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Rapamycin Attenuates H2O2-Induced Oxidative Stress-Related Senescence in Human Skin Fibroblasts

  • Original Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

BACKGROUND:

Oxidative stress plays an important role in the skin aging process. Rapamycin has been shown to have anti-aging effects, but its role in oxidative senescence of skin cells remains unclear. The aim of this study was to explore the effect of rapamycin on oxidative stress-induced skin cell senescence and to illustrate the mechanism.

METHODS:

Primary human skin fibroblasts (HSFs) were extracted and a model of H2O2-induced oxidative senescence was constructed, and the effects of rapamycin on their value-added and migratory capacities were detected by CCK-8 and scratch assays. SA-β-gal was utilized to detect senescence, oxidatively closely related factors were also assessed. Gene and protein expressions of senescence, oxidative, and autophagy were detected by western blotting and quantitative-PCR. The data were analyzed by one-way analysis of variance.

RESULTS:

Rapamycin (0.1 nmol/L for 48 h) promoted the proliferative and migration of H2O2-treated HSFs (p < 0.05), decreased senescent phenotypes SA-β-gal staining and the expression of P53, and MMP-1 proteins, and increased the expression level of COL1A-1 (p < 0.001). Rapamycin also enhanced the activities of SOD and HO-1, and effectively removed intracellular ROS, MDA levels (p < 0.05), in addition, autophagy-related proteins and genes were significantly elevated after rapamycin pretreatment (p < 0.001). Rapamycin upregulated the autophagy pathway to exert its protective effects.

CONCLUSION:

Our findings indicate that rapamycin shields HSFs from H2O2-induced oxidative damage, the mechanism is related to the reduction of intracellular peroxidation and upregulation of autophagy pathway. Therefore, rapamycin has the potential to be useful in the investigation and prevention of signs of aging and oxidative stress.

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Data availability

The datasets that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Wang Y, Wang L, Wen X, Hao D, Zhang N, He G, Jiang X. NF-κB signaling in skin aging. Mech Ageing Dev. 2019;184:111160–71.

    Article  CAS  PubMed  Google Scholar 

  2. Gu Y, Han J, Jiang C, Zhang Y. Biomarkers, oxidative stress and autophagy in skin aging. Ageing Res Rev. 2020;59:10136–68.

    Article  Google Scholar 

  3. Seo SH, Jeong GS. Fisetin inhibits TNF-α-induced inflammatory action and hydrogen peroxide-induced oxidative damage in human keratinocyte HaCaT cells through PI3K/AKT/Nrf-2-mediated heme oxygenase-1 expression. Int Immunopharmacol. 2015;29:246–53.

    Article  CAS  PubMed  Google Scholar 

  4. Picca A, Faitg J, Auwerx J, Ferrucci L, D’Amico D. Mitophagy in human health, ageing and disease. Nat Metab. 2023;5:2047–61.

    Article  PubMed  Google Scholar 

  5. Peters AE, Mihalas BP, Bromfield EG, Roman SD, Nixon B, Sutherland JM. Autophagy in female fertility: a role in oxidative stress and aging. Antioxid Redox Signal. 2020;32:550–68.

    Article  CAS  PubMed  Google Scholar 

  6. Sosulski ML, Gongora R, Danchuk S, Dong C, Luo F, Sanchez CG. Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGFβ1. Aging Cell. 2015;14:774–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. 2015;125:25–32.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Liu Y, Xiong Y. Plant target of rapamycin signaling network: complexes, conservations, and specificities. J Integr Plant Biol. 2022;64:342–70.

    Article  CAS  PubMed  Google Scholar 

  9. Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: a review of the evidence. Kidney Int. 2001;59:3–16.

    Article  CAS  PubMed  Google Scholar 

  10. Ganesh SK, Subathra DC. Molecular and therapeutic insights of rapamycin: a multi-faceted drug from Streptomyces hygroscopicus. Mol Biol Rep. 2023;50:3815–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Meng LH, Zheng XF. Toward rapamycin analog (rapamycinlog)-based precision cancer therapy. Acta Pharmacol Sin. 2015;36:1163–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Selvarani R, Mohammed S, Richardson A. Effect of rapamycin on aging and age-related diseases-past and future. Geroscience. 2021;43:1135–58.

