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The Antioxidant Effects of Isorhamnetin Contribute to Inhibit COX-2 Expression in Response to Inflammation: A Potential Role of HO-1

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Abstract

Previously, we reported that isorhamnentin, a 3′-O-methylated metabolite of quercetin, reduced inducible nitric oxide synthase (iNOS) expression and NO production. The present study further investigated the underlying mechanism of anti-inflammatory and antioxidant effects of isorhamnentin. Administration of isorhamnetin decreased the number of cyclooxygenase-2 (COX-2) positive cells in rats with carrageenan-induced paw edema. Isorhamnetin also suppressed lipopolysaccharide (LPS)-induced expression of COX-2 in cells. It is well known that LPS-induced reactive oxygen species (ROS) production leads to COX-2 induction. Isorhamnetin decreased LPS-induced ROS production and apoptosis. In addition, the basal expression of heme oxygenase-1 (HO-1) was increased by isorhamnetin treatment in agreement with the increase in nuclear translocation of NF-E2-related factor-2 (Nrf2), an essential transcription factor for the regulation of HO-1 expression. Moreover, pretreatment of tin protoporphyrin IX (SnPP), a chemical inhibitor of HO-1, reversed the ability of isothamnetin to inhibit COX-2 expression. These results demonstrate that induction of HO-1 by isorhamnetin leads to a reduction in ROS production and its antioxidant property might contribute to the inhibition of COX-2 expression in response to inflammation.

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Abbreviations

AMPK:

AMP-activated protein kinase

CO:

Carbon monoxide

COX-2:

Cyclooxygenase-2

DCFH-DA:

2′,7′-Dichlorofluorescein diacetate

HO-1:

Heme oxygenase-1

IKK:

IκB kinase

IκBα:

Inhibitory κB α

iNOS:

Inducible nitric oxide synthase

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

NAC:

N-Acetyl cystein

NADPH oxidase:

Nicotinamide adenine dinucleotide phosphate oxidase

NF-κB:

Nuclear factor-kappaB

Nrf2:

NF-E2-related factor-2

PGE2 :

Prostaglandin E2

PMA:

Phorbol 12-myristate 13-acetate

PPARγ:

Peroxisome proliferator-activated receptorγ

ROS:

Reactive oxygen species

SnPP:

Tin protoporphyrin IX

TLR:

Toll-like receptor

TNFα:

Tumor necrosis factor alpha

References

  1. Oberholzer, A., C. Oberholzer, and L.L. Moldawer. 2001. Sepsis syndromes: understanding the role of innate and acquired immunity. Shock 16: 83–96.

    Article  CAS  PubMed  Google Scholar 

  2. Rocha, V.Z., and P. Libby. 2009. Obesity, inflammation, and atherosclerosis. Nature Reviews Cardiology 6: 399–409.

    Article  CAS  PubMed  Google Scholar 

  3. Ben-Neriah, Y., and M. Karin. 2011. Inflammation meets cancer, with NF-[kappa]B as the matchmaker. Nature Immunology 12: 715–723.

    Article  CAS  PubMed  Google Scholar 

  4. Maling, H.M., M.E. Webster, M.A. Williams, W. Saul, and W. Anderson. 1974. Inflammation induced by histamine, serotonin, bradykinin and compound 48/80 in the rat: Antagonists and mechanisms of action. Journal of Pharmacology and Experimental Therapeutics 191: 300–310.

    CAS  PubMed  Google Scholar 

  5. Mosser, D.M., and J.P. Edwards. 2008. Exploring the full spectrum of macrophage activation. Nature Reviews Immunology 8: 958–969.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Cannon, P.J. 1984. Eicosanoids and the blood vessel wall. Circulation 70: 523–528.

    Article  CAS  PubMed  Google Scholar 

  7. Leslie, J.B., and W.D. Watkins. 1985. Eicosanoids in the central nervous system. Journal of Neurosurgery 63: 659–668.

    Article  CAS  PubMed  Google Scholar 

  8. Williams, C.S., M. Mann, and R.N. DuBois. 1999. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 18: 7908–7916.

    Article  CAS  PubMed  Google Scholar 

  9. Baeuerle, P.A., and D. Baltimore. 1996. NF-κB: Ten years after. Cell 87: 13–20.

    Article  CAS  PubMed  Google Scholar 

  10. Kiritoshi, S., T. Nishikawa, K. Sonoda, D. Kukidome, T. Senokuchi, T. Matsuo, T. Matsumura, H. Tokunaga, M. Brownlee, and E. Araki. 2003. Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: Potential role in diabetic nephropathy. Diabetes 52: 2570–2577.

