DOI QR코드

DOI QR Code

Inhibitory Effect of Scopoletin Isolated from Sorbus commixta on TNF-α-Induced Inflammation in Human Vascular Endothelial EA.hy926 Cells through NF-κB Signaling Pathway Suppression

마가목 수피에서 분리한 scopoletin의 EA.hy926 혈관내피세포에서 NF-κB 신호전달을 통한 TNF-α로 유도된 혈관염증 저해 효과

  • Kang, Hye Ryung (National Institute for Korean Medicine Development) ;
  • Kim, Hyo Jung (National Institute for Korean Medicine Development) ;
  • Kim, Bomi (National Institute for Korean Medicine Development) ;
  • Kim, Sun-Gun (National Institute for Korean Medicine Development) ;
  • So, Jai-Hyun (National Institute for Korean Medicine Development) ;
  • Cho, Soo Jeong (Department of Pharmaceutical Engineering, Gyeongnam National University of Science and Technology) ;
  • Kwon, Hyun Sook (National Institute for Korean Medicine Development)
  • Received : 2020.01.06
  • Accepted : 2020.02.24
  • Published : 2020.04.30

Abstract

Sorbus commixta Hedl. has traditionally been used as a remedy for cough, asthma, and other bronchial disorders. In this study, three major triterpenoids-lupeol, β-sitosterol, and ursolic acid and a coumarin, scopoletin, were isolated from a CHCl3-soluble fragment of the bark of S. commixta. Their structures were identified by spectroscopic analyses, including mass spectrometry (MS), 1D-, and 2D- nuclear magnetic resonance spectroscopy (NMR), as well as by comparing the data with data reported in the literature. Scopoletin was isolated from this plant for the first time. It is a nutraceutical compound contained in many plants that has been reported to exert diverse biological activities, including anti-inflammatory effects. This study examined the inhibitory effect of scopoletin on TNF-α-induced vascular endothelial inflammation. Unlike the marginal impact of other compounds against low-density lipoprotein (LDL) oxidation and vascular endothelial inflammation, scopoletin showed remarkable activity on LDL oxidation (IC50 = 10.2 μM) and exerted vascular anti-inflammatory effects in EA.hy926 human endothelial cells activated by TNF-α. It suppressed the expression of adhesion molecules, such as ICAM-1, VCAM-1, and E-selectin, and blocked the adhesion between THP-1 monocytes and EA. hy926 endothelial cells. It also inhibited TNF-α-induced NF-κB translocation from the cytosol to the nucleus. Moreover, IκBα phosphorylation, which was increased by TNF-α treatment, was reduced after treatment with scopoletin. Thus, scopoletin inhibited TNF-α-induced vascular inflammation in endothelial cells by suppressing the NF-κB signaling pathway. These results demonstrate that owing to its anti-inflammatory activity in the vascular endothelium, scopoletin has the potential to inhibit atherosclerosis development.

