Skip to main content

Advertisement

SpringerLink
Log in

Anti-Inflammatory Effects of Hyperoside in Human Endothelial Cells and in Mice

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

High-mobility group box 1 (HMGB1) was recently shown to be an important extracellular mediator of systemic inflammation, and endothelial cell protein C receptor (EPCR) has been shown to be involved in vascular inflammation. Hyperoside is an active compound isolated from Rhododendron brachycarpum G. Don (Ericaceae) that was reported to have anti-oxidant, anti-hyperglycemic, anti-cancer, and anti-coagulant activities. Here, we show, for the first time, the anti-septic effects of hyperoside in HMGB1-mediated inflammatory responses and on the shedding of EPCR in vitro and in vivo. The data showed that hyperoside posttreatment suppressed lipopolysaccharide (LPS)-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangement. Hyperoside also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice and phorbol-12-myristate 13-acetate (PMA) of cecal ligation and puncture (CLP)-induced EPCR shedding. In addition, hyperoside inhibited the production of tumor necrosis factor-α (TNF-α) and the HMGB1-mediated activation of Akt, nuclear factor-κB (NF-κB), and extracellular regulated kinase (ERK) 1/2 in HUVECs. Hyperoside also reduced the CLP-induced release of HMGB1, the production of interleukin (IL)-1β, and septic mortality. Collectively, these results suggest hyperoside as a candidate therapeutic agent for the treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Russell, J.A., and K.R. Walley. 2013. Update in sepsis 2012. American Journal of Respiratory and Critical Care Medicine 187: 1303–1307.

    Article  PubMed  Google Scholar 

  2. Lotze, M.T., and K.J. Tracey. 2005. High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal. Nature Reviews Immunology 5: 331–342.

    Article  CAS  PubMed  Google Scholar 

  3. Bae, J.S. 2012. Role of high mobility group box 1 in inflammatory disease: Focus on sepsis. Archives of Pharmacal Research 35: 1511–1523.

    Article  CAS  PubMed  Google Scholar 

  4. Wang, H., O. Bloom, M. Zhang, et al. 1999. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248–251.

    Article  CAS  PubMed  Google Scholar 

  5. Hori, O., J. Brett, T. Slattery, et al. 1995. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. Journal of Biological Chemistry 270: 25752–25761.

    Article  CAS  PubMed  Google Scholar 

  6. Park, J.S., D. Svetkauskaite, Q. He, et al. 2004. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. Journal of Biological Chemistry 279: 7370–7377.

    Article  CAS  PubMed  Google Scholar 

  7. Bae, J.S., and A.R. Rezaie. 2011. Activated protein C inhibits high mobility group box 1 signaling in endothelial cells. Blood 118: 3952–3959.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Yang, H., M. Ochani, J. Li, et al. 2004. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proceedings of the National Academy of Sciences of the United States of America 101: 296–301.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Mossier, L.O., B.V. Zlokovic, and J.H. Griffin. 2007. The cytoprotective protein C pathway. Blood 109: 3161–3172.

    Article  Google Scholar 

  10. Xu, J., D. Qu, N.L. Esmon, and C.T. Esmon. 2000. Metalloproteolytic release of endothelial cell protein C receptor. Journal of Biological Chemistry 275: 6038–6044.

    Article  CAS  PubMed  Google Scholar 

  11. Kurosawa, S., D.J. Stearns-Kurosawa, C.W. Carson, A. D’Angelo, P. Della Valle, and C.T. Esmon. 1998. Plasma levels of endothelial cell protein C receptor are elevated in patients with sepsis and systemic lupus erythematosus: Lack of correlation with thrombomodulin suggests involvement of different pathological processes. Blood 91: 725–727.

    CAS  PubMed  Google Scholar 

  12. Persson, P.B., and A.B... Persson. 2012. Age your garlic for longevity! Acta Physiologica (Oxford, England) 205: 1–2.

  13. Middleton Jr., E., and G. Drzewiecki. 1984. Flavonoid inhibition of human basophil histamine release stimulated by various agents. Biochemical Pharmacology 33: 3333–3338.

    Article  CAS  PubMed  Google Scholar 

  14. Mukaida, N. 2000. Interleukin-8: An expanding universe beyond neutrophil chemotaxis and activation. International Journal of Hematology 72: 391–398.

    CAS  PubMed  Google Scholar 

  15. Hirano, T., S. Higa, J. Arimitsu, et al. 2006. Luteolin, a flavonoid, inhibits AP-1 activation by basophils. Biochemical and Biophysical Research Communications 340: 1–7.