    Article  CAS  PubMed  Google Scholar 

  11. Barbieri, S.S., S. Eligini, M. Brambilla, E. Tremoli, and S. Colli. 2003. Reactive oxygen species mediate cyclooxygenase-2 induction during monocyte to macrophage differentiation: Critical role of NADPH oxidase. Cardiovascular Research 60: 187–197.

    Article  CAS  PubMed  Google Scholar 

  12. Drummond, G.R., S. Selemidis, K.K. Griendling, and C.G. Sobey. 2011. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nature Reviews Drug Discovery 10: 453–471.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Cathcart, M.K. 2004. Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: Contributions to atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology 24: 23–28.

    Article  CAS  PubMed  Google Scholar 

  14. Li, N., M.I. Venkatesan, A. Miguel, R. Kaplan, C. Gujuluva, J. Alam, and A. Nel. 2000. Induction of heme oxygenase-1 expression in macrophages by diesel exhaust particle chemicals and quinones via the antioxidant-responsive element. The Journal of Immunology 165: 3393–3401.

    Article  CAS  PubMed  Google Scholar 

  15. Ryter, S.W., and A.M. Choi. 2005. Heme oxygenase-1: Redox regulation of a stress protein in lung and cell culture models. Antioxidants and Redox Signaling 7: 80–91.

    Article  CAS  PubMed  Google Scholar 

  16. Zabalgoitia, M., J.T. Colston, S.V. Reddy, J.W. Holt, R.F. Regan, D.E. Stec, J.M. Rimoldi, A.J. Valente, and B. Chandrasekar. 2008. Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB–PTEN-dependent human cardiac endothelial cell death. Free Radical Biology and Medicine 44: 284–298.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Li, X., M.G. Schwacha, I.H. Chaudry, and M.A. Choudhry. 2008. Heme oxygenase-1 protects against neutrophil-mediated intestinal damage by down-regulation of neutrophil p47phox and p67phox activity and O2 − production in a two-hit model of alcohol intoxication and burn injury. The Journal of Immunology 180: 6933–6940.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Pengfei, L., D. Tiansheng, H. Xianglin, and W. Jianguo. 2009. Antioxidant properties of isolated isorhamnetin from the sea buckthorn marc. Plant Foods for Human Nutrition 64: 141–145.

    Article  PubMed  Google Scholar 

  19. Teng, B.-S., Y.-H. Lu, Z.-T. Wang, X.-Y. Tao, and D.-Z. Wei. 2006. In vitro anti-tumor activity of isorhamnetin isolated from Hippophae rhamnoides L. against BEL-7402 cells. Pharmacological Research 54: 186–194.

    Article  CAS  PubMed  Google Scholar 

  20. Yang, J.H., S.C. Kim, B.Y. Shin, S.H. Jin, M.J. Jo, K.H. Jegal, Y.W. Kim, J.R. Lee, S.K. Ku, I.J. Cho, and S.H. Ki. 2013. O-methylated flavonol isorhamnetin prevents acute inflammation through blocking of NF-κB activation. Food and Chemical Toxicology 59: 362–372.

    Article  CAS  PubMed  Google Scholar 

  21. Kang, T.J., J.S. Moon, S.K. Lee, and D.S. Yim. 2011. Polyacetylene compound from Cirsium japonicum var. ussuriense inhibits the LPS-induced inflammatory reaction via suppression of NF-κB activity in RAW 264.7 cells. Biomolecules & Therapeutics 19: 97–101.

    Article  CAS  Google Scholar 

  22. Lim, H.J., H. Li, J.Y. Kim, and J.H. Ryu. 2011. Quercetin derivatives from Siegesbeckia glabrescens inhibit the expression of COX-2 through the suppression of NF-κB activation in microglia. Biomolecules & Therapeutics 19: 27–32.

    Article  CAS  Google Scholar 

  23. Jaeschke, H. 2000. Reactive oxygen and mechanisms of inflammatory liver injury. Journal of Gastroenterology and Hepatology 15: 718–724.

    Article  CAS  PubMed  Google Scholar 

  24. Park, H.S., H.Y. Jung, E.Y. Park, J. Kim, W.J. Lee, and Y.S. Bae. 2004. Cutting edge: Direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-κB. The Journal of Immunology 173: 3589–3593.

    Article  CAS  PubMed  Google Scholar 

  25. Sanchez, M., F. Lodi, R. Vera, I.C. Villar, A. Cogolludo, R. Jimenez, L. Moreno, M. Romero, J. Tamargo, F. Perez-Vizcaino, and J. Duarte. 2007. Quercetin and isorhamnetin prevent endothelial dysfunction, superoxide production, and overexpression of p47phox induced by angiotensin II in rat aorta. The Journal of Nutrition 137: 910–915.

