Skip to main content

Advertisement

Log in

Quercetin Prevents Lipopolysaccharide-Induced Experimental Preterm Labor in Mice and Increases Offspring Survival Rate

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Premature labor is still a worldwide problem, causing serious social economic burden and family burden. Currently, there is no effective way to prevent preterm labor. Since inflammation increases the risk of preterm birth and quercetin is reported to have anti-inflammation, immune-enhancement, and antioxidative effects, this study aims to explore whether quercetin exerts inhibitory effect on preterm labor in mice and increases offspring survival. Lipopolysaccharide (LPS) is one of the commonly used drugs in the inflammatory animal model of preterm birth. On day 15 of pregnancy, mice received a dose of vehicle phosphate-buffered saline (PBS) or a dose of quercetin (low concentration, 30 mg/kg; medium concentration, 90 mg/kg; high concentrations, 150 mg/kg) via oral gavage. After 2 h, mice received a dose of LPS (50 μg/kg) or vehicle intraperitoneally (i.p.). In the absence of quercetin, a 100% incidence of preterm labor was observed in LPS-treated mice, and the fetuses were all died. Medium concentration of quercetin significantly prevented 63.5% of LPS-induced inflammatory preterm labor, and the survival rate of pups on day 22 was 83.76%. Specifically, quercetin significantly inhibited LPS-induced upregulation of NF-kappa-B/P65(RELA), AP-1/C-JUN(JUN), cyclooxygenase-2(PTGS2), and interleukin 6(IL6) in mice myometrium on mRNA level and inhibited the upregulation of P65 and C-JUN on protein level. Based on these observations, we concluded that quercetin exerts inhibitory effect on LPS-induced experimental mice preterm labor and increases offspring survival through a mechanism involving NF-κB/AP-1 pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet. 2012;379(9832):2151–61.

    PubMed  Google Scholar 

  2. Zou L, Wang X, Ruan Y, Li G, Chen Y, Zhang W. Preterm birth and neonatal mortality in China in 2011. Int J Gynecol Obstet. 2014;127(3):243–7.

    Google Scholar 

  3. Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE, et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet. 2012;379(9832):2151–61.

    PubMed  Google Scholar 

  4. Romero R, Espinoza J, Kusanovic JP, et al. The preterm parturition syndrome. BJOG. 2006;113(Suppl 3):17–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.

    PubMed  Google Scholar 

  7. Kemp MW. Preterm birth, intrauterine infection, and fetal inflammation. Front Immunol. 2014;5.

  8. Edey LF, O'Dea KP, Herbert BR, Hua R, Waddington SN, MacIntyre D, et al. The local and systemic immune response to intrauterine LPS in the prepartum mouse. Biol Reprod. 2016;95(6):125.

    PubMed  PubMed Central  Google Scholar 

  9. MacIntyre DA, Lee YS, Migale R, Herbert BR, Waddington SN, Peebles D, et al. Activator protein 1 is a key terminal mediator of inflammation-induced preterm labor in mice. FASEB J. 2014;28(5):2358–68.

    CAS  PubMed  Google Scholar 

  10. Zhang WS, Xie QS, Wu XH, Liang QH. Neuromedin B and its receptor induce labor onset and are associated with the RELA (NFKB P65)/IL6 pathway in pregnant mice. Biol Reprod. 2011;84(1):113–7.

    CAS  PubMed  Google Scholar 

  11. Zhang WS, Fei KL, Wu MT, Wu XH, Liang QH. Neuromedin B and its receptor influence the activity of myometrial primary cells in vitro through regulation of Il6 expression via the Rela/p65 pathway in mice. Biol Reprod. 2012;86(5):154 1-7.

    PubMed  Google Scholar 

  12. Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, et al. Quercetin, Inflammation and Immunity. Nutrients. 2016;8(3):167.

    PubMed  PubMed Central  Google Scholar 

  13. Ekinci AF, Gulcin I, Karagoz B, Soslu R. Quercetin protects rat skeletal muscle from ischemia reperfusion injury. J Enzyme Inhib Med Chem. 2016;31(sup2):162–166.

  14. Leiherer A, Stoemmer K, Muendlein A, et al. Quercetin impacts expression of metabolism- and obesity-associated genes in SGBS adipocytes. Nutrients. 2016;8(5).

  15. Xiao L, Liu L, Guo X, Zhang S, Wang J, Zhou F, et al. Quercetin attenuates high fat diet-induced atherosclerosis in apolipoprotein E knockout mice: a critical role of NADPH oxidase. Food Chem Toxicol. 2017;105:22–33.

