DOI QR코드

DOI QR Code

생물전환을 통한 음나무발효물의 LPS에 대한 경쟁적 억제제 효과 및 내독소혈증 억제 효과

The Inhibitory Effect of Fermented Kalopanax pictus by Bioconversion on Endotoxemia and the Competitive Inhibitor Activity on LPS

  • 김성필 ((주)에스티알바이오텍 중앙연구소) ;
  • 이화영 ((주)에스티알바이오텍 중앙연구소) ;
  • 인수아 ((주)에스티알바이오텍 중앙연구소) ;
  • 성은영 ((주)에스티알바이오텍 중앙연구소) ;
  • 김진만 ((주)에스티알바이오텍 중앙연구소) ;
  • 남석현 (아주대학교 생명과학과)
  • 투고 : 2019.03.07
  • 심사 : 2019.03.17
  • 발행 : 2019.04.30

초록

The objective of this study was to evaluate the effect of fermented Kalopanax pictus (KP-F) on macrophage activation and its effect as a competitive inhibitor of LPS and inhibitory effect on endotoxemia. The results showed that KP-F could activate macrophage in a dose-dependent manner, and KP-F was confirmed to act as a ligand for TLR4. Also, it was found that KP-F did not exhibit the same biotoxicity as LPS in intraperitoneal injection, and that it could suppress the neutrophil migration induced by LPS administration. In normal mice, the body weight, tissue weight, and amount of nitrite and pro-inflammatory cytokines in serum showed no significant changes with KP-F diet for 2 weeks, confirming that administration of KP-F in normal mice did not lead to over activation of immune response and biotoxicity. In the mouse model of endotoxemia induced by LPS and D-galactosamine(D-GalN) in sub-lethal dose, the diet of KP-F effectively inhibited the amount of nitrite and cytokines in the blood, and thus was found to be able to relieve the hepatic and kidney injury. In addition, in the endotoxemia mouse model induced by LPS and D-GalN of lethal dose, the survival rate was increased by KP-F diet in a dose-dependent manner.

키워드

HGSPB1_2019_v32n2_106_f0001.png 이미지

Fig. 1. Effect of KP-F on production of nitric oxide in macrophage (A) and cell cytotoxicity (B).

HGSPB1_2019_v32n2_106_f0002.png 이미지

Fig. 2. Effect of KP-F on neutrophil migration induced by LPS treatment.

HGSPB1_2019_v32n2_106_f0003.png 이미지

Fig. 3. Effect of KP-F on the mortality of the lethal shock in mice challenged by LPS/D-GalN.

Table 1. Body weight and organ weight changes by KP-F administration in normal mice

HGSPB1_2019_v32n2_106_t0001.png 이미지

Table 2. Nitrite and cytokines production by KP-F administration in normal mice

HGSPB1_2019_v32n2_106_t0002.png 이미지

Table 3. Effect of KP-F on nitrite and cytokines production in endotoxemia mice induced by LPS/D-GalN

