Skip to main content
SpringerLink
Log in

Cerium oxide nanozymes alleviate oxidative stress in tenocytes for Achilles tendinopathy healing

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

Background

Reactive oxygen species (ROS) is considered as ubiquitous and highly active chemicals that influence tendon integrity and orchestrate tendon repair. With significant recent advances in nanomaterials, cerium oxide nanoparticles (CeO2 NPs) exhibit superoxide dismutase- and catalase-like activities. Herein, we introduced a therapeutic approach of CeO2 NPs for Achilles tendinopathy (AT) healing.

Methods

CeO2 NPs were synthesized to examine their effect as ROS scavengers on AT healing in vitro and in vivo. The mRNA levels of inflammatory factors were evaluated in AT after CeO2 NPs treatment in vitro. The mechanisms underlying CeO2 NPs-mediated stimulation of NRF2 translocation and ERK signaling were verified through immunofluorescence and Western blot analysis. The efficacy of CeO2 NPs was tested in an AT rat model in comparison with the control.

Results

CeO2 NPs not only significantly scavenged multiple ROS and suppressed ROS-induced inflammatory reactions but also protected cell proliferation under oxidative stress induced by tert-butyl hydroperoxide (TBHP). Moreover, CeO2 NPs could promote NRF2 nuclear translocation for anti-oxidation and anti-inflammation through the ERK signaling pathway. In a rat model of collagenase-induced tendon injuries, CeO2 NPs showed significant therapeutic efficacy by ameliorating tendon damage.

Conclusion

The present study provides valuable insights into the molecular mechanism of CeO2 NPs to ameliorate ROS in tenocytes via the ERK/NRF2 signaling pathway, which underscores the potential of CeO2 NPs for application in the treatment of enthesopathy healing.

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. De Jonge, S.; Van Den Berg, C.; De Vos, R. J.; Van Der Heide, H. J. L.; Weir, A.; Verhaar, J. A. N.; Bierma-Zeinstra, S. M. A.; Tol, J. L. Incidence of midportion Achilles tendinopathy in the general population. Br. J. Sports Med. 2011, 45, 1026–1028.

    Article  CAS  Google Scholar 

  2. Magnusson, S. P.; Langberg, H.; Kjaer, M. The pathogenesis of tendinopathy: Balancing the response to loading. Nat. Rev. Rheumatol. 2010, 6, 262–268.

    Article  Google Scholar 

  3. Vo, T. P.; Ho, G. W. K.; Andrea, J. Achilles tendinopathy, a brief review and update of current literature. Curr. Sports Med. Rep. 2021, 20, 453–461.

    Article  Google Scholar 

  4. Murrell, G. A. C. Oxygen free radicals and tendon healing. J. Shoulder Elbow Surg. 2007, 16, S208–S214.

    Article  Google Scholar 

  5. Millar, N. L.; Murrell, G. A. C.; McInnes, I. B. Alarmins in tendinopathy: Unravelling new mechanisms in a common disease. Rheumatology (Oxford). 2013, 52, 769–779.

    Article  CAS  Google Scholar 

  6. Bestwick, C. S.; Maffulli, N. Reactive oxygen species and tendinopathy: Do they matter? Br. J. Sports Med. 2004, 38, 672–674.

    Article  CAS  Google Scholar 

  7. Millar, N. L.; Murrell, G. A. C.; McInnes, I. B. Inflammatory mechanisms in tendinopathy—towards translation. Nat. Rev. Rheumatol. 2017, 13, 110–122.

    Article  CAS  Google Scholar 

  8. Li, X. Y.; Fang, P.; Mai, J.; Choi, E. T.; Wang, H.; Yang, X. F. Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J. Hematol. Oncol. 2013, 6, 19.

    Article  CAS  Google Scholar 

  9. Yao, J.; Cheng, Y.; Zhou, M.; Zhao, S.; Lin, S. C.; Wang, X. Y.; Wu, J. J. X.; Li, S. R.; Wei, H. ROS scavenging Mn3O4 nanozymes for in vivo anti-inflammation. Chem. Sci. 2018, 9, 2927–2933.

