DOI QR코드

DOI QR Code

The Long Search for Pharmacologically Useful Anti-Inflammatory Flavonoids and Their Action Mechanisms: Past, Present, and Future

  • Kim, Hyun Pyo (College of Pharmacy, Kangwon National University)
  • Received : 2022.01.06
  • Accepted : 2022.01.13
  • Published : 2022.03.01

Abstract

Flavonoids are known to exert anti-inflammatory effects. Their pharmacological activities have been proved using various in vitro and in vivo models. Although their action spectrum and potencies are not adequate to alleviate acute inflammatory disorders, they have the potential to treat chronic inflammatory diseases. Recent investigations have revealed that inflammatory processes are involved in many disease processes and conditions. Some examples are skin disorders, cartilage diseases, metabolic inflammatory diseases, and aging. The effects of flavonoids on these disorders have been examined. Several possible application areas for flavonoids have been studied. Local treatment of these disorders with flavonoids is favorable to avoid systemic transformation. In this review, the findings based on the experimental results from my laboratory are summarized and the future possibility of using flavonoids clinically is discussed.

Keywords

References

  1. Bondonno, N. P., Dalgaard, F., Kyro, C., Murray, K., Bondonno, C. P., Lewis, J. R., Croft, K. D., Gislason, G., Scalbert, A., Cassidy, A., Tjonneland, A., Overvad, K. and Hodgson, J. M. (2019) Flavonoid intake is associated with lower mortality in the Danish Diet Cancer and Health Cohort. Nat. Commun. 10, 3651. https://doi.org/10.1038/s41467-019-11622-x
  2. Che, H., Park, B. K., Lim, H., Kim, H. P., Chang, H. W., Jeong, J.-H. and Park, H. (2009) Synthesis of biflavones having a 6-O-7'' linkage and effects on cyclooxygenase-2 and inducible nitric oxide synthase. Bioorg. Med. Chem. Lett. 19, 74-76. https://doi.org/10.1016/j.bmcl.2008.11.017
  3. 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
  4. 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 the 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
  5. 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
  6. Chi, Y. S. and Kim, H. P. (2005) Suppression of cyclooxygenase-2 expression of skin fibroblasts by wogonin, a plant flavone from Scutellaria radix. Prostaglandins Leukot. Essent. Fatty Acids 72, 59-66. https://doi.org/10.1016/j.plefa.2004.04.009
  7. Chi, Y. S., Lim, H., Park, H. and Kim, H. P. (2003) Effects 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
  8. Choi, H. R., Lim, H., Lee, J. H., Park, H. and Kim, H. P. (2021) Interruption of Helicobacter pylori-induced NLRP3 inflammasome activation by chalcone derivatives. Biomol. Ther. (Seoul) 29, 410-418. https://doi.org/10.4062/biomolther.2020.192
  9. Dao, T. T., Chi, Y. S., Kim, J., Kim, H. P., Kim, S. and Park, H. (2003a) Synthesis and PGE2 inhibitory activity of 5,7-dihydroxyflavones and their O-methylated flavone analogs. Arch. Pharm. Res. 26, 345-350. https://doi.org/10.1007/BF02976690
  10. Dao, T. T., Chi, Y. S., Kim, J., Kim, H. P., Kim, S. and Park, H. (2004a) Synthesis and inhibitory activity against COX-2 catalyzed prostaglandin production of chrysin derivatives. Bioorg. Med. Chem. Lett. 14, 1165-1167. https://doi.org/10.1016/j.bmcl.2003.12.087
  11. Dao, T. T., Kim, S. B., Sin, K.-S., Kim, S., Kim, H. P. and Park, H. (2004b) Synthesis and biological activities of 8-arylflavones. Arch. Pharm. Res. 27, 278-282. https://doi.org/10.1007/BF02980059
  12. Dao, T. T., Oh, J. W., Chi, Y. S., Kim, H. P., Sin, K.-S. and Park, H. (2003b) Synthesis and PGE2 inhibitory activity of vinylated and allylated chrysin analogues. Arch. Pharm. Res. 26, 581-584. https://doi.org/10.1007/BF02976703
  13. Gurung, S. K., Kim, H. P. and Park, H. (2009) Inhibition of prostaglandin E2 production by synthetic wogonin analogs. Arch. Pharm. Res. 32, 1503-1508. https://doi.org/10.1007/s12272-009-2101-5
