Advertisement

Inflammation

, Volume 38, Issue 1, pp 445–455 | Cite as

Aspalathin and Nothofagin from Rooibos (Aspalathus linearis) Inhibits High Glucose-Induced Inflammation In Vitro and In Vivo

  • Sae-Kwang Ku
  • Soyoung Kwak
  • Yaesol Kim
  • Jong-Sup BaeEmail author
Article

Abstract

Vascular inflammation plays a key role in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Aspalathin (Asp) and nothofagin (Not) are two major active dihydrochalcones found in green rooibos, which have been reported for their antioxidant activity. In this study, we assessed whether Asp or Not can suppress vascular inflammation induced by high glucose (HG) in human umbilical vein endothelial cells (HUVECs) and mice. We monitored the effects of Asp or Not on HG-induced vascular hyperpermeability, expression of cell adhesion molecules (CAMs), formation of reactive oxygen species (ROS), and activation of nuclear factor (NF)-κB in vitro and in vivo. Our data indicate that HG markedly increased vascular permeability, monocyte adhesion, expression of CAMs, formation of ROS, and activation of NF-κB. Remarkably, treatment of Asp or Not inhibited HG-mediated vascular hyperpermeability, adhesion of monocytes toward HUVECs, and expression of CAMs. In addition, Asp or Not suppressed the formation of ROS and the activation of NF-κB. Since vascular inflammation induced by HG is critical in the development of diabetic complications, our results suggest that Asp or Not may have significant benefits in the treatment of diabetic complications.

KEY WORDS

aspalathin nothofagin high glucose diabetes mellitus inflammation 

Notes

Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) funded by the Korea government [MSIP] (Grant Nos. 2013-067053).

Conflict of Interest

None declared.