    Article  CAS  Google Scholar 

  10. Korsvik, C.; Patil, S.; Seal, S.; Self, W. T. Superoxide dismutase mimetic properties exhibited by vacancy engineered ceria nanoparticles. Chem. Commun. 2007, 1056–1058.

  11. Zhao, S.; Li, Y. X.; Liu, Q. Y.; Li, S. R.; Cheng, Y.; Cheng, C. Q.; Sun, Z. Y.; Du, Y.; Butch, C. J.; Wei, H. An orally administered CeO2@montmorillonite nanozyme targets inflammation for inflammatory bowel disease therapy. Adv. Funct. Mater. 2020, 30, 2004692.

    Article  CAS  Google Scholar 

  12. Yu, Y. J.; Zhao, S.; Gu, D. A.; Zhu, B. J.; Liu, H. X.; Wu, W. L.; Wu, J. J. X.; Wei, H.; Miao, L. Y. Cerium oxide nanozyme attenuates periodontal bone destruction by inhibiting the ROS-NF κB pathway. Nanoscale 2022, 14, 2628–2637.

    Article  CAS  Google Scholar 

  13. Lin, A. Q.; Liu, Q. Y.; Zhang, Y. H.; Wang, Q.; Li, S. R.; Zhu, B. J.; Miao, L. Y.; Du, Y.; Zhao, S.; Wei, H. A dopamine-enabled universal assay for catalase and catalase-like nanozymes. Anal. Chem. 2022, 94, 10636–10642.

    Article  CAS  Google Scholar 

  14. Farías, G. G.; Guardia, C. M.; Britt, D. J.; Guo, X. L.; Bonifacino, J. S. Sorting of dendritic and axonal vesicles at the pre-axonal exclusion zone. Cell Rep. 2015, 13, 1221–1232.

    Article  Google Scholar 

  15. Rizvi, F.; Shukla, S.; Kakkar, P. Essential role of pH domain and leucine-rich repeat protein phosphatase 2 in Nrf2 suppression via modulation of Akt/GSK3β/Fyn kinase axis during oxidative hepatocellular toxicity. Cell Death Dis. 2014, 5, e1153.

    Article  CAS  Google Scholar 

  16. Millar, N. L.; Silbernagel, K. G.; Thorborg, K.; Kirwan, P. D.; Galatz, L. M.; Abrams, G. D.; Murrell, G. A. C.; McInnes, I. B.; Rodeo, S. A. Tendinopathy. Nat. Rev. Dis. Primers 2021, 7, 1.

    Article  Google Scholar 

  17. Challoumas, D.; Biddle, M.; Millar, N. L. Recent advances in tendinopathy. Fac. Rev. 2020, 9, 16.

    Article  Google Scholar 

  18. Riley, G. Chronic tendon pathology: Molecular basis and therapeutic implications. Expert Rev. Mol. Med. 2005, 7, 1–25.

    Article  Google Scholar 

  19. D’Addona, A.; Maffulli, N.; Formisano, S.; Rosa, D. Inflammation in tendinopathy. Surgeon 2017, 15, 297–302.

    Article  Google Scholar 

  20. Zhang, X. Y.; Eliasberg, C. D.; Rodeo, S. A. Mitochondrial dysfunction and potential mitochondrial protectant treatments in tendinopathy. Ann. N Y Acad. Sci. 2021, 1490, 29–41.

    Article  Google Scholar 

  21. Liu, Y. C.; Wang, H. L.; Huang, Y. Z.; Weng, Y. H.; Chen, R. S.; Tsai, W. C.; Yeh, T. H.; Lu, C. S.; Chen, Y. L.; Lin, Y. W. et al. Alda-1, an activator of ALDH2, ameliorates Achilles tendinopathy in cellular and mouse models. Biochem. Pharmacol. 2020, 175, 113919.

    Article  CAS  Google Scholar 

  22. Lee, J. M.; Hwang, J. W.; Kim, M. J.; Jung, S. Y.; Kim, K. S.; Ahn, E. H.; Min, K.; Choi, Y. S. Mitochondrial transplantation modulates inflammation and apoptosis, alleviating tendinopathy both in vivo and in vitro. Antioxidants (Basel) 2021, 10, 696.

