Skip to main content
Log in

Resveratrol regulates the inflammation and oxidative stress of granulosa cells in PCOS via targeting TLR2

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

Polycystic ovary syndrome (PCOS) is featured as a common endocrine disorder in reproductive-aged women, while its pathophysiology is not fully illustrated. This study examined potential actions of resveratrol in PCOS cellular model and explored the underlying interaction between resveratrol and toll-like receptor 2 (TLR2). This study performed the bioinformatics analysis on two microarray datasets (GSE34526 and GSE138518). We found that TLR2 was one of potential hub genes that may be associated with PCOS. Further examination showed that TLR2 was highly expressed in granulosa cells from PCOS group compared with control. The in vitro studies showed that LPS intervention caused an increased expression of TLR2 and the pro-inflammatory mediators, and induced oxidative stress in the granulosa cells, which was concentration-dependently antagonized by resveratrol treatment. TLR2 silence significantly attenuated LPS-induced increase TNF-α, IL-1β, IL-6 and IL-8 expression and oxidative stress of granulosa cells. Furthermore, TLR2 overexpression promoted inflammatory response and oxidative stress in the granulosa cells, which was antagonized by resveratrol treatment. In conclusion, resveratrol could attenuate LPS-induced inflammation and oxidative stress in granulosa cells, and the underlying mechanisms may be related to the inhibitory effect of resveratrol on TLR2 expression in granulosa cells.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

Data will be provided on reasonable request.

References

  • Ajmal N, Khan SZ, Shaikh R (2019) Polycystic ovary syndrome (PCOS) and genetic predisposition: A review article. Eur J Obstet Gynecol Reprod Biol X 3:100060

    Article  CAS  Google Scholar 

  • Akhter N, Madhoun A, Arefanian H, Wilson A, Kochumon S, Thomas R, Shenouda S, Al-Mulla F, Ahmad R, Sindhu S (2019) Oxidative Stress Induces Expression of the Toll-Like Receptors (TLRs) 2 and 4 in the Human Peripheral Blood Mononuclear Cells: Implications for Metabolic Inflammation. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol 53(1):1–18

    Article  CAS  Google Scholar 

  • Bahramrezaie M, Amidi F, Aleyasin A, Saremi A, Aghahoseini M, Brenjian S, Khodarahmian M, Pooladi A (2019) Effects of resveratrol on VEGF & HIF1 genes expression in granulosa cells in the angiogenesis pathway and laboratory parameters of polycystic ovary syndrome: a triple-blind randomized clinical trial. J Assist Reprod Genet 36(8):1701–1712

    Article  Google Scholar 

  • Bezerra MÉS, Gouveia BB, Barberino RS, Menezes VG, Macedo TJS, Cavalcante AYP, Monte APO, Santos JMS, Matos MHT (2018) Resveratrol promotes in vitro activation of ovine primordial follicles by reducing DNA damage and enhancing granulosa cell proliferation via phosphatidylinositol 3-kinase pathway. Reprod Domest Anim Zuchthygiene 53(6):1298–1305

    Article  CAS  Google Scholar 

  • Brenjian S, Moini A, Yamini N, Kashani L, Faridmojtahedi M, Bahramrezaie M, Khodarahmian M, Amidi F (2020) Resveratrol treatment in patients with polycystic ovary syndrome decreased pro-inflammatory and endoplasmic reticulum stress markers. Am J Reprod Immunol (New York, N.Y. : 1989) 83(1):e13186

    Google Scholar 

  • Carter LG, D’Orazio JA, Pearson KJ (2014) Resveratrol and cancer: focus on in vivo evidence. Endocr Relat Cancer 21(3):R209–R225

    Article  CAS  Google Scholar 

  • Coyle C, Campbell RE (2019) Pathological pulses in PCOS. Mol Cell Endocrinol 498:110561

    Article  CAS  Google Scholar 

  • Dai J, Gu L, Su Y, Wang Q, Zhao Y, Chen X, Deng H, Li W, Wang G, Li K (2018) Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-κB pathways. Int Immunopharmacol 54:177–187

    Article  CAS  Google Scholar 

  • De Leo V, Musacchio MC, Cappelli V, Massaro MG, Morgante G, Petraglia F (2016) Genetic, hormonal and metabolic aspects of PCOS: an update. Reprod Biol Endocrinol: RB&E 14(1):38

    Article  Google Scholar 

  • Deng S, Yu K, Jiang W, Li Y, Wang S, Deng Z, Yao Y, Zhang B, Liu G, Liu Y, Lian Z (2017) Over-expression of Toll-like receptor 2 up-regulates heme oxygenase-1 expression and decreases oxidative injury in dairy goats. J Anim Sci Biotechnol 8:3

    Article  Google Scholar 

  • Devarbhavi P, Telang L, Vastrad B, Tengli A, Vastrad C, Kotturshetti I (2021) Identification of key pathways and genes in polycystic ovary syndrome via integrated bioinformatics analysis and prediction of small therapeutic molecules. Reprod Biol Endocrinol: RB&E 19(1):31

