Updated on 2024/10/18

写真a

 
IGARASHI Kento
 
Organization
Research Field in Dentistry, Medical and Dental Sciences Area Graduate School of Medical and Dental Sciences Advanced Therapeutics Course Functional Biology and Pharmacology Assistant Professor
Title
Assistant Professor

Degree

  • 博士(生命科学) ( 2017.6   東京大学 )

Education

  • The University of Tokyo

    2013.10 - 2017.6

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    Country: Japan

  • Kyoto University

    - 2012.3

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    Country: Japan

Research History

  • Kagoshima University   Research Field in Dentistry, Medical and Dental Sciences Area Graduate School of Medical and Dental Sciences Advanced Therapeutics Course Functional Biology and Pharmacology   Assistant Professor

    2018.5

 

Papers

  • Kitanaka N., Arai K., Takehara K., Hall F.S., Tomita K., Igarashi K., Sato T., Uhl G.R., Kitanaka J. .  Opioid receptor antagonists reduce motivated wheel-running behavior in mice .  Behavioural Pharmacology35 ( 2-3 ) 114 - 121   2024.4

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    Language:Japanese   Publisher:Behavioural Pharmacology  

    We hypothesized that opioid receptor antagonists would inhibit motivated behavior produced by a natural reward. To evaluate motivated responses to a natural reward, mice were given access to running wheels for 71.5h in a multi-configuration testing apparatus. In addition to a running wheel activity, locomotor activity (outside of the wheel), food and water intake, and access to a food container were measured in the apparatus. Mice were also tested separately for novel-object exploration to investigate whether naloxone affects behavior unrelated to natural reward. In untreated mice wheel running increased from day 1 to day 3. The selective µ-opioid receptor antagonist β-funaltrexamine (β-FNA) (5 mg/kg) slightly decreased wheel running, but did not affect the increase in wheel running from day 1 to day 3. The non-selective opioid receptor antagonist naloxone produced a greater reduction in wheel running than β-FNA and eliminated the increase in wheel running that occurred over time in the other groups. Analysis of food access, locomotor behavior, and behavior in the novel-object test suggested that the reduction in wheel running was selective for this highly reinforcing behavior. These results indicate that opioid receptor antagonism reduces responses to the natural rewarding effects of wheel running and that these effects involve multiple opioid receptors since the non-selective opioid receptor antagonist had greater effects than the selective µ-opioid receptor antagonist. It is possible that at the doses employed, other receptor systems than opioid receptors might be involved, at least in part, in the effect of naloxone and β-FNA.

    DOI: 10.1097/FBP.0000000000000769

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  • Tomita K., Oohara Y., Igarashi K., Kitanaka J., Kitanaka N., Tanaka K.i., Roudkenar M.H., Roushandeh A.M., Sugimura M., Sato T. .  Kamishoyosan and Kamikihito protect against decreased KCC2 expression induced by the P. gingivalis lipopolysaccharide treatment in PC-12 cells and improve behavioral abnormalities in male mice .  Heliyon9 ( 12 ) e22784   2023.12

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    Language:Japanese   Publisher:Heliyon  

    Kamishoyosan (KSS) and Kamikihito (KKT) have been traditionally prescribed for neuropsychiatric symptoms in Japan. However, the molecular mechanism of its effect is not elucidated enough. On the other hand, it has been reported that lipopolysaccharide derived from Porphyromonas gingivalis (P. g LPS) is involved not only in periodontal disease but also in the systemic diseases such as psychiatric disorders via neuroinflammation. Here, we investigated the molecular mechanism of KSS and KKT treatment by LPS-induced neuropathy using PC-12 cells. When P. g LPS was administrated during the NGF treatment, the KCC2 expression was decreased in PC-12 cells. P. g LPS treatment also decreased the WNK and phospho SPAK (pSPAK) expression and enhanced GSK-3β expression that negatively regulates WNK-SPAK signaling. Moreover, when KSS or KKT was administrated before P. g LPS treatment, the decrease of KCC2, WNK and pSPAK was rescued. KSS and KKT treatment also rescued the enhancement of GSK3β expression by P. g LPS treatment. Furthermore, KSS, KKT and/or oxytocin could rescue behavioral abnormalities caused by P. g LPS treatment by animal experiments. These effects were not shown in the Goreisan treatment, which has been reported to act on the central nervous system. These results indicate that KSS and KKT are candidates for therapeutic agents for neural dysfunction.

    DOI: 10.1016/j.heliyon.2023.e22784

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  • Tomita K., Kuwahara Y., Igarashi K., Kitanaka J., Kitanaka N., Takashi Y., Tanaka K.i., Roudkenar M.H., Roushandeh A.M., Kurimasa A., Nishitani Y., Sato T. .  Therapeutic potential for KCC2-targeted neurological diseases .  Japanese Dental Science Review59   431 - 438   2023.12

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    Language:Japanese   Publisher:Japanese Dental Science Review  

    Patients with neurological diseases, such as schizophrenia, tend to show low K+-Cl- co-transporter 2 (KCC2) levels in the brain. The cause of these diseases has been associated with stress and neuroinflammation. However, since the pathogenesis of these diseases is not yet fully investigated, drug therapy is still limited to symptomatic therapy. Targeting KCC2, which is mainly expressed in the brain, seems to be an appropriate approach in the treatment of these diseases. In this review, we aimed to discuss about stress and inflammation, KCC2 and Gamma-aminobutyric acid (GABA) function, diseases which decrease the KCC2 levels in the brain, factors that regulate KCC2 activity, and the possibility to overcome neuronal dysfunction targeting KCC2. We also aimed to discuss the relationships between neurological diseases and LPS caused by Porphyromonas gingivalis (P. g), which is a type of oral bacterium. Clinical trials on oxytocin, sirtuin 1 (SIRT1) activator, and transient receptor potential cation channel subfamily V Member 1 activator have been conducted to develop effective treatment methods. We believe that KCC2 modulators that regulate mitochondria, such as oxytocin, glycogen synthase kinase 3β (GSK3β), and SIRT1, can be potential targets for neurological diseases.