    Article  CAS  PubMed  Google Scholar 

  13. Deng Z, Chen M, Liu Y, Xu S, Ouyang Y, Shi W, et al. A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea. EMBO Mol Med. 2021;13:e13560–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Peng Q, Sha K, Liu Y, Chen M, Xu S, Xie H, et al. mTORC1-Mediated angiogenesis is required for the development of rosacea. Front Cell Dev Biol. 2021;9:751–85.

    Article  Google Scholar 

  15. Gao M, Si X. Rapamycin ameliorates psoriasis by regulating the expression and methylation levels of tropomyosin via ERK1/2 and mTOR pathways in vitro and in vivo. Exp Dermatol. 2018;27:1112–9.

    Article  CAS  PubMed  Google Scholar 

  16. Kim HR, Kim JC, Kang SY, Kim HO, Park CW, Chung BY. Rapamycin alleviates 2,3,7,8-tetrachlorodibenzo-p-dioxin-Induced aggravated dermatitis in mice with imiquimod-induced psoriasis-like dermatitis by inducing autophagy. Int J Mol Sci. 2021;22:3968–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bai GL, Wang P, Huang X, Wang ZY, Cao D, Liu C, et al. Rapamycin protects skin fibroblasts from UVA-induced photoaging by inhibition of p53 and phosphorylated HSP27. Front Cell Dev Biol. 2021;9:633331–41.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Qin D, Ren R, Jia C, Lu Y, Yang Q, Chen L, et al. Rapamycin protects skin fibroblasts from ultraviolet B-induced photoaging by suppressing the production of reactive oxygen species. Cell Physiol Biochem. 2018;46:1849–60.

    Article  CAS  PubMed  Google Scholar 

  19. Sakura M, Chiba Y, Kamiya E, Furukawa A, Kawamura N, Niwa M, et al. Spontaneous occurrence of photoageing-like phenotypes in the dorsal skin of old SAMP1 mice, an oxidative stress model. Exp Dermatol. 2013;22:62–4.

    Article  CAS  PubMed  Google Scholar 

  20. Di D’addaFagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008;8:512–22.

    Article  Google Scholar 

  21. Xiao X, Xu M, Yu H, Wang L, Li X, Rak J, et al. Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src. Signal Transduct Target Ther. 2021;6:354–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yamaguchi T, Yamamoto Y, Egashira K, Sato A, Kondo Y, Saiki S, et al. Oxidative stress inhibits endotoxin tolerance and may affect periodontitis. J Dent Res. 2023;102:331–9.

    Article  CAS  PubMed  Google Scholar 

  23. Lee JJ, Ng SC, Hsu JY, Liu H, Chen CJ, Huang CY, et al. Galangin Reverses HO-Induced dermal fibroblast senescence via SIRT1-PGC-1α/Nrf2 signaling. Int J Mol Sci. 2022;23:1387–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shi X, Cheng W, Wang Q, Zhang J, Wang C, Li M, et al. Exploring the protective and reparative mechanisms of G lucidum polysaccharides against HO-Induced oxidative stress in human skin fibroblasts. Clin Cosmet Investig Dermatol. 2021;14:1481–96.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Battaglioni S, Benjamin D, Wälchli M, Maier T, Hall MN. mTOR substrate phosphorylation in growth control. Cell. 2022;185:1814–36.

    Article  CAS  PubMed  Google Scholar 

  26. Foster DA, Toschi A. Targeting mTOR with rapamycin: one dose does not fit all. Cell Cycle. 2009;8:1026–9.

    Article  CAS  PubMed  Google Scholar 

  27. Qi H, Su FY, Wan S, Chen Y, Cheng YQ, Liu AJ. The antiaging activity and cerebral protection of rapamycin at micro-doses. CNS Neurosci Ther. 2014;20:991–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mohamad Kamal NS, Safuan S, Shamsuddin S, Foroozandeh P. Aging of the cells: Insight into cellular senescence and detection Methods. Eur J Cell Biol. 2020;99:151108–21.

    Article  CAS  PubMed  Google Scholar 

  29. Kuypers DR. Benefit-risk assessment of sirolimus in renal transplantation. Drug Saf. 2005;28:153–81.

    Article  CAS  PubMed  Google Scholar 

  30. Polager S, Ginsberg D. p53 and E2f: partners in life and death. Nat Rev Cancer. 2009;9:738–48.

    Article  CAS  PubMed  Google Scholar 

  31. Chen Q, Sun X, Luo X, Wang J, Hu J, Feng Y. PIK3R3 inhibits cell senescence through p53/p21 signaling. Cell Death Dis. 2020;11:798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Quan T, Fisher GJ. Role of age-associated alterations of the dermal extracellular matrix microenvironment in human skin aging: a mini-review [J]. Gerontolog. 2015;61:427–34.

