Skip to main content

Advertisement

SpringerLink
Log in

Citral protects against LPS-induced endometritis by inhibiting ferroptosis through activating Nrf2 signaling pathway

  • Original Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Introduction

Endometritis is the inflammatory condition of the uterus. Citral, a component of lemongrass oil, is known to exhibit anti-inflammatory activity.

Aim

The effects of citral on LPS-induced endometritis were tested and the mechanisms were investigated.

Methods

LPS-induced endometritis mice model was established and the effects of citral were detected using this model. Inflammatory cytokines were tested by ELISA. Ferroptosis was assessed by detecting GSH, ATP, MDA, and Fe2+ levels. Signaling pathway was tested by western blot analysis.

Results

Citral prevented LPS-induced endometritis through attenuating uterine pathological changes and inflammatory cytokine release. Meanwhile, citral prevents LPS-induced ferroptosis through attenuating MDA and Fe2+ levels, as well as increasing ATP and GSH levels. Furthermore, citral up-regulated Nrf2 and HO-1 expression and attenuated NF-κB activation. In addition, in Nrf2 knockdown mice, the inhibitory roles of citral on ferroptosis and endometritis were largely reversed.

Conclusion

Taken together, citral inhibited LPS-induced endometritis through preventing ferroptosis, which were regulated by Nrf2 signaling pathway.

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

Access this article

Log in via an institution

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

All relevant data of this research can be requested from the corresponding author.

References

  • Boby J, Kumar H, Gupta HP, Jan MH, Singh SK, Patra MK, Nandi S, Abraham A, Krishnaswamy N (2017) Endometritis increases pro-inflammatory cytokines in follicular fluid and cervico-vaginal mucus in the buffalo cow. Anim Biotechnol 28:163–167

    Article  CAS  PubMed  Google Scholar 

  • Bulun SE, Cheng YH, Yin P, Imir G, Utsunomiya H, Attar E, Innes J, Julie Kim J (2006) Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol 248:94–103

    Article  CAS  PubMed  Google Scholar 

  • Christoffersen M, Woodward EM, Bojesen AM, Petersen MR, Squires EL, Lehn-Jensen H, Troedsson MH (2012) Effect of immunomodulatory therapy on the endometrial inflammatory response to induced infectious endometritis in susceptible mares. Theriogenology 78:991–1004

    Article  CAS  PubMed  Google Scholar 

  • Eckert LO, Hawes SE, Wolner-Hanssen PK, Kiviat NB, Wasserheit JN, Paavonen JA, Eschenbach DA, Holmes KK (2002) Endometritis: the clinical-pathologic syndrome. Am J Obstet Gynecol 186:690–695

    Article  PubMed  Google Scholar 

  • French LM, Smaill FM (2002) Antibiotic regimens for endometritis after delivery. Cochrane Database Syst Rev 1:CD001067

    Google Scholar 

  • Fu KQ, Lv XP, Li WS, Wang Y, Li HT, Tian WR, Cao RF (2015) Berberine hydrochloride attenuates lipopolysaccharide-induced endometritis in mice by suppressing activation of NF-kappa B signal pathway. Int Immunopharmacol 24:128–132

    Article  CAS  PubMed  Google Scholar 

  • Harada N, Kanayama M, Maruyama A, Yoshida A, Tazumi K, Hosoya T, Mimura J, Toki T, Maher JM, Yamamoto M, Itoh K (2011) Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages. Arch Biochem Biophys 508:101–109

    Article  CAS  PubMed  Google Scholar 

  • Jiang XJ, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Bio 22:266–282

    Article  Google Scholar 

  • Ka SM, Lin JC, Lin TJ, Liu FC, Chao LK, Ho CL, Yeh LT, Sytwu HK, Hua KF, Chen A (2015) Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation. Arthritis Res Ther 17:331

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim IH, Kang HG, Jeong JK, Hur TY, Jung YH (2014) Inflammatory cytokine concentrations in uterine flush and serum samples from dairy cows with clinical or subclinical endometritis. Theriogenology 82:427–432

    Article  CAS  PubMed  Google Scholar 

  • Krakauer T (2004) Molecular therapeutic targets in inflammation: cyclooxygenase and NF-kappaB. Curr Drug Targets Inflamm Allergy 3:317–324

    Article  CAS  PubMed  Google Scholar 

  • Kushnir VA, Solouki S, Sarig-Meth T, Vega MG, Albertini DF, Darmon SK, Deligdisch L, Barad DH, Gleicher N (2016) Systemic inflammation and autoimmunity in women with chronic endometritis. Am J Reprod Immunol 75:672–677

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Jeong HS, Kim DJ, Noh YH, Yuk DY, Hong JT (2008) Inhibitory effect of citral on NO production by suppression of iNOS expression and NF-kappa B activation in RAW264.7 cells. Arch Pharm Res 31:342–349

    Article  CAS  PubMed  Google Scholar 

  • Liu JF, Wu ZM, Guo S, Zhang T, Ma XF, Jiang KF, Guo XF, Deng GZ (2021) IFN-tau attenuates LPS-induced endometritis by restraining HMGB1/NF-kappa B activation in bEECs. Inflammation 44:1478–1489