    DOI: 10.1016/j.jdsr.2023.11.001

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  • Kitanaka J., Kitanaka N., Tomita K., Hall F.S., Igarashi K., Uhl G.R., Sato T. .  Glycogen Synthase Kinase-3 Inhibitors Block Morphine-Induced Locomotor Activation, Straub Tail, and Depression of Rearing in Mice Via a Possible Central Action .  Neurochemical Research48 ( 7 ) 2230 - 2240   2023.7

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    Language:Japanese   Publisher:Neurochemical Research  

    We investigated morphine-induced Straub’s tail reaction (STR) in mice pretreated with or without glycogen synthase kinase-3 (GSK-3) inhibitors (SB216763 and AR-A014418) by using a newly modified, infrared beam sensor-based automated apparatus. Mice treated with a single injection of morphine (30 mg/kg, i.p.) showed a significant STR with a plateau level at a time point of 20 min after morphine challenge. Pretreatment of mice with SB216763 (5 mg/kg, s.c.) or AR-A014418 (3 mg/kg, i.p.) significantly inhibited morphine-induced STR and attenuated the duration of STR in a dose-dependent fashion. In the striatum and the nucleus accumbens, expression of pGSK-3βTyr216 but not GSK3β or pGSK-3βSer9 was largely but not significantly reduced after treatment with SB216763 (5 mg/kg, s.c.) in combination with/without morphine, indicating that the inhibitory effect of GSK-3 inhibitors on morphine-induced STR and hyperlocomotion might not depend on the direct blockade of GSK-3β function. In constipated mice after morphine challenge (30 mg/kg), the effect of GSK-3 inhibitors on gastrointestinal transit was examined to reveal whether the action of GSK-3 inhibitors on morphine effects was central and/or peripheral. Pretreatment with SB216763 (5 mg/kg) did not block constipation in morphine-injected mice. The mechanism of action seems to be central but not peripheral, although the underlying subcellular mechanism of GSK-3 inhibitors is not clear. Our measurement system is a useful tool for investigating the excitatory effects of morphine in experimental animals.

    DOI: 10.1007/s11064-023-03902-2

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  • Igarashi K, Kuchiiwa S, Kuchiiwa T, Tomita K, Sato T .  Comparative data on emotional (psychotic) aggressive biting behavior in mice of ddY strain measured by using two devices; Aggressive response meter and powerlab-compatible type aggressive response meter. .  Data in brief48   109231   2023.6Comparative data on emotional (psychotic) aggressive biting behavior in mice of ddY strain measured by using two devices; Aggressive response meter and powerlab-compatible type aggressive response meter.

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    DOI: 10.1016/j.dib.2023.109231

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  • Yasuda T., Nakazawa T., Hirakawa K., Matsumoto I., Nagata K., Mori S., Igarashi K., Sagara H., Oda S., Mitani H. .  Retinal regeneration after injury induced by gamma-ray irradiation during early embryogenesis in medaka, Oryzias latipes .  International Journal of Radiation Biology100 ( 1 ) 1 - 8   2023

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    Language:English   Publisher:International Journal of Radiation Biology  

    Purpose: Zebrafish, a small fish model, exhibits a multipotent ability for retinal regeneration after damage throughout its lifetime. Compared with zebrafish, birds and mammals exhibit such a regenerative capacity only during the embryonic period, and this capacity decreases with age. In medaka, another small fish model that has also been used extensively in biological research, the retina’s inner nuclear layer (INL) failed to regenerate after injury in the hatchling at eight days postfertilization (dpf). We characterized the regenerative process of the embryonic retina when the retinal injury occurred during the early embryonic period in medaka. Methods: We employed a 10 Gy dose of gamma-ray irradiation to initiate retinal injury in medaka embryos at 3 dpf and performed histopathological analyses up to 21 dpf. Results: One day after irradiation, numerous apoptotic neurons were observed in the INL; however, these neurons were rarely observed in the ciliary marginal zone and the photoreceptor layer. Numerous pyknotic cells were clustered in the irradiated retina until two days after irradiation. These disappeared four days after irradiation, but the abnormal bridging structures between the INL and ganglion cell layer (GCL) were present until 11 days after irradiation, and the neural layers were completely regenerated 18 days after irradiation. After gamma-ray irradiation, the spindle-like Müller glial cells in the INL became rounder but did not lose their ability to express SOX2. Conclusions: Irradiated retina at 3 dpf of medaka embryos could be completely regenerated at 18 days after irradiation (21 dpf), although the abnormal layer structures bridging the INL and GCL were transiently formed in the retinas of all the irradiated embryos. Four days after irradiation, embryonic medaka Müller glia were reduced in number but maintained SOX2 expression as in nonirradiated embryos. This finding contrasts with previous reports that 8 dpf medaka larvae could not fully regenerate damaged retinas because of loss of SOX2 expression.

    DOI: 10.1080/09553002.2023.2242932

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  • Tomomi Watanabe-Asaka, Maki Niihori, Hiroki Sonobe, Kento Igarashi, Shoji Oda, Ken-ichi Iwasaki, Yoshihiko Katada, Toshikazu Yamashita, Masahiro Terada, Shoji A Baba, Hiroshi Mitani, Chiaki Mukai .  Acquirement of the autonomic nervous system modulation evaluated by heart rate variability in medaka (Oryzias latipes) .    17 ( 12 ) e0273064   2022.12Reviewed

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    DOI: doi.org/10.1371/journal.pone.0273064

  • Igarashi K, Iwai H, Tanaka KI, Kuwahara Y, Kitanaka J, Kitanaka N, Kurimasa A, Tomita K, Sato T .  Neuroprotective effect of oxytocin on cognitive dysfunction, DNA damage, and intracellular chloride disturbance in young mice after cranial irradiation. .  Biochemical and biophysical research communications612   1 - 7   2022.4

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    Cranial radiation therapy (CRT) is an effective treatment for brain tumors; however, it also causes brain injuries. The pediatric brain is considered especially vulnerable compared to the adult brain; thus, brain injuries caused by CRT may severely affect their quality of life. In this study, we determined the neuroprotective effects of nasal oxytocin administration following cranial radiation in mice. We investigated the cognitive behavior of mice (novel object recognition test and novel object location test), phosphorylated histone H2AX (γ-H2AX) and K+-Cl− transporter (KCC2) by immunohistochemical analysis of the hippocampal sections, and neuronal cells by immunocytochemistry after radiation and oxytocin administration. We found that the number of γ-H2AX foci was increased, and the surface signal intensity of KCC2 immunofluorescence was decreased in cells that were irradiated with X-rays (1.5 Gy, for three consecutive days) compared with cells that were not. Furthermore, using MQAE, we found that the intracellular chloride ion concentration was downregulated in oxytocin-treated cells by increasing surface KCC2 expression. These results indicate that nasal oxytocin administration after cranial irradiation attenuates cognitive dysfunction in mice and exerts multifaceted neuroprotective effects on DNA damage and maintains chloride ion concentration in neuronal cells.

