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Lignans from Saururus chinensis exhibit anti-inflammatory activity by influencing the Nrf2/HO-1 activation pathway

  • Yeon Woo Jung
  • Bo Mi Lee
  • Manh Tuan Ha
  • Manh Hung Tran
  • Jeong Ah Kim
  • Suhyun Lee
  • Jeong Hyung LeeEmail author
  • Mi Hee Woo
  • Byung Sun MinEmail author
Research Article
  • 143 Downloads

Abstract

As part of our ongoing program to develop anti-inflammatory agents, an extract derived from Saururus chinensis collected in Korea was found to inhibit nitric oxide (NO) production in RAW264.7 cells. Bioassay-guided fractionation led to the isolation two new (1 and 2) and six known dineolignans (38). To the best of our knowledge, manassatin B1 (3) was isolated from S. chinensis for the first time. All structures were elucidated using extensive spectroscopic analysis. Of these compounds, 2 and 8 inhibited lipopolysaccharide (LPS)-induced production of NO and showed IC50 values of 5.80 and 1.52 µM, respectively. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) was also significantly suppressed by the administration of 2 and 8. In addition, these lignans induced the expression of heme oxygenase-1 (HO-1) in a concentration-dependent manner. Nuclear translocation of nuclear-E2-related factor 2 (Nrf2), a key regulator of HO-1 protein expression, was also induced in RAW264.7 cells treated with 2 and 8. These findings suggested that these lignans exerted anti-inflammatory effects in RAW264.7 cells through modulation of the Nrf2/HO-1 pathway and that they were potential HO-1 inducers for preventing or treating inflammation.

Keywords

Saururus chinensis Saururaceae Lignan Anti-inflammatory Nrf2 HO-1 

Notes

Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF-2016R1D1A1B03930246) by the Ministry of Education, Korea. We are grateful to the Korea Basic Science Institute (KBSI) for mass spectrometric measurements.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

12272_2018_1093_MOESM1_ESM.doc (6.2 mb)
Supplementary material 1 (DOC 6380 kb)

