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The Pharmaceutical Society of Korea (대한약학회)
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A Curcuminoid and Two Sesquiterpenoids from Curcuma zedoaria as Inhibitors of Nitric Oxide Synthesis in Activated Macrophages

  • Jang, Mi-Kyung (College of Pharmacy, Sookmyung Women's University) ;
  • Lee, Hwa-Jin (College of Pharmacy, Sookmyung Women's University) ;
  • Kim, Ji-Sun (College of Pharmacy, Sookmyung Women's University) ;
  • Ryu , Jae-Ha (College of Pharmacy, Sookmyung Women's University)
  • Published : 2004.01.01
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Abstract

The overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) is known to be responsible for vasodilation and hypotension observed in septic shock and inflammation. Inhibitors of iNOS, thus, may be useful candidates for the treatment of inflammatory diseases accompanied by overproduction of NO. In the course of screening oriental anti-inflammatory herbs for the inhibitory activity of NO synthesis, a crude methanolic extract of Curcuma zedoaria exhibited significant activity. The activity-guided fractionation and repetitive chromatographic procedures with the EtOAc soluble fraction allowed us to isolate three active compounds. They were identified as 1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-one (1), procurcumenol (2) and epiprocurcumenol (3) by spectral data analyses. Their concentrations for the 50% inhibition of NO production $(IC_{50})$ in lipopolysaccharide (LPS)-activated macrophages were 8, 75, 77 ${\mu}M$, respectively. Compound 1 showed the most potent inhibitory activity for NO production in LPS-activated macrophages, while the epimeric isomers, compound 2 and 3 showed weak and similar potency. Inhibition of NO synthesis by compound 1 was very weak when activated macrophages were treated with 1 after iNOS induction. In the immunoblot analysis, compound 1 suppressed the expression of iNOS in a dose-dependent manner. In summary, 1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-one from Curcuma zedoaria inhibited NO production in LPS-activated macrophages through suppression of iNOS expression. These results imply that the traditional use of C. zedoaria rhizome as anti-inflammatory drug may be explained at least in part, by inhibition of NO production.