    DOI: 10.1016/j.bbrc.2022.04.099

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  • Kitanaka N, Hall FS, Tanaka KI, Tomita K, Igarashi K, Nishiyama N, Sato T, Uhl GR, Kitanaka J .  Are histamine H3 antagonists the definitive treatment for acute methamphetamine intoxication? .  Current drug research reviews14 ( 3 ) 162 - 170   2022.4

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    Language:English   Publisher:Current Drug Research Reviews  

    Background: Methamphetamine (METH) is classified as a Schedule II stimulant drug under the United Nations Convention on Psychotropic Substances of 1971. METH and other amphetamine analogues (AMPHs) are powerful addictive drugs. Treatments are needed to treat the symptoms of METH addiction, chronic METH use, and acute METH overdose. No effective treatment for METH abuse has been established because alterations of brain functions under the excessive intake of abused drug intake are largely irreversible due in part to brain damage that occurs in the course of chronic METH use. Objective: Modulation of brain histamine neurotransmission is involved in several neuropsychiatric disorders, including substance use disorders. This review discusses the possible mechanisms underlying the therapeutic effects of histamine H3 receptor antagonists on symptoms of methamphetamine abuse. Conclusion: Treatment of mice with centrally acting histamine H3 receptor antagonists increases hypothalamic histamine contents and reduces high-dose METH effects while potentiating lowdose effects via histamine H1 receptors that bind released histamine. On the basis of experimental evidence, it is hypothesized that histamine H3 receptors may be an effective target for the treatment METH use disorder or other adverse effects of chronic METH use.

    DOI: 10.2174/2589977514666220414122847

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  • Kazuo Tomita, Sayuri Yamanishi-Taira, Kento Igarashi, Yuichi Oogai, Yoshikazu Kuwahara, Mehryar Habibi Roudkenar, Amaneh Mohammadi Roushandeh, Shouichi Miyawaki, Akihiro Kurimasa, Tomoaki Sato .  Oxytocin ameliorates KCC2 decrease induced by oral bacteria-derived LPS that affect rat primary cultured cells and PC-12 cells .  Peptides150   170734   2022.4

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    Language:Japanese   Publisher:Peptides  

    Inflammation, especially neuroinflammation, which is caused by stress, leads to central nervous system (CNS) dysfunction. Because lipopolysaccharides (LPSs) cause neuroinflammation, we investigated the effect of LPSs to CNS. In PC-12 cells, LPSs derived from oral bacteria reduced the expression of KCC2, a Cl− transporter. LPS derived from P. gingivalis (P. g) administered to rat primary cultured cells also reduced the KCC2 expression. However, LPSs derived from E. coli did not reduce the KCC2 expression. LPS treatment activated TLR4, IL-1β, and REST gene expressions, which led to KCC2 inactivation in PC-12 cells. The mechanism of KCC2 has been shown to play an important role in brain maturation, function (such as the GABA switch), and behavioral problems, we investigated the GABA function. We found that the GABA function was changed from inhibitory to excitatory by the LPS derived from P. g treatment. We demonstrated that the GSK3β also involved in the KCC2 reduction by LPS treatment. We show that oxytocin rescued the reduction in KCC2 expression caused by LPSs by inhibiting GSK3β signaling but vasopressin could not. Considered together, our results indicate that the LPSs from oral bacteria but not the LPS from E. coli increase the risk for brain disorders and oxytocin might be a candidate to overcome the abnormal behavior caused by brain disorders such as psychiatric disorders.

    DOI: 10.1016/j.peptides.2021.170734

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  • Kuwahara Y, Tomita K, Roudkenar MH, Roushandeh AM, Urushihara Y, Igarashi K, Kurimasa A, Sato T .  Decreased mitochondrial membrane potential is an indicator of radioresistant cancer cells. .  Life sciences286   120051   2021.10Decreased mitochondrial membrane potential is an indicator of radioresistant cancer cells.Reviewed International coauthorship International journal

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    DOI: 10.1016/j.lfs.2021.120051

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  • Igarashi K, Kuchiiwa T, Kuchiiwa S, Iwai H, Tomita K, Sato T .  Kamishoyosan (a Japanese traditional herbal formula), which effectively reduces the aggressive biting behavior of male and female mice, and potential regulation through increase of Tph1, Tph2, and Esr2 mRNA levels .  Brain Research1768   147580   2021.10Reviewed

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    DOI: 10.1016/j.brainres.2021.147580

    DOI: 10.1016/j.brainres.2021.147580

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  • Kitanaka N, Hall FS, Kobori S, Kushihara S, Oyama H, Sasaoka Y, Takechi M, Tanaka K, Tomita K, Igarashi K, Nishiyama N, Sato T, Uhl GR, Kitanaka J .  Metoprine, a histamine N-methyltransferase inhibitor, attenuates methamphetamine-induced hyperlocomotion via activation of histaminergic neurotransmission in mice Author links open overlay panel .  Pharmacology Biochemistry and Behavior209   173257   2021.10Reviewed International coauthorship

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    DOI: 10.1016/j.pbb.2021.173257

    DOI: 10.1016/j.pbb.2021.173257

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  • Tomita K., Kuwahara Y., Igarashi K., Roudkenar M.H., Roushandeh A.M., Kurimasa A., Sato T. .  Mitochondrial dysfunction in diseases, longevity, and treatment resistance: Tuning mitochondria function as a therapeutic strategy .  Genes12 ( 9 )   2021.9

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    Language:Japanese   Publisher:Genes  

    Mitochondria are very important intracellular organelles because they have various functions. They produce ATP, are involved in cell signaling and cell death, and are a major source of reactive oxygen species (ROS). Mitochondria have their own DNA (mtDNA) and mutation of mtDNA or change the mtDNA copy numbers leads to disease, cancer chemo/radioresistance and aging including longevity. In this review, we discuss the mtDNA mutation, mitochondrial disease, longevity, and importance of mitochondrial dysfunction in cancer first. In the later part, we particularly focus on the role in cancer resistance and the mitochondrial condition such as mtDNA copy number, mitochondrial membrane potential, ROS levels, and ATP production. We suggest a therapeutic strategy employing mitochondrial transplantation (mtTP) for treatment-resistant cancer.

