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matsunaga naoya Last modified date:2019.06.19

Associate Professor / Department of Glocal Health Care, Faculty of Pharmaceutical Sciences, Kyushu University
Department of Pharmaceutical Health Care and Sciences
Faculty of Pharmaceutical Sciences

Academic Degree
Country of degree conferring institution (Overseas)
Field of Specialization
Chronopharmacology, Chronopharmaceutics(chrono-DDS),Chrono drug discovery, Microcurrent therapy of molecular clock
Total Priod of education and research career in the foreign country
Research Interests
  • Microcurrent therapy of circadina clock
    keyword : Microcurrent therapy circadina clock
  • Drug discovery of anti-cancer and anti-inflammatory based on circadian machinery
    keyword : chrono-drug discovery
  • Study on proper use for medicine of which it is basic is biological rhythm

    New DDS development of which it is basic is biological rhythm
    keyword : chronopharmacology  chronotherapy
Academic Activities
1. Ohdo S, Koyanagi S, Matsunaga N. , Chronopharmacological strategies: Intra- and inter-individual variability of molecular clock. , Adv Drug Deliv Rev., 2010.08.
2. Ohdo S, Koyanagi S, Matsunaga N, Hamdan A., Molecular basis of chronopharmaceutics., J Pharm Sci., 2011.09.
1. Matsunaga N, Yoshida Y, Kitajou N, Shiraishi A, Kusunose N, Koyanagi S, Ohdo S., Microcurrent stimulation activates the circadian machinery in mice., Biochem Biophys Res Commun. , 10.1016/j.bbrc.2019.02.022. , (19), 30203-30207, 2019.03, The circadian rhythm, which regulates various body functions, is transcriptionally controlled by a series of clock gene clusters. The clock genes are related to the pathology of various kinds of diseases, which in turn, is related to aging. Aging in humans is a worldwide problem; it induces sleep disorders and disruption of the circadian rhythm. It also decreases ocular vision and appetite and weakens the synchronization of clock genes by light and food. Therefore, a simple method for the synchronization of clock genes in the body is required. In this study, the influence of microcurrent stimulation (MCS) on the circadian machinery in wild-type (WT) and Clock mutant (Clk/Clk) mice was investigated. MCS induced Per1 mRNA expression in cultured mouse astrocytes; cAMP response element (CRE) in the Per1 mouse promoter was found to be important for the induction of Per1 mRNA. In addition, MCS increased the Per1 mRNA levels in mouse livers and caused the phase advance of the Per1 expression rhythm. The protein expression rhythm of phosphor-cAMP response element-binding protein (pCREB) was altered and the phase of expression of pCREB protein advanced. Finally, the influence of MCS on the locomotor activity rhythm in WT and Clk/Clk mice was investigated. MCS caused the phase advance of the locomotor activity rhythm in WT and Clk/Clk mice. The results of this study indicate that MCS activated the clock machinery in mice; MCS may thus improve the quality of new treatment modalities in the future..
2. Matsunaga Naoya, Takashi Ogino, Yukinori Hara, Takahiro Tanaka, Koyanagi Satoru, Shigehiro Ohdo, Optimized dosing schedule based on circadian dynamics of mouse breast cancer stem cells improves the antitumor effects of aldehyde dehydrogenase inhibitor, Cancer Research, 10.1158/0008-5472.CAN-17-4034, 78, 13, 3698-3708, 2018.07, Although malignant phenotypes of triple-negative breast cancer (TNBC) are subject to circadian alterations, the role of cancer stem cells (CSC) in defining this circadian change remains unclear. CSC are often characterized by high aldehyde dehydrogenase (ALDH) activity, which is associated with the malignancy of cancer cells and is used for identification and isolation of CSC. Here, we show that the population of ALDH-positive cells in a mouse 4T1 breast tumor model exhibits pronounced circadian alterations. Alterations in the number of ALDHpositive cells were generated by time-dependent increases and decreases in the expression of Aldh3a1. Importantly, circadian clock genes were rhythmically expressed in ALDH-negative cells, but not in ALDH-positive cells. Circadian expression of Aldh3a1 in ALDH-positive cells was dependent on the timedependent release of Wingless-type mmtv integration site family 10a (WNT10a) from ALDH-negative cells. Furthermore, antitumor and antimetastatic effects of ALDH inhibitor N,N-diethylaminobenzaldehyde were enhanced by administration at the time of day when ALDH activity was increased in 4T1 tumor cells. Our findings reveal a new role for the circadian clock within the tumor microenvironment in regulating the circadian dynamics of CSC. These results should enable the development of novel therapeutic strategies for treatment of TNBC with ALDH inhibitors. Significance: This seminal report reveals that circadian dynamics of CSC are regulated by the tumor microenvironment and provides a proof of principle of its implication for chronotherapy in TNBC..
  • A molecular clock mechanism of cytochrome P450 (CYP) genes expression in serum-shocked HepG2 cells
    Circadian rhythms have been observed in many biological systems and physiological functions. The effectiveness and toxicity of many drugs vary depending on the dosage in association with 24-hr rhythms of biochemical, physiological, and behavioral processes under the control of the circadian clock. Although the pharmacokinetics of several drugs, which are mainly eliminated by cytochrome P450 (CYP) metabolism, vary according to their dosing time, mechanism of the variation remains poorly understood. In this study, we investigated how the 24 hr oscillation in the expression of CYP was generated in hepatic cells.