  14. Han, C. K., Son, M. J., Chang, H. W., Chi, Y. S., Park, H. and Kim, H. P. (2005) Inhibition of prostaglandin production by a structurally-optimized flavonoid derivative, 2',4',7-trimethoxyflavone and cellular action mechanism. Biol. Pharm. Bull. 28, 1366-1370. https://doi.org/10.1248/bpb.28.1366
  15. Jang, J., Kim, H. P. and Park, H. (2005) Structure and antiinflammatory activity relationships of wogonin derivatives. Arch. Pharm. Res. 28, 877-884. https://doi.org/10.1007/BF02973870
  16. Jin, J. H., Lim, H., Kwon, S. Y., Son, K. H. and Kim, H. P. (2010a) Anti-inflammatory activity of the total flavonoid fraction from Broussonetia papyrifera in combination with Lonicera japonica. Biomol. Ther. (Seoul) 18, 197-204. https://doi.org/10.4062/biomolther.2010.18.2.197
  17. Jin, J. H., Kim, J. S., Kang, S. S., Son, K. H., Chang, H. W. and Kim, H. P. (2010b) Anti-inflammatory and anti-arthritic activity of total flavonoids of the roots of Sophora flavescens. J. Ethnopharmacol. 127, 589-595. https://doi.org/10.1016/j.jep.2009.12.020
  18. Kim, B. J., Kim, J. H., Heo, M. Y. and Kim, H. P. (1998a) Anti-oxidative and anti-inflammatory activities of the mung bean. Cosmetics and Toiletries 113, 71-74.
  19. 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
  20. Kim, H. K., Cheon, B. S., Kim, Y. H., Kim, S. Y. and Kim, H. P. (1999a) 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
  21. Kim, H. K., Namgoong, S. Y. and Kim, H. P. (1993) Antiinflammatory activity of flavonoids: mouse ear edema inhibition. Arch. Pharm. Res. 16, 18-24. https://doi.org/10.1007/BF02974122
  22. Kim, H. K., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (1999b) Inhibition of rat adjuvant-induced arthritis by ginkgetin, a biflavone from Ginkgo biloba leaves. Planta Med. 65, 465-467. https://doi.org/10.1055/s-2006-960815
  23. Kim, H. P. (2005) Histopathological comparison of animal models of skin inflammation and inhibition of the inflammatory responses by plant flavonoid, wogonin. J. Appl. Pharmacol. 13, 133-137.
  24. Kim, H. P. (2007) Molecular events on experimental skin inflammation and modulation by topical anti-inflammatory flavonoids. J. Appl. Pharmacol. 15, 7-15.
  25. 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. Prostaglandins Leukot. Essent. Fatty Acids 58, 17-24. https://doi.org/10.1016/S0952-3278(98)90125-9
  26. Kim, H. P., Park, H., Son, K. H., Chang, H. W. and Kang, S. S. (2008) Biochemical pharmacology of biflavonoids: implications for antiinflammatory action. Arch. Pharm. Res. 31, 265-273. https://doi.org/10.1007/s12272-001-1151-3
  27. Kim, H. P., Son, K. H., Chang, H. W. and Kang, S. S. (1996) Flavonoids: potential antiinflammatory agents. Nat. Prod. Sci. 2, 1-8.
  28. Kim, H. P., Son, K. H., Chang, H. W. and Kang, S. S. (2000) Effects of naturally occurring flavonoids on inflammatory responses and their action mechanisms. Nat. Prod. Sci. 6, 170-178.
  29. Kim, H. P., Son, K. H., Chang, H. W. and Kang, S. S. (2004) Antiinflammatory plant flavonoids and cellular action mechanisms. J. Pharmacol. Sci. 96, 229-245. https://doi.org/10.1254/jphs.CRJ04003X
  30. Kim, Y. H., Kim, J., Park, H. and Kim, H. P. (2007) Anti-inflammatory activity of the synthetic chalcone derivatives: inhibition of inducible nitric oxide synthase-catalyzed nitric oxide production from lipopolysaccharide-treated RAW 264.7 cells. Biol. Pharm. Bull. 30, 1450-1455. https://doi.org/10.1248/bpb.30.1450
  31. Ko, H. J., Kwon, O. S., Jin, J. H., Son, K. H. and Kim, H. P. (2013) Inhibition of experimental systemic inflammation (septic inflammation) and chronic bronchitis by new phytoformula BL containing Broussonetia papyrifera and Lonicera japonica. Biomol. Ther. (Seoul) 21, 66-71. https://doi.org/10.4062/biomolther.2012.081
  32. Kwak, W. J., Han, C. K., Son, K. H., Chang, H. W., Kang, S. S., Park, B. K. and Kim, H. P. (2002) Effects 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
  33. Lee, S. J., Baek, H. J., Lee, C. H. and Kim, H. P. (1994) Antiinflammatory activity of isoflavonoids from Pueraria radix and biochanin A derivatives. Arch. Pharm. Res. 17, 31-35. https://doi.org/10.1007/BF02978244