    DOI: 10.3390/genes12091348

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  • Tomita K, Kuwahara Y, Igarashi K, Roudkenar MH, Roushandeh AM, Kurimasa A, Sato T .  Mitochondrial Dysfunction in Diseases, Longevity, and Treatment Resistance: Tuning Mitochondria Function as a Therapeutic Strategy .  Genes   2021.8Mitochondrial Dysfunction in Diseases, Longevity, and Treatment Resistance: Tuning Mitochondria Function as a Therapeutic StrategyReviewed International coauthorship

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  • Tomita K, Nagasawa T, Kuwahara Y, Torii S, Igarashi K, Roudkenar MH, Roushandeh AM, Kurimasa A, Sato T .  MiR-7-5p Is Involved in Ferroptosis Signaling and Radioresistance Thru the Generation of ROS in Radioresistant HeLa and SAS Cell Lines .  International Journal of Molecular Sciences22 ( 15 )   2021.8Reviewed International coauthorship

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    DOI: 10.3390/ijms22158300

    DOI: 10.3390/ijms22158300

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  • Dutta Bibek, Asami Taichi, Imatomi Tohru, Igarashi Kento, Nagata Kento, Watanabe-Asaka Tomomi, Yasuda Takako, Oda Shoji, Shartl Manfred, Mitani Hiroshi .  遺伝子導入による腫瘍形成の系統差と電離放射線の抑制効果(Strain difference in transgene-induced tumorigenesis and suppressive effect of ionizing radiation) .  Journal of Radiation Research62 ( 1 ) 12 - 24   2021.1遺伝子導入による腫瘍形成の系統差と電離放射線の抑制効果(Strain difference in transgene-induced tumorigenesis and suppressive effect of ionizing radiation)

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    Language:English   Publisher:(一社)日本放射線影響学会  

    発癌に関わるEGFレセプター遺伝子変異体であるXiphophorus melanoma receptor tyrosine kinase(xmrk)遺伝子を導入したメダカを用いて、腫瘍形成の系統差とγ線による抑制効果を調査した。Hd-rR系統のメダカと、Hd-rRおよびHNI系統メダカを交配したHd-rR/HNIメダカにxmrk遺伝子を導入した結果、色素沈着過剰はHd-rRメダカに比べ、Hd-rR/HNIメダカでは高頻度に認められ、悪性腫瘍の発生は、Hd-rRメダカに比べ、Hd-rR/HNIメダカでは発生頻度が低かった。また、1.3Gyのγ線単回照射により、Hd-rRおよびHd-rR/HNIメダカの色素沈着過剰と腫瘍形成は有意に抑制されたが、色素沈着過剰においては、Hd-rRメダカに比べHd-rR/HNIメダカでは、高頻度に認められた。以上より、xmrk遺伝子導入による色素沈着過剰と腫瘍形成は、Hd-rRメダカとHd-rR/HNIメダカの系統間では異なり、電離放射線はxmrk遺伝子導入による色素沈着過剰と腫瘍形成に対し、抑制効果を示すことが明らかにされた。

  • Kuwahara Y, Tomita K, Roudkenar MH, Roushandeh AM, Urushihara Y, Igarashi K, Nagasawa T, Kurimasa A, Fukumoto M, Sato T .  The Effects of Hydrogen Peroxide and/or Radiation on the Survival of Clinically Relevant Radioresistant Cells .  Technology in cancer research & treatment19   1533033820980077   2020.12Reviewed International coauthorship International journal

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Technology in cancer research & treatment  

    DOI: 10.1177/1533033820980077

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  • Dutta B, Asami T, Imatomi T, Igarashi K, Nagata K, Watanabe-Asaka T, Yasuda T, Oda S, Shartl M, Mitani H .  Strain difference in transgene-induced tumorigenesis and suppressive effect of ionizing radiation. .  Journal of radiation research62 ( 1 ) 12 - 24   2020.11Strain difference in transgene-induced tumorigenesis and suppressive effect of ionizing radiation.Reviewed International coauthorship

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    DOI: 10.1093/jrr/rraa103

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  • Takashi Y, Tomita K, Kuwahara Y, Roudkenar MH, Roushandeh AM, Igarashi K, Nagasawa T, Nishitani Y, Sato T .  Mitochondrial dysfunction promotes aquaporin expression that controls hydrogen peroxide permeability and ferroptosis .  Free Radical Biology and Medicine   2020.9Mitochondrial dysfunction promotes aquaporin expression that controls hydrogen peroxide permeability and ferroptosis

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  • Roushandeh AM, Tomita K, YoKuwahara Y, Jahanian-Najafabadi A, Igarashi K, Roudkenar MH, Sato T .  Transfer of healthy fibroblast-derived mitochondria to HeLa ρ0 and SAS ρ0 cells recovers the proliferation capabilities of these cancer cells under conventional culture medium, but increase their sensitivity to cisplatin-induced apoptotic death .  Molecular Biology Reports47 ( 6 ) 4401 - 4411   2020.6International coauthorship International journal

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Molecular Biology Reports  

    DOI: 10.1007/s11033-020-05493-5

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  • 五十嵐健人, 富田和男, 佐藤友昭 .  隔離飼育ストレス負荷マウスの噛みつき行動に対する加味逍遙散の作用について .  鹿児島県歯科医師会報149 ( 728 ) 11 - 13   2020.3隔離飼育ストレス負荷マウスの噛みつき行動に対する加味逍遙散の作用について

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  • Tomita K. .  MiR-7-5p is a key factor that controls radioresistance via intracellular Fe<sup>2+</sup> content in clinically relevant radioresistant cells .  Biochemical and Biophysical Research Communications518 ( 4 ) 712 - 718   2019.10Reviewed International journal

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Biochemical and Biophysical Research Communications  