    [Materials and Methods]
    As brief exposure of HepG2 cells to 50% serum induced the 24 hr oscillation in the expression of clock genes, serum-shocked HepG2 cells were used as an in vitro model to study the molecular mechanism underlying the circadian clock in human liver. The amount of protein and mRNA were measured by Western blot analysis and RT-PCR. CYP- promoter activity was measured by Dual-Luciferase assay

    [Results and Discussion]
    The present study suggests that temporal variations of CYPs expression were controlled by the transcriptional level in cultured human hepatocyte. Transcription of the CYP promoter was rhythmically controlled by clock genes. Our present findings provide a molecular link between the circadian clock and xenobiotic metabolism. In addition, these cultured cell models may be useful in the analysis of the molecular clock mechanism of the human biological rhythm research.
  • Circadian rhythms have been observed in many biological systems and physiological functions. The effectiveness and toxicity of many drugs vary depending on the dosing time, associated with 24-hr rhythms of biochemical, physiological, and behavioral processes under the control of the circadian clock. Recently, several clock genes have been identified, and they control an array of circadian rhythms in physiology and behavior. According to the currently held model, the core circadian oscillator consists of an autoregulatory transcription-translation feedback loop (Fig). CLOCK and BMAL1 proteins form a heterodimer and then activate the transcription of Per and Cry genes. Once PER and CRY proteins have reached a critical concentration, they attenuate CLOCK:BMAL1-mediated activation of their own genes in a negative feedback loop.
    Time-dependent changes in pharmacokinetics proceed from 24 hr rhythms in each process, e.g. absorption, distribution, metabolism and elimination. Since the liver is a major organ of metabolism and detoxifcation, knowledge of circadian effects on transcriptional activities that govern daily biochemical and physiological processes in the liver may play a key role in toxicology. In mouse liver, circadian regulation of transcripts is demonstrated for the factor of phase I, II of drug metabolism such as Cyp17, Cyp2a4, Cyp2e1, Cyp2c22, Cyp3a, glutathione S-transferases (GST) and carboxylesterase so on. In the recent our study, the transactivation of the human CYP3a4 gene by DBP is repressed by the E4 promoter-binding protein-4 (E4BP4), a negative component of the circadian clock (Fig).1) On the other hand, hepatocyte nuclear factor-1 alpha (HNF-1α) and clock genes contribute to produce the 24-hr rhythm of CYP2e1 mRNA levels in mouse liver.2)
Other Educational Activities
  • 2019.04.
  • 2018.04.
  • 2017.04.
  • 2016.10.
  • 2015.12.
  • 2014.12.
  • 2013.12.
  • 2012.12.
  • 2011.12.
  • 2010.12.
  • 2009.12.
  • 2008.12.