    CAS  PubMed  Google Scholar 

  26. Cha, J.Y., J.Y. Jung, J.Y. Jung, J.R. Lee, I.J. Cho, S.K. Ku, S.H. Byun, Y.-T. Ahn, C.W. Lee, S.C. Kim, and W.G. An. 2013. Inhibitory effects of traditional herbal formula Pyungwi-San on inflammatory response in vitro and in vivo. Evidence-Based Complementary and Alternative Medicine 2013: 1–19.

    Article  Google Scholar 

  27. Sohn, K.H., M.J. Jo, W.J. Cho, J.R. Lee, I.J. Cho, S.C. Kim, Y.W. Kim, and S.Y. Jee. 2012. Bojesodok-eum, a herbal prescription, ameliorates acute inflammation in association with the inhibition of NF-B-mediated nitric oxide and proinflammatory cytokine production. Evidence-Based Complementary and Alternative Medicine 2012: 12.

    Article  Google Scholar 

  28. Huang, S.-S., C.-S. Chiu, T.-H. Lin, M.-M. Lee, C.-Y. Lee, S.-J. Chang, W.-C. Hou, G.-J. Huang, and J.-S. Deng. 2013. Antioxidant and anti-inflammatory activities of aqueous extract of Centipeda minima. Journal of Ethnopharmacology 147: 395–405.

    Article  CAS  PubMed  Google Scholar 

  29. Higgs, G.A., K.E. Eakins, K.G. Mugridge, S. Moncada, and J.R. Vane. 1980. The effects of non-steroid anti-inflammatory drugs on leukocyte migration in carrageenin-induced inflammation. European Journal of Pharmacology 66: 81–86.

    Article  CAS  PubMed  Google Scholar 

  30. Almeida, A.P., B.M. Bayer, Z. Horakova, and M.A. Beaven. 1980. Influence of indomethacin and other anti-inflammatory drugs on mobilization and production of neutrophils: studies with carrageenan-induced inflammation in rats. Journal of Pharmacology and Experimental Therapeutics 214: 74–79.

    CAS  PubMed  Google Scholar 

  31. Handy, R.L.C., and P.K. Moore. 1998. A comparison of the effects of l-NAME, 7-NI and l-NIL on carrageenan-induced hindpaw oedema and NOS activity. British Journal of Pharmacology 123: 1119–1126.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Nantel, F., D. Denis, R. Gordon, A. Northey, M. Cirino, K.M. Metters, and C.C. Chan. 1999. Distribution and regulation of cyclooxygenase-2 in carrageenan-induced inflammation. British Journal of Pharmacology 128: 853–859.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Old, L. 1985. Tumor necrosis factor (TNF). Science 230: 630–632.

    Article  CAS  PubMed  Google Scholar 

  34. Wagener, F.A.D.T.G., H.-D. Volk, D. Willis, N.G. Abraham, M.P. Soares, G.J. Adema, and C.G. Figdor. 2003. Different faces of the heme-heme oxygenase system in inflammation. Pharmacological Reviews 55: 551–571.

    Article  CAS  PubMed  Google Scholar 

  35. Kapturczak, M.H., C. Wasserfall, T. Brusko, M. Campbell-Thompson, T.M. Ellis, M.A. Atkinson, and A. Agarwal. 2004. Heme oxygenase-1 modulates early inflammatory responses: Evidence from the heme oxygenase-1-deficient mouse. The American Journal of Pathology 165: 1045–1053.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Nakahira, K., H.P. Kim, X.H. Geng, A. Nakao, X. Wang, N. Murase, P.F. Drain, X. Wang, M. Sasidhar, E.G. Nabel, T. Takahashi, N.W. Lukacs, S.W. Ryter, K. Morita, and A.M.K. Choi. 2006. Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts. The Journal of Experimental Medicine 203: 2377–2389.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Park, E.J., Y.M. Kim, S.W. Park, H.J. Kim, J.H. Lee, D.-U. Lee, and K.C. Chang. 2013. Induction of HO-1 through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice. Food and Chemical Toxicology 55: 386–395.

    Article  CAS  PubMed  Google Scholar 

  38. Motterlini, R., R. Foresti, R. Bassi, and C.J. Green. 2000. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radical Biology and Medicine 28: 1303–1312.

    Article  CAS  PubMed  Google Scholar 

  39. Chung, S.W., Y.-H. Chen, S.-F. Yet, M.D. Layne, and M.A. Perrella. 2006. Endotoxin-induced down-regulation of Elk-3 facilitates heme oxygenase-1 induction in macrophages. The Journal of Immunology 176: 2414–2420.

    Article  CAS  PubMed  Google Scholar 

  40. Kim, K.H., J.H. Lyu, S.T. Koo, S.-R. Oh, H.-K. Lee, K.-S. Ahn, R.T. Sadikot, and M. Joo. 2011. MyD88 is a mediator for the activation of Nrf2. Biochemical and Biophysical Research Communications 404: 46–51.