HGSPB1_2019_v32n2_106_t0003.png 이미지

Table 4. Effect of KP-F on liver injury induced by LPS/D-GalN

HGSPB1_2019_v32n2_106_t0004.png 이미지

Table 5. Effect of KP-F on kidney injury induced by LPS/D-GalN

HGSPB1_2019_v32n2_106_t0005.png 이미지

참고문헌

  1. Bang SY, Park GY, Park SY, Kim JH, Lee YK, Lee SJ, Kim YH. 2010. The stem bark of Kalopanax pictus exhibits anti-inflammatory effect through heme oxygenase-1 induction and NF-${\kappa}B$ suppression. Immune Netw 10:212-218 https://doi.org/10.4110/in.2010.10.6.212
  2. Brinkhoff A, Sieberichs A, Engler H, Dolff S, Benson S, Korth J, Schedlowski M, Kribben A, Witzke O, Wilde B. 2018. Pro-inflammatory Th1 and Th17 cells are suppressed during human experimental endotoxemia whereas anti-inflammatory IL-10 producing T-cells are unaffected. Front Immunol 9:1133 https://doi.org/10.3389/fimmu.2018.01133
  3. Caroff M, Karibian D, Cavaillon JM, Haeffner-Cavaillon N. 2002. Structural and functional analyses of bacterial lipopolysaccharides. Microbes Infect 4:915-926 https://doi.org/10.1016/S1286-4579(02)01612-X
  4. Cecilio CA, Costa EH, Ucelli P, Chaves CAA, Toffoli MC, Flores CA, Cunha FQ, Ferreira SH, Tamashiro WMSC. 1997. The neutrophil migration induced by tumour necrosis factor alpha in mice is unaffected by glucocorticoids. Mediators Inflamm 6:46-52 https://doi.org/10.1080/09629359791929
  5. Choi J, Huh K, Kim SH, Lee KT, Park HJ, Han YN. 2002. Antinociceptive and anti-rheumatoidal effects of Kalopanax pictus extract and its saponin components in experimental animals. J Ethnopharmacol 79:199-204 https://doi.org/10.1016/S0378-8741(01)00383-X
  6. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C. 2009. Molecular inflammation: Underpinnings of aging and age-related diseases. Ageing Res Rev 8:18-30 https://doi.org/10.1016/j.arr.2008.07.002
  7. Ding Y, Liu X, Bu L, Li H, Zhang S. 2012. Antimicrobialimmunomodulatory activities of zebrafish phosvitin-derived peptide Pt5. Peptides 37:309-313 https://doi.org/10.1016/j.peptides.2012.07.014
  8. Dobrovolskaia MA, Medvedev AE, Thomas KE, Cuesta N, Toshchakov V, Ren T, Cody MJ, Michalek SM, Rice NR, Vogel SN. 2003. Induction of in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages: effects of TLR "homotolerance" versus "heterotolerance" on NF-kB signaling pathway components. J Immunol 170:508-519 https://doi.org/10.4049/jimmunol.170.1.508
  9. Howe LM. 2000. Novel agents in the therapy of endotoxic shock. Expert Opin Invest Drugs 9:1363-1372 https://doi.org/10.1517/13543784.9.6.1363
  10. Jeong JJ, Jang SE, Joh EH, Han MJ, Kim DH. 2012. Kalopanaxsaponin B ameliorates TNBS-induced colitis in mice. Biomol Ther (Seoul) 20:457-462 https://doi.org/10.4062/biomolther.2012.20.5.457
  11. Jeong YH, Hyun JW, Kim Van Le T, Kim DH, Kim HS. 2013. Kalopanaxsaponin A exerts anti-inflammatory effects in lipopolysaccharide-stimulated microglia via inhibition of JNK and NF-${\kappa}B$/AP-1 pathways. Biomol Ther 21:332-337 https://doi.org/10.4062/biomolther.2013.069
  12. Joh EH, Jeong JJ, Kim DH. 2012. Kalopanaxsaponin B inhibits LPS-induced inflammation by inhibiting IRAK1 kinase. Cell Immunol 279:103-108 https://doi.org/10.1016/j.cellimm.2012.10.001
  13. Josephs MD, Bahjat FR, Fukuzuka K, Ksontini R, Solorzana CC, Edwards CK III, Tannahill CL, MacKay SLD, Copeland EM III, Moldawer LL. 2000. Lipopolysaccharide and Dgalactosamine-induced hepatic injury is mediated by TNFalpha and not by Fas ligand. Am J Physiol Regul Integr Comp Physiol 278:R1196-R1201 https://doi.org/10.1152/ajpregu.2000.278.5.R1196
  14. Kim SP, Park SO, Lee SJ, Nam SH, Friedman M. 2013. A polysaccharide isolated from the liquid culture of Lentinus edodes (Shiitake) mushroom mycelia containing black rice bran protects mice against a Salmonella lipopolysaccharideinduced endotoxemia. J Agric Food Chem 61:10987-10994 https://doi.org/10.1021/jf403173k
