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IGF-1 Alleviates Mitochondrial Apoptosis through the GSK3β/NF-κB/NLRP3 Signaling Pathway in LPS-Treated PC-12 Cells

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Abstract

Inflammation contributes to mitochondrial dysfunction and neuronal apoptosis. The aim of this study was to determine whether insulin-like growth factor-1 (IGF-1) alleviates mitochondrial apoptosis in lipopolysaccharide (LPS)-treated PC-12 cells, and to further explore the mechanism involved. Prepared PC-12 cells were treated with IGF-1, Mdivi-1 (DRP1 blocker), LY294002 (PI3K blocker), betulinic acid (NF-κB activator) or their combinations. Mitochondrial membrane potential and ATP generation were then measured to assess mitochondrial function. The rate of apoptosis was determined using flow cytometry. The expression of several apoptosis proteins (i.e. Bax, cleaved caspase-9 and cleaved caspase-3) and signaling proteins (i.e. p-GSK3β, NF-κB and NLRP3) was measured using western blotting. Compared with the control cells, the LPS-treated cells showed evidence of mitochondrial dysfunction, increased apoptosis and upregulation of apoptosis proteins, which were significantly alleviated by Mdivi-1. These findings indicate that neuronal apoptosis was activated partly through the mitochondrial pathway. IGF-1 treatment inhibited mitochondrial apoptosis in a dose-dependent manner in the LPS-treated cells. The reagent also increased the expression of p-GSK3β and decreased the expression of NF-κB and NLRP3. Both LY294002 and betulinic acid reversed the protective effect of IGF-1. In addition, LY294002 affected the expression of the three signaling proteins, while betulinic acid only affected the expression of NF-κB and NLRP3. These findings indicated a GSK3β/NF-κB/NLRP3 signaling pathway was existed and was involved in the protective mechanism of IGF-1. In conclusion, IGF-1 alleviated mitochondrial apoptosis through GSK3β/NF-κB/NLRP3 signaling pathway in LPS-treated PC-12 cells.

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Data Availability

These data cannot be shared because this is an ongoing study.

Code Availability

All analyses were performed using SPSS 18.0 software (USA).

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Acknowledgments

We want to thank Prof. JQ from TIANJIN UNIVERSITY (China) for the funding and laboratory support for this project.

Funding

This project is supported by the National Natural Science Fund (81471252; 81772060).

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Author notes

  1. Wang Feng and Wang Lu contributed to the work equally and should be regarded as co-first authors

Authors and Affiliations

  1. Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, 300052, China

    Feng Wang, Lu Wang, Mengtian Guo, Xiangyang Xiong & Ping Lei

  2. Department of Child and Adolescent Psychology, Tianjin Anding Hospital, Tianjin, 300074, China

    Guanghong Sui

  3. Department of Rehabilitation, Tianjin Anding Hospital, Tianjin, 300074, China

    Caixia Yang

  4. Department of Psychology, Tianjin Anding Hospital, Tianjin, 300074, China

    Zheng Chen

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  1. Feng Wang
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  2. Lu Wang
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Correspondence to Feng Wang.

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The study was approved by the ethics committees of Tianjin Medical University General Hospital and Tianjin Anding Hospital (Tianjin, China).

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Wang, F., Wang, L., Sui, G. et al. IGF-1 Alleviates Mitochondrial Apoptosis through the GSK3β/NF-κB/NLRP3 Signaling Pathway in LPS-Treated PC-12 Cells. J Mol Neurosci 71, 1320–1328 (2021). https://doi.org/10.1007/s12031-020-01759-6

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  • DOI: https://doi.org/10.1007/s12031-020-01759-6

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