    Article  CAS  PubMed  Google Scholar 

  16. Zou, Y., Y. Lu, and D. Wei. 2004. Antioxidant activity of a flavonoid-rich extract of Hypericum perforatum L. in vitro. Journal of Agricultural and Food Chemistry 52: 5032–5039.

    Article  CAS  PubMed  Google Scholar 

  17. Zhou, W., J. Oh, W. Li, D.W. Kim, S.H. Lee, and M. Na. 2013. Phytochemical studies of Korean endangered plants: A new flavone from Rhododendron brachycarpum G Don. Bulletin of the Korean Chemical Society 34: 2535–2538.

    Article  CAS  Google Scholar 

  18. Li, H.B., X. Yi, J.M. Gao, X.X. Ying, H.Q. Guan, and J.C. Li. 2008. The mechanism of hyperoside protection of ECV-304 cells against tert-butyl hydroperoxide-induced injury. Pharmacology 82: 105–113.

    Article  PubMed  Google Scholar 

  19. Verma, N., G. Amresh, P.K. Sahu, N. Mishra, V. Rao Ch, and A.P. Singh. 2013. Pharmacological evaluation of hyperin for antihyperglycemic activity and effect on lipid profile in diabetic rats. Indian Journal of Experimental Biology 51: 65–72.

    CAS  PubMed  Google Scholar 

  20. Li, F.R., F.X. Yu, S.T. Yao, Y.H. Si, W. Zhang, and L.L. Gao. 2012. Hyperin extracted from Manchurian rhododendron leaf induces apoptosis in human endometrial cancer cells through a mitochondrial pathway. Asian Pacific Journal of Cancer Prevention 13: 3653–3656.

    Article  PubMed  Google Scholar 

  21. Kim, S.J., J.Y. Um, and J.Y. Lee. 2011. Anti-inflammatory activity of hyperoside through the suppression of nuclear factor-kappaB activation in mouse peritoneal macrophages. American Journal of Chinese Medicine 39: 171–181.

    Article  CAS  PubMed  Google Scholar 

  22. Li, Z.L., J. Hu, Y.L. Li, et al. 2013. The effect of hyperoside on the functional recovery of the ischemic/reperfused isolated rat heart: Potential involvement of the extracellular signal-regulated kinase 1/2 signaling pathway. Free Radical Biology and Medicine 57: 132–140.

    Article  CAS  PubMed  Google Scholar 

  23. Ku, S.K., T.H. Kim, S. Lee, S.M. Kim, and J.S. Bae. 2012. Antithrombotic and profibrinolytic activities of isorhamnetin-3-O-galactoside and hyperoside. Food and Chemical Toxicology 53C: 197–204.

    Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ku, S.K., E.J. Yang, K.S. Song, and J.S. Bae. 2013. Rosmarinic acid down-regulates endothelial protein C receptor shedding in vitro and in vivo. Food and Chemical Toxicology 59: 311–315.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. Bae, J.S., L. Yang, C. Manithody, and A.R. Rezaie. 2007. The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 110: 3909–3916.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. 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.

  30. Valerio, D.A., T.M. Cunha, N.S. Arakawa, et al. 2007. Anti-inflammatory and analgesic effects of the sesquiterpene lactone budlein A in mice: Inhibition of cytokine production-dependent mechanism. European Journal of Pharmacology 562: 155–163.

    Article  CAS  PubMed  Google Scholar 

  31. Lee, W., S.K. Ku, J.A. Kim, T. Lee, and J.S. Bae. 2013. Inhibitory effects of epi-sesamin on HMGB1-induced vascular barrier disruptive responses in vitro and in vivo. Toxicology and Applied Pharmacology 267: 201–208.

    Article  CAS  PubMed  Google Scholar 

  32. Wang, H., H. Liao, M. Ochani, et al. 2004. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Medicine 10: 1216–1221.

    Article  CAS  PubMed  Google Scholar 

  33. Jang, G.U.J., S.U.C. Choi, and K.R.L. Lee. 2005. Cytotoxic constituents of Rhododendron brachycarpum. Yakhak Hoeji 49: 244–248.

    CAS  Google Scholar 

  34. Liu, Z., X. Tao, C. Zhang, Y. Lu, and D. Wei. 2005. Protective effects of hyperoside (quercetin-3-o-galactoside) to PC12 cells against cytotoxicity induced by hydrogen peroxide and tert-butyl hydroperoxide. Biomedicine and Pharmacotherapy 59: 481–490.

