Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of TNF-α-Mediated NF-κB Transcriptional Activity by Dammarane-Type Ginsenosides from Steamed Flower Buds of Panax ginseng in HepG2 and SK-Hep1 Cells

  • Received : 2013.11.13
  • Accepted : 2014.01.14
  • Published : 2014.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Panax ginseng is a medicinal herb that is used worldwide. Its medicinal effects are primarily attributable to ginsenosides located in the root, leaf, seed, and flower. The flower buds of Panax ginseng (FBPG) are rich in various bioactive ginsenosides, which exert immunomodulatory and anti-inflammatory activities. The aim of the present study was to assess the effect of 18 ginsenosides isolated from steamed FBPG on the transcriptional activity of NF-${\kappa}B$ and the expression of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$)-stimulated target genes in liver-derived cell lines. Noticeably, the ginsenosides $Rk_3$ and $Rs_4$ exerted the strongest activity, inhibiting NF-${\kappa}B$ in a dose-dependent manner. SF and $Rg_6$ also showed moderately inhibitory effects. Furthermore, these four compounds inhibited the TNF-${\alpha}$-induced expression of IL8, CXCL1, iNOS, and ICAM1 genes. Consequently, ginsenosides purified from steamed FBPG have therapeutic potential in TNF-${\alpha}$-mediated diseases such as chronic hepatic inflammation.

