Skip to main content
SpringerLink
Log in

Systems Pharmacology Uncovers Multiple Mechanisms of Erxian Decoction (二仙汤) for Treatment of Premature Ovarian Failure

  • Original Article
  • Published:
Chinese Journal of Integrative Medicine Aims and scope Submit manuscript

Abstract

Objective

To predict the chemical compositions and drug targets and to systematically dissect the pharmacological mechanism of Erxian Decoction (二仙汤, EXD) as a treatment for premature ovarian failure (POF) using a systems pharmacology approach.

Methods

The compounds present in EXD were obtained from three databases. The active ingredient was identified by analyzing the values of oral bioavailability (OB), drug-likeness (DL), and Lipinski’s rule (LR). The active ingredients were further searched in research articles, drug targets in the DrugBank database, and the C-T and T-P networks, as well as by pathway analysis using the Cytoscape platform.

Results

A total of 728 compounds were identified in EXD. Of these, 59 were identified as active compounds that conformed to the criteria with OB ⩾30% and DL ⩾0.18. By further searches in the literature, 126 related targets were identified that could interact with the active compounds. Additionally, it was found that the beneficial effects of EXD in POF are probably exerted via regulation of the immune system, modulation of estrogen levels, and anti-oxidative activities, and that it may act in a synergistic or cooperative manner with other therapeutic agents.

Conclusions

The systems pharmacology approach is a comprehensive system that was used to elucidate the pharmacological mechanism of EXD as a treatment for POF. The results of this study will also facilitate the application of traditional medicine in modern treatment strategies.

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

Similar content being viewed by others

References

  1. Cohen J, Chabbertbuffet N, Darai E. Diminished ovarian reserve, premature ovarian failure, poor ovarian responder—a plea for universal definitions. J Assist Reprod Gen 2015;32:1709–1712.

    Article  CAS  Google Scholar 

  2. Helen R, Martha H. Managing the menopause: an update. Maturitas 2016;86:53–58.

    Article  Google Scholar 

  3. Chapman C, Cree L, Shelling AN. The genetics of premature ovarian failure: current perspectives. Int J Women Health 2015;7:799–810.

    Google Scholar 

  4. Wu JJ, Lin Z, You ZL. The effect of Er-xian Decoction on relevant immune indexes of premature ovarian failure mice. Shanxi J Tradit Chin Med (Chin) 2013;29:47–49.

    Google Scholar 

  5. Berger SI, Iyengar R. Network analyses in systems pharmacology. Bioinformatics 2009;25:2466–2472.

    Article  CAS  Google Scholar 

  6. Huang C, Zheng C, Li Y, Wang, Y, Lu A, Yang L. Systems pharmacology in drug discovery and therapeutic insight for herbal medicines. Brief Bioinf 2014;15:710–733.

    Article  Google Scholar 

  7. Ru J, Li P, Wang J, Zhou W, Li B, Huang C, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminf 2014;6:13–18.

    Article  Google Scholar 

  8. Cave MR, Wragg J, Denys S, eds. Oral bioavailability: dealing with contaminated sites. 7th ed. Netherlands: Springer; 2011:287–324.

    Google Scholar 

  9. Xu X, Zhang W, Huang C, Li Y, Yu H, Wang YH, et al. A novel chemometric method for the prediction of human oral bioavailability. Int J Mol Sci 2012;13:6964–6982.

    Article  CAS  Google Scholar 

  10. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001;46:3–26.

    Article  CAS  Google Scholar 

  11. Ursu O, Rayan A, Goldblum A, Oprea TI. Understanding drug-likeness. Wires Comput Mol Sci 2011;1:760–781.

    Article  CAS  Google Scholar 

  12. Zheng C, Guo Z, Huang C, Wu Z, Li Y, Chen XT, et al. Large-scale direct targeting for drug repositioning and discovery. Sci Rep 2015;5:11970.

    Article  Google Scholar 

  13. Alqudah MA, Otoom NK, Aljaber HI, Saleh AM, Abu Zarga MH, Afifi FU, et al. New flavonol glycoside from Scabiosa prolifera L. aerial parts with in vitro antioxidant and cytotoxic activities. Nat Prod Res 2017;31:1–10.

    Article  Google Scholar 

  14. Zhang S, Wang X, Yi PF, Yu HF, Li B, Li XY, et al. Effects of icariin on the development of ovary and uterus in sexually matured female rats. J Tradit Chin Vet Med (Chin) 2007;26:15–18.

    Google Scholar 

  15. Nie X, Sheng W, Hou D, Liu Q, Wang R, Tan Y. Effect of hyperin and icariin on steroid hormone secretion in rat ovarian granulosa cells. Clin Chim Acta 2018;30213–30214.

  16. Ding LZ, Teng X, Zhang ZB, Zheng CJ, Chen SH. Angiferin inhibits apoptosis and oxidative stress via BMP2/Smad-1 signaling in dexamethasone-induced MC3T3-E1 cells. Int J Mol Med 2018;41:2517–2526.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. National Pharmacopoeia Committee. Pharmacopoeia of People’s Republic of China. Part 1. Beijing: Chemical Industry Press, 2015:Appendix 133–134.

    Google Scholar 

  18. Paiva LBD, Goldbeck R, Santos WDD, Squina FM. Ferulic acid and derivatives: molecules with potential application in the pharmaceutical field. Braz J Pharm Sci 2013;49:395–411.

    Article  Google Scholar 

  19. Cao ZY, Ding Y, Su ZZ, Li N, Cao L, Ding G, et al. Study on contribution of main components in Guizhi Fuling Capsule based on molecular imprinting technique and activity screening. China J Chin Mater Med (Chin) 2015;40:2420–2427.