    DOI: 10.1016/j.bbrc.2019.08.117

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  • Kazuo Tomita, Yuko Takashi, Yuya Ouchi, Yoshikazu Kuwahara, Kento Igarashi, Taisuke Nagasawa, Hideki Nabika, Akihiro Kurimasa, Manabu Fukumoto, Yoshihiro Nishitani, Tomoaki Sato .  Lipid peroxidation increases hydrogen peroxide permeability leading to cell death in cancer cell lines that lack mtDNA .  Cancer Science   2019.7Lipid peroxidation increases hydrogen peroxide permeability leading to cell death in cancer cell lines that lack mtDNAReviewed

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  • Kento Igarashi, Masafumi Funakoshi, Seiji Kato, Takahito Moriwaki, Yuichi Kato, Qiu-Mei Zhang-Akiyama .  CiApex1 has AP endonuclease activity and abrogated AP site repair disrupts early embryonic development in Ciona intestinalis .  Genes & Genetic Systems   2019.4CiApex1 has AP endonuclease activity and abrogated AP site repair disrupts early embryonic development in Ciona intestinalis

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  • 富田和男, 桑原義和, 五十嵐健人, 髙裕子, 長澤大成, 山西沙祐里, 西谷佳浩, 漆原佑介, 宮脇正一, 栗政明弘, 福本学, 佐藤友昭 .  細胞内鉄動態と酸化ストレス抵抗性 .  東北医科薬科大学研究誌66   25 - 31   2019細胞内鉄動態と酸化ストレス抵抗性

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  • 桑原義和, 富田和男, 高畠貴志, 漆原佑介, 五十嵐健人, 佐藤友昭, 栗政明弘, 福本学 .  臨床的放射線耐性細胞のこれまでとこれから .  東北医科薬科大学研究誌66   19 - 24   2019臨床的放射線耐性細胞のこれまでとこれから

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  • Igarashi Kento, Funakoshi Masafumi, Kato Seiji, Moriwaki Takahito, Kato Yuichi, Zhang-Akiyama Qiu-Mei .  CiApex1 has AP endonuclease activity and abrogated AP site repair disrupts early embryonic development in <i>Ciona intestinalis</i> .  Genes & Genetic Systems94 ( 2 ) 81 - 93   2019Reviewed

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:日本遺伝学会  

    <p>Apurinic/apyrimidinic (AP) sites are the most common form of cytotoxic DNA damage. Since AP sites inhibit DNA replication and transcription, repairing them is critical for cell growth. However, the significance of repairing AP sites during early embryonic development has not yet been clearly determined. Here, we focused on APEX1 from the ascidian <i>Ciona intestinalis</i> (CiApex1), a homolog of human AP endonuclease 1 (APEX1), and examined its role in early embryonic development. Recombinant CiApex1 protein complemented the drug sensitivities of an AP endonuclease-deficient <i>Escherichia coli</i> mutant, and exhibited Mg<sup>2+</sup>-dependent AP endonuclease activity, like human APEX1, <i>in vitro</i>. Next, the effects of abnormal AP site repair on embryonic development were investigated. Treatment with methyl methanesulfonate, which alkylates DNA bases and generates AP sites, induced abnormal embryonic development. This abnormal phenotype was also caused by treatment with methoxyamine, which inhibits AP endonuclease activity. Furthermore, we constructed dominant-negative CiApex1, which inhibits CiApex1 action, and found that its expression impaired embryonic growth. These results suggested that AP site repair is essential for embryonic development and CiApex1 plays an important role in AP site repair during early embryonic development in <i>C. intestinalis</i>.</p>

    DOI: 10.1266/ggs.18-00043

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  • Kazuo Tomita, Yoshikazu Kuwahara, Yuko Takashi, Kento Igarashi, Taisuke Nagasawa, Hideki Nabika, Akihiro Kurimasa, Manabu Fukumoto, Yoshihiro Nishitani, Tomoaki Sato .  Clinically relevant radioresistant cells exhibit resistance to H2O2 by decreasing internal H2O2 and lipid peroxidation .  Tumor Biology   2018.9Clinically relevant radioresistant cells exhibit resistance to H2O2 by decreasing internal H2O2 and lipid peroxidationReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SAGE Publications Inc.  

  • Tomita K. .  Clinically relevant radioresistant cells exhibit resistance to H<inf>2</inf>O<inf>2</inf> by decreasing internal H<inf>2</inf>O<inf>2</inf> and lipid peroxidation .  Tumor Biology40 ( 9 ) 1010428318799250   2018.9Reviewed International journal

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Tumor Biology  

    DOI: 10.1177/1010428318799250

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  • Sayed AEH, Igarashi K, Watanabe-Asaka T, Mitani H .  Double strand break repair and γ-H2AX formation in erythrocytes of medaka (Oryzias latipes) after γ-irradiation. .  Environmental pollution (Barking, Essex : 1987)224   35 - 43   2017.5Double strand break repair and γ-H2AX formation in erythrocytes of medaka (Oryzias latipes) after γ-irradiation.Reviewed International coauthorship International journal

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    DOI: 10.1016/j.envpol.2016.11.050

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MISC

  • 放射線耐性におけるミトコンドリアの役割

    富田 和男, 桑原 義和, 五十嵐 健人, 福本 学, 佐藤 友昭

    放射線生物研究   55 ( 4 )   370 - 383   2020.12

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    現在、2人に1人が人生で1度はがんに罹患するといわれている。がんの治療については、外科的手術、化学療法、放射線療法の3つの柱に加え、近年は分子標的薬や免疫チェックポイント阻害剤の開発も加わり、めざましい進歩を遂げてきている。しかしながら、放射線治療において耐性を示す細胞の出現は、がん患者に悪い予後をもたらす大きな問題のひとつである。そのため、放射線および薬物耐性のメカニズムを明らかにし、その性質を理解することができれば、治療効果が高まりがん克服へ大きな一歩が踏み出せると考えられる。そこで私たちは、複数のヒトがん細胞株から、従来の放射線治療で行われている2Gy/日の放射線照射に耐性を示す「臨床的放射線耐性がん細胞」(Clinically Relevant Radioresistant Cell:CRR細胞)を樹立し、その性質を解析してきた。現在までにCRR細胞は、放射線に耐性を示さない細胞に比べ、ミトコンドリアの膜状態やDNAコピー数、遊離の2価鉄量などが変化していることなどが示され、放射線耐性とミトコンドリアとの強い関連性が次第に明らかとなってきている。そこで本稿では、放射線耐性におけるミトコンドリアの役割について、CRR細胞の解析を中心に概説する。(著者抄録)

