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Nuciferine alleviates LPS-induced mastitis in mice via suppressing the TLR4-NF-κB signaling pathway

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Abstract

Background

Nuciferine, a major bioactive component from the lotus leaf, has been reported to have notable anti-inflammatory activities such as renal inflammation and acute lung injury in previous studies. Mastitis is one of the most prevalent diseases in the dairy cattle, which causes large economic losses for the dairy industry. However, the effects of nuciferine on lipopolysaccharide (LPS)-induced mastitis have not been reported.

Methods and results

Here, we investigated the anti-inflammatory effects of nuciferine on LPS-induced mastitis in mice and illuminated its potential mechanism on the TLR4-mediated signaling pathway in mouse mammary epithelial cells (mMECs). Histopathological changes and myeloperoxidase (MPO) activity assay showed that nuciferine treatment significantly alleviated the LPS-induced injury of mammary gland flocculus, inflammatory cells infiltration. qPCR and ELISA assays indicated that nuciferine dose-dependently reduced the levels of TNF-α and IL-1β, which indicated that nuciferine might have therapeutic effects on mastitis. Furthermore, nuciferine treatment significantly decreased the expression of TLR4 in a dose-dependent manner. Besides, nuciferine was also found to suppress LPS-induced NF-κB activation.

Conclusion

These findings indicate that nuciferine potently ameliorates LPS-induced mastitis by inhibition of the TLR4-NF-κB signaling pathway.

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References

  1. Taffurelli M, Pellegrini A, Santini D, Zanotti S, Di Simone D, Serra M. Recurrent periductal mastitis: surgical treatment. Surgery. 2016;160:1689–92.

    Article  Google Scholar 

  2. LeBlanc SJ, Lissemore KD, Kelton DF, Duffield TF, Leslie KE. Major advances in disease prevention in dairy cattle. J Dairy Sci. 2006;89:1267–79.

    Article  CAS  Google Scholar 

  3. Jiang KF, Zhao G, Deng GZ, Wu HC, Yin NN, Chen XY, et al. Polydatin ameliorates staphylococcus aureus-induced mastitis in mice via inhibiting tlr2-mediated activation of the p38 mapk/nf-κb pathway. Acta Pharmacol Sin. 2017;38(2):211–22.

    Article  CAS  Google Scholar 

  4. Yang W, Zerbe H, Petzl W, Brunner RM, Gunther J, Draing C, et al. Bovine TLR2 and TLR4 properly transduce signals from Staphylococcus aureus and E. coli, but S. aureus fails to both activate NF-kappaB in mammary epithelial cells and to quickly induce TNFalpha and interleukin-8 (CXCL8) expression in the udder. Mol Immunol. 2008;45:1385–97.

    Article  CAS  Google Scholar 

  5. Ibeagha-Awemu EM, Lee JW, Ibeagha AE, Bannerman DD, Paape MJ, Zhao X. Bacterial lipopolysaccharide induces increased expression of toll-like receptor (TLR) 4 and downstream TLR signaling molecules in bovine mammary epithelial cells. Vet Res. 2008;39:11.

    Article  Google Scholar 

  6. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.

    Article  CAS  Google Scholar 

  7. Roh E, Lee HS, Kwak JA, Jin TH, Nam SY, Jung SH, et al. MD-2 as the target of nonlipid chalcone in the inhibition of endotoxin LPS-induced TLR4 activity. J Infect Dis. 2011;203:1012–20.

    Article  CAS  Google Scholar 

  8. Wu H, Zhao G, Jiang K, Chen X, Rui G, Qiu C, et al. Ifn-tau alleviates lipopolysaccharide-induced inflammation by suppressing nf-κB and mapks pathway activation in mice. Inflammation. 2016;39(3):1141–50.

    CAS  PubMed  Google Scholar 

  9. Persson Waller K, Colditz IG, Lun S, Ostensson K. Cytokines in mammary lymph and milk during endotoxin-induced bovine mastitis. Res Vet Sci. 2003;74:31–6.

    Article  CAS  Google Scholar 

  10. Kayitsinga J, Schewe RL, Contreras GA, Erskine RJ. Antimicrobial treatment of clinical mastitis in the eastern united states: the influence of dairy farmers' mastitis management and treatment behavior and attitudes. J Dairy Sci. 2017;100(2):1388–407.

    Article  CAS  Google Scholar 

  11. Mehmeti I, Behluli B, Mestani M, Ademi A, Nes IF, Diep DB. Antimicrobial resistance levels amongst staphylococci isolated from clinical cases of bovine mastitis in Kosovo. J Infect Dev Ctries. 2016;10:1081–7.

    Article  CAS  Google Scholar 

  12. Wu H, Zhao G, Jiang K, Chen X, Zhu Z, Qiu C, et al. Plantamajoside ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-kappaB and MAPK activation. Int Immunopharmacol. 2016;35:315–22.