    Article  CAS  PubMed  Google Scholar 

  • Loboda A, Damulewicz M, Pyza E, Jozkowicz A, Dulak J (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73:3221–3247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lv XP, Fu KQ, Li WS, Wang Y, Wang JF, Li HT, Tian WR, Cao RF (2015) TIIA attenuates LPS-induced mouse endometritis by suppressing the NF-kappa B signaling pathway. Can J Physiol Pharm 93:967–971

    Article  CAS  Google Scholar 

  • McGaw LJ, Gehring R, Katsoulis L, Eloff JN (2005) Is the use of Gunnera perpensa extracts in endometritis related to antibacterial activity? Onderstepoort J Vet 72:129–134

    Article  CAS  Google Scholar 

  • McQueen DB, Perfetto CO, Hazard FK, Lathi RB (2015) Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss. Fertil Steril 104:927–931

    Article  PubMed  Google Scholar 

  • Oeckinghaus A, Ghosh S (2009) The NF-kappa B family of transcription factors and its regulation. Csh Perspect Biol 1:a000034

    Google Scholar 

  • Ortiz MI, Gonzalez-Garcia MP, Ponce-Monter HA, Castaneda-Hernandez G, Aguilar-Robles P (2010) Synergistic effect of the interaction between naproxen and citral on inflammation in rats. Phytomedicine 18:74–79

    Article  CAS  PubMed  Google Scholar 

  • Peipert JF, Ness RB, Soper DE, Bass D (2000) Association of lower genital tract inflammation with objective evidence of endometritis. Infect Dis Obstet Gynecol 8:83–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peipert JF, Ness RB, Blume J, Soper DE, Holley R, Randall H, Sweet RL, Sondheimer SJ, Hendrix SL, Amortegui A, Trucco G, Bass DC, Pelvic Inflammatory Disease, E., Clinical Health Study, I. (2001) Clinical predictors of endometritis in women with symptoms and signs of pelvic inflammatory disease. Am J Obstet Gynecol 184:856–863 (discussion 863-854)

    Article  CAS  PubMed  Google Scholar 

  • Ravel J, Moreno I, Simon C (2021) Bacterial vaginosis and its association with infertility, endometritis, and pelvic inflammatory disease. Am J Obstet Gynecol 224:251–257

    Article  CAS  PubMed  Google Scholar 

  • Shen Y, Sun Z, Guo X (2015) Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-gamma. Eur J Pharmacol 747:45–51

    Article  CAS  PubMed  Google Scholar 

  • Song Y, Zhao HF, Liu JY, Fang C, Miao RY (2016) Effects of Citral on Lipopolysaccharide-Induced Inflammation in Human Umbilical Vein Endothelial Cells. Inflammation 39:663–671

    Article  CAS  PubMed  Google Scholar 

  • Song XH, Long DX (2020) Nrf2 and ferroptosis: a new research direction for neurodegenerative diseases. Front Neurosci-Switz 14:267

    Article  Google Scholar 

  • Vitalakumar D, Sharma A, Flora SJS (2021) Ferroptosis: a potential therapeutic target for neurodegenerative diseases. J Biochem Mol Toxic 35:e22830

    Article  CAS  Google Scholar 

  • Vomund S, Schafer A, Parnham MJ, Brune B, von Knethen A (2017) Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci 18:2772

    Article  PubMed  PubMed Central  Google Scholar 

  • Wiesenfeld HC, Heine RP, Krohn MA, Hillier SL, Amortegui AA, Nicolazzo M, Sweet RL (2002) Association between elevated neutrophil defensin levels and endometritis. J Infect Dis 186:792–797

    Article  CAS  PubMed  Google Scholar 

  • Wu H, Zhao G, Jiang K, Li C, Qiu C, Deng G (2016) Engeletin alleviates lipopolysaccharide-induced endometritis in mice by inhibiting TLR4-mediated NF-kappaB activation. J Agric Food Chem 64:6171–6178

    Article  CAS  PubMed  Google Scholar 

  • Wu H, Dai A, Chen X, Yang X, Li X, Huang C, Jiang K, Deng G (2018) Leonurine ameliorates the inflammatory responses in lipopolysaccharide-induced endometritis. Int Immunopharmacol 61:156–161

    Article  CAS  PubMed  Google Scholar 

  • Yin B, Umar T, Ma X, Chen Y, Umar Z, Umer S, Deng G (2022) Andrograpanin mitigates lipopolysaccharides induced endometritis via TLR4/NF-kappaB pathway. Reprod Biol 22:100606

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from Natural Science Foundation of Science and Technology Department of Jilin Province (YDZJ202201ZYTS033).

Funding

The authors have not disclosed any funding.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, China-Japan Union Hospital of Jilin University, Changchun, 130033, Jilin, China

    Junrong Wang & Cong Ye

  2. Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Erdao District, 126 Sendai Street, Changchun, 130033, Jilin Province, China

    Weiliang Zhao

  3. Department of Urology, China-Japan Union Hospital of Jilin University, No.126, Xiantai Street, Changchun, 130033, China

    Yang Li

Authors
  1. Weiliang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Junrong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cong Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yang Li or Cong Ye.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, W., Wang, J., Li, Y. et al. Citral protects against LPS-induced endometritis by inhibiting ferroptosis through activating Nrf2 signaling pathway. Inflammopharmacol 31, 1551–1558 (2023). https://doi.org/10.1007/s10787-023-01211-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-023-01211-2

Keywords

Search

Navigation