DOI QR코드

DOI QR Code

Molecular Events on Experimental Skin Inflammation and Modulation by Topical Anti-inflammatory Flavonoids

  • Kim, Hyun-Pyo (College of Pharmacy, Kangwon National University)
  • Published : 2007.03.30

Abstract

There have been various animal models of skin inflammation. These models have been used for establishing anti-inflammatory activity of the topical agents including cosmetics. Here, the molecular mechanisms of most widely-used animal models of skin inflammation including contact irritation, acute and chronic inflammation, and delayed-type hypersensitivity are summarized. Against these animal models, varieties of plant flavonoids showed anti-inflammatory activity. The action mechanisms of anti-inflammation by topical flavonoids are presented. A therapeutic potential of flavonoids is discussed.

Keywords

References

  1. Adlercreutz, H., Markkanen, H. and Watanabe, S. (1993). Plasma concentrations of phyto-oestrogens in Japanese men. Lancet 342, 1209-1210 https://doi.org/10.1016/0140-6736(93)92188-Y
  2. Alford, J. G., Stanley, P. L., Todderud, G. and Tramposch, K. M. (1992). Temporal alteration of leukocyte subsets into mouse skin inflamed with phorbol ester. Agents Actions 37, 261-267
  3. Bouclier, M., Cavey, D., Kail, N. and Hensby, C. (1990). Experimental models in skin pharmacology. Pharmacol. Rev. 42, 127-153
  4. Burke, J. R. (2001). Targeting phospholipase A2 for the treatment of inflammatory skin diseases. Curr. Opin. Investig. Drugs 2, 1549-1552
  5. Chang, J., Carlson, R. P., Oneill-Davis, L., Lamb, B., Sharma, R. N. and Lewis, A. J. (1986). Correlation between mouse skin inflammation induced by arachidonic acid and eicosanoid synthesis. Inflammation 10, 205-214 https://doi.org/10.1007/BF00916116
  6. Chen, X., Yin, O. Q., Zuo, Z. and Chow, M. S. (2005). Pharmacokinetics and modeling of quercetin and metabolites. Pharm. Res. 22, 892-901 https://doi.org/10.1007/s11095-005-4584-1
  7. Cheon, B. S., Kim, Y. H., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (2000). Effects of prenylated flavonoids and biflavonoids on lipopolysaccharide-induced nitric oxide production from the mouse macrophage cell line RAW 264.7. Planta Med. 66, 596-600 https://doi.org/10.1055/s-2000-8621
  8. Chi, Y. S., Cheon, B. S. and Kim, H. P. (2001a). Effect of wogonin, a plant flavone from Scutellaria radix, on the suppression of cyclooxygenase-2 and induction of inducible nitric oxide synthase in lipopolysaccharide-treated RAW 264.7 cells. Biochem. Pharmacol. 61, 1195-1203 https://doi.org/10.1016/S0006-2952(01)00597-4
  9. Chi, Y. S., Jong, H. G., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (2001b). Effects of naturally occurring prenylated flavonoids on enzymes metabolizing arachidonic acid: Cyclooxygenases and lipoxygenases. Biochem. Pharmacol. 62, 1185-1191 https://doi.org/10.1016/S0006-2952(01)00773-0
  10. Chi, Y. S. and Kim, H. P. (2005). Suppression of cyclooxygenase-2 expression of skin fibroblasts by wogonin, a plant flavone from Scutellaria radix. Prostag. Leukot. Essent. Fatty Acids 72, 59-66 https://doi.org/10.1016/j.plefa.2004.04.009
  11. Chi, Y. S., Lim, H., Park, H. and Kim, H. P. (2003). Effect of wogonin, a plant flavone from Scutellaria radix, on skin inflammation: in vivo regulation of inflammation-associated gene expression. Biochem. Pharmacol. 66, 1271-1278 https://doi.org/10.1016/S0006-2952(03)00463-5