    Article  CAS  Google Scholar 

  13. Wu H, Zhao G, Jiang K, Li C, Qiu C, Deng G. Engeletin alleviates lipopolysaccharide-induced endometritis in mice by inhibiting TLR4-mediated NF-kappaB activation. J Agric Food Chem. 2016;64:6171–8.

    Article  CAS  Google Scholar 

  14. Nguyen KH, Ta TN, Pham TH, Nguyen QT, Pham HD, Mishra S, et al. Nuciferine stimulates insulin secretion from beta cells-an in vitro comparison with glibenclamide. J Ethnopharmacol. 2012;142:488–95.

    Article  CAS  Google Scholar 

  15. Guo F, Yang X, Li X, Feng R, Guan C, Wang Y, et al. Nuciferine prevents hepatic steatosis and injury induced by a high-fat diet in hamsters. PLoS One. 2013;8:e63770.

    Article  CAS  Google Scholar 

  16. Ma W, Lu Y, Hu R, Chen J, Zhang Z, Pan Y. Application of ionic liquids based microwave-assisted extraction of three alkaloids N-nornuciferine, O-nornuciferine, and nuciferine from lotus leaf. Talanta. 2010;80:1292–7.

    Article  CAS  Google Scholar 

  17. Wang MX, Liu YL, Yang Y, Zhang DM, Kong LD. Nuciferine restores potassium oxonate-induced hyperuricemia and kidney inflammation in mice. Eur J Pharmacol. 2015;747:59–70.

    Article  CAS  Google Scholar 

  18. Smalley MJ, Titley J, O’Hare MJ. Clonal characterization of mouse mammary luminal epithelial and myoepithelial cells separated by fluorescence-activated cell sorting. In Vitro Cell Dev Biol Anim. 1998;34:711–21.

    Article  CAS  Google Scholar 

  19. Jiang K, Ma X, Guo S, Zhang T, Zhao G, Wu H, et al. Anti-inflammatory effects of rosmarinic acid in lipopolysaccharide-induced mastitis in mice. Inflammation. 2017;41(2):437–48.

    Article  Google Scholar 

  20. Wu H, Yang Y, Guo S, Yang J, Jiang K, Zhao G, et al. Nuciferine ameliorates inflammatory responses by inhibiting the TLR4-mediated pathway in lipopolysaccharide-induced acute lung injury. Front Pharmacol. 2017;8:939. https://doi.org/10.3389/fphar.2017.00939.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Shao G, Tian Y, Wang H, Liu F, Xie G. Protective effects of melatonin on lipopolysaccharide-induced mastitis in mice. Int Immunopharmacol. 2015;29:263–8.

    Article  CAS  Google Scholar 

  22. Zhang L, Sun D, Bao Y, Shi Y, Cui Y, Guo M. Nerolidol protects against lps-induced acute kidney injury via inhibiting tlr4/nf-κb signaling. Phytotherapy Res. 2017;31(3):459.

    Article  CAS  Google Scholar 

  23. Yang Z, Yin R, Cong Y, Yang Z, Zhou E, Wei Z, et al. Oxymatrine lightened the inflammatory response of LPS-induced mastitis in mice through affecting NF-κB and MAPKs signaling pathways. Inflammation. 2014;37:2047–55.

    Article  CAS  Google Scholar 

  24. Zhang DD, Zhang JG, Wu X, Liu Y, Gu SY, Zhu GH, et al. Nuciferine downregulates Per-Arnt-Sim kinase expression during its alleviation of lipogenesis and inflammation on oleic acid-induced hepatic steatosis in HepG2 cells. Fronti Pharmacol. 2015;6:238.

    Google Scholar 

  25. Wang MX, Zhao XJ, Chen TY, et al. Nuciferine Alleviates Renal Injury by Inhibiting Inflammatory Responses in Fructose-Fed Rats[J]. J Agric Food Chem. 2016;64(42):7899–910.

    Article  CAS  Google Scholar 

  26. Hoeben D, Burvenich C, Trevisi E, Bertoni G, Hamann J, Bruckmaier RM, et al. Role of endotoxin and TNF-alpha in the pathogenesis of experimentally induced coliform mastitis in periparturient cows. J Dairy Res. 2000;67:503–14.

    Article  CAS  Google Scholar 

  27. Zhu Y, Fossum C, Berg M, Magnusson U. Morphometric analysis of proinflammatory cytokines in mammary glands of sows suggests an association between clinical mastitis and local production of IL-1beta, IL-6 and TNF-alpha. Vet Res. 2007;38:871–82.

    Article  CAS  Google Scholar 

  28. Gao XJ, Guo MY, Zhang ZC, Wang TC, Cao YG, Zhang NS. Bergenin plays an anti-inflammatory role via the modulation of MAPK and NF-kappaB signaling pathways in a mouse Model of LPS-induced mastitis. Inflammation. 2015;38:1142–50.

