Nat Prod Sci.  2018 Mar;24(1):59-65. 10.20307/nps.2018.24.1.59.

Lignans with NADPH Oxidase 2 (NOX2)-inhibitory Activity from the Fruits of Schisandra chinensis

• Park JM
• Pel P
• Chin YW
• Lee MY

• KMID: 2409611
• DOI: http://doi.org/10.20307/nps.2018.24.1.59

Abstract

An isoform of NADPH oxidase (NOX), NOX2 is a superoxide-generating enzyme involved in diverse pathophysiological events. Although its potential as a therapeutic target has been validated, there is no clinically available inhibitor. Herein, NOX2-inhibitory activity was screened with the constituents isolated from Schisandra chinensis, which has been reported to have antioxidant and reactive oxygen species (ROS)-scavenging effects. Among the partitions prepared from crude methanolic extract, a chloroform-soluble partition showed the highest NOX2-inhibitory activity in PLB-985 cell-based NOX2 assay. A total of twenty nine compounds (1 - 29) were identified from the chloroform fraction, including two first isolated compounds; dimethyl-malate (25) and 2-(2-hydroxyacetyl) furan (27) from this plants. Of these constituents, two compounds (gomisin T, and pregomisin) exhibited an NOX2-inhibitory effect with the ICâ‚…â‚€ of 9.4 ± 3.6, and 62.9 ± 11.3 µM, respectively. They are confirmed not to be nonspecific superoxide scavengers in a counter assay using a xanthine-xanthine oxidase system. These findings suggest the potential application of gomisin T (6) and other constituents of S. chinensis to inhibit NOX2.

Keyword

NADPH oxidase 2 (NOX2); NOX2 inhibitor; Schisandra chinensis; Gomisin T

MeSH Terms

Chloroform
Fruit*
Lignans*
Methanol
NADP*
NADPH Oxidase*
Oxidoreductases
Reactive Oxygen Species
Schisandra*
Superoxides
Chloroform
Lignans
Methanol
NADP
NADPH Oxidase
Oxidoreductases
Reactive Oxygen Species
Superoxides

Figure

• 

  Fig. 1 Inhibitory effects of S. chinensis extract and its constituents on NOX2. PLB-985 cells were pretreated with (A) methanolic extract of S. chinensis and its partitions or (B) 29 constituents isolated from chloroform partition for 60 min. NOX2 was activated with PMA, and the resultant ROS was measured with Amplex Red for 60 min. Acknowledged NOX inhibitors DPI and VAS2870 were used as a positive control. All values are mean ± standard error (n = 5 for A and 3 for B).

• 

  Fig. 2 Structures of compounds isolated from the chloroform-soluble extract of S. chinensis.

• 

  Fig. 3 Concentration-dependent NOX2-inhibitory activity of compounds 6, and 29. PLB-985 cells were pretreated with testing compounds, and PMA-stimulated NOX2 activity was assessed with Amplex Red. Values are mean ± standard error (n = 3 − 4).

• 

  Fig. 4 Assessment of superoxide-scavenging activity of compounds 6 and 29. Superoxide was produced by xanthine and xanthine oxidase in the presence or absence of testing compound and was quantified with WST-1. Values are mean ± standard error (n = 8).

• 

  Fig. 5 Effect of compounds 6 and 29 on HRP activity. HRP was treated with the indicated concentrations of compound 6 or 29, and its activity was determined by a colorimetric method using a peroxidase substrate o-dianisidine. The activity of heat-inactivated HRP was measured as a negative control. Values are mean ± standard error (n = 3).

Reference

1. Lee MY, Griendling KK. Antioxid Redox Signal. 2008; 10:1045–1059.

2. Jiang F, Zhang Y, Dusting GJ. Pharmacol Rev. 2011; 63:218–242.

3. Lassegue B, San Martin A, Griendling KK. Circ Res. 2012; 110:1364–1390.

4. Altenhofer S, Radermacher KA, Kleikers PW, Wingler K, Schmidt HH. Antioxid Redox Signal. 2015; 23:406–427.

5. Drummond GR, Selemidis S, Griendling KK, Sobey CG. Nat Rev Drug Discov. 2011; 10:453–471.

6. Panossian A, Wikman G. J Ethnopharmacol. 2008; 118:183–212.

7. Thandavarayan RA, Giridharan VV, Arumugam S, Suzuki K, Ko KM, Krishnamurthy P, Watanabe K, Konishi T. PLoS One. 2015; 10:e0119214.