    Article  CAS  PubMed  Google Scholar 

  41. Yang, J.H., Shin, B.Y., Han, J.Y., Kim, M.G., Wi, J.E., Kim, Y.W., Cho, I.J., Kim, S.C., Shin, S.M., and Ki, S.H. Isorhamnetin protects against oxidative stress by activating Nrf2 and inducing the expression of its target genes. Toxicology and Applied Pharmacology. doi:10.1016/j.taap.2013.10.026.

  42. Mo, C., Wang, L., Zhang, J., Numazawa, S., Tang, H., Tang, X., Han, X., Li, J., Yang, M., Wang, Z., Wei, D., and Xiao, H. 2013. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxidants and Redox Signaling. doi:10.1089/ars.2012.5116.

  43. Karin, M., Y. Cao, F.R. Greten, and Z.-W. Li. 2002. NF-κB in cancer: From innocent bystander to major culprit. Nature Reviews Cancer 2: 301–310.

    Article  CAS  PubMed  Google Scholar 

  44. Piskula, M.K., and J. Terao. 1998. Accumulation of (−)-epicatechin metabolites in rat plasma after oral administration and distribution of conjugation enzymes in rat tissues. The Journal of Nutrition 128: 1172–1178.

    CAS  PubMed  Google Scholar 

  45. Lan, K., X. Jiang, and J. He. 2007. Quantitative determination of isorhamnetin, quercetin and kaempferol in rat plasma by liquid chromatography with electrospray ionization tandem mass spectrometry and its application to the pharmacokinetic study of isorhamnetin. Rapid Communications in Mass Spectrometry 21: 112–120.

    Article  CAS  PubMed  Google Scholar 

  46. Ader, P., A. Wessmann, and S. Wolffram. 2000. Bioavailability and metabolism of the flavonol quercetin in the pig. Free Radical Biology and Medicine 28: 1056–1067.

    Article  CAS  PubMed  Google Scholar 

  47. Lin, W.-N., C.-C. Lin, H.-Y. Cheng, and C.-M. Yang. 2011. Regulation of cyclooxygenase-2 and cytosolic phospholipase A2 gene expression by lipopolysaccharide through the RNA-binding protein HuR: Involvement of NADPH oxidase, reactive oxygen species and mitogen-activated protein kinases. British Journal of Pharmacology 163: 1691–1706.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Ramachandran, L., K.A. Manu, M.K. Shanmugam, F. Li, K.S. Siveen, S. Vali, S. Kapoor, T. Abbasi, R. Surana, D.T. Smoot, H. Ashktorab, P. Tan, K.S. Ahn, C.W. Yap, A.P. Kumar, and G. Sethi. 2012. Isorhamnetin inhibits proliferation and invasion and induces apoptosis through the modulation of peroxisome proliferator-activated receptor γ activation pathway in gastric cancer. Journal of Biological Chemistry 287: 38028–38040.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Marx, N., B. Kehrle, K. Kohlhammer, M. Grüb, W. Koenig, V. Hombach, P. Libby, and J. Plutzky. 2002. PPAR activators as antiinflammatory mediators in human T lymphocytes: Implications for atherosclerosis and transplantation-associated arteriosclerosis. Circulation Research 90: 703–710.

    Article  CAS  PubMed  Google Scholar 

  50. von Knethen, A., H. Neb, V. Morbitzer, M.V. Schmidt, A.-M. Kuhn, L. Kuchler, and B. Brüne. 2011. PPARγ stabilizes HO-1 mRNA in monocytes/macrophages which affects IFN-β expression. Free Radical Biology and Medicine 51: 396–405.

    Article  Google Scholar 

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Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (Grant Number: 2012R1A1A1011956).

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Authors and Affiliations

  1. College of Pharmacy, Chosun University, Gwangju, 501-759, South Korea

    Kyuhwa Seo, Ji Hye Yang, Sung Hwan Ki & Sang Mi Shin

  2. Medical Research Center for Globalization of Herbal Formulation, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeonsangbukdo, 712-715, South Korea

    Sang Chan Kim & Sae Kwang Ku

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  1. Kyuhwa Seo
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  2. Ji Hye Yang
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  3. Sang Chan Kim
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Correspondence to Sang Mi Shin.

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K. Seo and J.H. Yang contributed equally to this work.

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Seo, K., Yang, J.H., Kim, S.C. et al. The Antioxidant Effects of Isorhamnetin Contribute to Inhibit COX-2 Expression in Response to Inflammation: A Potential Role of HO-1. Inflammation 37, 712–722 (2014). https://doi.org/10.1007/s10753-013-9789-6

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