Skip to main content

Advertisement

SpringerLink
Log in

Dihydroartemisinin ameliorates chronic nonbacterial prostatitis and epithelial cellular inflammation by blocking the E2F7/HIF1α pathway

  • Original Research Article
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

Chronic nonbacterial prostatitis (CNP) has remained one of the most prevalent urological diseases, particularly in older men. Dihydroartemisinin (DHA) has been identified as a semi-synthetic derivative of artemisinin that exhibits broad protective effects. However, the role of DHA in inhibiting CNP inflammation and prostatic epithelial cell proliferation remains largely unknown.

Materials and methods

CNP animal model was induced by carrageenan in C57BL/6 mouse. Enzyme linked immunosorbent assay (ELISA), Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to examine inflammatory cytokines and proliferation genes expression. Immunofluorescence and immunochemistry staining were used to detect and E2F7 expression. Human prostatic epithelial cells (HPECs) and RWPE-1 was induced by lipopolysaccharide (LPS) to mimic CNP model in vitro. Cell proliferation was determined using MTS assay.

Results

DHA significantly alleviated the rough epithelium and inhibited multilamellar cell formation in the prostatic gland cavity and prostatic index induced by carrageenan. In addition, DHA decreased the expression of TNF-α and IL-6 inflammatory factors in prostatitis tissues and in LPS-induced epithelial cells. Upregulation of transcription factor E2F7, which expression was inhibited by DHA, was found in CNP tissues, human BPH tissues and LPS-induced epithelial cells inflammatory response. Mechanically, we found that depletion of E2F7 by shRNA inhibited epithelial cell proliferation and LPS-induced inflammation while DHA further enhance these effects. Furthermore, HIF1α was transcriptional regulated by E2F7 and involved in E2F7-inhibited CNP and cellular inflammatory response. Interestingly, we found that inhibition of HIF1α blocks E2F7-induced cell inflammatory response but does not obstruct E2F7-promoted cell growth.

Conclusion

The results revealed that DHA inhibits the CNP and inflammation by blocking the E2F7/HIF1α pathway. Our findings provide new evidence for the mechanism of DHA and its key role in CNP, which may provide an alternative solution for the prevention and treatment of CNP.

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

Similar content being viewed by others

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Abbreviations

CNP:

Chronic nonbacterial prostatitis

DHA:

Dihydroartemisinin

LPS:

Lipopolysaccharide

TNF-α:

Tumor necrosis factor

IL-6:

Interleukin-6

ChIP:

Chromatin immunoprecipitation

qRT-PCR:

Quantitative polymerase chain reaction

FBS:

Fetal bovine serum

References

  1. Liu Q, et al. Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer. Int J Cancer. 2019;145:415–26.

    Article  CAS  Google Scholar 

  2. Polackwich AS, Shoskes DA. Chronic prostatitis/chronic pelvic pain syndrome: a review of evaluation and therapy. Prostate Cancer Prostatic Dis. 2016;19:132–8.

    Article  CAS  Google Scholar 

  3. Holt JD, Garrett WA, McCurry TK, Teichman JM. Common questions about chronic prostatitis. Am Fam Physician. 2016;93:290–6.

    PubMed  Google Scholar 

  4. Breser ML, Salazar FC, Rivero VE, Motrich RD. Immunological mechanisms underlying chronic pelvic pain and prostate inflammation in chronic pelvic pain syndrome. Front Immunol. 2017;8:898.

    Article  Google Scholar 

  5. Zhang L, et al. MicroRNA expression profile in chronic nonbacterial prostatitis revealed by next-generation small RNA sequencing. Asian J Androl. 2019;21:351–9.

    Article  CAS  Google Scholar 

  6. Tantawy SA, Elgohary HM, Kamel DM. Trans-perineal pumpkin seed oil phonophoresis as an adjunctive treatment for chronic nonbacterial prostatitis. Res Rep Urol. 2018;10:95–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Xiong Y, Zhou L, Qiu X, Miao C. Anti-inflammatory and anti-hyperplastic effect of Bazhengsan in a male rat model of chronic nonbacterial prostatitis. J Pharmacol Sci. 2019;139:201–8.

