Journal of Natural Medicines

, Volume 73, Issue 1, pp 244–251 | Cite as

Shikonofuran E plays an anti-inflammatory role by down-regulating MAPK and NF-κB signaling pathways in lipopolysaccharide-stimulated RAW264.7 macrophages

  • Lang Cao
  • Yong Xue
  • Zixiong Yang
  • Yanhong Li
  • Hongmei Li
  • Xuanqin Chen
  • Rongtao Li
  • Dan Liu


The anti-inflammatory effects of shikonofuran E from Onosma paniculatum on RAW 264.7 murine macrophage cells induced by lipopolysaccharide (LPS) were first time examined. A series of non-cytotoxic concentrations of shikonofuran E (< 10 μM) treatments were found to reduce the accumulation of pro-inflammatory cytokine, including tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), interleukin-1β (IL-1β), and inhibit the expression of nitric oxide synthase (iNOS) and cyclooxidase-2 (COX-2) in the LPS-stimulated macrophages as compared to the LPS-only treated cells. Nitric oxide (NO) production was also significantly suppressed in a dose-dependent manner (P < 0.05) with an IC50, the phosphorylation level of JNK of 3.5 µg/mL. In the anti-inflammatory pathway studies, ERK, p38 and IκBα were also decreased by shikonofuran E at 10 μM, in spite of the total levels of the MAPK isoforms and IκBα did not differ significantly. Our results indicate that shikonofuran E could exert an anti-inflammatory effect on LPS-induced RAW264.7 cells by down-regulating MAPK and NF-κB signaling pathways and regulating a series of cytokine production in lipopolysaccharide-stimulated RAW264.7 macrophages.


Shikonofuran E Onosma paniculatum Anti-inflammatory Inflammatory mediators Inflammatory signaling pathway 



