assessing severity of atopic dermatitis in infants and young children. Pediatr. Allergy Immunol. 14, 296-301. https://doi.org/10.1034/j.1399-3038.2003.00052.x
  16. Middleton, E. Jr, Kandaswami, C. and Theoharides, T. C. (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol. Rev. 52, 673-751.
  17. Min, Y. D., Choi, C. H., Bark, H., Son, H. Y., Park, H. H., Lee, S., Park, J. W., Park, E. K., Shin, H. I. and Kim, S. H. (2007) Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-kappaB and p38 MAPK in HMC-1 human mast cell line. Inflamm. Res. 56, 210-215. https://doi.org/10.1007/s00011-007-6172-9
  18. Miyata, Y., Tanaka, H., Shimada, A., Sato, T., Ito, A., Yamanouchi, T. and Kosano, H. (2011) Regulation of adipocytokine secretion and adipocyte hypertrophy by polymethoxyflavonoids, nobiletin and tangeretin. Life Sci. 88, 613-618. https://doi.org/10.1016/j.lfs.2011.01.024
  19. Murakami, A., Nakamura, Y., Torikai, K., Tanaka, T., Koshiba, T., Koshimizu, K., Kuwahara, S., Takahashi, Y., Ogawa, K., Yano, M., Tokuda, H., Nishino, H., Mimaki, Y., Sashida, Y., Kitanaka, S. and Ohigashi, H. (2000) Inhibitory effect of citrus nobiletin on phorbol ester-induced skin inflammation, oxidative stress, and tumor promotion in mice. Cancer Res. 60, 5059-5066.
  20. Nogata, Y., Sakamoto, K., Shiratsuchi, H., Ishii, T., Yano, M. and Ohta, H. (2006) Flavonoid composition of fruit tissues of citrus species. Biosci. Biotechnol. Biochem. 70, 178-192. https://doi.org/10.1271/bbb.70.178
  21. Panicker, S. R., Sreenivas, P., Babu, M. S., Karunagaran, D. and Kartha, C. C. (2010) Quercetin attenuates monocyte chemoattractant protein-1 gene expression in glucose primed aortic endothelial cells through NF-kappaB and AP-1. Pharmacol. Res. 62, 328-336. https://doi.org/10.1016/j.phrs.2010.06.003
  22. Pease, J. E. (2011) Targeting chemokine receptors in allergic disease. Biochem. J. 434, 11-24. https://doi.org/10.1042/BJ20101132
  23. Pivarcsi, A. and Homey, B. (2005) Chemokine networks in atopic dermatitis: traffic signals of disease. Curr. Allergy Asthma Rep. 5, 284-290. https://doi.org/10.1007/s11882-005-0068-y
  24. Saeki, H. and Tamaki, K. (2006) Thymus and activation regulated chemokine (TARC)/CCL17 and skin diseases. J. Dermatol. Sci. 43, 75-84. https://doi.org/10.1016/j.jdermsci.2006.06.002
  25. Schmeda-Hirschmann, G., Tapia, A., Theoduloz, C., Rodriguez, J., Lopez, S. and Feresin, G. E. (2004) Free radical scavengers and antioxidants from Tagetes mendocina. Z. Naturforsch. C. 59, 345-353.
  26. Silalahi, J. (2002) Anticancer and health protective properties of citrus fruit components. Asia Pac. J. Clin. Nutr. 11, 79-84. https://doi.org/10.1046/j.1440-6047.2002.00271.x
  27. Yamashita, U. and Kuroda, E. (2002) Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit. Rev. Immunol. 22, 105-114.
  28. Yang, X., Kang, S. M., Jeon, B. T., Kim, Y. D., Ha, J. H., Kim, Y. T. and Jeon, Y. J. (2011). Isolation and identification of an antioxidant flavonoid compound from citrus-processing by-product. J. Sci. Food Agric. 91, 1925-1927. https://doi.org/10.1002/jsfa.4402

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