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Alleviating Oxidative Damage–Induced Telomere Attrition: a Potential Mechanism for Inhibition by Folic Acid of Apoptosis in Neural Stem Cells

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Abstract

DNA oxidative damage can cause telomere attrition or dysfunction that triggers cell senescence and apoptosis. The hypothesis of this study is that folic acid decreases apoptosis in neural stem cells (NSCs) by preventing oxidative stress–induced telomere attrition. Primary cultures of NSCs were incubated for 9 days with various concentrations of folic acid (0–40 µM) and then incubated for 24 h with a combination of folic acid and an oxidant (100-µM hydrogen peroxide, H2O2), antioxidant (10-mM N-acetyl-L-cysteine, NAC), or vehicle. Intracellular folate concentration, apoptosis rate, cell proliferative capacity, telomere length, telomeric DNA oxidative damage, telomerase activity, intracellular reactive oxygen species (ROS) levels, cellular oxidative damage, and intracellular antioxidant enzyme activities were determined. The results showed that folic acid deficiency in NSCs decreased intracellular folate concentration, cell proliferation, telomere length, and telomerase activity but increased apoptosis, telomeric DNA oxidative damage, and intracellular ROS levels. In contrast, folic acid supplementation dose-dependently increased intracellular folate concentration, cell proliferative capacity, telomere length, and telomerase activity but decreased apoptosis, telomeric DNA oxidative damage, and intracellular ROS levels. Exposure to H2O2 aggravated telomere attrition and oxidative damage, whereas NAC alleviated the latter. High doses of folic acid prevented telomere attrition and telomeric DNA oxidative damage by H2O2. In conclusion, inhibition of telomeric DNA oxidative damage and telomere attrition in NSCs may be potential mechanisms of inhibiting NSC apoptosis by folic acid.

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Data Availability

All data generated or analyzed during this study are available from the corresponding author on reasonable request.

Abbreviations

CAT:

Catalase

DAPI:

4′,6-Diamidino-2-phenylindole

FPG:

Formamidopyrimidine DNA-glycosylase

GSH-PX:

Glutathione peroxidase

GSSG:

Oxidized glutathione

H2O2 :

Hydrogen peroxide

LDH:

Lactate dehydrogenase

LPO:

Lipid peroxide

MDA:

Malondialdehyde

MTS:

3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

8-OxoG:

8-Oxoguanine

PBS:

Phosphate-buffered saline

NAC:

N-acetyl-L-cysteine

NSC:

Neural stem cell

ROS:

Reactive oxygen species

SAMP8:

Senescence-accelerated mouse prone 8

SD:

Sprague–Dawley

SOD:

Superoxide dismutase

T-AOC:

Total antioxidant capacity

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Acknowledgements

We thank Huan Liu, Bei Xu, and Suhui Luo from National Demonstration Center for Experimental Preventive Medicine Education, Tianjin Medical University, for their suggestions and technical assistance.

Funding

This research was supported by a grant from the National Natural Science Foundation of China (No. 81730091) and Natural Science Foundation of Tianjin (No. 19JCQNJC11700).

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Author notes

  1. Zhenshu Li and Wen Li contributed equally to this study.

Authors and Affiliations

  1. Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China

    Zhenshu Li, Wen Li, Dezheng Zhou, Jing Zhao, Yue Ma, Ling Huang, Cuixia Dong & Guowei Huang

  2. Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin, 300070, China

    Wen Li & Guowei Huang

  3. Center for International Collaborative Research On Environment, Nutrition and Public Health, Tianjin, 300070, China

    Wen Li & Guowei Huang

  4. Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, 14214-8028, USA

    John X. Wilson

  5. The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, China

    Guowei Huang

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  1. Zhenshu Li
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Contributions

ZL and WL conducted data curation; ZL and WL wrote the original draft; ZL and DZ analyzed the data; JZ, YM, and LH contributed to the methodology; CD contributed to software; JXW and GH reviewed and edited the draft; GH and WL contributed to funding acquisition. All the authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Guowei Huang.

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The Tianjin Medical University Animal Ethics Committee approved all experimental protocols in this study.

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Li, Z., Li, W., Zhou, D. et al. Alleviating Oxidative Damage–Induced Telomere Attrition: a Potential Mechanism for Inhibition by Folic Acid of Apoptosis in Neural Stem Cells. Mol Neurobiol 59, 590–602 (2022). https://doi.org/10.1007/s12035-021-02623-3

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