This research work was financially supported by the grant from the National Natural Science Foundation of China (No. 21572082), the Fund of State Key Laboratory of Phytochemistry and Plant Resources in West China (No. P2015-KF01), the College Students Innovation and Entrepreneurship Training Program in Yunnan Province (No. 201610674082).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Dong M, Liu D, Li YH, Chen XQ, Luo K, Zhang YM, Li RT (2017) Naphthoquinones from onosma paniculatum with potential anti-inflammatory activity. Planta Med 83:631–635Google Scholar
  2. 2.
    Kumar N, Kumar R, Kishore K (2013) Onosma L.: a review of phytochemistry and ethnopharmacology. Pharmacogn Rev 7:140–151CrossRefGoogle Scholar
  3. 3.
    Yoo HG, Lee BH, Kim W, Lee JS, Kim GH, Chun OK, Koo SI, Kim DO (2014) Lithospermum erythrorhizon extract protects keratinocytes and fibroblasts against oxidative stress. J Med Food 17:1189–1196CrossRefGoogle Scholar
  4. 4.
    Choi WH, Hong SS, Lee SA, Xiang HH, Lee KS, Lee MK, Bang YH, Ro JS (2005) Monoamine oxidase inhibitory naphthoquinones from the roots of lithospermum erythrorhizon. Arch Pharm Res 28:400–404CrossRefGoogle Scholar
  5. 5.
    Ji YK, Jeong HJ, Park JY, Kim YM, Park SJ, Cho JK, Park KH, Ryu YB, Lee WS (2012) Selective and slow-binding inhibition of shikonin derivatives isolated from Lithospermum erythrorhizon on glycosyl hydrolase 33 and 34 sialidases. Bioorganic Med Chem 20:1740–1748CrossRefGoogle Scholar
  6. 6.
    Machelska H, Schopohl JK, Mousa SA, Labuz D, Schäfer M, Stein C (2003) Different mechanisms of intrinsic pain inhibition in early and late inflammation. J Neuroimmunol 141:30–39CrossRefGoogle Scholar
  7. 7.
    Iwaszkiewicz KS, Schneider JJ, Hua S (2013) Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions. Front Pharmacol 4:132CrossRefGoogle Scholar
  8. 8.
    Wallert M, Schmölz L, Koeberle A, Krauth V, Glei M, Galli F, Werz O, Birringer M, Lorkowski S (2015) α-Tocopherol long-chain metabolite α-13′-COOH affects the inflammatory response of lipopolysaccharide-activated murine RAW264.7 macrophages. Mol Nutr Food Res 59:1524–1534CrossRefGoogle Scholar
  9. 9.
    Kim MS, Ahn EK, Hong SS, Oh JS (2015) 2,8-Decadiene-1,10-diol inhibits lipopolysaccharide-induced inflammatory responses through inactivation of mitogen-activated protein kinase and nuclear Factor-κB Signaling Pathway. Inflammation 39:1–9Google Scholar
  10. 10.
    Ci X, Ren R, Xu K, Li H, Yu Q, Song Y, Wang D, Li R, Deng X (2010) Schisantherin a exhibits anti-inflammatory properties by down-regulating NF-κB and MAPK signaling pathways in lipopolysaccharide-treated RAW 264.7 cells. Inflammation 33:126–136CrossRefGoogle Scholar
  11. 11.
    Ng LT, Ko HJ (2012) Comparative effects of tocotrienol-rich fraction, α-tocopherol and α-tocopheryl acetate on inflammatory mediators and nuclear factor kappa B expression in mouse peritoneal macrophages. Food Chem 134:920–925CrossRefGoogle Scholar
  12. 12.
    Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335CrossRefGoogle Scholar
  13. 13.
    Cao L, Li R, Chen X, Xue Y, Liu D (2016) Neougonin a inhibits lipopolysaccharide-induced inflammatory responses via downregulation of the NF-kB signaling pathway in RAW 264.7 macrophages. Inflammation 39:1939–1948CrossRefGoogle Scholar
  14. 14.
    Fan Y, Sun L, Yang S, He C, Tai G, Zhou Y (2018) The roles and mechanisms of homogalacturonan and rhamnogalacturonan I pectins on the inhibition of cell migration. Int J Biol Macromol 106:207–217CrossRefGoogle Scholar
  15. 15.
    Su JJ, Son KH, Kim YS, Yong HC, Kim HP (2008) Inhibition of prostaglandin and nitric oxide production in lipopolysaccharide-treated RAW 264.7 cells by tanshinones from the roots of Salvia miltiorrhiza bunge. Arch Pharm Res 31:758–763CrossRefGoogle Scholar
  16. 16.
    Kim SH, Park JG, Lee J, Yang WS, Park GW, Kim HG, Yi YS, Baek KS, Sung NY, Hossen MJ (2015) The dietary flavonoid Kaempferol mediates anti-inflammatory responses via the Src, Syk, IRAK1, and IRAK4 molecular targets. Mediat Inflamm 2015:1–15Google Scholar
  17. 17.
    Yang WS, Son YJ, Kim MY, Kim S, Kim JH, Cho JY (2015) AP-1-targeted anti-inflammatory activities of the nanostructured, self-assembling S5 peptide. Mediat Inflamm 2015:1–9Google Scholar
  18. 18.
    Cheng X, Gao D, Chen B, Mao X (2015) Endotoxin-binding peptides derived from casein glycomacropeptide inhibit lipopolysaccharide-stimulated inflammatory responses via blockade of NF-κB activation in macrophages. Nutrients 7:3119–3137CrossRefGoogle Scholar
  19. 19.
    Li L, Wang L, Wu Z, Yao L, Wu Y, Huang L, Liu K, Zhou X, Gou D (2014) Anthocyanin-rich fractions from red raspberries attenuate inflammation in both RAW264.7 macrophages and a mouse model of colitis. Sci Rep 4:6234–6234CrossRefGoogle Scholar
  20. 20.
    Chae HS, Kang OH, Keum JH, Kim SB, Mun SH, Seo YS, Kim MR, Choi JG, Shin DW, Oh YC (2012) Anti-inflammatory effects of hylomecon hylomeconoides in RAW 264.7 cells. Eur Rev Med Pharmacol Sci 16(Suppl 3):121–125Google Scholar
  21. 21.
    Qi M, Elion EA (2005) MAP kinase pathways. J Cell Sci 118:3569–3572CrossRefGoogle Scholar
  22. 22.
    Pearson G, Robinson F, Beers GT, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:732–737Google Scholar
  23. 23.
    Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ (1996) MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen- activated protein kinase signal transduction pathway. Mol Cell Biol 16:1247–1255CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Medicinal Chemistry, Faculty of Life Science and TechnologyKunming University of Science and TechnologyKunmingPeople’s Republic of China

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