References

  1. Boyanapalli SSS, Paredes-Gonzalez X, Fuentes F, Zhang C, Guo Y, Pung D, Saw CLL, Kong A-NT (2014) Nrf2 knockout attenuates the anti-inflammatory effects of phenethyl isothiocyanate and curcumin. Chem Res Toxicol 27:2036–2043CrossRefGoogle Scholar
  2. Chin YW, Cai XF, Ahn KS, Lee HK, Oh SR (2010) Cytotoxic sesquilignans from the roots of Saururus chinensis. Bull Korean Chem Soc 31:2088–2090CrossRefGoogle Scholar
  3. Choo YY, Lee S, Nguyen PH, Lee W, Woo MH, Min BS, Lee JH (2015) Caffeoylglycolic acid methyl ester, a major constituent of sorghum, exhibits anti-inflammatory activity via the Nrf2/heme oxygenase-1 pathway. RSC Adv 5:17786–17796CrossRefGoogle Scholar
  4. Cui H, Xu B, Wu T, Xu J, Yuan Y, Gu Q (2013) Potential antiviral lignans from the roots of Saururus chinensis with activity against Epstein-Barr virus lytic replication. J Nat Prod 77:100–110CrossRefGoogle Scholar
  5. Gao X, He J, Wu XD, Peng LY, Dong LB, Deng X, Li Y, Cheng X, Zhao QS (2013) Further lignans from Saururus chinensis. Planta Med 79:1720–1723CrossRefGoogle Scholar
  6. Ha MT, Phan TN, Kim JA, Oh WK, Lee JH, Woo MH, Min BS (2018) Trichosanhemiketal A and B: two 13,14-seco-13,14-epoxyporiferastanes from the root of Trichosanthes kirilowii Maxim. Bioorg Chem 83:105–110CrossRefGoogle Scholar
  7. Hahm JC, Lee IK, Kang WK, Kim SU, Ahn YJ (2005) Cytotoxicity of neolignans identified in Saururus chinensis towards human cancer cell lines. Planta Med 71:464–469CrossRefGoogle Scholar
  8. Hai Dang N, Choo YY, Tien Dat N, Hoai Nam N, Van Minh C, Lee JH (2016) 7-Methoxy-(9H-β-carbolin-1-il)-(E)-1-propenoic acid, a β-carboline alkaloid from Eurycoma longifolia, exhibits anti-inflammatory effects by activating the Nrf2/Heme oxygenase-1 pathway. J Cell Biochem 117:659–670CrossRefGoogle Scholar
  9. Hanessian S, Reddy GJ, Chahal N (2006) Total synthesis and stereochemical confirmation of manassantin A, B, and B1. Org Lett 8:5477–5480CrossRefGoogle Scholar
  10. Hodges TW, Hossain CF, Kim YP, Zhou YD, Nagle DG (2004) Molecular-targeted antitumor agents: the Saururus cernuus dineolignans manassantin B and 4-O-demethylmanassantin B are potent inhibitors of hypoxia-activated HIF-1. J Nat Prod 67:767–771CrossRefGoogle Scholar
  11. Hossain CF, Kim Y-P, Baerson SR, Zhang L, Bruick RK, Mohammed KA, Agarwal AK, Nagle DG, Zhou Y-D (2005) Saururus cernuus lignans—potent small molecule inhibitors of hypoxia-inducible factor-1. Biochem Biophys Res Commun 333:1026–1033CrossRefGoogle Scholar
  12. Hwang BY, Lee JH, Nam JB, Hong YS, Lee JJ (2003) Lignans from Saururus chinensis inhibiting the transcription factor NF-κB. Phytochemistry 64:765–771CrossRefGoogle Scholar
  13. Jaramillo MC, Zhang DD (2013) The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev 27:2179–2191CrossRefGoogle Scholar
  14. Kapturczak MH, Wasserfall C, Brusko T, Campbell-Thompson M, Ellis TM, Atkinson MA, Agarwal A (2004) Heme oxygenase-1 modulates early inflammatory responses: evidence from the heme oxygenase-1-deficient mouse. Am J Pathol 165:1045–1053CrossRefGoogle Scholar
  15. Kim SR, Sung SH, Kang SY, Koo KA, Kim SH, Ma CJ, Lee HS, Park MJ, Kim YC (2004) Aristolactam BII of Saururus chinensis attenuates glutamate-induced neurotoxicity in rat cortical cultures probably by inhibiting nitric oxide production. Planta Med 70:391–396CrossRefGoogle Scholar
  16. Kim NH, Yang MH, Heo J-D, Sung SH, Jeong EJ (2016) Dihydrobenzofuran neolignans isolated from Euonymus alatus leaves and twigs attenuated inflammatory responses in the activated RAW264. 7 macrophage cells. Nat Prod Sci 22:53–59CrossRefGoogle Scholar
  17. Kwak HJ, Song JS, No ZS, Song JH, Yang SD, Cheon HG (2005) The inhibitory effects of roflumilast on lipopolysaccharide-induced nitric oxide production in RAW264. 7 cells are mediated by heme oxygenase-1 and its product carbon monoxide. Inflamm Res 54:508–513CrossRefGoogle Scholar
  18. Lee D-S, Kim KS, Ko W, Li B, Keo S, Jeong GS, Oh H, Kim YC (2014) The neoflavonoid latifolin isolated from MeOH extract of Dalbergia odorifera attenuates inflammatory responses by inhibiting NF-κB activation via Nrf2-mediated heme oxygenase-1 expression. Phyther Res 28:1216–1223CrossRefGoogle Scholar
