Journal Home > Volume 16 , Issue 5
Nano Research 2023, 16(5): 7364-7372 https://doi.org/10.1007/s12274-023-5416-5
Research Article | Issue | Published: 28 February 2023

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

Show Author's Information Xingquan Xu1,§,  Rongliang Wang1,§,  Yixuan Li1,§,  Rui Wu1,  Wenjin Yan1,  Sheng Zhao2,  Quanyi Liu3,4,  Yan Du3,4,  Wenli Gong1,  Weitong Li1,  Hui Wei2,5( ),  Dongquan Shi1( )
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
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
State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
University of Science and Technology of China, Hefei 230026, China
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

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

Keywords:
enthesiopathy, NRF2 translocation, ERK signaling, CeO2 nanozymes
Topics:
Enzymes
Cite this article:
Xu X, Wang R, Li Y, et al. Cerium oxide nanozymes alleviate oxidative stress in tenocytes for Achilles tendinopathy healing. Nano Research, 2023, 16(5): 7364-7372. https://doi.org/10.1007/s12274-023-5416-5
Download citation
EndNote(RIS)
BibTeX

4235

Views

97

Downloads

Citations

3

Crossref

3

WoS

3

Scopus

0

CSCD

Abstract Full text Electronic supplementary material About this article

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.


menu
Abstract
Full text
Outline
Electronic supplementary material
About this article

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

Show Author's information Xingquan Xu1,§, Rongliang Wang1,§, Yixuan Li1,§, Rui Wu1, Wenjin Yan1, Sheng Zhao2, Quanyi Liu3,4, Yan Du3,4, Wenli Gong1, Weitong Li1, Hui Wei2,5( ), Dongquan Shi1( )
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
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
State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
University of Science and Technology of China, Hefei 230026, China
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

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

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.

Keywords: enthesiopathy, NRF2 translocation, ERK signaling, CeO2 nanozymes

References(39)

[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.
DOI 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.
DOI 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.
DOI Google Scholar
[4]

Murrell, G. A. C. Oxygen free radicals and tendon healing. J. Shoulder Elbow Surg. 2007, 16, S208–S214.
DOI 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.
DOI Google Scholar
[6]

Bestwick, C. S.; Maffulli, N. Reactive oxygen species and tendinopathy: Do they matter? Br. J. Sports Med. 2004, 38, 672–674.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
Google Scholar
[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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI Google Scholar
[17]

Challoumas, D.; Biddle, M.; Millar, N. L. Recent advances in tendinopathy. Fac. Rev. 2020, 9, 16.
Google Scholar
[18]

Riley, G. Chronic tendon pathology: Molecular basis and therapeutic implications. Expert Rev. Mol. Med. 2005, 7, 1–25.
Google Scholar
[19]

D'Addona, A.; Maffulli, N.; Formisano, S.; Rosa, D. Inflammation in tendinopathy. Surgeon 2017, 15, 297–302.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI 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.
DOI Google Scholar
File
12274_2023_5416_MOESM1_ESM.pdf (404.6 KB)
Publication history
Copyright
Acknowledgements

Publication history

Received: 19 August 2022
Revised: 16 December 2022
Accepted: 17 December 2022
Published: 28 February 2023
Issue date: May 2023

Copyright

© Tsinghua University Press 2023

Acknowledgements

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).

Return