References

  1. Bae, J. T., Shim, G. S., Kim, J. H., Pyo, H. B., Yun, J. W. and Lee, B. C. 2007. Antioxidative activity of the hydrolytic enzyme treated Sorbus commixta Hedl. and its inhibitory effect on matrix metalloproteinase-1 in UV irradiated human dermal fibroblasts. Arch. Pharm. Res. 30, 1116-1123.
  2. Baeuerle, P. A. and Baltimore, D. 1988. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science 242, 540-546.
  3. Bosshart, H. and Heinzelmann, M. 2016. THP-1 cells as a model for human monocytes. Ann. Transl. Med. 4, 438.
  4. Chang, H. C., Yang, H. L., Pan, J. H, Korivi, M., Pan, J. Y., Hsieh, M. C., Chao, P. M., Huang, P. J., Tsai, C. T. and Hseu, Y. C. 2016. Hericium erinaceus inhibits TNF-$\alpha$-induced angiogenesis and ROS generation through suppression of MMP-9/NF-${\kappa}B$ signaling and activation of Nrf2-mediated antioxidant genes in human EA.hy926 endothelial cells. Oxid. Med. Cell Longev. 2016, 1-15.
  5. Cheng, A. S., Cheng, Y. H. and Chang, T. L. 2012. Scopoletin attenuates allergy by inhibiting Th2 cytokines production in EL-4T cells. Food Funct. 3, 886-890.
  6. Cho, Y. S., Kim, C. H., Ha, T. S., Lee, S. J. and Ahn, H. Y. 2013. Ginsenoside Rg2 inhibits lipopolysaccharide-induced adhesion molecule expression in human umbilical vein endothelial cell. Kor. J. Physiol. Pharmacol. 17, 133-137.
  7. De Martin, R., Hoeth, M., Hofer-Warbinek, R. and Schmid, J. A. 2000. The transcription factor NF-${\kappa}B$ and the regulation of vascular cell function. Arterioscler. Thromb. Vasc. Biol. 20, 83-88.
  8. Della Greca, M., Monaco, P. and Previtera, L. 1990. Stigmasterols from Typha latifolia. J. Nat. Prod. 53, 1430-1435.
  9. Frostegard, J., Haegerstrand, A., Gidlund, M. and Nilsson, J. 1991. Biologically modified LDL increases the adhesive properties of endothelial cells. Atherosclerosis 90, 119-126.
  10. Hien, T. T., Kim, N. D., Kim, H. S. and Kang, K. W. 2010. Ginsenoside Rg3 inhibits tumor necrosis factor-$\alpha$-induced expression of cell adhesion molecules in human endothelial cells. Pharmazie 65, 699-701.
  11. Kim, D. H., Bang, M. H., Song, M. C., Kim, S. U., Chang, Y. J. and Baek, N. I. 2005. Isolation of $\beta$-sitosterol, phytol and zingerone 4-O-$\beta$-D-glucopyranoside from Chrysanthemum Boreale Makino. Kor. J. Medicinal Crop Sci. 13, 284-287.
  12. Kim, D. K., Nam, I. Y., Kim, J. W., Shin, T. Y. and Lim, J. P. 2002. Pentacyclic triterpenoids from IIex macropoda. Arch. Pharm. Res. 25, 617-620.
  13. Lee, S. G. and Kim, M. M. 2015. Anti-inflammatory Effect of Scopoletin in RAW264.7 macrophages. J. Life Sci. 25, 1377-1383.
  14. Lee, S. O., Lee, H. W., Lee, I. S. and Im, H. G. 2006. The pharmacological potential of Sorbus commixta cortex on blood alcohol concentration and hepatic lipid peroxidation in acute alcohol-treated rats. J. Pharm. Pharmacol. 58, 685-893.
  15. Na, M., An, R. B., Min, B. S., Lee, S. M., Kim, Y. H. and Bae, K. 2002. Chemical constituents from Sorbus commixta. Nat. Prod. Sci. 8, 62-65.
  16. Nam, J. H., Choi, S. Z. and Lee, K. R. 2004. Phytochemical constituents of Synurus excelsus. Kor. J. Pharmacogen. 35, 116-121.
  17. Pan, R., Gao, X. H., Lu, D., Xu, X., Xia, Y. and Dai, Y. 2011. Prevention of FGF-2-induced angiogenesis by scopoletin, a coumarin compound isolated from Erycibe obtusifolia Benth, and its mechanism of action. Int. J. Immunopharmacol. 11, 2007-2016.
  18. Park, S. W., Yook, C. S. and Lee, H. K. 1994. Chemical components from the fruits of Crataegus pinnatifida var. psilosa. Kor. J. Pharmacogen. 25, 328-335.
  19. Price, D. T. and Loscalzo, J. 1999. Cellular adhesion molecules and atherogenesis. Am. J. Med. 107, 85-97.
  20. Ross, R. 1999. Atherosclerosis-an inflammatory disease. N. Engl. J. Med. 340, 115-126.
  21. Sohn, E. J., Kang, D. G., Mun, Y. J., Woo, W. H. and Lee, H. S. 2005a. Anti-atherogenic effects of the methanol extract of Sorbus cortex in atherogenic-diet rats. Biol. Pharmaceut. Bull. 28, 1444-1449.
  22. Sohn, E. J., Kang, D. G., Choi, D. H., Lee, A. S., Mun, Y. J., Woo, W. H., Kim, J. S. and Lee, H. S. 2005b. Effect of methanol extract of Sorbus cortex in rat model of L-NAMEinduced atherosclerosis. Biol. Pharmaceut. Bull. 28, 1239-1243.
  23. Yin, M. H., Kang, D. G., Choi, D. H., Kwon, T. O. and Lee, H. S. 2005. Screening of vasorelaxant activity of some medicinal plants used in Oriental medicines. J. Ethnopharmacol. 99, 113-117.
  24. Yu, T., Lee, Y. J., Jang, H. J., Kim, A. R., Hong, S., Kim, T. W., Kim, M. Y., Lee, J., Lee, Y. G. and Cho, J. Y. 2011. Anti-inflammatory activity of Sorbus commixta water extract and its molecular inhibitory mechanism. J. Ethnopharmacol. 134, 493-500.
  25. Zhang, L., Zhang, H., Li, X., Jia, B., Yang, Y., Zhou, P., Li, P. and Chen, J. 2016. Miltirone protects human EA.hy926 endothelial cells from oxidized low-density lipoprotein-derived oxidative stress via a heme oxygenase-1 and MAPK/Nrf2 dependent pathway. Phytomedicine 23, 1806-1813.
  26. Zhou, P., Xie, W., Luo, Yun., Lu, Shan., Dai, Ziru., Wang, R., Sun, G. and Sun, X. 2019. Protective effects of total saponins of Aralia elata (Miq.) on endothelial cell injury induced by TNF-$\alpha$ via modulation of the PI3K/Akt and NF-${\kappa}B$ signaling pathways. Int. J. Mol. Sci. 20, 36.
  27. Zhu, L., Yang, X. P., Janic, B., Rhaleb, N. E., Harding, P., Nakagawa, P., Peterson, E. L. and Carretero, O. A. 2016. Ac-SDKP suppresses TNF-$\alpha$-induced ICAM-1 expression in endothelial cells via inhibition of $I{\kappa}B$ kinase and NF-${\kappa}B$ activation. Am. J. Physiol. Heart Circ. Physiol. 310, 1176-1183.