    Article  CAS  Google Scholar 

  • Fitzgerald S, DiVasta A, Gooding H (2018) An update on PCOS in adolescents. Curr Opin Pediatr 30(4):459–465

    Article  Google Scholar 

  • Fu LL, Xu Y, Li DD, Dai XW, Xu X, Zhang JS, Ming H, Zhang XY, Zhang GQ, Ma YL, Zheng LW (2018) Expression profiles of mRNA and long noncoding RNA in the ovaries of letrozole-induced polycystic ovary syndrome rat model through deep sequencing. Gene 657:19–29

    Article  CAS  Google Scholar 

  • Guan HY, Xia HX, Chen XY, Wang L, Tang ZJ, Zhang W (2021) Toll-Like Receptor 4 Inhibits Estradiol Secretion via NF-κB Signaling in Human Granulosa Cells. Front Endocrinol 12:629554

    Article  Google Scholar 

  • Hashemi Taheri AP, Moradi B, Radmard AR, Sanginabadi M, Qorbani M, Mohajeri-Tehrani MR, Shirzad N, Hosseini S, Hekmatdoost A, Asadi S, Samadi M, Mansour A (2021) Effect of resveratrol administration on ovarian morphology, determined by transvaginal ultrasound for the women with polycystic ovary syndrome (PCOS). Br J Nutr: 1–6

  • Hoeger KM, Dokras A, Piltonen T (2021) Update on PCOS: consequences, challenges, and guiding treatment. J Clin Endocrinol Metab 106(3):e1071–e1083

    Article  Google Scholar 

  • Hou CY, Tain YL, Yu HR, Huang LT (2019) The effects of resveratrol in the treatment of metabolic syndrome. Int J Mol Sci 20(3):535

  • Huang X, Liu C, Hao C, Tang Q, Liu R, Lin S, Zhang L, Yan W (2016) Identification of altered microRNAs and mRNAs in the cumulus cells of PCOS patients: miRNA-509-3p promotes oestradiol secretion by targeting MAP3K8. Reproduction (Cambridge, England) 151(6):643–655

    Article  CAS  Google Scholar 

  • Jiao J, Shi B, Wang T, Fang Y, Cao T, Zhou Y, Wang X, Li D (2018) Characterization of long non-coding RNA and messenger RNA profiles in follicular fluid from mature and immature ovarian follicles of healthy women and women with polycystic ovary syndrome. Human Reprod (Oxford, England) 33(9):1735–1748

    Article  CAS  Google Scholar 

  • Jozkowiak M, Hutchings G, Jankowski M, Kulcenty K, Mozdziak P, Kempisty B, Spaczynski RZ, Piotrowska-Kempisty H (2020) The Stemness of human ovarian granulosa cells and the role of resveratrol in the differentiation of MSCs-A review based on cellular and molecular knowledge. Cells 9(6):1418

    Article  CAS  Google Scholar 

  • Kim S, Jin Y, Choi Y, Park T (2011) Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice. Biochem Pharmacol 81(11):1343–1351

    Article  CAS  Google Scholar 

  • Li J, Chen H, Gou M, Tian C, Wang H, Song X, Keefe DL, Bai X, Liu L (2021) Molecular features of polycystic ovary syndrome revealed by transcriptome analysis of oocytes and cumulus cells. Front Cell Dev Biol 9:735684

    Article  Google Scholar 

  • Lua J, Ekanayake K, Fangman M, Doré S (2021) Potential role of soluble Toll-like receptors 2 and 4 as therapeutic agents in stroke and brain hemorrhage. Int J Mol Sci 22(18):9977

    Article  CAS  Google Scholar 

  • Marks KE, Cho K, Stickling C, Reynolds JM (2021) Toll-like Receptor 2 in Autoimmune Inflammation. Immune Netw 21(3):e18

    Article  Google Scholar 

  • Moreira-Pinto B, Costa L, Felgueira E, Fonseca BM, Rebelo I (2021) Low doses of resveratrol protect human granulosa cells from induced-oxidative stress. Antioxidants (Basel, Switzerland) 10(4):561

    CAS  Google Scholar 

  • Nie Z, Zhang L, Chen W, Zhang Y, Hua R, Wang W, Zhang T, Wu H (2020) The protective effects of pretreatment with resveratrol in cyclophosphamide-induced rat ovarian granulosa cell injury: In vitro study. Reprod Toxicol (Elmsford, N.Y.) 95:66–74

    Article  CAS  Google Scholar 

  • Nie Z, Hua R, Zhang Y, Zhang N, Zhang Y, Li Q, Wu H (2021) Resveratrol protects human luteinised granulosa cells against hydrogen peroxide-induced oxidative injury through the Sirt1. Reprod Fertil Dev 33(16):831–840

    Article  CAS  Google Scholar 

  • Oliveira-Nascimento L, Massari P, Wetzler LM (2012) The Role of TLR2 in Infection and Immunity. Front Immunol 3:79