  15. Kim SP, Park SO, Lee SJ, Nam SH, Friedman M. 2014. A polysaccharide isolated from the liquid culture of Lentinus edodes (Shiitake) mushroom mycelia containing black rice bran protects mice against salmonellosis through upregulation of the Th1 immune reaction. J Agric Food Chem 62:2384-2391 https://doi.org/10.1021/jf405223q
  16. Kovacs-Nolan J, Kanatani H, Nakamura A, Ibuki M, Mine Y. 2013. ${\beta}$-1,4-mannobiose stimulates innate immune responses and induces TLR4-dependent activation of mouse macrophages but reduces severity of inflammation during endotoxemia in mice. J Nutr 143:3843-3891
  17. Kuznetsova TA, Besednova NN, Somova LM, Plekhova NG. 2014. Fucoidan extracted from Fucus evanescens prevents endotoxin-induced damage in a mouse model of endotoxemia. Mar Drugs 12:886-898 https://doi.org/10.3390/md12020886
  18. Lee JH, Moon SY, Cho BY, Choi SI, Jung TD, Choi SH, Kim JD, Lee OH. 2017. Stability of ethanolic extract from fermented Cirsium setidens Nakai by bioconversion during different storing conditions. Korean J Food Nutr 30:388-394 https://doi.org/10.9799/ksfan.2017.30.2.388
  19. Matsunaga N, Tsuchimori N, Matsumoto T, Ii M. 2011. TAK-242(resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol 79:34-41 https://doi.org/10.1124/mol.110.068064
  20. Miyazaki S, Ishikawa F, Fujikawa T, Nagata S, Yamaguchi K. 2004. Intraperitoneal injection of lipopolysaccharide induces dynamic migration of Gr-1high polymorphonuclear neutrophils in the murine abdominal cavity. Clin Diagn Lab Immunol 11:452-457 https://doi.org/10.1128/CDLI.11.3.452-457.2004
  21. Motobu M, Amer S, Koyama Y, Hikosaka K, Sameshima T, Yamada M, Nakamura K, Koge K, Kang CB, Hayasidani H, Hirota Y. 2006. Protective effects of sugar cane extract on endotoxic shock in mice. Phytother Res 20:359-363 https://doi.org/10.1002/ptr.1860
  22. Moulin F, Copple BL, Ganey PE, Roth RA. 2001. Hepatic and extrahepatic factors critical for liver injury during lipopolysaccharide exposure. Am J Physiol Gastrointest Liver Physiol 281:G1423-G1431 https://doi.org/10.1152/ajpgi.2001.281.6.G1423
  23. Murakami A, Gao G, Kim OK, Omura M, Yano M, ItoC, Furukawa H, Jiwajinda S, Koshimizu K, Ohigashi H. 1999. Identification of coumarins from the fruit of Citrus hystrix DC as inhibitors of nitric oxide generation in mouse macrophage RAW 264.7 cells. J Agric Food Chem 47:333-339 https://doi.org/10.1021/jf980523e
  24. Rahman MM, Kim HK, Kim SE, Kim MJ, Kim DH, Lee HS. 2018. Chondroprotective effects of a standardized extract (KBH-JP-040) from Kalopanax pictus, Hericium erinaceus, and Astragalus membranaceus in experimentally induced in vitro and in vivo osteoarthritis models. Nutrients 10:E356 https://doi.org/10.3390/nu10030356
  25. Sohn YA, Hwang SA, Lee SY, Hwang IY, Kim SW, Kim SY, Moon A, Lee YS, Kim YH, Kang KJ, Jeong CS. 2015. Protective effect of liriodendrin isolated from Kalopanax pictus against gastric injury. Biomol Ther (Seoul) 23:53-59 https://doi.org/10.4062/biomolther.2014.103
  26. Takahashi K, Mizukami H, Kamata K, Inaba W, Kato N, Hibi C, Yagihashi S. 2012. Amelioration of acute kidney injury in lipopolysaccharide-induced systemic inflammatory response syndrome by an aldose reductase inhibitor, fidarestat. PLoS One 7:e30134 https://doi.org/10.1371/journal.pone.0030134
  27. Triantafilou M, Triantafilou K. 2005. The dynamics of LPS recognition: complex orchestration of multiple receptors. J Endotoxin Res 11:5-11 https://doi.org/10.1177/09680519050110010401
  28. Werners AH. 2017. Treatment of endotoxaemia and septicaemia in the equine patient. J Vet Pharmacol Ther 40:1-15 https://doi.org/10.1111/jvp.12329
  29. Yoon BR, Kim YH, Lee JS, Hong HD, Rhee YK, Cho CW, Kim YC, Lee OH. 2013. Protective effect of ferments of hot-water extract mixture from Rhodiola sachalinensis and red ginseng on oxidative stress-induced C2C12 myoblast. Korean J Food Nutr 26:485-491 https://doi.org/10.9799/ksfan.2013.26.3.485