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Natural product P57 induces hypothermia through targeting pyridoxal kinase

Author

Listed:
  • Ruina Wang

    (Shanghai Medical College, Fudan University)

  • Lei Xiao

    (Shanghai Medical College, Fudan University)

  • Jianbo Pan

    (the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University)

  • Guangsen Bao

    (Shanghai Medical College, Fudan University)

  • Yunmei Zhu

    (the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University)

  • Di Zhu

    (Shanghai Medical College, Fudan University)

  • Jun Wang

    (Chinese Academy of Sciences)

  • Chengfeng Pei

    (Chinese Academy of Sciences)

  • Qinfeng Ma

    (the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University)

  • Xian Fu

    (the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University)

  • Ziruoyu Wang

    (Shanghai Medical College, Fudan University)

  • Mengdi Zhu

    (Chinese Academy of Sciences)

  • Guoxiang Wang

    (Shanghai Medical College, Fudan University)

  • Ling Gong

    (Shanghai Medical College, Fudan University)

  • Qiuping Tong

    (Shanghai Medical College, Fudan University)

  • Min Jiang

    (Shanghai Medical College, Fudan University)

  • Junchi Hu

    (the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University)

  • Miao He

    (Shanghai Medical College, Fudan University)

  • Yun Wang

    (Shanghai Medical College, Fudan University)

  • Tiejun Li

    (Naval Medical University)

  • Chunmin Liang

    (Basic Medical School of Fudan University)

  • Wei Li

    (China Pharmaceutical University)

  • Chunmei Xia

    (Shanghai Medical College, Fudan University)

  • Zengxia Li

    (Shanghai Medical College, Fudan University)

  • Dengke K. Ma

    (University of California San Francisco)

  • Minjia Tan

    (Chinese Academy of Sciences)

  • Jun Yan Liu

    (the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University)

  • Wei Jiang

    (Shanghai Medical College, Fudan University)

  • Cheng Luo

    (Chinese Academy of Sciences)

  • Biao Yu

    (Chinese Academy of Sciences)

  • Yongjun Dang

    (the Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University)

Abstract

Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus, and they may activate medial preoptic area (MPA) neurons in POA to induce hypothermia. Taken together, our findings demonstrate that P57 has a potential application in therapeutic hypothermia through regulation of vitamin B6 metabolism and PDXK serves as a previously unknown target of P57 in thermoregulation. In addition, P57 may serve as a chemical probe for exploring the neuron circuitry related to hypothermia state in mice.

Suggested Citation

  • Ruina Wang & Lei Xiao & Jianbo Pan & Guangsen Bao & Yunmei Zhu & Di Zhu & Jun Wang & Chengfeng Pei & Qinfeng Ma & Xian Fu & Ziruoyu Wang & Mengdi Zhu & Guoxiang Wang & Ling Gong & Qiuping Tong & Min J, 2023. "Natural product P57 induces hypothermia through targeting pyridoxal kinase," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41435-y
    DOI: 10.1038/s41467-023-41435-y
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    References listed on IDEAS

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