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Cedrela sinensis Leaves Suppress Oxidative Stress and Expressions of iNOS and COX-2 via MAPK Signaling Pathways in RAW 264.7 Cells

  • Bak, Min-Ji (Food Science Institute, School of Food and Life Sciences, Inje University) ;
  • Jeong, Jae-Han (Food Science Institute, School of Food and Life Sciences, Inje University) ;
  • Kang, Hye-Sook (Food Science Institute, School of Food and Life Sciences, Inje University) ;
  • Jin, Kyong-Suk (Food Science Institute, School of Food and Life Sciences, Inje University) ;
  • Ok, Seon (Food Science Institute, School of Food and Life Sciences, Inje University) ;
  • Jeong, Woo-Sik (Food Science Institute, School of Food and Life Sciences, Inje University)
  • Published : 2009.12.31

Abstract

Overproduction of reactive oxygen species (ROS), including nitric oxide (NO), could be associated with the pathogenesis of various diseases such as cancer and chronic inflammation. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are known to play key roles in the development of these diseases. Cedrela sinensis leaves have been used in Asian countries as a traditional remedy for enteritis, dysentery and itching. In the present study, we investigated the anti-inflammatory effects of Cedrela sinensis leaves in lipopolysaccharide (LPS)- stimulated RAW 264.7 macrophages. Powder of C. sinensis leaves was extracted with 95% ethanol and fractionated with a series of organic solvents including n-hexane, dichloromethane, ethyl acetate, n-butanol, and water. The dichloromethane (DCM) fraction strongly inhibited NO production possibly by down-regulating iNOS and COX-2 expression, as determined by Western blotting. Hydrogen peroxide-induced generation of reactive oxygen species (ROS) was also effectively inhibited by the DCM fraction from C. sinensis leaves. In addition, C. sinensis inhibited LPS-mediated p65 activation via the prevention of IκB-$\alpha$ phosphorylation. Furthermore, mitogen-activated protein kinases (MAPKs) such as ERK 1/2 and p38 were found to affect the expression of iNOS and COX-2 in the cells. Taken together, our data suggest that leaves of C. sinensis could be used as a potential source for anti-inflammatory agents.