    CAS  Google Scholar 

  20. Lin MK, Yu YL, Chen KC, Chang WT, Lee MS, Yang MJ, et al. Kaempferol from semen cuscutae attenuates the immune function of dendritic cells. Immunobiology 2011;216:1103–1109.

    Article  CAS  Google Scholar 

  21. Yenuganti VR, Vanselow J. Cultured bovine granulosa cells rapidly lose important features of their identity and functionality but partially recover under long-term culture conditions. Cell Tissue Res 2017;368:397–403.

    Article  CAS  Google Scholar 

  22. Podfigurna-Stopa A, Czyzyk A, Grymowicz M, Smolarczyk R, Katulski K, Czajkowski K, et al. Premature ovarian insufficiency: the context of long-term effects. J Endocrinol Invest 2016;39:983–990.

    Article  CAS  Google Scholar 

  23. Verma P, K Sharma A, Shankar H, Sharma A, Rao DN. Role of trace elements, oxidative stress and immune system: a triad in premature ovarian failure. Biol Trace Elem Res 2017;184:325–333.

    Article  Google Scholar 

  24. Blumenfeld Z, Katz G, Evron A. ’An ounce of prevention is worth a pound of cure’: the case for and against GnRH-agonist for fertility preservation. Ann Oncol Off J Eur Soc Med Oncol 2014;25:1719–1728.

    Article  CAS  Google Scholar 

  25. Su Y, Xue R, Li S, Cui X. Effect of yin and yang cycle sequential therapy for chemotherapy induced expression of VEGF POF in rat ovary. Shaanxi Coll Tradit Chin Med (Chin) 2014;37:83–87.

    Google Scholar 

  26. Zhang Y, Yu B, Chen J, Zhao Z, Wang JL, Huang F, et al. Effects of acupuncture on PI3K/AKT/MTOR signaling pathway in rats with premature ovarian failure. Chin Acupunct Moxibust (Chin) 2015;35:53–58.

    CAS  Google Scholar 

  27. Hillier SG. Gonadotropic control of ovarian follicular growth and development. Mol Cell Endocrinol 2001;179:39–46.

    Article  CAS  Google Scholar 

  28. Pratheeshkumar P, Son YO, Budhraja A, Wang X, Ding SZ, Wang L, et al. Luteolin inhibited the activation of AKT/ERK/mTOR/p70S6K/MMP-2/MMP-9 pathway in prostate cancer cells. PLoS ONE 2013;7:e52279.

    Article  Google Scholar 

  29. Ai H, Zhang H, Zhang Y, Liu Y. Genistein inhibits expression of matrix metalloproteinases-2 (MMP-2) in premature ovarian failure (POF) rats induced with cisplatin intraperitoneal injection. Afr J Microbiol Res 2012;6:6969–6972.

    CAS  Google Scholar 

  30. Chuang CH, Yeh CL, Yeh SL, Lin ES, Wang LY, Wang YH. Quercetin metabolites inhibit MMP-2 expression in A549 lung cancer cells by PPAR-γ associated mechanisms. J Nutr Biochem 2016;33:45–53.

    Article  CAS  Google Scholar 

  31. Hu W, Yang MH, Chen WJ, Zhu FF, Li XD. Effect of compatibility of Curculigo and Epimedium to ACTH and cAMP on the Kidney Yang deficiency mice. Chin J Modern Appl Pharm (Chin) 2015;317–323.

  32. Weng Q, Liu Z, Li B, Liu KQ, Wu WJ, Liu H. Oxidative stress induces mouse follicular granulosa cells apoptosis via JNK/FoxO1 pathway. Plos One 2016;11:e0167869.

    Article  Google Scholar 

  33. Jiang S, Fan J, Wang Q, Ju D, Feng DM, Li J, et al. Diosgenin induces ROS-dependent autophagy and cytotoxicity via mTOR signaling pathway in chronic myeloid leukemia cells. Phytomedicine 2016;23:243–252.

    Article  CAS  Google Scholar 

  34. Yang QS, He LP, Zhou XL, Zhao Y, Shen J, Xu P, et al. Kaempferol pretreatment modulates systemic inflammation and oxidative stress following hemorrhagic shock in mice. Chin Med 2015;10:6–13.

    Article  Google Scholar 

Download references

Acknowledgements

Thanks to the TCMSP database created by Prof. WANG YH’s team, which provides us with great convenience for our data retrieval.

Author information

Authors and Affiliations

  1. Key laboratory of Follicular Development and Reproductive Health of Liaoning Province, Jinzhou Medical University, Jinzhou, Liaoning Province, 121000, China

    Bo Du, Li-hong Liu, Yu-juan Lv & Hao Ai

  2. Department of Gynecology and Obstetrics, Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, 121000, China

    Bo Du, Li-hong Liu & Hao Ai

Authors
  1. Bo Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li-hong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-juan Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao Ai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Du B, Liu LH and Ai H developed the concept of the study. All authors contributed to data accumulation. Du B, Liu LH and Lv YJ contributed to data analysis. All authors contributed to data interpretation. Du B and Ai H wrote the manuscript. All authors contributed to revisions of the manuscript, and approved of the final submission.

Corresponding author

Correspondence to Hao Ai.

Ethics declarations

The authors declare that they have no competing interests.

Additional information

Supported by Liaoning Natural Science Foundation of China (No. 2017011854-301) and Jinzhou Science and Technology Project, China (No. 16B1G35)

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, B., Liu, Lh., Lv, Yj. et al. Systems Pharmacology Uncovers Multiple Mechanisms of Erxian Decoction (二仙汤) for Treatment of Premature Ovarian Failure. Chin. J. Integr. Med. 26, 106–113 (2020). https://doi.org/10.1007/s11655-019-3201-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11655-019-3201-9

Keywords

Search

Navigation