    Article  Google Scholar 

  • Pasquariello R, Verdile N, Brevini TAL, Gandolfi F, Boiti C, Zerani M, Maranesi M (2020) The role of resveratrol in mammalian reproduction. Molecules (Basel, Switzerland) 25(19):4554

    Article  CAS  Google Scholar 

  • Patel S (2018) Polycystic ovary syndrome (PCOS), an inflammatory, systemic, lifestyle endocrinopathy. J Steroid Biochem Mol Biol 182:27–36

    Article  CAS  Google Scholar 

  • Price JC, Bromfield JJ, Sheldon IM (2013) Pathogen-associated molecular patterns initiate inflammation and perturb the endocrine function of bovine granulosa cells from ovarian dominant follicles via TLR2 and TLR4 pathways. Endocrinology 154(9):3377–3386

    Article  Google Scholar 

  • Qi B, Shi C, Meng J, Xu S, Liu J (2018) Resveratrol alleviates ethanol-induced neuroinflammation in vivo and in vitro: Involvement of TLR2-MyD88-NF-κB pathway. Int J Biochem Cell Biol 103:56–64

    Article  CAS  Google Scholar 

  • Ragonese F, Monarca L, De Luca A, Mancinelli L, Mariani M, Corbucci C, Gerli S, Iannitti RG, Leonardi L, Fioretti B (2021) Resveratrol depolarizes the membrane potential in human granulosa cells and promotes mitochondrial biogenesis. Fertil Steril 115(4):1063–1073

    Article  CAS  Google Scholar 

  • Rosenfield RL, Ehrmann DA (2016) The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev 37(5):467–520

    Article  CAS  Google Scholar 

  • Shabani M, Sadeghi A, Hosseini H, Teimouri M, BabaeiKhorzoughi R, Pasalar P, Meshkani R (2020) Resveratrol alleviates obesity-induced skeletal muscle inflammation via decreasing M1 macrophage polarization and increasing the regulatory T cell population. Sci Rep 10(1):3791

    Article  CAS  Google Scholar 

  • Wang LP, Peng XY, Lv XQ, Liu L, Li XL, He X, Lv F, Pan Y, Wang L, Liu KF, Zhang XM (2019) High throughput circRNAs sequencing profile of follicle fluid exosomes of polycystic ovary syndrome patients. J Cell Physiol 234(9):15537–15547

  • Witchel SF, Teede HJ, Peña AS (2020) Curtailing PCOS. Pediatr Res 87(2):353–361

    Article  Google Scholar 

  • Xia N, Daiber A, Förstermann U, Li H (2017) Antioxidant effects of resveratrol in the cardiovascular system. Br J Pharmacol 174(12):1633–1646

    Article  CAS  Google Scholar 

  • Xie Y, Zhang K, Zhang K, Zhang J, Wang L, Wang X, Hu X, Liang Z, Li J (2020) Toll-like receptors and high mobility group box 1 in granulosa cells during bovine follicle maturation. J Cell Physiol 235(4):3447–3462

    Article  CAS  Google Scholar 

  • Yarmolinskaya M, Bulgakova O, Abashova E, Borodina V, Tral T (2021) The effectiveness of resveratrol in treatment of PCOS on the basis of experimental model in rats, Gynecological endocrinology : the official journal of the International Society of. Gynecol Endocrinol 37(sup1):54–57

    Article  CAS  Google Scholar 

  • Yin J, Peng Y, Wu J, Wang Y, Yao L (2014) Toll-like receptor 2/4 links to free fatty acid-induced inflammation and β-cell dysfunction. J Leukoc Biol 95(1):47–52

    Article  Google Scholar 

  • Zeng Z, Lin X, Xia T, Liu W, Tian X, Li M (2020) Identification of Crucial lncRNAs, miRNAs, mRNAs, and Potential Therapeutic Compounds for Polycystic Ovary Syndrome by Bioinformatics Analysis. Biomed Res Int 2020:1817094

    Article  Google Scholar 

  • Zuo T, Zhu M, Xu W, Wang Z, Song H (2017) Iridoids with Genipin Stem Nucleus Inhibit Lipopolysaccharide-Induced Inflammation and Oxidative Stress by Blocking the NF-κB Pathway in Polycystic Ovary Syndrome. Cell Physiol Biochem: Int J Exp Cell Physiol Biochem Pharmacol 43(5):1855–1865

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University.

Author information

Authors and Affiliations

Authors

Contributions

BY, SL and LF conceived the study; BY, SL and LF performed the experiments; JW and JM performed the data analysis; BL prepared the graphs; all the authors approved the manuscript for submission.

Corresponding author

Correspondence to Ben Yuan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethical statement

All the experiments were approved by Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University.

Additional information

Publisher's note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 71 KB) Supplemental Figure S1. PPI network of the common DEGs.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yuan, B., Luo, S., Feng, L. et al. Resveratrol regulates the inflammation and oxidative stress of granulosa cells in PCOS via targeting TLR2. J Bioenerg Biomembr 54, 191–201 (2022). https://doi.org/10.1007/s10863-022-09942-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-022-09942-7

Keywords

Navigation