    Article  CAS  Google Scholar 

  29. Gupta M, Babic A, Beck AH, Terry K. TNF-alpha expression, risk factors, and inflammatory exposures in ovarian cancer: evidence for an inflammatory pathway of ovarian carcinogenesis? Hum Pathol. 2016;54:82–91.

    Article  CAS  Google Scholar 

  30. Lin YC, Schlievert PM, Anderson MJ, Fair CL, Schaefers MM, Muthyala R, et al. Glycerol monolaurate and dodecylglycerol effects on Staphylococcus aureus and toxic shock syndrome toxin-1 in vitro and in vivo. PLoS One. 2009;4:e7499.

    Article  Google Scholar 

  31. Jiang K, Chen X, Zhao G, Wu H, Mi J, Qiu C, et al. IFN-tau plays an anti-inflammatory role in Staphylococcus aureus-induced endometritis in mice through the suppression of NF-kappaB pathway and MMP9 expression. J Interferon Cytokine Res. 2017;37:81–9.

    Article  CAS  Google Scholar 

  32. Mateu A, Ramudo L, Manso MA, De Dios I. Cross-talk between TLR4 and PPARgamma pathways in the arachidonic acid-induced inflammatory response in pancreatic acini. Int J Biochem Cell Biol. 2015;69:132–41.

    Article  CAS  Google Scholar 

  33. Zhang WJ, Frei B. Astragaloside IV inhibits NF-kappa B activation and inflammatory gene expression in LPS-treated mice. Mediators Inflamm. 2015;2015:274314.

    PubMed  PubMed Central  Google Scholar 

  34. Wu H, Zhao G, Jiang K, Chen X, Zhu Z, Qiu C, et al. Puerarin exerts an antiinflammatory effect by inhibiting NF-kB and MAPK activation in Staphylococcus aureus-induced mastitis. Phytother Res. 2016;30:1658–64.

    Article  CAS  Google Scholar 

  35. Jiang K, Guo S, Zhang T, Yang Y, Zhao G, Shaukat A, et al. Downregulation of TLR4 by miR-181a provides negative feedback regulation to lipopolysaccharide-induced inflammation. Front Pharmacol. 2018;9:142. https://doi.org/10.3389/fphar.2018.00142.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zhang F, Lu S, Jin S, Chen K, Li J, Huang B, et al. Lidanpaidu prescription alleviates lipopolysaccharide-induced acute kidney injury by suppressing the NF-κB signaling pathway. Biomed Pharmacother. 2018;99:245–52.

    Article  CAS  Google Scholar 

  37. Morris KR, Lutz RD, Choi HS, Kamitani T, Chmura K, Chan ED. Role of the NF-kappaB signaling pathway and kappaB cis-regulatory elements on the IRF-1 and iNOS promoter regions in mycobacterial lipoarabinomannan induction of nitric oxide. Infect Immun. 2003;71:1442–52.

    Article  CAS  Google Scholar 

  38. Jiang K, Zhang T, Yin N, Ma X, Zhao G, Wu H, et al. Geraniol alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis. Oncotarget. 2017;8:71038.

    PubMed  PubMed Central  Google Scholar 

  39. Li Q, Verma IM. NF-κB regulation in the immune system. Nat Rev Immunol. 2002;2:725–34.

    Article  CAS  Google Scholar 

  40. Straus DS, Pascual G, Li M, Welch JS, Ricote M, Hsiang CH, et al. 15-Deoxy-∆12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc Natl Acad Sci USA. 2000;97:4844.

    Article  CAS  Google Scholar 

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Acknowledgements

Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology (No. ZDSYS2017005).

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Authors and Affiliations

  1. College of Life Sciences of Longyan University, Longyan, 364012, Fujian, People’s Republic of China

    Xingxing Chen, Xintian Zheng, Min Zhang, Huifang Yin, Ailing Dai & Shoushen Yang

  2. Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Longyan, 364012, Fujian, People’s Republic of China

    Xingxing Chen, Xintian Zheng, Min Zhang, Huifang Yin, Haichong Wu, Ailing Dai & Shoushen Yang

  3. Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, People’s Republic of China

    Kangfeng Jiang & Haichong Wu

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  1. Xingxing Chen
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Correspondence to Ailing Dai or Shoushen Yang.

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Chen, X., Zheng, X., Zhang, M. et al. Nuciferine alleviates LPS-induced mastitis in mice via suppressing the TLR4-NF-κB signaling pathway. Inflamm. Res. 67, 903–911 (2018). https://doi.org/10.1007/s00011-018-1183-2

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  • DOI: https://doi.org/10.1007/s00011-018-1183-2

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