Saikosaponin A protects against experimental sepsis via inhibition of NOD2‑mediated NF‑κB activation

Zhao,Haiyan; Li,Shuping; Zhang,Haisheng; Wang,Gang; Xu,Gaolei; Zhang,Hongbo

doi:10.3892/etm.2015.2558

Saikosaponin A protects against experimental sepsis via inhibition of NOD2‑mediated NF‑κB activation

Authors:
- Haiyan Zhao
- Shuping Li
- Haisheng Zhang
- Gang Wang
- Gaolei Xu
- Hongbo Zhang
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Affiliations: Department of Anesthesiology, The Ninth People's Hospital of Zhengzhou City, Zhengzhou, Henan 450053, P.R. China, Department of Emergency Medicine, The People's Hospital of Zhengzhou City, Zhengzhou, Henan 450002, P.R. China, Department of Anatomy and Pathology, School of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
Published online on: June 10, 2015 https://doi.org/10.3892/etm.2015.2558
Pages: 823-827

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Abstract

The excessive production of inflammatory cytokines during invasive infection primarily mediates the pathophysiology of sepsis. To improve the survival of septic patients, many selective or mediator-specific anti-inflammatory agents have been developed. Saikosaponin A (SsA), a triterpenoid saponin isolated from Radix Bupleuri, inhibits the production of proinflammatory mediators in several cell types and protects against CCl4-induced liver injury in rats. However, whether SsA treatment provides protective effects against sepsis remains unknown. The aim of the present study was to investigate the anti-inflammatory role of SsA in septic rats and the possible involvement of the nucleotide-binding oligomerization domain 2 (NOD2)/NF-κB signaling pathway in the regulation of inflammatory cytokine expression. Sixty male Wistar rats were randomly divided into six groups (10 rats per group): Sham surgery, cecal ligation and puncture (CLP), CLP plus SsA (1.0 mg/kg), CLP plus SsA (2.5 mg/kg), CLP plus SsA (5.0 mg/kg) and sham surgery plus SsA (2.5 mg/kg) groups. Rats in the SsA groups were intraperitoneally (i.p.) injected with different doses of SsA following the CLP surgery. Tissues from the ileum were harvested 8 h after CLP or sham surgery and the levels of inflammatory cytokines and NOD2 mRNA, and the activation of NF-κB were measured. The concentrations of the cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6, as well as the NOD2 mRNA expression levels and NF-κB activation in the intestinal tissues were significantly increased in the septic rats of the CLP group compared with those in the sham group. SsA administration effectively suppressed the increase in the levels of TNF-α and IL-6. Moreover, the upregulation of NOD2 mRNA expression and phospho-NF-κB p65 levels was significantly inhibited following the administration of SsA. SsA may exert a protective role in the septic process by suppressing TNF-α and IL-6 concentrations in the intestines of septic rats and these effects appear to be mediated, at least partly, via inhibition of the NOD2/NF-κB signaling pathway.

