Kyushu University Academic Staff Educational and Research Activities Database
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matsunaga naoya Last modified date:2018.12.02

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)
Total Priod of education and research career in the foreign country
Research Interests
  • 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. Fumiyasu Okazaki, Matsunaga Naoya, Kengo Hamamura, Kayoko Suzuki, Takaharu Nakao, Hiroyuki Okazaki, Masahiko Kutsukake, Shiro Fukumori, Yasuhiro Tsuji, Hideto To, Administering xCT inhibitors based on circadian clock improves antitumor effects, Cancer Research, 10.1158/0008-5472.CAN-17-0720, 77, 23, 6603-6613, 2017.12, Clock genes encoding transcription factors that regulate circadian rhythms may inform chronomodulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here, we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects and that the Clock gene itself induces xCT expression and regulates its circadian rhythm. Our findings highlight the clinical potential of chronomodulated chemotherapy and the importance of xCT-mediated transcriptional regulation in the utility of such strategies..
2. Okazaki F, Matsunaga N, Okazaki H, Azuma H, Hamamura K, Tsuruta A, Tsurudome Y, Ogino T, Hara Y, Suzuki T, Hyodo K, Ishihara H, Kikuchi H, To H, Aramaki H, Koyanagi S, Ohdo S., Circadian Clock in a Mouse Colon Tumor Regulates Intracellular Iron Levels to Promote Tumor Progression., J Biol Chem., 291, (13), 7017-28, 2016.10.
3. Kusunose N, Matsunaga N, Kimoto K, Akamine T, Hamamura K, Koyanagi S, Ohdo S, Kubota T., Mitomycin C modulates the circadian oscillation of clock gene period 2 expression through attenuating the glucocorticoid signaling in mouse fibroblasts.
, Biochem Biophys Res Commun., 467(1):157-63. , 2015.09.
4. Matsunaga N, Itcho K, Hamamura K, Ikeda E, Ikeyama H, Furuichi Y, Watanabe M, Koyanagi S, Ohdo S., 24-hour rhythm of aquaporin-3 function in the epidermis is regulated by molecular clocks., J Invest Dermatol, 2014.01.
5. Okazaki H, Matsunaga N, Fujioka T, Okazaki F, Akagawa Y, Tsurudome Y, Ono M, Kuwano M, Koyanagi S, Ohdo S., Circadian regulation of mTOR by ubiquitin pathway in renal cell carcinoma. , Cancer Res, 2013.11.
6. Ikeda E, Matsunaga N, Kakimoto K, Hamamura K, Hayashi A, Koyanagi S, Ohdo S., Molecular mechanism regulating 24-hour rhythm of dopamine D3 receptor expression in mouse ventral striatum., Mol Pharmacol, 83, 959-967, 2013.03.
7. Hayashi A, Matsunaga N, Okazaki H, Kakimoto K, Kimura Y, Azuma H, Ikeda E, Shiba T, Yamato M, Yamada K, Koyanagi S, Ohdo S., A disruption mechanism of the molecular clock in a MPTP mouse model of Parkinson's disease. , Neuromolecular Med, 15, 238-251, 2013.05.
8. Tomishima Y, Ishitsuka Y, Matsunaga N, Nagatome M, Furusho H, Irikura M, Ohdo S, Irie T. , Ozagrel hydrochloride, a selective thromboxane A₂ synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice., BMC Gastroenterol, 30, 13-21, 2013.01.
9. Matsunaga N, Inoue M, Kusunose N, Kakimoto K, Hamamura K, Hanada Y, Toi A, Yoshiyama Y, Sato F, Fujimoto K, Koyanagi S, Ohdo S., Time-Dependent Interaction between Differentiated Embryo Chondrocyte-2 and CCAAT/Enhancer-Binding Protein α Underlies the Circadian Expression of CYP2D6 in Serum-Shocked HepG2 Cells., Mol Pharmacol, 81, 739-747, 2012.04.
10. Noda M, Yamakawa Y, Matsunaga N, Naoe S, Jodoi T, Yamafuji M, Akimoto N, Teramoto N, Fujita K, Ohdo S, Iguchi H., IL-6 Receptor Is a Possible Target against Growth of Metastasized Lung Tumor Cells in the Brain., Int J Mol Sci, 14, 515-526, 2012.12.
11. Tanimura N, Kusunose N, Matsunaga N, Koyanagi S, Ohdo S., Aryl hydrocarbon receptor-mediated Cyp1a1 expression is modulated in a CLOCK-dependent circadian manner.

, Toxicology., 290, (2-3):, 203-7., 2011.10.
12. Matsunaga N, Kohno Y, Kakimoto K, Hayashi A, Koyanagi S, Ohdo S., Influence of CLOCK on cytotoxicity induced by diethylnitrosamine in mouse primary hepatocytes.

, Toxicology., 27, 280, 144-51, 2011.02.
13. Fujioka T, Matsunaga N, Okazaki H, Koyanagi S, Ohdo S. , Hypoxia-response plasmid vector producing bcl-2 shRNA enhances the apoptotic cell death of mouse rectum carcinoma.

, J Pharmacol Sci, 2010.08.
14. Okazaki F, Matsunaga N, Okazaki H, Utoguchi N, Suzuki R, Maruyama K, Koyanagi S, Ohdo S., Circadian rhythm of transferrin receptor 1 gene expression controlled by c-Myc in colon cancer-bearing mice.

, Cancer Res, 70, 15, 6238-46, 2010.08.
15. Kim J, Matsunaga N, Koyanagi S, Ohdo S., Clock gene mutation modulates the cellular sensitivity to genotoxic stress through altering the expression of N-methylpurine DNA glycosylase gene., Biochemical Pharmacology , 2009.10.
16. Horiguchi M, Kim J, Matsunaga N, Kaji H, Egawa T, Makino K, Koyanagi S, Ohdo S., Glucocorticoid-dependent expression of O6-methylguanine-DNA methyltransferase gene modulates the dacarbazine-induced hepatotoxicity in mice., J Pharmacol Exp Ther , 333, (3), 782-7. , 2009.06.
17. Matsunaga N., Ikeda M., Takiguchi T., Koyanagi S., and Ohdo S. , The molecular mechanism regulating 24-hr rhythm of CYP2E1 expression in the mouse liver. , Hepatology , 2008.07.
18. Iwakiri T, Okumura M, Matsunaga N, Ichihara E, Shiotsuki S, Nagata M, Kumagai Y, Kai H, Arimori K. , Hepatocyte growth factor increases uptake of estradiol 17beta-D-glucuronide and Oatp1 protein level in rat hepatocytes. . , Eur. J. Pharmacol. , 580:19-26, 2008.01.
19. Viyoch J, Matsunaga N, Yoshida M, To H, Higuchi S, Ohdo S., Effect of haloperidol on mPer1 gene expression in mouse suprachiasmatic nuclei., Journal of Biological Chemistry, 10.1074/jbc.M411704200, 280, 8, 6309-6315,  280, 6309–6315, 2005.01.
20. Matsunaga N, Nakamura N, Yoneda N, Terazono H, To H, Higuchi S, Ohdo S., Influence of feeding schedule on 24-hr rhythm of hepatotoxicity induced by acetaminophen in mice., Journal of Pharmacology and Experimental Therapeutics, 10.1124/jpet.104.069062, 311, 2, 594-600, 311, 594-600, 2004.01.
  • 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
  • 2017.10.
  • 2016.10.
  • 2015.12.
  • 2014.12.
  • 2013.12.
  • 2012.12.
  • 2011.12.
  • 2010.12.
  • 2009.12.
  • 2008.12.