  • オキシトシンの精神作用と精神疾患治療への応用に向けたアプローチ

    五十嵐 健人, 富田 和男, 桑原 義和, 栗政 明弘, 佐藤 友昭

    東北医科薬科大学研究誌   ( 67 )   41 - 45   2020.12

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    オキシトシンは末梢組織に対する作用の他にも、中枢・精神作用を有しており、繁殖行動および攻撃行動といった社会性行動や信頼関係の構築に関与していると考えられ、多様な精神疾患症状に対する治療効果が期待されている。1)オキシトシンの投与とヒトに対する作用、2)実験動物でのオキシトシンの作用および生理学的役割の解析、3)オキシトシンと類似したペプチドホルモンとの比較、4)攻撃行動解析装置を用いたアプローチ、について述べた。

  • 標準的放射線療法に抵抗性を示すがん細胞の不思議な性質

    桑原 義和, 富田 和男, 北原 秀治, 五十嵐 健人, 漆原 佑介, 齋藤 陽平, 佐藤 友昭, 栗政 明弘, 福本 学

    東北医科薬科大学研究誌   ( 65 )   11 - 19   2018.12

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    臨床的放射線耐性(CRR)細胞は標準的放射線療法である2Gy/日のX線を照射し続けても増殖する。筆者らはCRRを複数のヒト由来癌細胞株から樹立し研究を行った。その結果、CRR腫瘍は血管密度が親株由来の腫瘍に比べて高く、酸素分圧が高いことから、CRR細胞が分割照射に抵抗性を示すためには酸素が必要不可欠であることが示唆された。CRR細胞のX線耐性メカニズムおよび放射線抵抗性腫瘍の不思議な性質について述べた。

  • ストレス関連病態におけるGABA応答障害の関与

    五十嵐 健人, 富田 和男, 桑原 義和, 山西 沙祐里, 古川 みなみ, 宮脇 正一, 栗政 明弘, 佐藤 友昭

    東北医科薬科大学研究誌   ( 65 )   7 - 10   2018.12

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    γ-アミノ酪酸(GABA)応答障害が様々な行動特性変化をもたらすとする仮説に基づき、社会的ストレスを模した負荷を経験したマウスのストレス応答について、行動生物学的手法および分子生物学的手法を用いて解析を進めている。GABA応答障害の改善は多くの疾患に共通するメカニズムを介して制御されていると考えられる。本稿では実験的ストレス負荷がどのように神経障害をきたすのか、成果を交えて概説した。

  • Data on the aquaporin gene expression differences among ρ<sup>0</sup>, clinically relevant radioresistant, and the parental cells of human cervical cancer and human tongue squamous cell carcinoma.

    Takashi Y, Tomita K, Kuwahara Y, Nabika H, Igarashi K, Nagasawa T, Kurimasa A, Fukumoto M, Nishitani Y, Sato T

    Data in brief   20   402 - 410   2018.10

  • DNA修復におけるNBS1 Q185E(C>G)多型の役割について

    五十嵐 健人, 三谷 啓志

    放射線生物研究   53 ( 1 )   44 - 54   2018.3

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    NBS1はゲノム不安定性をもたらす劣性遺伝病であるナイミーヘン症候群の原因遺伝子であり、様々なDSB修復因子との協調によりDNA二本鎖切断(DSB)を修復し、ゲノム安定性を維持する重要な役割を担うことが知られている。NBS1には、がん罹患リスクと関連が示唆されるNBS1 Q185E(C>G)多型が見出されており、NBS1 185Q残基もまたDNA修復において機能的重要性をもつと予想されるが、その役割は未だ明らかでない。本稿では疫学解析及びDNA修復についての知見を紹介し、DSB修復におけるNBS1 185Q残基の役割について考察する。(著者抄録)

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Presentations

  • 五十嵐健人、富田和男、佐藤友昭   加味逍遙散は隔離飼育マウスの噛みつき行動を低減する  

    第71回日本東洋医学会学術総会  2021.8  日本東洋医学会

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    Event date: 2021.8

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:Web   Country:Japan  

  • 富田 和男, 高 裕子, 五十嵐 健人, 西谷 佳浩, 佐藤 友昭   Mitochondrial dysfunction enhances hydrogen peroxide-induced ferroptosis by up-regulating the expression of aquaporin3, 5, and 8.  

    第62回歯科基礎医学会学術大会 

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    Event date: 2020.9 - 2020.10

    Language:English   Presentation type:Poster presentation  

    Venue:Web  

  • Igarashi Kento, Tomita Kazuo, Tanaka Koh-ichi, Kuwahara Yoshikazu, Kitanaka Junichi, Kitanaka Nobue, Nishiyama Nobuyoshi, Kurimasa Akihiro, Takemura Motohiko, Sato Tomoaki   An examination whether KCC2, a K+-Cl- co-transporter, is efficient as a target to attenuate the neuronal dysfunction that is associated with radiation therapy for brain tumor by using oxytocin.  

    第93回日本薬理学会年会 

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    Event date: 2020.3

    Language:English   Presentation type:Poster presentation  

  • 五十嵐健人, 富田和男, 佐藤友昭   加味逍遙散による隔離飼育マウスの攻撃性低下におけるエストロゲン受容体の関与   International conference

    第27回日本東洋医学会九州支部鹿児島県部会 

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    Event date: 2020.2

    Language:Japanese   Presentation type:Oral presentation (general)  

  • 五十嵐健人, 富田和男, 田中康一, 桑原義和, 西山信好, 栗政明弘, 佐藤友昭   放射線照射により惹起される脳機能障害に対する、K+-Cl-トランスポーターKCC2を標的とした薬物療法の有用性  

    第72回薬理学会西南部会 

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    Event date: 2019.11

    Language:Japanese   Presentation type:Oral presentation (general)  

  • Igarashi Kento, Tomita Kazuo, Tanaka Koh-ichi, Kuwahara Yoshikazu, Nishiyama Nobuyoshi, Kurimasa Akihiro and Sato Tomoaki   KCC2, a K+-Cl- co-transporter, is a possible target to attenuate the neuronal dysfunction that is associated with radiation therapy for brain tumor   International conference