8. Wang X, Hu D, Zhang L, Lian G, Zhao S, Wang C, Yin J, Wu C, Yang J. Food Chem Toxicol. 2014; 63:119–127.

9. Tucker KA, Lilly MB, Heck L Jr, Rado TA. Blood. 1987; 70:372–378.

10. Debeurme F, Picciocchi A, Dagher MC, Grunwald D, Beaumel S, Fieschi F, Stasia MJ. J Biol Chem. 2010; 285:33197–33208.

11. Liu H, Lai H, Jia X, Liu J, Zhang Z, Qi Y, Zhang J, Song J, Wu C, Zhang B, Xiao P. Phytomedicine. 2013; 20:1135–1143.

12. Ikeya Y, Taguchi H, Yosioka I, Iitaka Y, Kobayashi H. Chem Pharm Bull. 1979; 27:1395–1401.

13. Ikeya Y, Taguchi H, Yosioka I, Kobayashi H. Chem Pharm Bull. 1978; 26:3257–3260.

14. Ma WH, Lu Y, Huang H, Zhou P, Chen DF. Bioorg Med Chem Lett. 2009; 19:4958–4962.

15. Ikeya Y, Miki E, Okada M, Mitsuhashi H, Chai JG. Chem Pharm Bull. 1990; 38:1408–1411.

16. Kanatani H. Teraba.

17. Wan CK, Zhu GY, Shen XL, Chattopadhyay A, Dey S, Fong WF. Biochem Pharmacol. 2006; 72:824–837.

18. Cao YF, Zhang YY, Li J, Ge GB, Hu D, Liu HX, Huang T, Wang YC, Fang ZZ, Sun DX, Huo H, Yin J, Yang L. Xenobiotica. 2010; 40:38–47.

19. Ikeya Y, Taguchi H, Yosioka I. Chem Pharm Bull. 1978; 26:328–331.

20. Xue Y, Li X, Du X, Li X, Wang W, Yang J, Chen J, Pu J, Sun H. Phytochemistry. 2015; 116:253–261.

21. Sun H, Wu F, Zhang A, Wei W, Han Y, Wang X. Biomed Chromatogr. 2013; 27:1511–1519.

22. Park C, Choi YW, Hyun SK, Kwon HJ, Hwang HJ, Kim GY, Choi BT, Kim BW, Choi IW, Moon SK, Kim WJ, Choi YH. Int J Mol Med. 2009; 24:495–502.

23. Seo SM, Lee HJ, Park YK, Lee MK, Park JI, Paik KH. Nat Prod Sci. 2004; 10:104–108.

24. Ikeya Y, Taguchi H, Yosioka I. Chem Pharm Bull. 1982; 30:132–139.

25. Chen M, Xu X, Xu B, Yang P, Liao Z, Morris-Natschke SL, Lee KH, Chen D. Molecule. 2013; 18:2297–2306.

26. Ikeya Y, Taguchi H, Yosioka I. Chem Pharm Bull. 1980; 28:2422–2427.

27. Lee IS, Jung KY, Oh SR, Park SH, Ahn KS, Lee HK. Biol Pharm Bull. 1999; 22:265–267.

28. Denmark SE, Ahmad M. J Org Chem. 2007; 72:9630–9634.

29. Utaka M, Nakatani M, Takeda A. J Org Chem. 1986; 51:1140–1141.

30. Mascal M, Nikitin EB. Angew Chem Int Ed Engl. 2008; 47:7924–7926.

31. Xu LJ, Huang F, Chen SB, Li LN, Chen SL, Xiao PG. J Integr Plant Biol. 2006; 48:1493–1497.

32. Lee IS, Jung KY, Oh SR, Kim DS, Kim JH, Lee JJ, Lee HK, Lee SH, Kim EH, Cheong C. Arch Pharm Res. 1997; 20:633–636.