    Article  CAS  Google Scholar 

  33. Ezure T, Sugahara M, Amano S. Senescent dermal fibroblasts negatively influence fibroblast extracellular matrix-related gene expression partly via secretion of complement factor D [J]. BioFactors. 2019;45:556–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cui D, Qu R, Liu D, Xiong X, Liang T, Zhao Y. The cross talk between p53 and mTOR pathways in response to physiological and genotoxic stresses. Front Cell Dev Biol. 2021;9: 775507.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Chen Q, Zhang H, Yang Y, Zhang S, Wang J, Zhang D, Yu H. Metformin attenuates UVA-induced skin photoaging by suppressing mitophagy and the PI3K/AKT/mTOR pathway. Int J Mol Sci. 2022;23:6960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu Z, Zhuan Q, Zhang L, Meng L, Fu X, Hou Y. Polystyrene microplastics induced female reproductive toxicity in mice. J Hazard Mater. 2022;424:127629–35.

    Article  CAS  PubMed  Google Scholar 

  37. Borgstahl GEO, Oberley-Deegan RE. Superoxide dismutases (SODs) and SOD mimetics. Antioxidants (Basel). 2018;7:156–8.

    Article  PubMed  Google Scholar 

  38. Ryter SW. Heme oxygenase-1: an anti-inflammatory effector in cardiovascular, lung, and related metabolic disorders. Antioxidants (Basel). 2022;11:555–81.

    Article  CAS  PubMed  Google Scholar 

  39. Al-Bari MAA, Xu P. Molecular regulation of autophagy machinery by mTOR-dependent and -independent pathways. Ann N Y Acad Sci. 2020;1467:3–20.

    Article  CAS  PubMed  Google Scholar 

  40. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly drosophila melanogaster. Cell Metab. 2010;11:35–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen HW, Zhou JW, Zhang GZ, Luo ZB, Li L, Kang XW. Emerging role and therapeutic implication of mTOR signalling in intervertebral disc degeneration. Cell Prolif. 2023;56:e13338.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Funding for this project was supported by Sichuan Transfer Project (2021SNZY001); Provincial Science and Technology Plan Project of Sichuan Provincial Department of Science and Technology (2022SNZY001); Primary Health Development Research Center of Sichuan Province Program (SWFZ20-C-086); Science and Technology Project of Sichuan Provincial Health Commission (Appropriate Technology Base) (2022JDXM021); Science and Technology Research Project of Sichuan Administration of Traditional Chinese Medicine (2021MS100). This work was performed in the Basic Laboratory of Hospital.

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Author notes

  1. Yuyang Tang and Sen Yang have contributed to this equally.

Authors and Affiliations

  1. School of Stomatology, Zunyi Medical University, Zunyi, China

    Yuyang Tang, Zhen Qiu, Li Guan & Lijuan Guo

  2. Department of Stomatology, Suining Central Hospital, Suining, China

    Sen Yang, Yuanyu Tu & Lijuan Guo

  3. Nursing School, Zunyi Medical University, Zunyi, China

    Yigui Wang

  4. School of Stomatology, Southwest Medical University, Luzhou, China

    Guixin Li

  5. Department of Stomatology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Lijuan Guo

  6. Department of Medical Cosmetology, Suining Central Hospital, Chuanshan District, No.127, West Desheng RD, Suining, 629000, Sichuan Province, China

    Lijuan Guo

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  1. Yuyang Tang
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Correspondence to Lijuan Guo.

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Ethical Statement

The study protocol was approved by the institutional review board of Hospital's Ethics Committee (IRB No. KYLLKS2023010). Informed consent was confirmed by the IRB. There are no animal studies were conducted for this article.

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Tang, Y., Yang, S., Qiu, Z. et al. Rapamycin Attenuates H2O2-Induced Oxidative Stress-Related Senescence in Human Skin Fibroblasts. Tissue Eng Regen Med (2024). https://doi.org/10.1007/s13770-024-00660-2

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  • DOI: https://doi.org/10.1007/s13770-024-00660-2

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