    6th Congress of Asian College of Neuropsychopharmacology 

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    Event date: 2019.10

    Language:English   Presentation type:Poster presentation  

  • 五十嵐健人, 口岩俊子, 口岩聡, 富田和男, 佐藤友昭   マウスの噛みつき行動に対する加味逍遙散の作用  

    第21回応用薬理シンポジウム 

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    Event date: 2019.9

    Language:Japanese   Presentation type:Poster presentation  

  • Igarashi K, Tomita K, Sato T   The usefulness of KCC2 to analyze the effect of irradiation on rodent neuron  

    第92回日本薬理学会年会 

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    Event date: 2019.3

    Language:English   Presentation type:Poster presentation  

  • 五十嵐健人, 富田和男, 佐藤友昭   X線照射後の初代培養神経細胞におけるCl-トランスポーター発現解析  

    日本薬理学会 西南部会 

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    Event date: 2018.11

    Language:Japanese   Presentation type:Poster presentation  

  • 高 裕子, 富田 和男, 五十嵐 健人, 西谷 佳浩, 佐藤 友昭   過酸化水素処理によるρ0細胞の膜状態変化とその感受性  

    Journal of Oral Biosciences Supplement  2018.9  (一社)歯科基礎医学会

  • Nagasawa Taisuke, Nishiyama Nobuyoshi, Kunimasa Akihiro, Sato Tomoaki, Tomita Kazuo, Kuwahara Yoshikazu, Igarashi Kento, Takashi Yuko, Tanaka Koh-ichi, Kitanaka Junichi, Kitanaka Nobue, Takemura Motohiko   Analysis of hydrogen peroxide resistance mechanism on hydrogen peroxide resistant cancer cells.  

    Proceedings for Annual Meeting of The Japanese Pharmacological Society  2019  Japanese Pharmacological Society

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    <p>&lt;purpose&gt;</p><p>Hydrogen peroxide is known as one of ROS which gives oxidative stress to cells and induces apoptosis. However, details of the mechanism for cancer cells by hydrogen peroxide is still unknown.We have established "hydrogen peroxide resistant (HR) cancer cells" that are resistant to high concentration hydrogen peroxide. The mechanism of resistance to hydrogen peroxide acquired by HR cancer cells has not yet been elucidated, however if the mechanism becomes clear, it could be applied to cancer treatment. In this study, therefore, we aimed to elucidate its hydrogen peroxide resistance mechanism and carried out the following experiment.</p><p>&lt;method&gt;</p><p>Cell lines that continued to survive against graded hydrogen peroxide treatment of HeLa (up to 70 μM) and SAS (up to 35 μM) were subjected to hydrogen peroxide at the concentrations of 0, 25, 50, 75 and 100 μM respectively, and the cell viability was examined by WST assay. Subsequently, the endogenous catalase enzymatic activity of HR cancer cells was measured using Catalase Assey Kit (SIGMA).Furthermore, lipid peroxidation of HR cancer cells was analyzed by immunofluorescence using 4-hydroxynonenal (HNE) and 5-lipoxygenase (5-LOX) antibody. HNE is typical lipid peroxidation marker and 5-LOX is known as lipid peroxidase. </p><p>&lt;results and discussion&gt;</p><p>In HeLa and SAS parental cells, they survived to the extent of 25 μM by hydrogen peroxide treatment. On the other hand, stepwise hydrogen peroxide-treated cells survived up to100 μM (HeLa) and 50 μM (SAS), showingresistance to hydrogen peroxide. Analysis of catalase enzyme activity showed significant increase in HeLa HR cells compared with the HeLa parent, but there were no significant differences in SAS cells.</p><p>Furthermore, HNE and 5-LOX expression levels in HR cells were significantly decreased compared with the parental cells byimmunofluorescent staining. </p><p>As mentioned above, the membrane lipid peroxidation is regulated by the expression of 5-LOXrather than a catalase activity. The decreased 5-LOX expression may suppress lipids peroxidation in plasma membrane and leadto retention viability to hydrogen peroxide in HR cells.</p>

  • Tomita Kazuo, Takemura Motohiko, Nishiyama Nobuyoshi, Fukumoto Manabu, Nishitani Yoshihiro, Kurimasa Akihiro, Sato Tomoaki, Kuwahara Yoshikazu, Igarashi Kento, Takashi Yuko, Nagasawa Taisuke, Nabika Hideki, Tanaka Koh-ichi, Kitaknaka Junichi, Kitanaka Nobue   Involvement of ALOX in resistance or sensitivity of cancer treatment via plasma membrane oxidation state.  

    Proceedings for Annual Meeting of The Japanese Pharmacological Society  2019  Japanese Pharmacological Society

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    <p>Although radiation therapy is one of the choices to treat cancers and is an excellent local treatment method, existence of radiation resistant cell is a major problem. We established clinically relevant radioresistant (CRR) cells that can survive exposing to 2 Gy/day X-rays for more than 30 days. However, the mechanism to obtain resistance has not been elucidated yet. We investigated the relationships between resistant mechanism to hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and plasma membrane state in CRR cells. </p><p> CRR cells showed resistance to H<sub>2</sub>O<sub>2</sub>, but catalase enzyme activity was down-regulated. Plasma membrane potential were low, no internal H<sub>2</sub>O<sub>2 </sub>increase and no lipid peroxidation were seen even after 2 hours of H<sub>2</sub>O<sub>2 </sub>treatment in CRR cells. Administration of oxidized lipid led to further cell death after H<sub>2</sub>O<sub>2</sub> treatment in CRR cells. The lipoxygenase (ALOX) gene and protein expressions were down-regulated in CRR cells. We also established stress-sensitive ρ<sup>0</sup> cells that lack mitochondrial DNA. Gene and protein expressions of ALOX were up-regulated in ρ<sup>0</sup> cells. Expression of cyclooxygenase-2 does not seem to be involved in this mechanism. </p><p> These results suggest that the involvement of ALOX in resistance or sensitivity of cancer treatment.</p>

  • 富田 和男, 高 裕子, 五十嵐 健人, 西谷 佳浩, 佐藤 友昭   ミトコンドリアの機能不全は過酸化水素取り込みを制御するアクアポリン3, 5, 8の発現を亢進させ過酸化水素処理によるフェロトーシスを誘導する  