    CAS  PubMed  Google Scholar 

  16. Carrasco-Pozo C, Castillo RL, Beltran C, et al. Molecular mechanisms of gastrointestinal protection by quercetin against indomethacin-induced damage: role of NF-kappaB and Nrf2. J Nutr Biochem. 2016;27:289–98.

    CAS  PubMed  Google Scholar 

  17. Meng LQ, Yang FY, Wang MS, Shi BK, Chen DX, Chen D, et al. Quercetin protects against chronic prostatitis in rat model through NF-kappaB and MAPK signaling pathways. Prostate. 2018;78(11):790–800.

    CAS  PubMed  Google Scholar 

  18. Nadeau HCG, Subramaniam A, Andrews WW. Infection and preterm birth. Semin Fetal Neonatal Med. 2016;21(2):100–5.

    PubMed  Google Scholar 

  19. Migale R, Herbert BR, Lee YS, Sykes L, Waddington SN, Peebles D, et al. Specific lipopolysaccharide serotypes induce differential maternal and neonatal inflammatory responses in a murine model of preterm labor. Am J Pathol. 2015;185(9):2390–401.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nadeem L, Farine T, Dorogin A, Matysiak-Zablocki E, Shynlova O, Lye S. Differential expression of myometrial AP-1 proteins during gestation and labour. J Cell Mol Med. 2018;22(1):452–71.

    CAS  PubMed  Google Scholar 

  21. Willcockson AR, Nandu T, Liu CL, Nallasamy S, Kraus WL, Mahendroo M. Transcriptome signature identifies distinct cervical pathways induced in lipopolysaccharide-mediated preterm birth. Biol Reprod. 2018;98(3):408–21.

    PubMed  Google Scholar 

  22. Lee M, Yun S, Lee H, Yang J. Quercetin mitigates inflammatory responses induced by vascular endothelial growth factor in mouse retinal photoreceptor cells through suppression of nuclear factor kappa B. Int J Mol Sci. 2017;18(11):2497.

    PubMed Central  Google Scholar 

  23. Wang R, Zhang H, Wang Y, Song F, Yuan Y. Inhibitory effects of quercetin on the progression of liver fibrosis through the regulation of NF-кB/IкBα, p38 MAPK, and Bcl-2/Bax signaling. Int Immunopharmacol. 2017;47:126–33.

    CAS  PubMed  Google Scholar 

  24. Li T, Li F, Liu X, Liu J, Li D. Synergistic anti-inflammatory effects of quercetin and catechin via inhibiting activation of TLR4-MyD88-mediated NF-κB and MAPK signaling pathways. Phytother Res. 2019;33(3):756–67.

    CAS  PubMed  Google Scholar 

  25. Koyama Y, Kaidzu S, Kim YC, et al. Suppression of light-induced retinal degeneration by quercetin via the AP-1 pathway in rats. Antioxidants (Basel). 2019;8(4).

  26. Panicker SR, Sreenivas P, Babu MS, Karunagaran D, Kartha CC. Quercetin attenuates monocyte chemoattractant protein-1 gene expression in glucose primed aortic endothelial cells through NF-κB and AP-1. Pharmacol Res. 2010;62(4):328–36.

    CAS  PubMed  Google Scholar 

  27. Peng Q, Liu Y, Dong M, Xu F, Huang J, Chen J, et al. Interaction between NF-κB and AP-1 and their intracellular localization at labor in human late pregnant myometrial cells in vivo and in vitro. Medicine. 2018;97(38):e12494.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Min YD, Choi CH, Bark H, Son HY, Park HH, Lee S, et al. Quercetin inhibits expression of inflammatory cytokines through attenuation of NF-κB and p38 MAPK in HMC-1 human mast cell line. Inflamm Res. 2007;56(5):210–5.

    CAS  PubMed  Google Scholar 

  29. Carullo G, Cappello AR, Frattaruolo L, Badolato M, Armentano B, Aiello F. Quercetin and derivatives: useful tools in inflammation and pain management. Future Med Chem. 2017;9(1):79–93.

    CAS  PubMed  Google Scholar 

  30. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84.

    PubMed  Google Scholar 

  31. Yin N, Wang H, Zhang H, Ge H, Tan B, Yuan Y, et al. IL-27 induces a pro-inflammatory response in human fetal membranes mediating preterm birth. Int Immunopharmacol. 2017;50:361–9.