  12. Day, A. J., Mellon, F., Barron, D., Sarrazin, G., Morgan, M. R. and Williamson, G. (2001). Human metabolism of dietary flavonoids: identification of plasma metabolites of quercetin. Free Radic. Res. 35, 941-952 https://doi.org/10.1080/10715760100301441
  13. Della Loggia, R., Ragazzi, E., Tubaro, A., Fassina, G. and Vertua R. (1988). Anti-inflammatory activity of benzopyrones that are inhibitors of cyclo- and lipo-oxygenase. Pharmacol. Res. Comm. 20 (Suppl. V), 91-94
  14. Della Loggia, R., Tubaro, A., Dri, P., Zilli, C. and Del Negro, P. (1986). The role of flavonoids in the anti-inflammatory activity of Chamomilla recutita. In Plant flavonoids in biology and medicines, 1986 (Cody et al. Eds.), pp. 481-484. Alan R. Liss, New York
  15. De Young, L. M., Kheifets, J. B., Ballaron, S. J. and Young, J. M. (1989). Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents. Agents Actions 26, 335-341 https://doi.org/10.1007/BF01967298
  16. Enk, A. H. and Katz, S. J. (1992). Early molecular events in the induction phase of contact sensitivity. Proc. Nat'l. Acad. Sci. USA 89, 1398-1402 https://doi.org/10.1073/pnas.89.4.1398
  17. Erlund, I., Kosonen, T., Alfthan, G., Maenpaa, J., Perttunen, K., Kenraali, J., Parantainen, J. and Aro, A. (2000). Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur. J. Clin. Pharmacol. 56, 545-553 https://doi.org/10.1007/s002280000197
  18. Fogh, K. and Kragballe, K. (2000). Eicosanoids in inflammatory skin diseases. Prostag. Other Lipid Mediat. 63, 43-54 https://doi.org/10.1016/S0090-6980(00)00096-4
  19. Fuchs, J. and Milbradt, R. (1993). Skin anti-inflammatory activity of apigenin-7-glucoside in rats. Arzneim. Forsch. 43, 370-372
  20. Fujii, E., Irie, K., Uchida, Y., Ohba, K. and Muraki, T. (1995). Role of eicosanoids but not nitric oxide in the platelet-activating factor-induced increase in vascular permeability in mouse skin. Eur. J. Pharmacol. 273, 267-272 https://doi.org/10.1016/0014-2999(94)00697-6
  21. Gil, B., Sanz, M. J., Terencio, M. C., Ferrandiz, M. L., Bustos, G., Paya, M., Gunasegaran, R. and Alcaraz, M. J. (1994). Effects of flavonoids on Naja naja and human recombinant synovial phospholipase A2 and inflammatory responses in mice. Life Sci. 54, PL333-338 https://doi.org/10.1016/0024-3205(94)90021-3
  22. Hara, H., Sukamoto, T., Ohtaka, H., Abe, K., Tatumi, Y., Saito, Y., Suzuki, A. and Tsukamoto, G. (1992). Effects of baicalein and $\alpha$-tocopherol on lipid peroxidation, free radical scavenging activity and 12-O-tetradecanoylphorbol acetate-induced ear edema. Eur. J. Pharmacol. 221, 193-198 https://doi.org/10.1016/0014-2999(92)90700-E
  23. Hertog, M. G. L., Hollman, P. C. H. and Katan, M. B. (1992). Content of potentially anticarcinogenic flavonoids of 28 vegetables and 9 fruits commonly consumed in the Netherlands. J. Agri. Food Chem. 40, 2379-2383 https://doi.org/10.1021/jf00024a011
  24. Hollman, P. C. H., van Trijp, J. M. P., Mengelers, M. J. B., de Vries, J. H. M. and Katan, M. B. (1997). Bioavailability of the dietary antioxidant flavonol quercetin in man. Cancer Lett. 114, 139-140 https://doi.org/10.1016/S0304-3835(97)04644-2
  25. Hsiu, S. L., Huang, T. Y., Hou, Y. C., Chin, D. H. and Chao, P. D. (2002). Comparison of metabolic pharmacokinetics of naringin and naringenin in rabbits. Life Sci. 70, 1481-1489 https://doi.org/10.1016/S0024-3205(01)01491-6
  26. Inoue, H., Mori, T. and Koshihara, Y. (1988). Sulfidopeptide-leukotrienes are major mediators of arachidonic acid-induced mouse ear edema. Prostaglandins 36, 731-739 https://doi.org/10.1016/0090-6980(88)90016-0