References

  1. LI P. 1980. Medicinal plants of East and Southeast Asia; attributed properties and uses. MIT press, Cambridge, USA. p 264
  2. Ga S. 1911. Chinese material medica, vegetable kingdom. American presbyterian mission press, Shanghai, China. p 100
  3. Mitsui K, Maejima M, Fukaya H, Hitotsuyanagi Y, Takeya K. 2004. Limonoids from Cedrela sinensis. Phytochemistry 65: 3075-3081 https://doi.org/10.1016/j.phytochem.2004.08.041
  4. Luo XD, Wu SH, Ma YB, Wu DG. 2000. Limonoids and phytol derivatives from Cedrela sinensis. Fitoterapia 71: 492-496 https://doi.org/10.1016/S0367-326X(00)00158-1
  5. Park JC, Yu YB, Lee JH, Kim NJ. 1994. Studies on the chemical components and biological activities of edible plants in Korea. J Korean Soc Food Nutr 23: 116-119
  6. Chang HL, Hsu HK, Su JH, Wang PH, Chung YF, Chia YC, Tsai LY, Wu YC, Yuan SS. 2006. The fractionated Toona sinensis leaf extract induces apoptosis of human ovarian cancer cells and inhibits tumor growth in a murine xenograft model. Gynecol Oncol 102: 309-314 https://doi.org/10.1016/j.ygyno.2005.12.023
  7. Yang YC, Hsu HK, Hwang JH, Hong SJ. 2003. Enhancement of glucose uptake in 3T3-L1 adipocytes by Toona sinensis leaf extract. Kaohsiung J Med Sci 19: 327-333 https://doi.org/10.1016/S1607-551X(09)70433-4
  8. Zhang JF, Yang JY, Wen J, Wang DY, Yang M, Liu QQ. 2008. Experimental studies on hypoglycemic effects of total flavonoid from Toona sinensis. Zhong Yao Cai 31: 1712-1714
  9. Poon SL, Leu SF, Hsu HK, Liu MY, Huang BM. 2005. Regulatory mechanism of Toona sinensis on mouse leydig cell steroidogenesis. Life Sci 76: 1473-1487 https://doi.org/10.1016/j.lfs.2004.08.026
  10. Chen HM, Wu YC, Chia YC, Chang FR, Hsu HK, Hsieh YC, Chen CC, Yuan SS. 2009. Gallic acid, a major component of Toona sinensis leaf extracts, contains a ROS- mediated anti-cancer activity in human prostate cancer cells. Cancer Lett 286: 161-171 https://doi.org/10.1016/j.canlet.2009.05.040
  11. Uttara B, Singh AV, Zamboni P, Mahajan RT. 2009. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7: 65-74 https://doi.org/10.2174/157015909787602823
  12. Moncada S, Palmer RM, Higgs EA. 1991. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43: 109-142
  13. Nathan C, Xie QW. 1994. Nitric oxide synthases: roles, tolls, and controls. Cell 78: 915-918 https://doi.org/10.1016/0092-8674(94)90266-6
  14. Rockey DC, Chung JJ, McKee CM, Noble PW. 1998. Stimulation of inducible nitric oxide synthase in rat liver by hyaluronan fragments. Hepatology 27: 86-92 https://doi.org/10.1002/hep.510270115
  15. Geller DA, Lowenstein CJ, Shapiro RA, Nussler AK, Di Silvio M, Wang SC, Nakayama DK, Simmons RL, Snyder SH, Billiar TR. 1993. Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes. Proc Natl Acad Sci USA 90: 3491-3495 https://doi.org/10.1073/pnas.90.8.3491
  16. Wu KK. 1996. Cyclooxygenase 2 induction: molecular mechanism and pathophysiologic roles. J Lab Clin Med 128: 242-245 https://doi.org/10.1016/S0022-2143(96)90023-2
  17. Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. 1997. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res 57: 1276-1280
  18. Subbaramaiah K, Telang N, Bansal MB, Weksler BB, Dannenberg AJ. 1997. Cyclooxygenase-2 gene expression is upregulated in transformed mammary epithelial cells. Ann N Y Acad Sci 833: 179-185 https://doi.org/10.1111/j.1749-6632.1997.tb48606.x
  19. Tucker ON, Dannenberg AJ, Yang EK, Zhang F, Teng L, Daly JM, Soslow RA, Masferrer JL, Woerner BM, Koki AT, Fahey TJ. 1999. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 59: 987-990
  20. Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimaki A. 1998. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 58: 4997-5001
  21. Yip-Schneider MT, Barnard DS, Billings SD, Cheng L, Heilman DK, Lin A, Marshall SJ, Crowell PL, Marshall MS, Sweeney CJ. 2000. Cyclooxygenase-2 expression in human pancreatic adenocarcinomas. Carcinogenesis 21: 139-146 https://doi.org/10.1093/carcin/21.2.139
  22. Kawabe A, Shimada Y, Uchida S, Maeda M, Sato F, Itami A, Imamura M. 2002. Expression of cyclooxygenase-2 is associated with carcinogenesis of the lower part of thoracic esophageal squamous cell carcinoma and p53 expression. Oncology 62: 46-54 https://doi.org/10.1159/000048246
  23. Da Cunha EF, Ramalho TC, Josa D, Caetano MS, de Souza TC. 2007. Targeting inhibition of COX-2: a review of patents, 2002-2006. Recent Pat Inflamm Allergy Drug Discov 1: 108-123 https://doi.org/10.2174/187221307780979928
  24. Bae JH, Jang BC, Suh SI, Ha E, Baik HH, Kim SS, Lee MY, Shin DH. 2006. Manganese induces inducible nitric oxide synthase (iNOS) expression via activation of both MAP kinase and PI3K/Akt pathways in BV2 microglial cells. Neurosci Lett 398: 151-154 https://doi.org/10.1016/j.neulet.2005.12.067