    CAS  PubMed  Google Scholar 

  32. Romero R, Chaemsaithong P, Chaiyasit N, et al. CXCL10 and IL-6: markers of two different forms of intra-amniotic inflammation in preterm labor. Am J Reprod Immunol. 2017;78(1):e12685.

    PubMed Central  Google Scholar 

  33. Shahshahan Z, Hashemi L. Maternal serum cytokines in the prediction of preterm labor and response to tocolytic therapy in preterm labor women. Adv Biomed Res. 2014;3:126.

    PubMed  PubMed Central  Google Scholar 

  34. Toda A, Sawada K, Fujikawa T, Wakabayashi A, Nakamura K, Sawada I, et al. Targeting inhibitor of κB kinase β prevents inflammation-induced preterm delivery by inhibiting IL-6 production from amniotic cells. Am J Pathol. 2016;186(3):616–29.

    CAS  PubMed  Google Scholar 

  35. Farina L, Winkelman C. A review of the role of proinflammatory cytokines in labor and noninfectious preterm labor. Biol Res Nurs. 2005;6(3):230–8.

    PubMed  Google Scholar 

  36. Friebe-Hoffmann U, Chiao JP, Rauk PN. Effect of IL-1beta and IL-6 on oxytocin secretion in human uterine smooth muscle cells. Am J Reprod Immunol. 2001;46(3):226–31.

    CAS  PubMed  Google Scholar 

  37. Boots AW, Haenen GRMM, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008;585(2–3):325–37.

    CAS  PubMed  Google Scholar 

  38. Rahman I. Oxidative stress, transcription factors and chromatin remodelling in lung inflammation. Biochem Pharmacol. 2002;64(5–6):935–42.

    CAS  PubMed  Google Scholar 

  39. Lim W, Yang C, Park S, Bazer FW, Song G. Inhibitory effects of quercetin on progression of human choriocarcinoma cells are mediated through PI3K/AKT and MAPK signal transduction cascades. J Cell Physiol. 2017;232(6):1428–40.

    CAS  PubMed  Google Scholar 

  40. Vanhees K, Godschalk RW, Sanders A, van Waalwijk Van Doorn-Khosrovani SB, van Schooten FJ. Maternal quercetin intake during pregnancy results in an adapted iron homeostasis at adulthood. Toxicology. 2011;290(2–3):350–8.

    PubMed  Google Scholar 

  41. Shahzad H, Giribabu N, Sekaran M, Salleh N. Quercetin induces dose-dependent differential morphological and proliferative changes in rat uteri in the presence and in the absence of estrogen. J Med Food. 2015;18(12):1307–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Shahzad H, Giribabu N, Muniandy S, Salleh N. Quercetin induces morphological and proliferative changes of rat's uteri under estrogen and progesterone influences. Int J Clin Exp Pathol. 2014;7(9):5484.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Xu L, Sun L, Lu L, et al. Effects of quercetin on CYP450 and cytokines in Aroclor 1254 injured endometrial cells of the pregnant rats. Biomed Res Int. 2014;2014:1–7.

    Google Scholar 

  44. Wang X, Yan Y, Yang L, Li M, Zhong X. Effect of quercetin on the expression of Bcl-2/Bax apoptotic proteins in endometrial cells of lipopolysaccharide-induced-abortion. J Tradit Chin Med. 2016;36(6):737–42.

    PubMed  Google Scholar 

  45. Li Y, Yao J, Han C, et al. Quercetin, Inflammation and Immunity. Nutrients. 2016;8(3):167.

    PubMed  PubMed Central  Google Scholar 

  46. D'Andrea G. Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia. 2015;106:256–71.

    CAS  PubMed  Google Scholar 

  47. Walle T, Walle UK, Halushka PV. Carbon dioxide is the major metabolite of quercetin in humans. J Nutr. 2001;131(10):2648–52.

    CAS  PubMed  Google Scholar 

  48. Nieoczym D, Socała K, Raszewski G, Wlaź P. Effect of quercetin and rutin in some acute seizure models in mice. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;54:50–8.

    CAS  Google Scholar 

  49. Harwood M, Danielewska-Nikiel B, Borzelleca JF, et al. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol. 2007;45(11):2179–205.

    CAS  PubMed  Google Scholar 

  50. Moon YJ, Wang L, DiCenzo R, Morris ME. Quercetin pharmacokinetics in humans. Biopharm Drug Dispos. 2008;29(4):205–17.