References

  1. 1.
    Whiting, D.R., L. Guariguata, C. Weil, and J. Shaw. 2011. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Research and Clinical Practice 94: 311–321.CrossRefPubMedGoogle Scholar
  2. 2.
    Grundy, S.M., I.J. Benjamin, G.L. Burke, et al. 1999. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 100: 1134–1146.CrossRefPubMedGoogle Scholar
  3. 3.
    Thomas, J.E., and J.M. Foody. 2007. The pathophysiology of cardiovascular disease in diabetes mellitus and the future of therapy. Journal of the Cardiometabolic Syndrome 2: 108–113.CrossRefPubMedGoogle Scholar
  4. 4.
    Roglic, G., N. Unwin, P.H. Bennett, et al. 2005. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 28: 2130–2135.CrossRefPubMedGoogle Scholar
  5. 5.
    Rubino, F., and M. Gagner. 2002. Potential of surgery for curing type 2 diabetes mellitus. Annals of Surgery 236: 554–559.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Day, C. 1998. Traditional plant treatments for diabetes mellitus: pharmaceutical foods. British Journal of Nutrition 80: 5–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Li, G.Q., A. Kam, K.H. Wong, et al. 2012. Herbal medicines for the management of diabetes. Advances in Experimental Medicine and Biology 771: 396–413.PubMedGoogle Scholar
  8. 8.
    Prior, R.L., and G. Cao. 1999. Antioxidant capacity and polyphenolic components of teas: implications for altering in vivo antioxidant status. Proceedings of the Society for Experimental Biology and Medicine 220: 255–261.CrossRefPubMedGoogle Scholar
  9. 9.
    Warren, C.P. 1999. Antioxidant effects of herbs. Lancet 353: 676.CrossRefPubMedGoogle Scholar
  10. 10.
    McKay, D.L., and J.B. Blumberg. 2007. A review of the bioactivity of South African herbal teas: rooibos (Aspalathus linearis) and honeybush (Cyclopia intermedia). Phytotherapy Research 21: 1–16.CrossRefPubMedGoogle Scholar
  11. 11.
    Kazuno, S., M. Yanagida, N. Shindo, and K. Murayama. 2005. Mass spectrometric identification and quantification of glycosyl flavonoids, including dihydrochalcones with neutral loss scan mode. Analytical Biochemistry 347: 182–192.CrossRefPubMedGoogle Scholar
  12. 12.
    Lee, W., S.K. Ku, and J.S. Bae. 2013. Emodin-6-O-beta-D-glucoside down-regulates endothelial protein C receptor shedding. Archives of Pharmacal Research 36: 1160–1165.CrossRefPubMedGoogle Scholar
  13. 13.
    Bae, J.S., and A.R. Rezaie. 2013. Thrombin inhibits HMGB1-mediated proinflammatory signaling responses when endothelial protein C receptor is occupied by its natural ligand. BMB Reports 46: 544–549.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Kim, T.H., S.K. Ku, I.C. Lee, and J.S. Bae. 2012. Anti-inflammatory functions of purpurogallin in LPS-activated human endothelial cells. BMB Reports 45: 200–205.CrossRefPubMedGoogle Scholar
  15. 15.
    Bae, J.S., W. Lee, and A.R. Rezaie. 2012. Polyphosphate elicits proinflammatory responses that are counteracted by activated protein C in both cellular and animal models. Journal of Thrombosis and Haemostasis 10: 1145–1151.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Lee, J.D., J.E. Huh, G. Jeon, et al. 2009. Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models. International Immunopharmacology 9: 268–276.CrossRefPubMedGoogle Scholar
  17. 17.
    Bae, J.S., W. Lee, J.O. Nam, J.E. Kim, S.W. Kim, and I.S. Kim. 2014. Transforming growth factor beta-induced protein promotes severe vascular inflammatory responses. American Journal of Respiratory and Critical Care Medicine 189: 779–786.CrossRefPubMedGoogle Scholar
  18. 18.
    Lee, W., S.K. Ku, D. Lee, T. Lee, and J.S. Bae. 2014. Emodin-6-O-beta-D–glucoside inhibits high-glucose-induced vascular inflammation. Inflammation 37: 306–313.CrossRefPubMedGoogle Scholar
  19. 19.
    Mackman, N., K. Brand, and T.S. Edgington. 1991. Lipopolysaccharide-mediated transcriptional activation of the human tissue factor gene in THP-1 monocytic cells requires both activator protein 1 and nuclear factor kappa B binding sites. Journal of Experimental Medicine 174: 1517–1526.CrossRefPubMedGoogle Scholar
  20. 20.
    Fuseler, J.W., D.M. Merrill, J.A. Rogers, M.B. Grisham, and R.E. Wolf. 2006. Analysis and quantitation of NF-kappaB nuclear translocation in tumor necrosis factor alpha (TNF-alpha) activated vascular endothelial cells. Microscopy and Microanalysis 12: 269–276.CrossRefPubMedGoogle Scholar
  21. 21.
    Lee, W., S.K. Ku, and J.S. Bae. 2014. Vascular barrier protective effects of orientin and isoorientin in LPS-induced inflammation in vitro and in vivo. Vascular Pharmacology 62: 3–14.CrossRefPubMedGoogle Scholar
  22. 22.
    Joubert, E., W.C. Gelderblom, A. Louw, and D. de Beer. 2008. South African herbal teas: aspalathus linearis, Cyclopia spp. and Athrixia phylicoides—a review. Journal of Ethnopharmacology 119: 376–412.CrossRefPubMedGoogle Scholar
  23. 23.
    Ku, S.K., S. Kwak, and J.S. Bae. 2014. Orientin inhibits high glucose-induced vascular inflammation in vitro and in vivo. Inflammation. (in press).Google Scholar
  24. 24.
    Kim, J.A., J.A. Berliner, R.D. Natarajan, and J.L. Nadler. 1994. Evidence that glucose increases monocyte binding to human aortic endothelial cells. Diabetes 43: 1103–1107.CrossRefPubMedGoogle Scholar
  25. 25.
    Lee, Y.J., D.G. Kang, J.S. Kim, and H.S. Lee. 2008. Lycopus lucidus inhibits high glucose-induced vascular inflammation in human umbilical vein endothelial cells. Vascular Pharmacology 48: 38–46.CrossRefPubMedGoogle Scholar
  26. 26.
    Takaishi, H., T. Taniguchi, A. Takahashi, Y. Ishikawa, and M. Yokoyama. 2003. High glucose accelerates MCP-1 production via p38 MAPK in vascular endothelial cells. Biochemical and Biophysical Research Communications 305: 122–128.CrossRefPubMedGoogle Scholar