Keywords

References

  1. Baek, N. I., Kim, D. S., Lee, Y. H., Park, J. D., Lee, C. B. and Kim, S. I. (1996) Ginsenoside Rh4, a genuine dammarane glycoside from Korean red ginseng. Planta Med. 62, 86-87. https://doi.org/10.1055/s-2006-957816
  2. Berasain, C., Castillo. J., Perugorria, M. J., Latasa, M. U., Prieto, J. and Avila, M. A. (2009) Inflammation and liver cancer: new molecular links. Ann. N. Y. Acad. Sci. 1155, 206-221. https://doi.org/10.1111/j.1749-6632.2009.03704.x
  3. Christensen, L. P. (2009) Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv. Food Nutr. Res. 55, 1-99.
  4. Elsharkawy, A. M. and Mann, D. A. (2007) Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 46, 590-597. https://doi.org/10.1002/hep.21802
  5. Ernst, E. (2010) Panax ginseng: An Overview of the Clinical Evidence. J. Ginseng Res. 34, 259-263. https://doi.org/10.5142/jgr.2010.34.4.259
  6. Farinati, F., Piciocchi, M., Lavezzo, E., Bortolami, M. and Cardin, R. (2010) Oxidative stress and inducible nitric oxide synthase induction in carcinogenesis. Dig. Dis. 28, 579-584. https://doi.org/10.1159/000320052
  7. Funakoshi-Tago, M., Nakamura, K., Tago, K., Mashino, T. and Kasahara, T. (2011) Anti-inflammatory activity of structurally related flavonoids, apigenin, luteolin and fisetin. Int. Immunopharmacol. 11, 1150-1159. https://doi.org/10.1016/j.intimp.2011.03.012
  8. Gasparini, C. and Feldmann, M. (2012) NF-${\kappa}B$ as a target for modulating inflammatory responses. Curr. Pharm. Des. 18, 5735-5745 https://doi.org/10.2174/138161212803530763
  9. Hofseth, L. J. and Wargovich, M. J. (2007) Inflammation, cancer, and targets of ginseng. J. Nutr. 137, 183S-185S. https://doi.org/10.1093/jn/137.1.183S
  10. Holt, A. P., Salmon, M., Buckley, C. D. and Adams, D. H. (2008) Immune interactions in hepatic fibrosis. Clin. Liver Dis. 12, 861-882. https://doi.org/10.1016/j.cld.2008.07.002
  11. Kawanishi, S., Hiraku, Y., Pinlaor, S. and Ma, N. (2006) Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol. Chem. 387, 365-372.
  12. Kim, S. E., Lee, Y. H., Park, J. H. and Lee, S. K. (1999) Ginsenoside-$Rs_4$, a new type of ginseng saponin concurrently induces apoptosis and selectively elevates protein levels of p53 and p21WAF1 in human hepatoma SK-HEP-1 cells. Eur. J. Cancer 35, 507-11. https://doi.org/10.1016/S0959-8049(98)00415-8
  13. Lee, I. A., Hyam, S. R., Jang, S. E., Han, M. J. and Kim, D. H. (2012) Ginsenoside Re ameliorates inflammation by inhibiting the binding of lipopolysaccharide to TLR4 on macrophages. J. Agric. Food Chem. 60, 9595-9602 https://doi.org/10.1021/jf301372g
  14. Lee, J. G., Baek, S. H., Lee, Y. Y., Park, S. Y. and Park, J. H. (2011) Anti-complementary ginsenosides isolated from processed ginseng. Biol. Pharm. Bull. 34, 898-900. https://doi.org/10.1248/bpb.34.898
  15. Lentsch, A. B. and Ward, P. A. (2000) The NFkappaBb/IkappaB system in acute inflammation. Arch. Immunol. Ther. Exp. (Warsz) 48, 59-63.
  16. Li, Q. and Verma, I. M. (2002) NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2, 725-734. https://doi.org/10.1038/nri910
  17. Liu, G. Y., Li, X. W., Wang, N. B., Zhou, H. Y., Wei, W., Gui, M. Y., Yang, B. and Jin, Y. R. (2010) Three new dammarane-type triterpene saponins from the leaves of Panax ginseng C.A. Meyer. J. Asian Nat. Prod. Res. 12, 865-873. https://doi.org/10.1080/10286020.2010.508035
  18. Luqman, S. and Pezzuto, J. M. (2010) NFkappaB: a promising target for natural products in cancer chemoprevention. Phytother. Res. 24, 949-963.
  19. Mantovani, A., Allavena, P., Sica, A. and Balkwill, F. (2008) Cancer-related inflammation. Nature 454, 436-444. https://doi.org/10.1038/nature07205
  20. Nam, N. H. (2006) Naturally occurring NF-kappaB inhibitors. Mini Rev. Med. Chem. 6, 945-951. https://doi.org/10.2174/138955706777934937
  21. Park, T. Y., Park, M. H., Shin, W. C., Rhee, M. H., Seo, D. W., Cho, J. Y. and Kim, H. M. (2008) Anti-metastatic potential of ginsenoside Rp1, a novel ginsenoside derivative. Biol. Pharm. Bull. 31, 1802-1805. https://doi.org/10.1248/bpb.31.1802
  22. Song, S. B., Tung, N. H., Quang, T. H., Ngan, N. T., Kim, K. E. and Kim, Y. H. (2012) Inhibition of TNF-${\alpha}$-mediated NF-${\kappa}B$ transcriptional activity in HepG2 cells by dammarane-type saponins from Panax ginseng leaves. J. Ginseng Res. 36, 146-152. https://doi.org/10.5142/jgr.2012.36.2.146
  23. Sun, J., Sun, G., Meng, X., Wang, H., Wang, M., Qin, M., Ma, B., Luo, Y., Yu, Y., Chen, R., Ai, Q. and Sun, X. (2013) Ginsenoside RK3_prevents hypoxia-reoxygenation induced apoptosis in H9c2 cardiomyocytes via AKT and MAPK pathway. Evid. Based Complement Alternat. Med. 2013, 690190.
  24. Toh, D. F., Patel, D. N., Chan, E. C., Teo, A., Neo, S. Y. and Koh, H. L. (2011) Anti-proliferative effects of raw and steamed extracts of Panax notoginseng and its ginsenoside constituents on human liver cancer cells. Chin. Med. 6, 4. https://doi.org/10.1186/1749-8546-6-4
  25. Tung, N. H., Song, G. Y., Park, Y. J. and Kim, Y. H. (2009) Two new dammarane-type saponins from the leaves of Panax ginseng. Chem. Pharm. Bull. (Tokyo) 57, 1412-1414. https://doi.org/10.1248/cpb.57.1412
  26. Tung, N. H., Song, G. Y., Minh, C. V., Kiem, P. V., Jin, L. G., Boo, H. J., Kang, H. K. and Kim, Y. H. (2010a) Steamed ginseng-leaf components enhance cytotoxic effects on human leukemia HL-60 cells. Chem. Pharm. Bull. (Tokyo) 58, 1111-1115. https://doi.org/10.1248/cpb.58.1111
  27. Tung, N. H., Cho, K., Kim, J. A., Song, G. Y. and Kim, Y. H. (2010b) Dammarane-type glycosides from the steamed flower-buds of Panax ginseng. Bull. Korean Chem. Soc. 31, 1381-1384. https://doi.org/10.5012/bkcs.2010.31.5.1381
  28. Tung, N. H., Song, G. Y., Kim, J. A., Hyun, J. H., Kang, H. K. and Kim, Y. H. (2010c) Dammarane-type saponins from the flower buds of Panax ginseng and their effects on human leukemia Cells. Bioorg. Med. Chem. Lett. 20, 309-314. https://doi.org/10.1016/j.bmcl.2009.10.110
  29. Tung, N. H., Song, G. Y., Nhiem, N. X., Ding, Y., Tai, B.H., Jin, L. G., Lim, C. M., Hyun, J. W., Park, C. J., Kang, H. K. and Kim, Y. H. (2010d) Dammarane-type saponins from the flower buds of Panax ginseng and their intracellular radical scavenging capacity. J. Agric. Food Chem. 58, 868-874. https://doi.org/10.1021/jf903334g
  30. Tung, N. H., Quang, T. H., Son, J. H., Koo, J. E., Hong, H. J., Koh, Y. S., Song, G. Y. and Kim, Y. H. (2011) Inhibitory effect of ginsenosides from steamed ginseng-leaves and flowers on the LPS-stimulated IL-12 production in bone marrow-derived dendritic cells. Arch. Pharm. Res. 34, 681-685. https://doi.org/10.1007/s12272-011-0419-2
  31. Vuksan, V., Sievenpipper, J., Jovanovski, E. and Jenkins, A. L. (2010) Current clinical evidence for Korean red ginseng in management of diabetes and vascular disease: a Toronto's ginseng clinical testing program. J. Ginseng Res. 34, 264-273. https://doi.org/10.5142/jgr.2010.34.4.264
  32. Wang, H., Peng, D. and Xie, J. (2009) Ginseng leaf-stem: bioactive constituents and pharmacological functions. Chin. Med. 4, 20. https://doi.org/10.1186/1749-8546-4-20
  33. Wang, L., Zhang, Y., Wang, Z., Li, S., Min, G., Wang, L., Chen, J., Cheng, J. and Wu, Y. (2012) Inhibitory effect of ginsenoside-Rd on carrageenan-induced inflammation in rats. Can. J. Physiol. Pharmacol. 90, 229-236. https://doi.org/10.1139/y11-127