    Journal of Oral Biosciences Supplement  2020.9  (一社)歯科基礎医学会

  • 富田 和男, 桑原 義和, 五十嵐 健人, 栗政 明弘, 福本 学, 佐藤 友昭   細胞内遊離鉄がストレス抵抗性を制御する  

    日本癌学会総会記事  2020.10  (一社)日本癌学会

  • 富田 和男, 高 裕子, 五十嵐 健人, 西谷 佳浩, 佐藤 友昭   ALOXはρ0細胞において脂質過酸化と過酸化水素取り込みを制御する  

    Journal of Oral Biosciences Supplement  2019.10  (一社)歯科基礎医学会

  • 富田 和男, 桑原 義和, 高 裕子, 五十嵐 健人, 長澤 大成, 山西 沙祐里, 大内 裕也, 並河 英紀, 田中 康一, 北中 純一, 北中 順惠, 漆原 佑介, 宮脇 正一, 栗政 明弘, 西谷 佳浩, 福本 学, 佐藤 友昭   CRR細胞における過酸化水素耐性機構の解析  

    応用薬理  2018.7  応用薬理研究会

  • 五十嵐 健人, 浅香 智美, 保田 隆子, 小林 純也, 藤原 智子[石川], 藤堂 剛, 尾田 正二, 三谷 啓志   DNA-PKcs R3715X変異体メダカ胚由来細胞を用いたメダカ種内変異型Nbs1(H170)のDSB修復機能の解析  

    生命科学系学会合同年次大会  2017.12  生命科学系学会合同年次大会運営事務局

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  • 富田 和男, 桑原 義和, 五十嵐 健人, 高 裕子, 長澤 大成, 山西 沙祐里, 漆原 佑介, 宮脇 正一, 栗政 明弘, 西谷 佳浩, 福本 学, 佐藤 友昭   miR-7-5pは細胞内Fe2+抑制を介して放射線抵抗性を制御する  

    応用薬理  2019.7  応用薬理研究会

  • 桑原 義和, 富田 和男, 五十嵐 健人, 佐藤 友昭, 栗政 明弘, 福本 学   X線照射で誘発されるがん細胞の細胞死(What is the mode of cell death after exposure to X-rays in cancer cells?)  

    日本癌学会総会記事  2019.9  日本癌学会

  • 富田 和男, 桑原 義和, 五十嵐 健人, 栗政 明弘, 福本 学, 佐藤 友昭   がんの治療抵抗性を制御する細胞膜動態とリポキシゲナーゼの関与(Involvement of lipoxygenase in resistance of cancer treatment through plasma membrane oxidation state)  

    日本癌学会総会記事  2019.9  日本癌学会

  • 富田 和男, 高 裕子, 五十嵐 健人, 西谷 佳浩, 佐藤 友昭   治療耐性がん細胞は親株に比べ内在性過酸化水素と過酸化脂質の上昇のタイミングの遅延により過酸化水素に耐性を示す  

    Journal of Oral Biosciences Supplement  2018.9  (一社)歯科基礎医学会

  • 大原 由紀子, 古川 紗圭, 五十嵐 健人, 野口 和行, 杉村 光隆, 富田 和男, 佐藤 友昭   PC-12細胞において加味逍遙散または加味帰脾湯はWNK-SPAK経路を介して歯周病菌由来LPS処理によるKCC2発現減少を回復させる(Kamishoyosan and Kamikihito enhance WNK-SPAK signaling and rescue the decreased KCC2 expression by the P gingivalis LPS treatment in PC-12 cells)  

    Journal of Oral Biosciences Supplement  2022.9  (一社)歯科基礎医学会

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  • 保田 隆子, 中澤 拓哉, 平川 慶, 松本 郁美, 永田 健斗, 森 俊太, 五十嵐 健人, 相良 洋, 三谷 啓志, 尾田 正二   メダカ初期胚ミュラーグリア細胞が放射線誘発性の網膜損傷を修復する可能性(Evidence for possible contribution of Mueller glia in retinal regeneration after gamma-ray irradiation in early embryonic medaka, Oryzias latipes)  

    日本放射線影響学会大会講演要旨集  2022.9  (一社)日本放射線影響学会

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  • 五十嵐 健人, 富田 和男, 佐藤 友昭   加味逍遙散は隔離飼育マウスの噛みつき行動を低減する  

    日本東洋医学雑誌  2021.7  (一社)日本東洋医学会

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  • 富田 和男, 五十嵐 健人, 佐藤 友昭   歯周病原菌由来LPSによる神経炎症への加味逍遙散,加味帰脾湯の効果  

    歯科薬物療法  2023.4  (一社)日本歯科薬物療法学会

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  • 富田 和男, 五十嵐 健人, 佐藤 友昭   歯周病原菌由来LPSはミトコンドリア機能低下を介しKCC2を減少させる  

    応用薬理  2023.8  応用薬理研究会

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  • 富田 和男, 五十嵐 健人, 北中 純一, 北中 順惠, 田中 康一, 佐藤 友昭   歯周病菌由来LPSによる神経機能障害に対する加味逍遙散と加味帰脾湯の効果  

    和漢医薬学会学術大会要旨集  2023.8  (一社)和漢医薬学会

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  • 富田 和男, 五十嵐 健人, 佐藤 友昭   歯周病菌由来LPS処理による神経系細胞のミトコンドリアへの影響(Effect on mitochondria by periodontal disease-derived LPS treatment in PC-12 cells)  

    Journal of Oral Biosciences Supplement  2021.10  (一社)歯科基礎医学会

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  • 富田 和男, 松本 卓也, 五十嵐 健人, 佐藤 友昭   神経系細胞であるPC-12細胞において歯周病菌由来LPSによるKCC2減少は加味逍遙散と加味帰脾湯により回復する  

    日本東洋医学雑誌  2022.5  (一社)日本東洋医学会

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Research Projects

  • 放射線照射の惹起する認知機能障害からの回復を目的としたKCC2発現制御機序の解明

    Grant number:23K16159  2023.4 - 2026.3

    科学研究費補助金  若手研究(B)

  • 放射線治療後の脳機能低下を惹起しうるKCC2分子病態の解析

    Grant number:19K19170  2019.4 - 2023.3

    科学研究費補助金  若手研究(B)