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Anti-inflammatory effects of Rubus coreanus Miquel through inhibition of NF-${\kappa}B$ and MAP Kinase

  • Lee, Jung Eun (Department of Home Economics Education, Chung-Ang University) ;
  • Cho, Soo-Muk (Functional Food & Nutrition Division, Rural Development Administration) ;
  • Park, Eunkyo (Department of Home Economics Education, Chung-Ang University) ;
  • Lee, Seung Min (Department of Food and Nutrition, College of Human Ecology, Yonsei University) ;
  • Kim, Yuri (Department of Nutritional Science and Food Management, Ewha Womans University) ;
  • Auh, Joong Hyuck (Department of Food Science & Technology, Chung-Ang University) ;
  • Choi, Hyung-Kyoon (College of Pharmacy, Chung-Ang University) ;
  • Lim, Sohee (Department of Life Science, Chung-Ang University) ;
  • Lee, Sung Chul (Department of Life Science, Chung-Ang University) ;
  • Kim, Jung-Hyun (Department of Home Economics Education, Chung-Ang University)
  • Received : 2013.10.21
  • Accepted : 2013.12.28
  • Published : 2014.10.01

Abstract

BACKGROUND/OBJECTIVES: Rubus Coreanus Miquel (RCM), used as a traditional Korean medicine, reduces chronic inflammatory diseases such as cancer and rheumatoid arthritis. However, its mechanism has not been elucidated. In this study, we examine the anti-inflammatory effects of RCM and their possible mechanisms using RAW 264.7 cells. MATERIALS/METHODS: Unripe RCM ethanol extract (UE), unripe RCM water extract (UH), ripe RCM ethanol extract (RE), and ripe RCM water extract (RH) were prepared. Inflammatory response was induced with LPS treatment, and expression of pro-inflammatory mediators (iNOS, COX-2, TNF-${\alpha}$, IL-$1{\beta}$, and IL-6) and NO and $PGE_2$ productions were assessed. To determine the anti-inflammatory mechanism of RCM, we measured NF-${\kappa}B$ and MAPK activities. RESULTS: UE and UH treatment significantly reduced NF-${\kappa}B$ activation and JNK and p38 phosphorylation and reduced transcriptional activities decreased iNOS, COX-2, and pro-inflammatory cytokines expressions, and NO and $PGE_2$ productions. RE and RH treatments reduced IL-$1{\beta}$ and IL-6 expressions through suppressions of JNK and p38 phosphorylation. CONCLUSIONS: In this study, we showed that RCM had anti-inflammatory effects by suppression of pro-inflammatory mediator expressions. Especially, unripe RCM showed strong anti-inflammatory effects through suppression of NF-${\kappa}B$ and MAPK activation. These findings suggest that unripe RCM might be used as a potential functional material to reduce chronic inflammatory responses.

