2. Academic Validation
  3. Modulation of circadian clock by crude drug extracts used in Japanese Kampo medicine

Modulation of circadian clock by crude drug extracts used in Japanese Kampo medicine

  • Sci Rep. 2021 Oct 26;11(1):21038. doi: 10.1038/s41598-021-00499-w.
Manhui Zhang 1 2,  Kohei Kobayashi 1 2,  Haruki Atsumi 1 2,  Yuma Katada 1 2,  Yusuke Nakane 1 2,  Junfeng Chen 1 2,  Ryo Nagano 1 2,  Naoya Kadofusa 1,  Taeko Nishiwaki-Ohkawa 1 2,  Naohiro Kon 1 2,  Tsuyoshi Hirota 1,  Ayato Sato 1,  Toshiaki Makino 3,  Takashi Yoshimura 4 5
Affiliations

Affiliations

  • 1 Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
  • 2 Laboratory of Animal Integrative Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
  • 3 Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-ku, Nagoya, 467-8603, Japan.
  • 4 Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan. [email protected].
  • 5 Laboratory of Animal Integrative Physiology, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan. [email protected].
PMID: 34702865 DOI: 10.1038/s41598-021-00499-w
Abstract

Circadian rhythm is an approximately 24 h endogenous biological rhythm. Chronic disruption of the circadian clock leads to an increased risk of diabetes, Cardiovascular Disease, and Cancer. Hence, it is important to develop circadian clock modulators. Natural organisms are a good source of several medicines currently in use. Crude drugs used in Japanese traditional Kampo medicine or folk medicines are an excellent source for drug discovery. Furthermore, identifying new functions for existing drugs, known as the drug repositioning approach, is a popular and powerful tool. In this study, we screened 137 crude drug extracts to act as circadian clock modulators in human U2OS cells stably expressing the clock reporter Bmal1-dLuc, and approximately 12% of these modulated the circadian rhythm. We further examined the effects of several crude drugs in Rat-1 fibroblasts stably expressing Per2-luc, explant culture of lung from Per2::Luciferase knockin mice, and zebrafish larvae in vivo. Notably, more than half of the major ingredients of these crude drugs were reported to target Akt and its relevant signaling pathways. As expected, analysis of the major ingredients targeting Akt signaling confirmed the circadian clock-modulating effects. Furthermore, activator and inhibitor of Akt, and triple knockdown of Akt isoforms by siRNA also modulated the circadian rhythm. This study, by employing the drug repositioning approach, shows that Kampo medicines are a useful source for the identification of underlying mechanisms of circadian clock modulators and could potentially be used in the treatment of circadian clock disruption.

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