  34. Lee, S. J., Son, K. H., Chang, H. W., Do, J. C., Jung, K. Y., Kang, S. S. and Kim, H. P. (1993) Antiinflammatory activity of naturally occurring flavone and flavonol glycosides. Arch. Pharm. Res. 16, 25-28. https://doi.org/10.1007/BF02974123
  35. Lim, H., Jin, J. H., Park, H. and Kim, H. P. (2011a) New synthetic anti-inflammatory chrysin analog, 5,7-dihydroxy-8-(pyridine-4yl) flavone. Eur. J. Pharmacol. 670, 617-622. https://doi.org/10.1016/j.ejphar.2011.09.010
  36. Lim, H. and Kim, H. P. (2007) Inhibition of mammalian collagenase, matrix metalloproteinase-1, by naturally-occurring flavonoids. Planta Med. 73, 1267-1274. https://doi.org/10.1055/s-2007-990220
  37. Lim, H. and Kim, H. P. (2011) Matrix metalloproteinase-13 expression in IL-1β-treated chondrocytes by activation of the p38 MAPK/c-Fos/AP-1 and JAK/STAT pathways. Arch. Pharm. Res. 34, 109-117. https://doi.org/10.1007/s12272-011-0113-4
  38. Lim, H., Kim, S. B., Park, H., Chang, H. W. and Kim, H. P. (2009) New anti-inflammatory synthetic biflavonoid with C-C (6-6") linkage: differential effects on cyclooxygenase-2 and inducible nitric oxide synthase. Arch. Pharm. Res. 32, 1525-1531. https://doi.org/10.1007/s12272-009-2104-2
  39. Lim, H., Kwon, Y. S., Kim, D., Lee, J. and Kim, H. P. (2020) Flavonoids from Scutellaria baicalensis inhibit senescence-associated secretory phenotype production by interrupting IκBζ/C/EBPβ pathway: Inhibition of age-related inflammation. Phytomedicine 76, 153255. https://doi.org/10.1016/j.phymed.2020.153255
  40. Lim, H., Min, D. S., Park, H. and Kim, H. P. (2018) Flavonoids interfere with NLRP3 inflammasome activation. Toxicol. Appl. Pharmacol. 355, 93-102. https://doi.org/10.1016/j.taap.2018.06.022
  41. 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
  42. Lim, H., Park, H. and Kim, H. P. (2011b) Effects of flavonoids on matrix metalloproteinase-13 expression of interleukin-1β-treated articular chondrocytes and their cellular mechanisms: Inhibition of c-Fos/AP-1 and JAK/STAT signaling pathways. J. Pharmacol. Sci. 116, 221-231. https://doi.org/10.1254/jphs.11014FP
  43. Lim, H., Park, H. and Kim, H. P. (2015) Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycininduced senescence in BJ fibroblasts. Biochem. Pharmacol. 96, 337-348. https://doi.org/10.1016/j.bcp.2015.06.013
  44. Lim, H., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (2006a) Effects of anti-inflammatory biflavonoid, ginkgetin, on chronic skin inflammation. Biol. Pharm. Bull. 29, 1046-1049. https://doi.org/10.1248/bpb.29.1046
  45. Lim, H., Son, K. H., Chang, H. W., Kang, S. S. and Kim, H. P. (2006b) Inhibition of chronic skin inflammation by topical anti-inflammatory flavonoid preparation, Ato Formula®. Arch. Pharm. Res. 29, 503-507. https://doi.org/10.1007/BF02969424
  46. Lim, H. J., Jin, H. G., Woo, E. R., Lee, S. K. and Kim, H. P. (2013) The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation. J. Ethnopharmacol. 149, 169-175. https://doi.org/10.1016/j.jep.2013.06.017
  47. 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
  48. Park, H., Dao, T. T. and Kim, H. P. (2005) Synthesis and inhibition of PGE2 production of 6,8-disubstituted chrysin derivatives. Eur. J. Med. Chem. 40, 943-948. https://doi.org/10.1016/j.ejmech.2005.04.013
  49. Park, H., Kim, Y. H., Chang, H. W. and Kim, H. P. (2006a) Anti-inflammatory activity of the synthetic C-C biflavonoids. J. Pharm. Pharmacol. 58, 1661-1667. https://doi.org/10.1211/jpp.58.12.0014
  50. Park, H., Sin, B. Y. and Kim, H. P. (2006b) Inhibition of collagenase by anti-inflammatory synthetic flavones. J. Appl. Pharmacol. 14, 36-39.
  51. Sin, B. Y. and Kim, H. P. (2005) Inhibition of collagenase by naturally-occurring flavonoids. Arch. Pharm. Res. 28, 1152-1155. https://doi.org/10.1007/BF02972978
  52. You, K. M., Jong, H.-G. and Kim, H. P. (1999) Inhibition of cyclooxygenase/lipoxygenase from human platelets by polyhydroxylated/methoxylated flavonoids isolated from medicinal plants. Arch. Pharm. Res. 22, 18-24. https://doi.org/10.1007/BF02976430