  27. 27.
    Morigi, M., S. Angioletti, B. Imberti, et al. 1998. Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion. Journal of Clinical Investigation 101: 1905–1915.CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Kashiwagi, A., T. Asahina, Y. Nishio, et al. 1996. Glycation, oxidative stress, and scavenger activity: glucose metabolism and radical scavenger dysfunction in endothelial cells. Diabetes 45(Suppl 3): S84–S86.CrossRefPubMedGoogle Scholar
  29. 29.
    Du, X., K. Stocklauser-Farber, and P. Rosen. 1999. Generation of reactive oxygen intermediates, activation of NF-kappaB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase? Free Radical Biology and Medicine 27: 752–763.CrossRefPubMedGoogle Scholar
  30. 30.
    Laakso, M. 1999. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 48: 937–942.CrossRefPubMedGoogle Scholar
  31. 31.
    Kannel, W.B., and D.L. McGee. 1979. Diabetes and cardiovascular disease. The Framingham study. JAMA 241: 2035–2038.CrossRefPubMedGoogle Scholar
  32. 32.
    Nannipieri, M., L. Rizzo, A. Rapuano, A. Pilo, G. Penno, and R. Navalesi. 1995. Increased transcapillary escape rate of albumin in microalbuminuric type II diabetic patients. Diabetes Care 18: 1–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Wardle, E.N. 1994. Vascular permeability in diabetics and implications for therapy. Diabetes Research and Clinical Practice 23: 135–139.CrossRefPubMedGoogle Scholar
  34. 34.
    Tooke, J.E. 1995. Microvascular function in human diabetes. A physiological perspective. Diabetes 44: 721–726.CrossRefPubMedGoogle Scholar
  35. 35.
    Gerrity, R.G. 1981. The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions. American Journal of Pathology 103: 181–190.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Esposito, C., G. Fasoli, A.R. Plati, et al. 2001. Long-term exposure to high glucose up-regulates VCAM-induced endothelial cell adhesiveness to PBMC. Kidney International 59: 1842–1849.CrossRefPubMedGoogle Scholar
  37. 37.
    Hamuro, M., J. Polan, M. Natarajan, and S. Mohan. 2002. High glucose induced nuclear factor kappa B mediated inhibition of endothelial cell migration. Atherosclerosis 162: 277–287.CrossRefPubMedGoogle Scholar
  38. 38.
    Lopes-Virella, M.F., and G. Virella. 1992. Immune mechanisms of atherosclerosis in diabetes mellitus. Diabetes 41(Suppl 2): 86–91.CrossRefPubMedGoogle Scholar
  39. 39.
    Bae, J.S. 2012. Role of high mobility group box 1 in inflammatory disease: focus on sepsis. Archives of Pharmacal Research 35: 1511–1523.CrossRefPubMedGoogle Scholar
  40. 40.
    Kado, S., T. Wakatsuki, M. Yamamoto, and N. Nagata. 2001. Expression of intercellular adhesion molecule-1 induced by high glucose concentrations in human aortic endothelial cells. Life Sciences 68: 727–737.CrossRefPubMedGoogle Scholar
  41. 41.
    Hansson, G.K., and P. Libby. 2006. The immune response in atherosclerosis: a double-edged sword. Nature Reviews Immunology 6: 508–519.CrossRefPubMedGoogle Scholar
  42. 42.
    Boisvert, W.A. 2004. Modulation of atherogenesis by chemokines. Trends in Cardiovascular Medicine 14: 161–165.CrossRefPubMedGoogle Scholar
  43. 43.
    Inoguchi, T., P. Li, F. Umeda, et al. 2000. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49: 1939–1945.CrossRefPubMedGoogle Scholar
  44. 44.
    Dunlop, M. 2000. Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney International. Supplement 77: S3–S12.CrossRefPubMedGoogle Scholar
  45. 45.
    Han, H.J., Y.J. Lee, S.H. Park, J.H. Lee, and M. Taub. 2005. High glucose-induced oxidative stress inhibits Na+/glucose cotransporter activity in renal proximal tubule cells. American Journal of Physiology. Renal Physiology 288: F988–F996.CrossRefPubMedGoogle Scholar
  46. 46.
    Rimbach, G., G. Valacchi, R. Canali, and F. Virgili. 2000. Macrophages stimulated with IFN-gamma activate NF-kappa B and induce MCP-1 gene expression in primary human endothelial cells. Molecular Cell Biology Research Communications 3: 238–242.CrossRefPubMedGoogle Scholar
  47. 47.
    Uemura, S., H. Matsushita, W. Li, et al. 2001. Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress. Circulation Research 88: 1291–1298.CrossRefPubMedGoogle Scholar
  48. 48.
    Nakamura, Y., S. Watanabe, N. Miyake, H. Kohno, and T. Osawa. 2003. Dihydrochalcones: evaluation as novel radical scavenging antioxidants. Journal of Agricultural and Food Chemistry 51: 3309–3312.CrossRefPubMedGoogle Scholar
  49. 49.
    Rezk, B.M., G.R. Haenen, W.J. van der Vijgh, and A. Bast. 2002. The antioxidant activity of phloretin: the disclosure of a new antioxidant pharmacophore in flavonoids. Biochemical and Biophysical Research Communications 295: 9–13.CrossRefPubMedGoogle Scholar
  50. 50.
    Krafczyk, N., F. Woyand, and M.A. Glomb. 2009. Structure-antioxidant relationship of flavonoids from fermented rooibos. Molecular Nutrition & Food Research 53: 635–642.CrossRefGoogle Scholar
  51. 51.
    Snijman, P.W., E. Joubert, D. Ferreira, et al. 2009. Antioxidant activity of the dihydrochalcones aspalathin and nothofagin and their corresponding flavones in relation to other rooibos (Aspalathus linearis) flavonoids, epigallocatechin gallate, and trolox. Journal of Agricultural and Food Chemistry 57: 6678–6684.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Sae-Kwang Ku
    • 1
  • Soyoung Kwak
    • 2
  • Yaesol Kim
    • 2
  • Jong-Sup Bae
    • 2
    Email author
  1. 1.Department of Anatomy and Histology, College of Korean MedicineDaegu Haany UniversityGyeongsanRepublic of Korea
  2. 2.College of Pharmacy, CMRI, Research Institute of Pharmaceutical SciencesKyungpook National UniversityDaeguRepublic of Korea

Personalised recommendations