  19. Lim CJ, Cuong TD, Hung TM, Ryoo S, Lee JH, Kim EH, Woo MH, Choi JS, Min BS (2012) Arginase II inhibitory activity of phenolic compounds from Saururus chinensis. Bull Korean Chem Soc 33:3079–3082CrossRefGoogle Scholar
  20. Liu J, Wang L, Zhao D, Cheng D, Xu T, Zhou X, Yang X, Liu Y (2010) A new lignan from Saururus chinensis. Chem Nat Compd 46:631–633CrossRefGoogle Scholar
  21. Ma Q, Battelli L, Hubbs AF (2006) Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am J Pathol 168:1960–1974CrossRefGoogle Scholar
  22. Maines MD (2005) The heme oxygenase system: update 2005. Antioxid Redox Signal 7:1761–1766CrossRefGoogle Scholar
  23. Moon TC, Kim JC, Song SE, Suh SJ, Seo CS, Kim YK, Jin M, Yang JH, Son JK, Jahng Y, Kim CH, Chang HW (2008) Saucerneol D, a naturally occurring sesquilignan, inhibits LPS-induced iNOS expression in RAW264. 7 cells by blocking NF-κB and MAPK activation. Int Immunopharmacol 8:1395–1400CrossRefGoogle Scholar
  24. Oh KS, Choi YH, Ryu SY, Oh BK, Seo HW, Yon GH, Kim YS, Lee BH (2008) Cardiovascular effects of lignans isolated from Saururus chinensis. Planta Med 74:233–238CrossRefGoogle Scholar
  25. Otterbein LE, Bach FH, Alam J, Soares M, Lu HT, Wysk M, Davis RJ, Flavell RA, Choi AMK (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6:422–428CrossRefGoogle Scholar
  26. Park HJ, Kim RG, Seo B-R, Ha J, Ahn BT, Bok SH, Lee YS, Kim HJ, Lee KT (2003) Saucernetin-7 and saucernetin-8 isolated from Saururus chinensis inhibit the LPS-induced production of nitric oxide and prostaglandin E2 in macrophage RAW264. 7 cells. Planta Med 69:947–950CrossRefGoogle Scholar
  27. Rao KV, Alvarez FM (1982) Chemistry of Saururus cernuus. I. Saucernetin, a new neolignan. J Nat Prod 45:393–397CrossRefGoogle Scholar
  28. Rao KV, Alvarez FM (1983) Manassantins A/B and saucerneol: novel biologically active lignoids from Saururus cernuus. Tetrahedron Lett 24:4947–4950CrossRefGoogle Scholar
  29. Ryu HS, Lee HK, Kim JS, Kim YG, Pyo M, Yun J, Hwang BY, Hong JT, Kim Y, Han S-B (2015) Saucerneol D inhibits dendritic cell activation by inducing heme oxygenase-1, but not by directly inhibiting toll-like receptor 4 signaling. J Ethnopharmacol 166:92–101CrossRefGoogle Scholar
  30. Suh GY, Jin Y, Yi A-K, Wang XM, Choi AMK (2006) CCAAT/enhancer-binding protein mediates carbon monoxide-induced suppression of cyclooxygenase-2. Am J Respir Cell Mol Biol 35:220–226CrossRefGoogle Scholar
  31. Sung SH (2006) A new dineolignan from Saururus chinensis root. Fitoterapia 77:487–488CrossRefGoogle Scholar
  32. Sung SH, Kim YC (2000) Hepatoprotective diastereomeric lignans from Saururus chinensis herbs. J Nat Prod 63:1019–1021CrossRefGoogle Scholar
  33. Sung SH, Huh MS, Kim YC (2001) New tetrahydrofuran-type sesquilignans of Saururus chinensis root. Chem Pharm Bull 49:1192–1194CrossRefGoogle Scholar
  34. Wiesel P, Foster LC, Pellacani A, Layne MD, Hsieh C-M, Huggins GS, Strauss P, Yet SF, Perrella MA (2000) Thioredoxin facilitates the induction of heme oxygenase-1 in response to inflammatory mediators. J Biol Chem 275:24840–24846CrossRefGoogle Scholar
  35. Yang C, Zhao J, Cheng Y, Le XC, Rong J (2015) N-propargyl caffeate amide (PACA) potentiates nerve growth factor (NGF)-induced neurite outgrowth and attenuates 6-hydroxydopamine (6-OHDA)-induced toxicity by activating the Nrf2/HO-1 pathway. ACS Chem Neurosci 6:1560–1569CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  • Yeon Woo Jung
    • 1
  • Bo Mi Lee
    • 1
  • Manh Tuan Ha
    • 1
  • Manh Hung Tran
    • 1
  • Jeong Ah Kim
    • 2
  • Suhyun Lee
    • 3
  • Jeong Hyung Lee
    • 3
    Email author
  • Mi Hee Woo
    • 1
  • Byung Sun Min
    • 1
    Email author
  1. 1.College of Pharmacy, Drug Research and Development CenterDaegu Catholic UniversityGyeongbukRepublic of Korea
  2. 2.College of Pharmacy, Research Institute of Pharmaceutical SciencesKyungpook National UniversityDaeguRepublic of Korea
  3. 3.Department of Biochemistry, College of Natural SciencesKangwon National UniversityChuncheonRepublic of Korea

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