    Article  CAS  Google Scholar 

  23. Li, K. Q.; Deng, G. M.; Deng, Y.; Chen, S. W.; Wu, H. T.; Cheng, C. Y.; Zhang, X. R.; Yu, B.; Zhang, K. R. High cholesterol inhibits tendon-related gene expressions in tendon-derived stem cells through reactive oxygen species-activated nuclear factor-κB signaling. J. Cell. Physiol. 2019, 234, 18017–18028.

    Article  CAS  Google Scholar 

  24. Kucukler, S.; Benzer, F.; Yildirim, S.; Gur, C.; Kandemir, F. M.; Bengu, A. S.; Ayna, A.; Caglayan, C.; Dortbudak, M. B. Protective effects of chrysin against oxidative stress and inflammation induced by lead acetate in rat kidneys: A biochemical and histopathological approach. Biol. Trace Elem. Res. 2021, 199, 1501–1514.

    Article  CAS  Google Scholar 

  25. Yardım, A.; Kandemir, F. M.; Çomaklı, S.; Özdemir, S.; Caglayan, C.; Kucukler, S.; Çelik, H. Protective effects of curcumin against paclitaxel-induced spinal cord and sciatic nerve injuries in rats. Neurochem. Res. 2021, 46, 379–395.

    Article  Google Scholar 

  26. Wei, H.; Wang, E. K. Nanomaterials with enzyme-like characteristics (nanozymes): Next-generation artificial enzymes. Chem. Soc. Rev. 2013, 42, 6060–6093.

    Article  CAS  Google Scholar 

  27. Szymanski, C. J.; Munusamy, P.; Mihai, C.; Xie, Y. M.; Hu, D. H.; Gilles, M. K.; Tyliszczak, T.; Thevuthasan, S.; Baer, D. R.; Orr, G. Shifts in oxidation states of cerium oxide nanoparticles detected inside intact hydrated cells and organelles. Biomaterials 2015, 62, 147–154.

    Article  CAS  Google Scholar 

  28. Kwon, H. J.; Kim, D.; Seo, K.; Kim, Y. G.; Han, S. I.; Kang, T.; Soh, M.; Hyeon, T. Ceria nanoparticle systems for selective scavenging of mitochondrial, intracellular, and extracellular reactive oxygen species in Parkinson’s disease. Angew. Chem., Int. Ed. 2018, 57, 9408–9412.

    Article  CAS  Google Scholar 

  29. Bao, Q. Q.; Hu, P.; Xu, Y. Y.; Cheng, T. S.; Wei, C. Y.; Pan, L. M.; Shi, J. L. Simultaneous blood-brain barrier crossing and protection for stroke treatment based on edaravone-loaded ceria nanoparticles. ACS Nano 2018, 12, 6794–6805.

    Article  CAS  Google Scholar 

  30. Son, D.; Lee, J.; Lee, D. J.; Ghaffari, R.; Yun, S. M.; Kim, S. J.; Lee, J. E.; Cho, H. R.; Yoon, S.; Yang, S. et al. Bioresorbable electronic stent integrated with therapeutic nanoparticles for endovascular diseases. ACS Nano 2015, 9, 5937–5946.

    Article  CAS  Google Scholar 

  31. Kim, J.; Hong, G.; Mazaleuskaya, L.; Hsu, J. C.; Rosario-Berrios, D. N.; Grosser, T.; Cho-Park, P. F.; Cormode, D. P. Ultrasmall antioxidant cerium oxide nanoparticles for regulation of acute inflammation. ACS Appl. Mater. Interfaces 2021, 13, 60852–60864.

    Article  CAS  Google Scholar 

  32. Adebayo, O. A.; Akinloye, O.; Adaramoye, O. A. Cerium oxide nanoparticles attenuate oxidative stress and inflammation in the liver of diethylnitrosamine-treated mice. Biol. Trace Elem. Res. 2020, 193, 214–225.

    Article  CAS  Google Scholar 

  33. Soh, M.; Kang, D. W.; Jeong, H. G.; Kim, D.; Kim, D. Y.; Yang, W.; Song, C.; Baik, S.; Choi, I. Y.; Ki, S. K. et al. Ceria-zirconia nanoparticles as an enhanced multi-antioxidant for sepsis treatment. Angew. Chem., Int. Ed. 2017, 56, 11399–11403.