Keywords

References

  1. Laroux FS. Mechanisms of inflammation: the good, the bad and the ugly. Front Biosci 2004;9:3156-62. https://doi.org/10.2741/1468
  2. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336: 1066-71. https://doi.org/10.1056/NEJM199704103361506
  3. Blackwell TS, Christman JW. The role of nuclear factor-kappa B in cytokine gene regulation. Am J Respir Cell Mol Biol 1997;17:3-9. https://doi.org/10.1165/ajrcmb.17.1.f132
  4. Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol 2011;12:715-23. https://doi.org/10.1038/ni.2060
  5. Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, Azambuja MI, Tracy RP, Heiss G. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 1999;353: 1649-52. https://doi.org/10.1016/S0140-6736(99)01046-6
  6. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F; Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511. https://doi.org/10.1161/01.CIR.0000052939.59093.45
  7. Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest 2001;107:7-11. https://doi.org/10.1172/JCI11830
  8. Lee JI, Burckart GJ. Nuclear factor kappa B: important transcription factor and therapeutic target. J Clin Pharmacol 1998;38:981-93. https://doi.org/10.1177/009127009803801101
  9. Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY, Ballard DW. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation. Mol Cell Biol 1995;15:2809-18. https://doi.org/10.1128/MCB.15.5.2809
  10. Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol 1994;10:405-55. https://doi.org/10.1146/annurev.cb.10.110194.002201
  11. Chen C, Chen YH, Lin WW. Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide-induced iNOS and COX-2 expression in J774 macrophages. Immunology 1999;97:124-9. https://doi.org/10.1046/j.1365-2567.1999.00747.x
  12. Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell Signal 2001;13:85-94. https://doi.org/10.1016/S0898-6568(00)00149-2
  13. Kim EJ, Lee YJ, Shin HK, Park JH. Induction of apoptosis by the aqueous extract of Rubus coreanum in HT-29 human colon cancer cells. Nutrition 2005;21:1141-8. https://doi.org/10.1016/j.nut.2005.02.012
  14. Ra JC, Lee HY, Choi MK, Park HG, Kang KS. Effect of decreasing body weight with plant extracts containing Rubi fructus. J Toxicol Public Health 2004;20:167-72.
  15. Yang HM, Oh SM, Lim SS, Shin HK, Oh YS, Kim JK. Antiinflammatory activities of Rubus coreanus depend on the degree of fruit ripening. Phytother Res 2008;22:102-7. https://doi.org/10.1002/ptr.2274
  16. Yang HM, Lim SS, Lee YS, Shin HK, Oh YS, Kim JK. Comparison of the anti-inflammatory effects of the extracts from Rubus coreanus and Rubus occidentalis. Korean J Food Sci Technol 2007;39:342-7.
  17. Kim Y, Kim J, Lee SM, Lee HA, Park S, Kim Y, Kim JH. Chemopreventive effects of Rubus coreanus Miquel on prostate cancer. Biosci Biotechnol Biochem 2012;76:737-44. https://doi.org/10.1271/bbb.110857
  18. Kim YH, Choi JH, Rim HK, Kang HJ, Chang SG, Park JH, Park HJ, Choi JW, Kim SD, Lee KT. 23-Hydroxytormentic acid and nigaichgoside f(1) isolated from Rubus coreanus attenuate cisplatininduced cytotoxicity by reducing oxidative stress in renal epithelial LLC-PK(1) cells. Biol Pharm Bull 2011;34:906-11. https://doi.org/10.1248/bpb.34.906
  19. Lee J, Dossett M, Finn CE. Rubus fruit phenolic research: the good, the bad, and the confusing. Food Chem 2012;130:785-96. https://doi.org/10.1016/j.foodchem.2011.08.022
  20. Pang KC, Kim MS, Lee MW. Hydrolyzable tannins from the fruits of Rubus coreanum. Korean J Pharmacogn 1996;27:366-70.
  21. Kim HS, Park SJ, Hyun SH, Yang SO, Lee J, Auh JH, Kim JH, Cho SM, Marriott PJ, Choi HK. Biochemical monitoring of black raspberry (Rubus coreanus Miquel) fruits according to maturation stage by 1H-NMR using multiple solvent systems. Food Res Int 2011;44: 1977-88. https://doi.org/10.1016/j.foodres.2011.01.023
  22. Ellis CL, Edirisinghe I, Kappagoda T, Burton-Freeman B. Attenuation of meal-induced inflammatory and thrombotic responses in overweight men and women after 6-week daily strawberry (Fragaria) intake. A randomized placebo-controlled trial. J Atheroscler Thromb 2011;18:318-27. https://doi.org/10.5551/jat.6114
  23. Terra X, Montagut G, Bustos M, Llopiz N, Ardevol A, Blade C, Fernandez-Larrea J, Pujadas G, Salvado J, Arola L, Blay M. Grapeseed procyanidins prevent low-grade inflammation by modulating cytokine expression in rats fed a high-fat diet. J Nutr Biochem 2009;20:210-8. https://doi.org/10.1016/j.jnutbio.2008.02.005