  27. Iversen, L. and Kragballe, K. (2000). Arachidonic acid metabolism in skin health and disease. Prostag. Other Lipid Mediat. 63, 25-42 https://doi.org/10.1016/S0090-6980(00)00095-2
  28. Jang, M. and Pezzuto, J. M. (1998). Effects of resveratrol on 12-O-tetradecanoylphorbol-13-acetate-induced oxidative events and gene expression in mouse skin. Cancer Lett. 134, 81-89 https://doi.org/10.1016/S0304-3835(98)00250-X
  29. Kato, R., Nakadate, T., Yamamoto, S. and Sugimura, T. (1983). Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and ornithine decarboxylase activity by quercetin: possible involvement of lipoxygenase inhibition. Carcinogenesis 4, 1301-1305 https://doi.org/10.1093/carcin/4.10.1301
  30. Kennard, M. D, Kang, D. C., Montgomery, R. L. and Butler, A. P. (1995). Expression of epidermal ornithine decarboxylase and nuclear proto-oncogene in phorbol ester tumor promotor-sensitive and -resistant mice. Mol. Carcinog. 12, 14-22 https://doi.org/10.1002/mc.2940120104
  31. Kim, D. W., Chi, Y. S., Son, K. H., Chang, H. W., Kim, J. S., Kang, S. S. and Kim, H. P. (2002). Effects of sophoraflavanone G, a prenylated flavonoid from Sophora flavescens on cyclooxygenase-2 and in vivo inflammatory response. Arch. Pharm. Res. 25, 329-335 https://doi.org/10.1007/BF02976635
  32. Kim, H., Kim, Y. S., Kim, S. Y. and Suk, K. (2001). The plant flavonoid wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production. Neurosci. Lett. 309, 67-71 https://doi.org/10.1016/S0304-3940(01)02028-6
  33. Kim, H. K., Cheon, B. S., Kim, Y. H., Kim, S. Y. and Kim, H. P. (1999). Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264.7 and their structure-activity relationships. Biochem. Pharmacol. 58, 759-765 https://doi.org/10.1016/S0006-2952(99)00160-4
  34. Kim, H. K., Namgoong, S. Y. and Kim, H. P. (1993). Antiinflammatory activity of flavonoids: Mice ear edema inhibition. Arch. Pharm. Res. 16, 18-24 https://doi.org/10.1007/BF02974122
  35. Kim, H. K., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (1998a). Amentoflavone, a plant biflavone: A new potential anti-inflammatory agent. Arch. Pharm. Res. 21, 406-410 https://doi.org/10.1007/BF02974634
  36. Kim, H. P., Mani, I., Iversen, L. and Ziboh, V. A. (1998b). Effects of naturally occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs. Prostag. Leukot. Essent. Fatty Acids 58, 17-24 https://doi.org/10.1016/S0952-3278(98)90125-9
  37. Kim, H. P., Son, K. H., Chang, H. W. and Kang, S. S. (2004). Anti-inflammatory plant flavonoids and cellular action mechanisms. J. Pharmacol. Sci. 96, 229-245 https://doi.org/10.1254/jphs.CRJ04003X
  38. Kubo, M., Matsuda, H., Tanaka, M., Kimura, Y., Okuda, H., Higashino, M., Tani, T., Namba, K. and Arichi, S. (1984). Studies on Scutellaria radix. VII. Anti-arthritic and anti-inflammatory actions of methanolic extract and flavonoid components from Scutellaria radix. Chem. Pharm. Bull. 32, 2724-2729 https://doi.org/10.1248/cpb.32.2724
  39. Kuhnau J. (1976). The flavonoids: A class of semi-essential food components: their role in human nutrition. World Rev. Nutr. Diet 24, 117-191
  40. Kwak, W-J., Han, C. K., Son, K. H., Chang, H. W., Kang, S. S., Park, B. K. and Kim, H. P. (2002). Effect of ginkgetin from Ginkgo biloba leaves on cyclooxygenases and in vivo skin inflammation. Planta Med. 68, 316-321 https://doi.org/10.1055/s-2002-26742