    Article  CAS  Google Scholar 

  34. Wang, P.; Geng, J.; Gao, J. H.; Zhao, H.; Li, J. H.; Shi, Y. R.; Yang, B. Y.; Xiao, C.; Linghu, Y. Y.; Sun, X. F. et al. Macrophage achieves self-protection against oxidative stress-induced ageing through the Mst-Nrf2 axis. Nat. Commun. 2019, 10, 755.

    Article  CAS  Google Scholar 

  35. Tohidnezhad, M.; Varoga, D.; Wruck, C. J.; Brandenburg, L. O.; Seekamp, A.; Shakibaei, M.; Sönmez, T. T.; Pufe, T.; Lippross, S. Platelet-released growth factors can accelerate tenocyte proliferation and activate the anti-oxidant response element. Histochem. Cell Biol. 2011, 135, 453–460.

    Article  CAS  Google Scholar 

  36. Gañán-Gómez, I.; Wei, Y.; Yang, H.; Boyano-Adánez, M. C.; García-Manero, G. Oncogenic functions of the transcription factor Nrf2. Free Radic. Biol. Med. 2013, 65, 750–764.

    Article  Google Scholar 

  37. Carvajal, S.; Perramón, M.; Casals, G.; Oró, D.; Ribera, J.; Morales-Ruiz, M.; Casals, E.; Casado, P.; Melgar-Lesmes, P.; Fernández-Varo, G. et al. Cerium oxide nanoparticles protect against oxidant injury and interfere with oxidative mediated kinase signaling in human-derived hepatocytes. Int. J. Mol. Sci. 2019, 20, 5959.

    Article  CAS  Google Scholar 

  38. Saita, M.; Kaneko, J.; Sato, T.; Takahashi, S. S.; Wada-Takahashi, S.; Kawamata, R.; Sakurai, T.; Lee, M. C. I.; Hamada, N.; Kimoto, K. et al. Novel antioxidative nanotherapeutics in a rat periodontitis model: Reactive oxygen species scavenging by redox injectable gel suppresses alveolar bone resorption. Biomaterials 2016, 76, 292–301.

    Article  CAS  Google Scholar 

  39. Liu, A. L.; Wang, Q.; Zhao, Z. N.; Wu, R.; Wang, M. C.; Li, J. W.; Sun, K. Y.; Sun, Z. Y.; Lv, Z. Y.; Xu, J. et al. Nitric oxide nanomotor driving exosomes-loaded microneedles for achilles tendinopathy healing. ACS Nano 2021, 15, 13339–13350.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81941009, 81991514, 32271409, and 82202778), Nanjing Distinguished Youth Fund (No. JQX20001), Jiangsu Provincial Key R&D Program (No. BE2022836), China Postdoctoral Science Foundation (No. 2020M671456), National Basic Research Program of China (No. 2021YFA1201404), Jiangsu Provincial Key Medical Center Foundation, Jiangsu Provincial Medical Outstanding Talent Foundation, Jiangsu Provincial Medical Youth Talent Foundation and Jiangsu Provincial Key Medical Talent Foundation, and the Fundamental Research Funds for the Central Universities (Nos. 14380493 and 14380494).

Author information

Author notes

  1. Xingquan Xu, Rongliang Wang, and Yixuan Li contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China

    Xingquan Xu, Rongliang Wang, Yixuan Li, Rui Wu, Wenjin Yan, Wenli Gong, Weitong Li & Dongquan Shi

  2. Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing National Laboratory of Microstructures, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, 210023, China

    Sheng Zhao & Hui Wei

  3. State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China

    Quanyi Liu & Yan Du

  4. University of Science and Technology of China, Hefei, 230026, China

    Quanyi Liu & Yan Du

  5. State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210023, China

    Hui Wei

Authors
  1. Xingquan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rongliang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yixuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenjin Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sheng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Quanyi Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wenli Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Weitong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hui Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dongquan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hui Wei or Dongquan Shi.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, X., Wang, R., Li, Y. et al. Cerium oxide nanozymes alleviate oxidative stress in tenocytes for Achilles tendinopathy healing. Nano Res. 16, 7364–7372 (2023). https://doi.org/10.1007/s12274-023-5416-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-023-5416-5

Keywords

Search

Navigation