    CAS  PubMed  Google Scholar 

  51. Sullivan M, Follis RJ, Hilgartner M. Toxicology of podophyllin. Proc Soc Exp Biol Med. 1951;77(2):269–72.

    CAS  PubMed  Google Scholar 

  52. Willhite CC. Teratogenic potential of quercetin in the rat. Food Chem Toxicol. 1982;20(1):75–9.

    CAS  PubMed  Google Scholar 

  53. Wang S, Su R, Nie S, Sun M, Zhang J, Wu D, et al. Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals. J Nutr Biochem. 2014;25(4):363–76.

    CAS  PubMed  Google Scholar 

  54. Bovet C, Plet B, Ruff M, Eiler S, Granger F, Panagiotidis A, et al. Towards high-throughput identification of endocrine disrupting compounds with mass spectrometry. Toxicol in Vitro. 2009;23(4):704–9.

    CAS  PubMed  Google Scholar 

  55. Shahzad H, Giribabu N, Karim K, Muniandy S, Kassim NM, Salleh N. Quercetin alters uterine fluid volume and aquaporin (AQP) subunits (AQP-1, 2, 5 & 7) expression in the uterus in the presence of sex-steroids in rats. Reprod Toxicol. 2017;69:276–85.

    CAS  PubMed  Google Scholar 

  56. Collins-Burow BM, Burow ME, Duong BN, McLachlan JA. Estrogenic and antiestrogenic activities of flavonoid phytochemicals through estrogen receptor binding-dependent and -independent mechanisms. Nutr Cancer. 2000;38(2):229–44.

    CAS  PubMed  Google Scholar 

  57. Mesiano S, Welsh TN. Steroid hormone control of myometrial contractility and parturition. Semin Cell Dev Biol. 2007;18(3):321–31.

    CAS  PubMed  Google Scholar 

  58. Menon R, Bonney EA, Condon J, Mesiano S, Taylor RN. Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition. Hum Reprod Update. 2016;22(5):535–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. López BA. The regulation of uterine relaxation. Semin Cell Dev Biol. 2007;18(3):340–7.

    Google Scholar 

  60. Senior J, Marshall K, Sangha R, Clayton JK. In vitro characterization of prostanoid receptors on human myometrium at term pregnancy. Brit J Pharmacol. 1993;108(2):501–6.

    CAS  Google Scholar 

  61. Hsia S, Kuo Y, Chiang W, Wang PS. Effects of adlay hull extracts on uterine contraction and Ca2+ mobilization in the rat. Am J Physiol-Endoc M. 2008;295(3):E719–26.

    CAS  Google Scholar 

  62. Challis JR, Sloboda DM, Alfaidy N, Lye SJ, Gibb W, Patel FA, et al. Prostaglandins and mechanisms of preterm birth. Reproduction. 2002;124(1):1–17.

    CAS  PubMed  Google Scholar 

  63. Simhan HN, Caritis SN. Prevention of preterm delivery. N Engl J Med. 2007;357(5):477–87.

    CAS  PubMed  Google Scholar 

  64. Sakai M, Tanebe K, Sasaki Y, Momma K, Yoneda S, Saito S. Evaluation of the tocolytic effect of a selective cyclooxygenase-2 inhibitor in a mouse model of lipopolysaccharide-induced preterm delivery. Mol Hum Reprod. 2001;7(6):595–602.

    CAS  PubMed  Google Scholar 

  65. Rezaeizadeh G, Hantoushzadeh S, Ghiasi S, Nikfar S, Abdollahi M. A systematic review of the uterine relaxant effect of herbal sources. Curr Pharm Biotechnol. 2016;17(11):934.

    CAS  PubMed  Google Scholar 

  66. Ajay M, Gilani AH, Mustafa MR. Effects of flavonoids on vascular smooth muscle of the isolated rat thoracic aorta. Life Sci. 2003;74(5):603–12.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was financially supported by the grants from Hunan Provincial Innovation Foundation for Postgraduate (CX2017B067) and the National Natural Science Foundation of China (NSFC) programs (81270719 and 81571516).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Weishe Zhang.

Ethics declarations

Conflict of Interests

The author(s) declare(s) that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, X., Peng, Q., Zhang, J. et al. Quercetin Prevents Lipopolysaccharide-Induced Experimental Preterm Labor in Mice and Increases Offspring Survival Rate. Reprod. Sci. 27, 1047–1057 (2020). https://doi.org/10.1007/s43032-019-00034-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-019-00034-3

Keywords

Navigation