    Article  CAS  Google Scholar 

  8. Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985;228:1049–55.

    Article  CAS  Google Scholar 

  9. Zhang F, et al. Dihydroartemisinin inhibits TCTP-dependent metastasis in gallbladder cancer. J Exp Clin Cancer Res. 2017;36:68.

    Article  Google Scholar 

  10. Yang B, et al. Dihydroartemisinin alleviates high glucose-induced vascular smooth muscle cells proliferation and inflammation by depressing the miR-376b-3p/KLF15 pathway. Biochem Biophys Res Commun. 2020;530:574–80.

    Article  CAS  Google Scholar 

  11. Guo L, et al. Dihydroartemisinin inhibits vascular endothelial growth factor-induced endothelial cell migration by a p38 mitogen-activated protein kinase-independent pathway. Exp Ther Med. 2014;8:1707–12.

    Article  CAS  Google Scholar 

  12. Dong F, et al. Dihydroartemisinin targets VEGFR2 via the NF-kappaB pathway in endothelial cells to inhibit angiogenesis. Cancer Biol Ther. 2014;15:1479–88.

    Article  CAS  Google Scholar 

  13. Xiang S, et al. E2F1 and E2F7 differentially regulate KPNA2 to promote the development of gallbladder cancer. Oncogene. 2019;38:1269–81.

    Article  CAS  Google Scholar 

  14. Ankers JM, et al. Dynamic NF-kappaB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation. Elife. 2016. https://doi.org/10.7554/eLife.10473.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Crosby ME, Almasan A. Opposing roles of E2Fs in cell proliferation and death. Cancer Biol Ther. 2004;3:1208–11.

    Article  CAS  Google Scholar 

  16. Ghari F, et al. Citrullination-acetylation interplay guides E2F-1 activity during the inflammatory response. Sci Adv. 2016;2:e1501257.

    Article  Google Scholar 

  17. Wang S, Wang L, Wu C, Sun S, Pan JH. E2F2 directly regulates the STAT1 and PI3K/AKT/NF-kappaB pathways to exacerbate the inflammatory phenotype in rheumatoid arthritis synovial fibroblasts and mouse embryonic fibroblasts. Arthritis Res Ther. 2018;20:225.

    Article  Google Scholar 

  18. Disner GR, Falcao MAP, Lima C, Lopes-Ferreira M. In silico target prediction of overexpressed microRNAs from LPS-challenged Zebrafish (Danio rerio) treated with the novel anti-inflammatory peptide TnP. Int J Mol Sci. 2021;22:7117.

    Article  CAS  Google Scholar 

  19. Liang R, et al. SNHG6 functions as a competing endogenous RNA to regulate E2F7 expression by sponging miR-26a-5p in lung adenocarcinoma. Biomed Pharmacother. 2018;107:1434–46.

    Article  CAS  Google Scholar 

  20. Ma YS, et al. MicroRNA-302a/d inhibits the self-renewal capability and cell cycle entry of liver cancer stem cells by targeting the E2F7/AKT axis. J Exp Clin Cancer Res. 2018;37:252.

    Article  CAS  Google Scholar 

  21. Saleh AD, et al. Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and potential therapeutic nanomedicine in head and neck cancer. Clin Cancer Res. 2019;25:2860–73.

    Article  CAS  Google Scholar 

  22. Yang R, et al. E2F7-EZH2 axis regulates PTEN/AKT/mTOR signalling and glioblastoma progression. Br J Cancer. 2020. https://doi.org/10.1038/s41416-020-01032-y.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sandhu C, Peehl DM, Slingerland J. p16INK4A mediates cyclin dependent kinase 4 and 6 inhibition in senescent prostatic epithelial cells. Can Res. 2000;60:2616–22.

    CAS  Google Scholar 

  24. Weijts BG, et al. E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1. EMBO J. 2012;31:3871–84.

    Article  CAS  Google Scholar 

  25. Neubert P, et al. HIF1A and NFAT5 coordinate Na(+)-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting. Autophagy. 2019;15:1899–916.

    Article  CAS  Google Scholar 

  26. Rohwer N, et al. Non-canonical HIF-1 stabilization contributes to intestinal tumorigenesis. Oncogene. 2019;38:5670–85.