  25. Ku KT, Huang YL, Huang YJ, Chiou WF. 2008. Miyabenol A inhibits LPS-induced NO production via IKK/IkappaB inactivation in RAW 264.7 macrophages: possible involvement of the p38 and PI3K pathways. J Agric Food Chem 56: 8911-8918 https://doi.org/10.1021/jf8019369
  26. Kang OH, Lee GH, Choi HJ, Park PS, Chae HS, Jeong SI, Kim YC, Sohn DH, Park H, Lee JH, Kwon DY. 2007. Ethyl acetate extract from Angelica Dahuricae Radix inhibits lipopolysaccharide-induced production of nitric oxide, prostaglandin E2 and tumor necrosis factor-alphavia mitogen-activated protein kinases and nuclear factor-kappaB in macrophages. Pharmacol Res 55: 263-270 https://doi.org/10.1016/j.phrs.2006.12.001
  27. Chen C, Chen YH, Lin WW. 1999. Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide- induced iNOS and COX-2 expression in J774 macrophages. Immunology 97: 124-129 https://doi.org/10.1046/j.1365-2567.1999.00747.x
  28. Jiao HL, Zhao BL. 2002. Cytotoxic effect of peroxisome proliferator fenofibrate on human HepG2 hepatoma cell line and relevant mechanisms. Toxicol Appl Pharmacol 185: 172-179 https://doi.org/10.1006/taap.2002.9538
  29. Allen JB, Keng T, Privalle C. 1998. Nitric oxide and peroxynitrite production in ocular inflammation. Environ Health Perspect 106 (Suppl 5): 1145-1149 https://doi.org/10.1289/ehp.98106s51145
  30. Tak PP, Firestein GS. 2001. NF-kappaB: a key role in inflammatory diseases. J Clin Invest 107: 7-11 https://doi.org/10.1172/JCI11830
  31. Geronikaki AA, Gavalas AM. 2006. Antioxidants and inflammatory disease: synthetic and natural antioxidants with anti-inflammatory activity. Comb Chem High Throughput Screen 9: 425-442 https://doi.org/10.2174/138620706777698481
  32. Wadsworth TL, Koop DR. 2001. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide- induced release of nitric oxide. Chem Biol Interact 137: 43-58 https://doi.org/10.1016/S0009-2797(01)00208-3
  33. Keum YS, Han SS, Chun KS, Park KK, Park JH, Lee SK, Surh YJ. 2003. Inhibitory effects of the ginsenoside Rg3 on phorbol ester-induced cyclooxygenase-2 expression, NF-kappaB activation and tumor promotion. Mutat Res 523-524: 75-85 https://doi.org/10.1016/S0027-5107(02)00323-8
  34. Harada N, Okajima K, Uchiba M, Katsuragi T. 2002. Ischemia/reperfusion-induced increase in the hepatic level of prostacyclin is mainly mediated by activation of capsaicin-sensitive sensory neurons in rats. J Lab Clin Med 139: 218-226 https://doi.org/10.1067/mlc.2002.121856
  35. Yongfen MA, Jung JY, Jung YJ, Choi JH, Jeong WS, Song YS, Kang JS, Kaishun Bi, Kim MJ. 2009. Anti-inflammatory activities of coumarins isolated from Angelica gigas Nakai on LPS-stimulated RAW 264.7 cells. J Food Sci Nutr 12: 174-179 https://doi.org/10.3746/jfn.2009.14.3.179
  36. Lappas M, Permezel M, Georgiou HM, Rice GE. 2002. Nuclear factor kappa B regulation of proinflammatory cytokines in human gestational tissues in vitro. Biol Reprod 67: 668-673 https://doi.org/10.1095/biolreprod67.2.668
  37. Moynagh PN. 2005. The NF-kappaB pathway. J Cell Sci 118: 4589-4592 https://doi.org/10.1242/jcs.02579
  38. Magnani M, Crinelli R, Bianchi M, Antonelli A. 2000. The ubiquitin-dependent proteolytic system and other potential targets for the modulation of nuclear factor-kB (NF-kB). Curr Drug Targets 1: 387-399 https://doi.org/10.2174/1389450003349056
  39. Ahn KS, Noh EJ, Zhao HL, Jung SH, Kang SS, Kim YS. 2005. Inhibition of inducible nitric oxide synthase and cyclooxygenase II by Platycodon grandiflorum saponins via suppression of nuclear factor-kappaB activation in RAW 264.7 cells. Life Sci 76: 2315-2328 https://doi.org/10.1016/j.lfs.2004.10.042
  40. Terra X, Valls J, Vitrac X, Merrillon JM, Arola L, Ardevol A, Blade C, Fernandez-Larrea J, Pujadas G, Salvado J, Blay M. 2007. Grape-seed procyanidins act as antiinflammatory agents in endotoxin-stimulated RAW 264.7 macrophages by inhibiting NFkB signaling pathway. J Agric Food Chem 55: 4357-4365 https://doi.org/10.1021/jf0633185
  41. Garrington TP, Johnson GL. 1999. Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11: 211-218 https://doi.org/10.1016/S0955-0674(99)80028-3
  42. Pan MH, Hsieh MC, Hsu PC, Ho SY, Lai CS, Wu H, Sang S, Ho CT. 2008. 6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. Mol Nutr Food Res 52: 1467-1477 https://doi.org/10.1002/mnfr.200700515
  43. Pan MH, Chang YH, Tsai ML, Lai CS, Ho SY, Badmaev V, Ho CT. 2008. Pterostilbene suppressed lipopolysac-charide-induced up-expression of iNOS and COX-2 in murine macrophages. J Agric Food Chem 56: 7502-7509 https://doi.org/10.1021/jf800820y
  44. Guo LY, Hung TM, Bae KH, Shin EM, Zhou HY, Hong YN, Kang SS, Kim HP, Kim YS. 2008. Anti-inflammatory effects of schisandrin isolated from the fruit of Schisandra chinensis Baill. Eur J Pharmacol 591: 293-299 https://doi.org/10.1016/j.ejphar.2008.06.074

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