  24. Seymour EM, Lewis SK, Urcuyo-Llanes DE, Tanone II, Kirakosyan A, Kaufman PB, Bolling SF. Regular tart cherry intake alters abdominal adiposity, adipose gene transcription, and inflammation in obesityprone rats fed a high fat diet. J Med Food 2009;12:935-42. https://doi.org/10.1089/jmf.2008.0270
  25. Kim HH, Choi PH, Yoo JS, Jeon H, Chae BS, Park JS, Kim SH, Shin TY. Ripe fruit of Rubus coreanus inhibits mast cell-mediated allergic inflammation. Int J Mol Med 2012;29:303-10.
  26. Sangiovanni E, Vrhovsek U, Rossoni G, Colombo E, Brunelli C, Brembati L, Trivulzio S, Gasperotti M, Mattivi F, Bosisio E, Dell'Agli M. Ellagitannins from Rubus berries for the control of gastric inflammation: in vitro and in vivo studies. PLoS One 2013;8:e71762. https://doi.org/10.1371/journal.pone.0071762
  27. Lin Q, Lee YJ, Yun Z. Differentiation arrest by hypoxia. J Biol Chem 2006;281:30678-83. https://doi.org/10.1074/jbc.C600120200
  28. Kim JM, Shin M. Characteristics of Rubus coreanus Miq. Fruits at different ripening stages. Korean J Food Sci Technol 2011;43:341-47. https://doi.org/10.9721/KJFST.2011.43.3.341
  29. Wang SY, Lin HS. Antioxidant activity in fruits and leaves of blackberry, raspberry, and strawberry varies with cultivar and developmental stage. J Agric Food Chem 2000;48:140-6. https://doi.org/10.1021/jf9908345
  30. Gonzalez R, Ballester I, Lopez-Posadas R, Suarez MD, Zarzuelo A, Martinez-Augustin O, Sanchez de Medina F. Effects of flavonoids and other polyphenols on inflammation. Crit Rev Food Sci Nutr 2011;51:331-62. https://doi.org/10.1080/10408390903584094
  31. Herlaar E, Brown Z. p38 MAPK signalling cascades in inflammatory disease. Mol Med Today 1999;5:439-47. https://doi.org/10.1016/S1357-4310(99)01544-0
  32. Fujioka S, Niu J, Schmidt C, Sclabas GM, Peng B, Uwagawa T, Li Z, Evans DB, Abbruzzese JL, Chiao PJ. NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity. Mol Cell Biol 2004;24:7806-19. https://doi.org/10.1128/MCB.24.17.7806-7819.2004
  33. Whitmarsh AJ, Davis RJ. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl) 1996;74:589-607. https://doi.org/10.1007/s001090050063
  34. Korhonen R, Lahti A, Kankaanranta H, Moilanen E. Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy 2005;4:471-9. https://doi.org/10.2174/1568010054526359
  35. Nussler AK, Billiar TR. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol 1993;54:171-8. https://doi.org/10.1002/jlb.54.2.171
  36. Kleinert H, Pautz A, Linker K, Schwarz PM. Regulation of the expression of inducible nitric oxide synthase. Eur J Pharmacol 2004; 500:255-66. https://doi.org/10.1016/j.ejphar.2004.07.030
  37. MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol 1997;15:323-50. https://doi.org/10.1146/annurev.immunol.15.1.323
  38. Murakami A, Ohigashi H. Targeting NOX, INOS and COX-2 in inflammatory cells: chemoprevention using food phytochemicals. Int J Cancer 2007;121:2357-63. https://doi.org/10.1002/ijc.23161
  39. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, Lipsky PE. Cyclooxygenase in biology and disease. FASEB J 1998;12:1063-73. https://doi.org/10.1096/fasebj.12.12.1063
  40. Lin CC, Lee IT, Yang YL, Lee CW, Kou YR, Yang CM. Induction of COX-2/PGE(2)/IL-6 is crucial for cigarette smoke extract-induced airway inflammation: role of TLR4-dependent NADPH oxidase activation. Free Radic Biol Med 2010;48:240-54. https://doi.org/10.1016/j.freeradbiomed.2009.10.047
  41. Willoughby DA, Moore AR, Colville-Nash PR. COX-1, COX-2, and COX-3 and the future treatment of chronic inflammatory disease. Lancet 2000;355:646-8. https://doi.org/10.1016/S0140-6736(99)12031-2
  42. Tao JY, Zheng GH, Zhao L, Wu JG, Zhang XY, Zhang SL, Huang ZJ, Xiong FL, Li CM. Anti-inflammatory effects of ethyl acetate fraction from Melilotus suaveolens Ledeb on LPS-stimulated RAW 264.7 cells. J Ethnopharmacol 2009;123:97-105. https://doi.org/10.1016/j.jep.2009.02.024
  43. Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci 1997;2:d12-26. https://doi.org/10.2741/A171
  44. Weber CK, Liptay S, Wirth T, Adler G, Schmid RM. Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology 2000; 119:1209-18. https://doi.org/10.1053/gast.2000.19458
  45. Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 2002;96:23-43. https://doi.org/10.1016/S0163-7258(02)00297-8
  46. Rogler G. Gastrointestinal and liver adverse effects of drugs used for treating IBD. Best Pract Res Clin Gastroenterol 2010;24:157-65.
  47. Schubert SY, Neeman I, Resnick N. A novel mechanism for the inhibition of NF-${\kappa}$B activation in vascular endothelial cells by natural antioxidants. FASEB J 2002;16:1931-3. https://doi.org/10.1096/fj.02-0147fje

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