    Article  CAS  Google Scholar 

  27. Nadler RB, et al. IL-1beta and TNF-alpha in prostatic secretions are indicators in the evaluation of men with chronic prostatitis. J Urol. 2000;164:214–8.

    Article  CAS  Google Scholar 

  28. Wang W, Chen R, Wang J. Procyanidin B2 ameliorates carrageenan-induced chronic nonbacterial prostatitis in rats via anti-inflammatory and activation of the Nrf2 pathway. Biochem Biophys Res Commun. 2017;493:794–9.

    Article  CAS  Google Scholar 

  29. Paulis G. Inflammatory mechanisms and oxidative stress in prostatitis: the possible role of antioxidant therapy. Res Rep Urol. 2018;10:75–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Xu BH, et al. Deletion of Smad3 prevents renal fibrosis and inflammation in type 2 diabetic nephropathy. Metabolism. 2020;103:154013.

    Article  CAS  Google Scholar 

  31. Liu CH, et al. HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis. J Clin Invest. 2019;129:5357–73.

    Article  CAS  Google Scholar 

  32. Popovics P, Schally AV, Salgueiro L, Kovacs K, Rick FG. Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells. Proc Natl Acad Sci U S A. 2017;114:1359–64.

    Article  CAS  Google Scholar 

  33. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol. 2014;9:47–71.

    Article  CAS  Google Scholar 

  34. Ma C, et al. PAFAH1B2 is a HIF1a target gene and promotes metastasis in pancreatic cancer. Biochem Biophys Res Commun. 2018;501:654–60.

    Article  CAS  Google Scholar 

  35. Yang Y, Sun M, Wang L, Jiao B. HIFs, angiogenesis, and cancer. J Cell Biochem. 2013;114:967–74.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was partially supported by Scientific Research Project of Hebei Provincial Administration of Traditional Chinese Medicine (No. 2020012 and 2020013); Natural Science Foundation of Hebei Province (No. H2021423018); Hebei Provincial Health Commission Project (20210302).

Author information

Authors and Affiliations

  1. Department of Urology, Hebei Province of Chinese Medicine/Affiliated Hospital of Hebei University of Chinese Medicine, No. 389, Zhongshan East Road, Shijiazhuang, 050000, Hebei Province, People’s Republic of China

    Yan Zhou, Jun-hao Wang, Jian-peng Han, Jian-yong Feng, Kuo Guo, Fei Du, Wen-bin Chen & Yong-zhang Li

Authors
  1. Yan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun-hao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jian-peng Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jian-yong Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kuo Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fei Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wen-bin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yong-zhang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design: Y.Z., Y.L. Development of methodology: Y.Z., J.W., J.H., J.F., and K.G. Acquisition of the data (provided animals, provided facilities and so on): F.D., W.C., and Y.Z. Analysis and interpretation of the data (for example, statistical analysis, biostatistics and computational analysis): J.W., J.H., and K.G. Writing, review and/or revision of the manuscript: Y.Z., J.W., K.G., and Y.L. Administrative, technical or material support (that is, reporting or organizing the data, constructing the databases): Y.Z., J.H., F.D., and W.C. Study supervision: K.G., W.C., and Y.L.

Corresponding author

Correspondence to Yong-zhang Li.

Ethics declarations

Conflict of interest

The authors declare that there are no conflict of interest.

Ethical approval

The present study was authorized Ethics Committee of Hospital of Hebei University of Chinese Medicine. All animal studies were approved by the Institutional Animal Care and Use Committee of Hospital of Hebei University of Chinese Medicine (20090037) and were made to minimize suffering.

Additional information

Responsible Editor: John Di Battista.

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 (DOCX 17 KB)

Supplementary file2 (DOCX 605 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, Y., Wang, Jh., Han, Jp. et al. Dihydroartemisinin ameliorates chronic nonbacterial prostatitis and epithelial cellular inflammation by blocking the E2F7/HIF1α pathway. Inflamm. Res. 71, 449–460 (2022). https://doi.org/10.1007/s00011-022-01544-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-022-01544-8

Keywords

Search

Navigation