  41. Lee, S. J., Son, K. H., Chang, H. W., Do, J. C., Jung, K. Y., Kang, S. S. and Kim, H. P. (1993). Anti-inflammatory activity of naturally occurring flavones and flavonol glycosides. Arch. Pharm. Res. 16, 25-28 https://doi.org/10.1007/BF02974123
  42. Li, B. and Birt, D. F. (1996). In vivo and in vitro percutaneous absorption of cancer preventive flavonoid apigenin in different vehicles in mouse skin. Pharmaceutical Res. 13, 1710-1715 https://doi.org/10.1023/A:1016453009818
  43. Lim, H., Park, H. and Kim, H. P. (2004). Inhibition of contact dermatitis in animal models and suppression of proinflammatory gene expression by topically applied flavonoid, wogonin. Arch. Pharm. Res. 27, 442-448 https://doi.org/10.1007/BF02980087
  44. Lim, H., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (2006a). Inhibition of chronic skin inflammation by topical anti-inflammatory flavonoid preparation, Ato $Formular^\circledR$. Arch. Pharm. Res. 29, 503-507 https://doi.org/10.1007/BF02969424
  45. Lim, H., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (2006b). Effects of anti-inflammatory biflavonoid, ginkgetin, on chronic skin inflammation. Biol. Pharm. Bull. 29, 1046-1049 https://doi.org/10.1248/bpb.29.1046
  46. Maldve, R. E., Kim, Y., Muga, S. J. and Fisher, S. M. (2000). Prostaglandin E2 regulation of cyclooxygenase expression in keratinocytes is mediated via cyclic nucleotide-linked prostaglandin receptors. J. Lipd Res. 41, 873-881
  47. Manach, C. and Donovan, J. (2004). Pharmacokinetics and metabolism of dietary flavonoids in human. Free Radical Res. 38, 771-185 https://doi.org/10.1080/10715760410001727858
  48. Manach, C., Williamson, G., Morand, C., Scalbert, A. and Remesy, C. (2005). Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr. 81(Suppl.), 230S-242S https://doi.org/10.1093/ajcn/81.1.230S
  49. Mitsui, G., Mitsui, K., Hirano, T., Ohara, O., Kato, M. and Niwano, Y. (2003). Kinetic profiles of sequential gene expressions for chemokines in mice with contact hypersensitivity. Immunol. Lett. 68, 191-197 https://doi.org/10.1016/S0165-2478(03)00017-8
  50. Mizutani, H., Yamanaka, K., Konishi, H. and Murakami, T. (2003). Animal models of psoriasis and pustular psoriasis. Arch. Dermatol. Res. 295, S67-S68 https://doi.org/10.1007/s00403-002-0374-3
  51. Moon, J-H., Tsushida, T., Nakahara, K. and Terao, J. (2001). Identification of quercetin 3-O-$\beta$-D-glucuronide as an antioxidative metabolite in rat plasma after oral administration of quercetin. Free Radic. Biol. Med. 30, 1274-1285 https://doi.org/10.1016/S0891-5849(01)00522-6
  52. Morita, H., Hori, M. and Kitano, Y. (1996). Modulation of picryl chloride-induced contact hypersensitivity reaction in mice by nitric oxide. J. Invest. Dermatol. 107, 549-552 https://doi.org/10.1111/1523-1747.ep12582805
  53. 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
  54. Murakami, M., Yoshihara, K., Shimbara, S., Lambeau, G., Singer, A., Gelb, M. H., Sawada, M., Inagaki, N., Nagai, H. and Kudo, I. (2002). Arachidonate release and eicosanoid generation by group IIE phospholipase $A_2$. Biochem. Biophys. Res. Comm. 292, 689-696 https://doi.org/10.1006/bbrc.2002.6716
  55. Murota, K. and Terao, J. (2003). Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism. Arch. Biochem. Biophys. 417, 12-17 https://doi.org/10.1016/S0003-9861(03)00284-4
  56. Nickoloft, B. J., Griffiths, C. E. M. and Barker, J. N. W. N. (1990). The role of adhesion molecules, chemotactic factors, and cytokines in inflammatory and neoplastic skin disease-1990 update. J. Invest. Dermatol. 94, 151S-157S https://doi.org/10.1111/1523-1747.ep12876134
