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Vitamin C Attenuates Sodium Fluoride-Induced Mitochondrial Oxidative Stress and Apoptosis via Sirt1-SOD2 Pathway in F9 Cells

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Abstract

Increasing evidence has suggested an important role played by reactive oxygen species (ROS) in the pathogenesis of fluorosis. Accumulating evidence demonstrates that vitamin C administration ameliorate sodium fluoride (NaF)-induced oxidative stress. However, the potentially beneficial effects of vitamin C against NaF-induced cytotoxicity and the underlying molecular mechanisms of this protection are not fully understood. Here, we found that NaF stimulated cytotoxicity, increased mitochondrial reactive oxygen species (mROS) production, and induced apoptosis in F9 embryonic carcinoma cells. Consistent with this finding, NaF exposure was associated with decreased Sirtuin 1 (Sirt1) protein expression, thus promoted the acetylation of manganese superoxide dismutase (SOD2), a key enzyme involved in regulating mROS production. However, all NaF-induced mitochondrial oxidative injuries were efficiently ameliorated by overexpression of Sirt1 or incubation with Mito-TEMPO (a SOD2 mimetic). Moreover, pretreatment with vitamin C enhanced the expression of Sirt1 and decreased NaF-induced mitochondrial oxidative stress and apoptosis. Knockdown of Sirt1 blocked the vitamin C-mediated reduction in mROS and apoptosis via inhibiting Sirt1-SOD2 signaling. Importantly, sodium-dependent vitamin C transporter 2 (SVCT-2) siRNA was found to partially block the ability of vitamin C to promote Sirt1/SOD2 signaling. In summary, our data indicate that Sirt1 plays a pivotal role in the ability of vitamin C to stimulate SOD2 activity and attenuate mitochondrial oxidative stress, which partially through vitamin C receptor in NaF-induced F9 cells injury.

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Abbreviations

NaF:

Sodium fluoride

ROS:

Reactive oxygen species

mROS:

Mitochondrial reactive oxygen species

Sirt1:

Sirtuin 1

SOD2:

Manganese superoxide dismutase

SVCT-2:

Sodium-dependent vitamin C transporter 2

GLUT1:

Glucose transporter 1

Bax:

Bcl2 associated X protein

Bcl-2:

B cell CLL/lymphoma 2

COX IV:

Cytochrome C oxidase subunit IV isoform 1

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

O2•− :

Superoxide

Co-IP:

Coimmunoprecipitation pull-down

MMP:

Mitochondrial membrane potential

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Funding

This work was supported by the National Natural Science Foundation of China (No. 31702205) and Natural Science Basic Research Plan in Shaanxi Province of China (No. 2017JQ3028).

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Authors and Affiliations

  1. College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China

    Wei Peng & Yong Zhang

  2. Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest A&F University, Yangling, 712100, Shaanxi, China

    Wei Peng & Yong Zhang

  3. Institute of Veterinary Medicine, Qinghai Academy of Animal Science and Veterinary Medicine, Xining, 810016, Qinghai, China

    Shangrong Xu & Jun Zhang

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  1. Wei Peng
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Correspondence to Jun Zhang or Yong Zhang.

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Peng, W., Xu, S., Zhang, J. et al. Vitamin C Attenuates Sodium Fluoride-Induced Mitochondrial Oxidative Stress and Apoptosis via Sirt1-SOD2 Pathway in F9 Cells. Biol Trace Elem Res 191, 189–198 (2019). https://doi.org/10.1007/s12011-018-1599-0

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