    Article  CAS  PubMed  Google Scholar 

  35. Yoo, H., S.K. Ku, Y.D. Baek, and J.S. Bae. 2013. Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo. Inflammation Research

  36. Mullins, G.E., J. Sunden-Cullberg, A.S. Johansson, et al. 2004. Activation of human umbilical vein endothelial cells leads to relocation and release of high-mobility group box chromosomal protein 1. Scandinavian Journal of Immunology 60: 566–573.

    Article  CAS  PubMed  Google Scholar 

  37. Buras, J.A., B. Holzmann, and M. Sitkovsky. 2005. Animal models of sepsis: Setting the stage. Nature Reviews Drug Discovery 4: 854–865.

    Article  CAS  PubMed  Google Scholar 

  38. Sama, A.E., J. D’Amore, M.F. Ward, G. Chen, and H. Wang. 2004. Bench to bedside: HMGB1-a novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department. Academic Emergency Medicine 11: 867–873.

    PubMed  Google Scholar 

  39. Berman, R.S., J.D. Frew, and W. Martin. 1993. Endotoxin-induced arterial endothelial barrier dysfunction assessed by an in vitro model. British Journal of Pharmacology 110: 1282–1284.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Goldblum, S.E., X. Ding, T.W. Brann, and J. Campbell-Washington. 1993. Bacterial lipopolysaccharide induces actin reorganization, intercellular gap formation, and endothelial barrier dysfunction in pulmonary vascular endothelial cells: Concurrent F-actin depolymerization and new actin synthesis. Journal of Cellular Physiology 157: 13–23.

    Article  CAS  PubMed  Google Scholar 

  41. Wolfson, R.K., E.T. Chiang, and J.G. Garcia. 2011. HMGB1 induces human lung endothelial cell cytoskeletal rearrangement and barrier disruption. Microvascular Research 81: 189–197.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Yang, H., H. Wang, C.J. Czura, and K.J. Tracey. 2005. The cytokine activity of HMGB1. Journal of Leukocyte Biology 78: 1–8.

    Article  CAS  PubMed  Google Scholar 

  43. Qin, Y.H., S.M. Dai, G.S. Tang, et al. 2009. HMGB1 enhances the proinflammatory activity of lipopolysaccharide by promoting the phosphorylation of MAPK p38 through receptor for advanced glycation end products. Journal of Immunology 183: 6244–6250.

    Article  CAS  Google Scholar 

  44. Sun, C., C. Liang, Y. Ren, et al. 2009. Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic Research in Cardiology 104: 42–49.

    Article  CAS  PubMed  Google Scholar 

  45. Schnittler, H.J., S.W. Schneider, H. Raifer, et al. 2001. Role of actin filaments in endothelial cell-cell adhesion and membrane stability under fluid shear stress. Pflügers Archiv 442: 675–687.

    Article  CAS  PubMed  Google Scholar 

  46. Friedl, J., M. Puhlmann, D.L. Bartlett, et al. 2002. Induction of permeability across endothelial cell monolayers by tumor necrosis factor (TNF) occurs via a tissue factor-dependent mechanism: Relationship between the procoagulant and permeability effects of TNF. Blood 100: 1334–1339.

    CAS  PubMed  Google Scholar 

  47. Petrache, I., A. Birukova, S.I. Ramirez, J.G. Garcia, and A.D. Verin. 2003. The role of the microtubules in tumor necrosis factor-alpha-induced endothelial cell permeability. American Journal of Respiratory Cell and Molecular Biology 28: 574–581.

    Article  CAS  PubMed  Google Scholar 

  48. Qu, D., Y. Wang, Y. Song, N.L. Esmon, and C.T. Esmon. 2006. The Ser219→Gly dimorphism of the endothelial protein C receptor contributes to the higher soluble protein levels observed in individuals with the A3 haplotype. Journal of Thrombosis and Haemostasis 4: 229–235.

    Article  CAS  PubMed  Google Scholar 

  49. Qu, D., Y. Wang, N.L. Esmon, and C.T. Esmon. 2007. Regulated endothelial protein C receptor shedding is mediated by tumor necrosis factor-alpha converting enzyme/ADAM17. Journal of Thrombosis and Haemostasis 5: 395–402.

    Article  CAS  PubMed  Google Scholar 

  50. Menschikowski, M., A. Hagelgans, G. Eisenhofer, and G. Siegert. 2009. Regulation of endothelial protein C receptor shedding by cytokines is mediated through differential activation of MAP kinase signaling pathways. Experimental Cell Research 315: 2673–2682.

    Article  CAS  PubMed  Google Scholar 

  51. Andersson, U., H. Wang, K. Palmblad, et al. 2000. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. Journal of Experimental Medicine 192: 565–570.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Hansson, G.K., and P. Libby. 2006. The immune response in atherosclerosis: A double-edged sword. Nature Reviews Immunology 6: 508–519.