  57. Norris, P., Poston, R. N., Thomas, D. S., Thorhill, M., Hawk, J. and Haskard, D. O. (1991). The expression of endothelial leukocyte adhesion molecule-1 (ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in experimental cutaneous inflammation: A comparison of ultraviolet B erythema and delayed hypersensitivity. J. Invest. Dermatol. 96, 763-770 https://doi.org/10.1111/1523-1747.ep12471720
  58. Opas, E. E., Bonney, R. J. and Humes, J. L. (1985). Prostaglandin and leukotriene synthesis in mouse ears inflamed by arachidonic acid. J. Invest. Dermatol. 84, 253-256 https://doi.org/10.1111/1523-1747.ep12265320
  59. Paganga, G. and Rice-Evans, C. A. (1997). The identification of flavonoids as glucosides in human plasma. FEBS Lett. 401, 78-82 https://doi.org/10.1016/S0014-5793(96)01442-1
  60. Park, B. K., Heo, M. Y., Park, H. and Kim, H. P. (2001). Inhibition of TPA-induced cyclooxygenase-2 expression and skin inflammation in mice by wogonin, a plant flavone from Scutellaria radix. Eur. J. Pharmacol. 425, 153-157 https://doi.org/10.1016/S0014-2999(01)01187-6
  61. Piguet, P. F., Grau, G. E., Hauser, C. and Vassali, P. (1991). Tumor necrosis factor is a critical mediator in hapten-induced irritant and contact hypersensitivity reactions. J. Exp. Med. 173, 673-679 https://doi.org/10.1084/jem.173.3.673
  62. Raederstorff, D., Pantze, M., Bachmann, H. and Moser, U. (1996). Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-ester-induced mouse ear inflammation. Int. Arch. Allergy Immunol. 111, 284-290 https://doi.org/10.1159/000237379
  63. Raick, A. N. (1973). Ultrastructural, histological and biochemical alterations produced by 12-O-tetradecanoylphorbol-13-acetate on mouse epidermis and their relevance to skin tumor promotion. Cancer Res. 33, 269-286
  64. Reynolds, N. J., McCombie, S. W., Shankar, B. B., Bishop, W. R. and Fisher, G. J. (1997). SCH 47112, a novel staurosporine derivative, inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and epidermal hyperplasia in hairless mouse skin. Arch. Dermatol. Res. 289, 540-546 https://doi.org/10.1007/s004030050236
  65. Ross, J. A. and Kasum, C. M. (2002). Dietary flavonoids: Bioavailability, metabolic effects and safety. Ann. Rev. Nutr. 22, 19-34 https://doi.org/10.1146/annurev.nutr.22.111401.144957
  66. Sanchez, T. and Moreno, J. J. (1999a). Role of prostaglandin H synthase isoforms in murine ear edema induced by phorbol ester application on skin. Prostag. Other Lipid Mediat. 57, 119-131 https://doi.org/10.1016/S0090-6980(98)00078-1
  67. Sanchez, T. and Moreno, J. J. (1999b). Role of leukocyte influx in tissue prostaglandin-H synthase-2 overexpression induced by phorbol ester and arachidonic acid in skin. Biochem. Pharmacol. 58, 877-879 https://doi.org/10.1016/S0006-2952(99)00169-0
  68. Schlingemann, J., Hess, J., Wrobel, G., Breitenbach, U., Gebhardt, C., Steinlein, P., Kramer, H., Furstenberger, G., Hahn, M., Angel, P. and Lichter, P. (2003). Profile of gene expression involved by the tumor promoter TPA in murine epithelial cells. Int. J. Cancer 104, 699-708 https://doi.org/10.1002/ijc.11008
  69. Schon, M. P. (1999). Animal models of psoriasis - What can we learn from them?. J. Invest. Dermatol. 112, 405-410 https://doi.org/10.1046/j.1523-1747.1999.00538.x