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1	Hotchkiss RS and Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med. 348:138–150. 2003. View Article : Google Scholar : PubMed/NCBI
2	Martin GS, Mannino DM, Eaton S and Moss M: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 348:1546–1554. 2003. View Article : Google Scholar : PubMed/NCBI
3	Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J and Pinsky MR: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med. 29:1303–1310. 2001. View Article : Google Scholar : PubMed/NCBI
4	Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE and Ognibene FP: Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 113:227–242. 1990. View Article : Google Scholar : PubMed/NCBI
5	Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ and Dupont E: Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest. 103:565–575. 1993. View Article : Google Scholar : PubMed/NCBI
6	Blackwell TS and Christman JW: Sepsis and cytokines: Current status. Br J Anaesth. 77:110–117. 1996. View Article : Google Scholar : PubMed/NCBI
7	Ashour ML and Wink M: Genus Bupleurum: A review of its phytochemistry, pharmacology and modes of action. J Pharm Pharmacol. 63:305–321. 2011. View Article : Google Scholar : PubMed/NCBI
8	Park KH, Park J, Koh D and Lim Y: Effect of saikosaponin-A, a triterpenoid glycoside, isolated from Bupleurum falcatum on experimental allergic asthma. Phytother Res. 16:359–363. 2002. View Article : Google Scholar : PubMed/NCBI
9	Lu CN, Yuan ZG, Zhang XL, Yan R, Zhao YQ, Liao M and Chen JX: Saikosaponin a and its epimer saikosaponin d exhibit anti-inflammatory activity by suppressing activation of NF-κB signaling pathway. Int Immunopharmacol. 14:121–126. 2012. View Article : Google Scholar : PubMed/NCBI
10	Kim SO, Park JY, Jeon SY, Yang CH and Kim MR: Saikosaponin a, an active compound of Radix Bupleuri, attenuates inflammation in hypertrophied 3T3-L1 adipocytes via ERK/NF-κB signaling pathways. Int J Mol Med. 35:1126–1132. 2015.PubMed/NCBI
11	Rittirsch D, Huber-Lang MS, Flierl MA and Ward PA: Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc. 4:31–36. 2009. View Article : Google Scholar : PubMed/NCBI
12	Fry DE: Sepsis, systemic inflammatory response, and multiple organ dysfunction: The mystery continues. Am Surg. 78:1–8. 2012.PubMed/NCBI
13	Yu M, Shao D, Liu J, Zhu J, Zhang Z and Xu J: Effects of ketamine on levels of cytokines, NF-kappaB and TLRs in rat intestine during CLP-induced sepsis. Int Immunopharmacol. 7:1076–1082. 2007. View Article : Google Scholar : PubMed/NCBI
14	Zhu J, Luo C, Wang P, He Q, Zhou J and Peng H: Saikosaponin A mediates the inflammatory response by inhibiting the MAPK and NF-κB pathways in LPS-stimulated RAW 264.7 cells. Exp Ther Med. 5:1345–1350. 2013.PubMed/NCBI
15	Han NR, Kim HM and Jeong HJ: Inactivation of cystein-aspartic acid protease (caspase)-1 by saikosaponin A. Biol Pharm Bull. 34:817–823. 2011. View Article : Google Scholar : PubMed/NCBI
16	Sun Y, Cai TT, Zhou XB and Xu Q: Saikosaponin A inhibits the proliferation and activation of T cells through cell cycle arrest and induction of apoptosis. Int Immunopharmacol. 9:978–983. 2009. View Article : Google Scholar : PubMed/NCBI
17	Wu SJ, Lin YH, Chu CC, Tsai YH and Chao JC: Curcumin or saikosaponin A improves hepatic antioxidant capacity and protects against CCl₄-induced liver injury in rats. J Med Food. 11:224–229. 2008. View Article : Google Scholar : PubMed/NCBI
18	Wu SJ, Tam KW, Tsai YH, Chang CC and Chao JC: Curcumin and saikosaponin A inhibit chemical-induced liver inflammation and fibrosis in rats. Am J Chin Med. 38:99–111. 2010. View Article : Google Scholar : PubMed/NCBI
19	Hayden MS and Ghosh S: Shared principles in NF-kappaB signaling. Cell. 132:344–362. 2008. View Article : Google Scholar : PubMed/NCBI
20	Arnalich F, Garcia-Palomero E, López J, Jiménez M, Madero R, Renart J, Vázquez JJ and Montiel C: Predictive value of nuclear factor kappaB activity and plasma cytokine levels in patients with sepsis. Infect Immun. 68:1942–1945. 2000. View Article : Google Scholar : PubMed/NCBI
21	Feng X, Ren B, Xie W, Huang Z, Liu J, Guan R, Duan M and Xu J: Influence of hydroxyethyl starch 130/0.4 in pulmonary neutrophil recruitment and acute lung injury during polymicrobial sepsis in rats. Acta Anaesthesiol Scand. 50:1081–1088. 2006. View Article : Google Scholar : PubMed/NCBI
22	Feng X, Yan W, Liu X, Duan M, Zhang X and Xu J: Effects of hydroxyethyl starch 130/0.4 on pulmonary capillary leakage and cytokines production and NF-kappaB activation in CLP-induced sepsis in rats. J Surg Res. 135:129–136. 2006. View Article : Google Scholar : PubMed/NCBI
23	Frutuoso MS, Hori JI, Pereira MS, Junior DS, Sônego F, Kobayashi KS, Flavell RA, Cunha FQ and Zamboni DS: The pattern recognition receptors Nod1 and Nod2 account for neutrophil recruitment to the lungs of mice infected with Legionella pneumophila. Microbes Infect. 12:819–827. 2010. View Article : Google Scholar : PubMed/NCBI
24	Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Núñez G and Inohara N: A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J. 27:373–383. 2008. View Article : Google Scholar : PubMed/NCBI
25	Magalhaes JG, Lee J, Geddes K, Rubino S, Philpott DJ and Girardin SE: Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands. Eur J Immunol. 41:1445–1455. 2011. View Article : Google Scholar : PubMed/NCBI
26	Hu C, Sun L, Hu Y, Lu D, Wang H and Tang S: Functional characterization of the NF-kappaB binding site in the human NOD2 promoter. Cell Mol Immunol. 7:288–295. 2010. View Article : Google Scholar : PubMed/NCBI
27	Brenmoehl J, Herfarth H, Glück T, Audebert F, Barlage S, Schmitz G, Froehlich D, Schreiber S, Hampe J, Schölmerich J, et al: Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients. Intensive Care Med. 33:1541–1548. 2007. View Article : Google Scholar : PubMed/NCBI
28	Girardin E, Grau GE, Dayer JM, Roux-Lombard P and Lambert PH: Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med. 319:397–400. 1988. View Article : Google Scholar : PubMed/NCBI
29	Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P and Lamy M: Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg. 215:356–362. 1992. View Article : Google Scholar : PubMed/NCBI
30	Wang P, Wu P, Siegel MI, Egan RW and Billah MM: Interleukin (IL)-10 inhibits nuclear factor kappaB (NF kappaB) activation in human monocytes. IL-10 and IL-4 suppress cytokine synthesis by different mechanisms. J Biol Chem. 270:9558–9563. 1995. View Article : Google Scholar : PubMed/NCBI
31	Lentsch AB, Shanley TP, Sarma V and Ward PA: In vivo suppression of NF-kappaB and preservation of I kappaB alpha by interleukin-10 and interleukin-13. J Clin Invest. 100:2443–2448. 1997. View Article : Google Scholar : PubMed/NCBI