    Article  CAS  PubMed  Google Scholar 

  53. Andersson, U., and K.J. Tracey. 2011. HMGB1 is a therapeutic target for sterile inflammation and infection. Annual Review of Immunology 29: 139–162.

    Article  CAS  PubMed  Google Scholar 

  54. Wang, F.P., L. Li, J. Li, J.Y. Wang, L.Y. Wang, and W. Jiang. 2013. High Mobility Group Box-1 Promotes the Proliferation and Migration of Hepatic Stellate Cells via TLR4-Dependent Signal Pathways of PI3K/Akt and JNK. Plops One 8: e64373.

    Article  CAS  Google Scholar 

  55. Locker, J.M., J.S. Colladay, W.L. Alperin-Lea, T. Hammond, and A.J. Buda. 1998. Inhibition of nuclear factor-kappaB-mediated adhesion molecule expression in human endothelial cells. Circulation Research 82: 314–320.

    Article  Google Scholar 

  56. Rose, B.A., T. Force, and Y. Wang. 2010. Mitogen-activated protein kinase signaling in the heart: Angels versus demons in a heart-breaking tale. Physiological Reviews 90: 1507–1546.

    Article  CAS  PubMed  Google Scholar 

  57. Park, J.S., F. Gamboni-Robertson, Q. He, et al. 2006. High mobility group box 1 protein interacts with multiple Toll-like receptors. American Journal of Physiology - Cellular Physiology 290: C917–924.

    Article  CAS  Google Scholar 

  58. Yang, H., and K.J. Tracey. 2010. Targeting HMGB1 in inflammation. Biochimica et Biophysica Acta 1799: 149–156.

    Article  CAS  PubMed  Google Scholar 

  59. Cohen, J. 2002. The immunopathogenesis of sepsis. Nature 420: 885–891.

    Article  CAS  PubMed  Google Scholar 

  60. Bhatia, M., M. He, H. Zhang, and S. Moochhala. 2009. Sepsis as a model of SIRS. Frontiers in Bioscience 14: 4703–4711.

    Article  CAS  Google Scholar 

  61. Tracey, K.J., Y. Fong, D.G. Hessen, et al. 1987. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330: 662–664.

    Article  CAS  PubMed  Google Scholar 

  62. Wichterman, K.A., A.E. Baue, and I.H. Chaudry. 1980. Sepsis and septic shock—A review of laboratory models and a proposal. Journal of Surgical Research 29: 189–201.

    Article  CAS  PubMed  Google Scholar 

  63. Wang, H., H. Yang, C.J. Czura, A.E. Sama, and K.J. Tracey. 2001. HMGB1 as a late mediator of lethal systemic inflammation. American Journal of Respiratory and Critical Care Medicine 164: 1768–1773.

    Article  CAS  PubMed  Google Scholar 

  64. Haggag, E.G., M.I.S. Abdelhady, and A.M. Kamal. 2013. Phenolic content of Ruprechtia salicifolia leaf and its immunomodulatory, anti-inflammatory, anticancer and antibacterial activity. Journal of Pharmacy Research 6: 696–703.

    Article  CAS  Google Scholar 

  65. Yoo, H., S.K. Ku, Y.D. Baek, and J.S. Bae. 2014. Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo. Inflammation Research 63: 197–206.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF), funded by the Korean government [MSIP] (Grant No. 2013-067053).

Conflict of Interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Anatomy and Histology, College of Korean Medicine, Daegu Haany University, Gyeongsan, 712-715, Republic of Korea

    Sae-Kwang Ku

  2. College of Pharmacy, Chungnam National University, Daejeon, 305-764, Republic of Korea

    Wei Zhou & MinKyun Na

  3. College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea

    Wonhwa Lee & Jong-Sup Bae

  4. Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, 702-701, Republic of Korea

    Wonhwa Lee

  5. Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital, Daegu, 701-600, Republic of Korea

    Min-Su Han

Authors
  1. Sae-Kwang Ku
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wonhwa Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Min-Su Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. MinKyun Na
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jong-Sup Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to MinKyun Na or Jong-Sup Bae.

Additional information

Sae-Kwang Ku, Wei Zhou, and Wonhwa Lee contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ku, SK., Zhou, W., Lee, W. et al. Anti-Inflammatory Effects of Hyperoside in Human Endothelial Cells and in Mice. Inflammation 38, 784–799 (2015). https://doi.org/10.1007/s10753-014-9989-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-014-9989-8

KEY WORDS

Search

Navigation