  70. Shornick, L. P., De Togni, P., Mariathasan, S., Goellner, J., Strauss-Schoenberger, J., Karr, R. W., Ferguson, T. A. and Chaplin, D. D. (1996). Mice deficient in IL-1$\beta$ manifest impaired contact hypersensitivity to trinitrochlorobenzene. J. Exp. Med. 183, 1427-1436 https://doi.org/10.1084/jem.183.4.1427
  71. Stanley, P. L., Steiner, S., Havens, M. and Tramposch, K. M. (1991). Mouse skin inflammation induced by multiple topical application of 12-O-tetradecanoylphorbol-13-acetate. Skin Pharmacol. 4, 262-271 https://doi.org/10.1159/000210960
  72. Tarayre, J. P., Barbara, M., Aliaga, M. and Tsne-Versailles, J. (1990). Comparative actions of immunosuppressants, glucocorticoids and non-steroidal anti-inflammatory drugs on various models of delayed hypersensitivity and in a non-immune inflammation in mice. Arzneim. Forsch. 40, 1125-1131
  73. Teixeira, M. M., Williams, T. J. and Hellewell, P. G. (1993). Role of prostaglandins and nitric oxide in acute inflammatory reactions in guinea-pig skin. Br. J. Pharmacol. 110, 1515-1521 https://doi.org/10.1111/j.1476-5381.1993.tb13994.x
  74. Tsuji, F., Miyake, Y., Horiuchi, M. and Mita, S. (1998). Involvement of leukotriene $B_4$ in murine dermatitis models. Biochem. Pharmacol. 55, 297-304 https://doi.org/10.1016/S0006-2952(97)00464-4
  75. Walle, T., Otake, Y., Brubaker, J. A., Walle, U. K. and Halushka, P. V. (2001). Disposition and metabolism of the flavonoid chrysin in normal volunteers. Br. J. Clin. Pharmacol. 51, 143-146 https://doi.org/10.1111/j.1365-2125.2001.01317.x
  76. Wang, H. Q. and Smart, R. C. (1999). Overexpression of protein kinase C$\alpha$ in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-$\alpha$ expression but not tumor promotion. J. Cell Sci. 112 (Pt 20), 3497-3506
  77. Wedmore, C. V. and Williams, T. J. (1981). Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature 289, 646-650 https://doi.org/10.1038/289646a0
  78. Wille, J. J., Kydonieus, A. F. and Kalish, R. S. (1998). Inhibition of irritation and contact hypersensitivity by ethacrynic acid. Skin Pharmacol. Appl. Skin Physiol. 11, 279-288 https://doi.org/10.1159/000029838
  79. Williamson, G. and Manach, C. (2005). Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. Am. J. Clin. Nutr. 81(Suppl.), 243S-255S https://doi.org/10.1093/ajcn/81.1.243S
  80. Wittig, J., Herderich, M., Graefe, E. U. and Veit, M. J. (2001). Identification of quercetin glucuronides in human plasma by high-performance liquid chromatography-tandem mass spectrometry. Chromatography B Biomed. Sci. Appl. 753, 237-243 https://doi.org/10.1016/S0378-4347(00)00549-1
  81. Yamamoto, S., Aizu, E., Jiang, H., Nakadate, T., Kiyoto, I., Wang, J. C. and Kato, K. (1991). The potent anti-tumor promoting agent isoliquiritigenin. Carcinogenesis 12, 317-323 https://doi.org/10.1093/carcin/12.2.317
  82. Yasukawa, K., Takido, M., Takeuchi, M. and Nakagawa, S. (1989). Effect of chemical constituents from plants on 12-O-tetradecanoylphorbol-13-acetate-induced inflammation in mice. Chem. Pharm. Bull. 37, 1071-1073 https://doi.org/10.1248/cpb.37.1071
  83. Yoshizawa, S., Suganuma, M., Fugiki, H., Fukai, T., Nomura, T. and Sigimura, T. (1989). Morusin, isolated from root bark of Morus alba L., inhibits tumor promotion of teleocidin. Phytotherapy Res. 3, 193-195 https://doi.org/10.1002/ptr.2650030508
  84. Young, J. M., Spires, D. A., Bedord, C. J., Wagner, B., Ballaron, S. J. and De Young, L. M. (1984). The mouse ear inflammatory response to topical arachidonic acid. J. Invest. Dermatol. 82, 367-371 https://doi.org/10.1111/1523-1747.ep12260709