Keywords

References

  1. Achike, F. I. and Kwan, C. Y., Nitric oxide, human diseases and the herbal products that affect the nitric oxide signaling pathway. Clin. Exp. Pharmacol. Physiol., 30, 605-615 (2003) https://doi.org/10.1046/j.1440-1681.2003.03885.x
  2. Bredt, D. S. and Snyder, S. H., Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. U.S.A., 87, 682-685 (1990) https://doi.org/10.1073/pnas.87.2.682
  3. Chi, Y. S., Cheon, B. S., and Kim, H. P, 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 (2001) https://doi.org/10.1016/S0006-2952(01)00597-4
  4. Green, L. C., Wagner, D. A., Glogowski, J., Skipper, P. L., Wishnok, J. S., and Tannenbaum, S. R., Analysis of nitrate, nitrite, and [$^{15}N$] nitrate in biological fluids. Anal. Biochem., 126, 131-138 (1982) https://doi.org/10.1016/0003-2697(82)90118-X
  5. Hong, C. H., Noh, M. S., Lee, W .Y., and Lee, S. K., Inhibitory effects of natural sesquiterpenoids isolated from the rhizomes of Curcuma zedoaria on prostaglandin $E_2$ and nitric oxide production. Planta Med., 68, 545-547 (2002) https://doi.org/10.1055/s-2002-32560
  6. Kim, E. J., Jin, H. K., Kim, Y. K., Lee, H. Y, Lee, S. Y., Lee, K. R., Zee, O. P., Han, J. W., and Lee, H. W., Suppression by .a sesquiterpene lactone from Carpesium divaricatum of inducible nitric oxide synthase by inhibiting nuclear factor-kappaB activation. Biochem. Pharmacol., 61, 903-910 (2001) https://doi.org/10.1016/S0006-2952(01)00538-X
  7. Kuroyanagi, M., Ueno, A., Koyama, K., and Natori, S., Structures of esquiterpene of Curcuma aromatica SALISB. II. Studies on minor esquiterpenes. Chem. Pham. Bull., 38, 55-58 (1990) https://doi.org/10.1248/cpb.38.55
  8. Lowenstein, C. J., Glatt, C. S., Bredt, D. S., and Snyder S. H., Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc. Natl. Acad. Sci. U.S.A., 89, 6711-6715 (1992) https://doi.org/10.1073/pnas.89.15.6711
  9. Matsuda, H., Morikawa, T., Toguchida, I., Ninomiya, K., and Yoshikawa, M., Medicinal foodstuffs. XXVIII. Inhibitors of nitric oxide productionand new sesquiterpenes,zedoarofuran, 4-epicurcumenol, neocurcumenol, gajutsulactones A and B, and zedoarolides A and B, from Zedoariae Rhizoma. Chem. & Pharm. Bull., 49, 1558-1566 (2001a) https://doi.org/10.1248/cpb.49.1558
  10. Matsuda, H., Morikawa,T., Toguchida, I., Ninomiya, K., and Yoshikawa, M., Inhibitors of nitric oxide production and new sesquiterpenes, 4-epi-curcumenol, neocurcumenol, gajutsulactones A and B, and zedoarolides A and B from Zedoariae Rhizoma. Heterocycles, 55, 841-846 (2001b) https://doi.org/10.3987/COM-01-9178
  11. Mosmann, T., RaPid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 65, 55-63 (1983) https://doi.org/10.1016/0022-1759(83)90303-4
  12. Nakayama, R., Tamura, Y., Yamanaka, H., Kikuzaki, H., and Nakatani, N., Two curcuminoid pigments from Curcuma domestice. Phytochem., 33, 501-502 (1993) https://doi.org/10.1016/0031-9422(93)85548-6
  13. Oshima, H. and Bartsch, H., Chronic infectious and inflammation process as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat. Res., 305, 253-264 (1994) https://doi.org/10.1016/0027-5107(94)90245-3
  14. Ryu, J.-H., Son, H. J., Lee, S. H., and Sohn, D. H., Two neolignans from Perilla frutescens and their inhibition of nitric oxide synthase and tumor necrosis factor-a expression in murine macrophage cell line RAW 264.7. Bioorg. Med. Chem. Lett., 12, 649-651 (2002) https://doi.org/10.1016/S0960-894X(01)00812-5
  15. Ryu, J.-H., Ahn, H., Kim, J. Y., and Kim, Y.-K., Inhibitory activity of plant extracts on nitric oxide synthesis in LPS-activated macrophages. Phytother. Res., 17, 485-489 (2003) https://doi.org/10.1002/ptr.1180
  16. Syu, W-J, Shen, C-C, Don, M-J, Ou, J-C, Lee, G-H, and Sun, C-M., Cytotoxicity of curcuminoids and some novel compounds from Curcuma zedoaria. J. Nat. Prod., 61, 1531-1534 (1988) https://doi.org/10.1021/np980269k
  17. Thiemermann, C. and Vane, J., Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipbpolysaccharides in the rat in vivo. Eur. J. Pharmacol., 182, 591-595 (1990) https://doi.org/10.1016/0014-2999(90)90062-B
  18. Thomsen, L. L., Ching, L. M., and Baguley, B. C., Evidence for the production of nitric oxide by activated macrophages treated with the antitumor agents flavone-8-acetic acid and xanthenone-4-acetic acid. Cancer Res., 50, 6966-6970(1990)
  19. Yoshihara, M., Yang, C., Zheng, C., Shibuya, H., Hamamoto, Y., Tanaka, N., and Kitagawa, I., Chemical conversion of (4S, 5S)-(+)-germacrone 4,5-epoxide, a plausible biogenetic intermediate found in the essential oil of zedoariae rhizoma from Yakushima, Japan. Chem. Pharm. Bull., 34, 434-437 (1986) https://doi.org/10.1248/cpb.34.434
  20. Yoshioka, T., Fujii, E., Endo, M., Wada, K., Tokunaga., Shiba, N., Hohsho, H., Shibuya, H., and Muraki, T., Antiinflammatory potency of dehydrocurdione, a zedoary-derived sesquiterpene. Inflam. Res., 47, 476-481 (1998) https://doi.org/10.1007/s000110050361