Dietary nitrate supplementation prevents radiotherapy-induced xerostomia

Abstract

Management of salivary gland hypofunction caused by irradiation (IR) therapy for head and neck cancer remains lack of effective treatments. Salivary glands, especially the parotid gland, actively uptake dietary nitrate and secrete it into saliva. Here, we investigated the effect of dietary nitrate on the prevention and treatment of IR-induced parotid gland hypofunction in miniature pigs, and elucidated the underlying mechanism in human parotid gland cells (hPGCs). We found that nitrate administration prevented IR-induced parotid gland damage in a dose-dependent manner, by maintaining the function of irradiated parotid gland tissue. Nitrate could increase sialin expression, a nitrate transporter expressed in the parotid gland, making the nitrate-sialin feedback loop that facilitates nitrate influx into cells for maintaining cell proliferation and inhibiting apoptosis. Furthermore, nitrate enhanced cell proliferation via the epidermal growth factor receptor (EGFR)-protein kinase B (AKT)-mitogen-activated protein kinase (MAPK) signaling pathway in irradiated parotid gland tissue. Collectively, nitrate effectively prevented IR-induced xerostomia via the EGFR–AKT-MAPK signaling pathway. Dietary nitrate supplementation may provide a novel, safe, and effective way to resolve IR-induce xerostomia.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for: Figure 1G, Figure 2E, Figure 3A-D, and Figure 6 A,C,D and E, available on Dryad Digital Repository (doi:10.5061/dryad.fn2z34ttq).

The following data sets were generated

Article and author information

Author details

  1. Xiaoyu Feng

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Zhifang Wu

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Junji Xu

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yipu Xu

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Bin Zhao

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Baoxing Pang

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Xingmin Qu

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Liang Hu

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Lei Hu

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Zhipeng Fan

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Luyuan Jin

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Dengsheng Xia

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Shimin Chang

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Jingsong Wang

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Chunmei Zhang

    Capital Medical University School of Stomatology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Songlin Wang

    Capital Medical University School of Stomatology, Beijing, China
    For correspondence
    slwang@ccmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7066-2654

Funding

National Natural Science Foundation of China (82030031)

  • Songlin Wang

National Natural Science Foundation of China (91649124)

  • Songlin Wang

National Natural Science Foundation of China (81600883)

  • Songlin Wang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal studies were conducted according to the NIH's Guide for the Care and Use of Laboratory Animals, and approved by the Animal Care and Use Committee of Capital Medical University

Human subjects: Human parotid gland biopsy sample was obtained under a protocol approved by the ethics committee of Beijing Stomatological Hospital, Capital Medical University

Reviewing Editor

  1. Wafik S El-Deiry, Brown University, United States

Publication history

  1. Received: May 26, 2021
  2. Accepted: September 22, 2021
  3. Accepted Manuscript published: September 28, 2021 (version 1)
  4. Version of Record published: November 2, 2021 (version 2)

Copyright

© 2021, Feng et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Xiaoyu Feng
  2. Zhifang Wu
  3. Junji Xu
  4. Yipu Xu
  5. Bin Zhao
  6. Baoxing Pang
  7. Xingmin Qu
  8. Liang Hu
  9. Lei Hu
  10. Zhipeng Fan
  11. Luyuan Jin
  12. Dengsheng Xia
  13. Shimin Chang
  14. Jingsong Wang
  15. Chunmei Zhang
  16. Songlin Wang
(2021)
Dietary nitrate supplementation prevents radiotherapy-induced xerostomia
eLife 10:e70710.
https://doi.org/10.7554/eLife.70710
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