Cited by

  1. A Strategy for Simultaneous Isolation of Less Polar Ginsenosides, Including a Pair of New 20-Methoxyl Isomers, from Flower Buds of Panax ginseng vol.22, pp.3, 2017, https://doi.org/10.3390/molecules22030442
  2. Mitochondria-related miR-141-3p contributes to mitochondrial dysfunction in HFD-induced obesity by inhibiting PTEN vol.5, pp.1, 2015, https://doi.org/10.1038/srep16262
  3. Effects of Complementary Combination Therapy of Korean Red Ginseng and Antiviral Agents in Chronic Hepatitis B vol.22, pp.12, 2016, https://doi.org/10.1089/acm.2015.0206
  4. Isolation, Purification and Quantification of Ginsenoside F5 and F3 Isomeric Compounds from Crude Extracts of Flower Buds of Panax ginseng vol.21, pp.3, 2016, https://doi.org/10.3390/molecules21030315
  5. Intraconversion of Polar Ginsenosides, Their Transformation into Less-Polar Ginsenosides, and Ginsenoside Acetylation in Ginseng Flowers upon Baking and Steaming vol.23, pp.4, 2018, https://doi.org/10.3390/molecules23040759
  6. Modified Ginseng Extract Induces Apoptosis in HepG2 Cancer Cells by Blocking the CXCL8-Mediated Akt/Nuclear Factor-κB Signaling Pathway vol.46, pp.07, 2018, https://doi.org/10.1142/S0192415X18500842
  7. -Mix on Lipopolysaccharide-Stimulated RAW 264.7 Murine Macrophage Cells vol.21, pp.10, 2018, https://doi.org/10.1089/jmf.2018.4180
  8. Boosting the autophagy‐lysosomal pathway by phytochemicals: A potential therapeutic strategy against Alzheimer's disease vol.72, pp.11, 2014, https://doi.org/10.1002/iub.2369
  9. Vina-Ginsenoside R4 from Panax ginseng Leaves Alleviates 6-OHDA-Induced Neurotoxicity in PC12 Cells Via the PI3K/Akt/GSK-3β Signaling Pathway vol.68, pp.51, 2014, https://doi.org/10.1021/acs.jafc.0c06474