記述言語：英語   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

記述言語：英語   出版者・発行元：Biochemical and Biophysical Research Communications  

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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記述言語：英語   出版者・発行元：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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記述言語：日本語   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.lfs.2021.120051

PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Brain Research  

Kamishoyosan (KSS), a Japanese traditional herbal formula, is used to treat symptoms related to the autonomic nervous system in men and women; it is especially known for improving the symptoms of irritability (e.g., bad temper and persistent anger). Although clinical and ethological studies of KSS have been conducted, its efficacy in reducing irritability remains to be validated. In the present study, male and female ddY-strain mice were isolation-reared for 8 weeks (from the third postnatal week) to induce pathologically aggressive biting behavior (ABB), which was used as an indicator of irritability. The ABB of mice toward metal rods was measured using the Aggressive Response Meter. An intraperitoneal administration of KSS (100 mg/kg) effectively reduced ABB in male and female mice at 2 h after the administration; however, this effect was canceled by prior administration of WAY-100635 [a 5-hydroxytryptoamine (5-HT)-1A receptor antagonist; 0.5 mg/kg] and bicuculline (a type-A gamma-aminobutyric acid receptor antagonist; 1.0 mg/kg). Additionally, tamoxifen, ICI-182780, and G-15 (all estrogen receptor antagonists) inhibited the action of KSS in a dose-dependent manner. Furthermore, gene expression of tryptophan hydroxylase (Tph) 1 and Tph2 were increased and 5-HT immunofluorescence was slightly increased in the dorsal raphe nucleus (DRN) of isolation-reared mice administered with KSS. Collectively, these results indicate that KSS effectively reduces ABB in isolation-reared male and female mice through stimulation of 5-HT production in the DRN. Our findings also suggest that gene expression of estrogen receptor (Esr) 2 increased in the DRN might be associated with the reduction of ABB.

DOI： 10.1016/j.brainres.2021.147580

DOI： 10.1016/j.brainres.2021.147580

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Pharmacology Biochemistry and Behavior  

Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes [horizontal locomotion, appetitive behavior (food access), and food and water intake]. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.

DOI： 10.1016/j.pbb.2021.173257

DOI： 10.1016/j.pbb.2021.173257

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記述言語：日本語   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Molecular Sciences  

In cancer therapy, radioresistance or chemoresistance cells are major problems. We established clinically relevant radioresistant (CRR) cells that can survive over 30 days after 2 Gy/day X-ray exposures. These cells also show resistance to anticancer agents and hydrogen peroxide (H2 O2). We have previously demonstrated that all the CRR cells examined had up-regulated miR-7-5p and after miR-7-5p knockdown, they lost radioresistance. However, the mechanism of losing radioresistance remains to be elucidated. Therefore, we investigated the role of miR-7-5p in radioresistance by knock-down of miR-7-5p using CRR cells. As a result, knockdown of miR-7-5p increased reactive oxygen species (ROS), mitochondrial membrane potential, and intracellular Fe2+ amount. Furthermore, miR-7-5p knockdown results in the down-regulation of the iron storage gene expression such as ferritin, up-regulation of the ferroptosis marker ALOX12 gene expression, and increases of Liperfluo amount. H2 O2 treatment after ALOX12 overexpression led to the enhancement of intracellular H2 O2 amount and lipid peroxidation. By contrast, miR-7-5p knockdown seemed not to be involved in COX-2 and glycolysis signaling but affected the morphology of CRR cells. These results indicate that miR-7-5p control radioresistance via ROS generation that leads to ferroptosis.

DOI： 10.3390/ijms22158300

DOI： 10.3390/ijms22158300

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記述言語：英語   出版者・発行元：(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。

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Technology in cancer research & treatment  

DOI： 10.1177/1533033820980077

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/jrr/rraa103

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Molecular Biology Reports  

DOI： 10.1007/s11033-020-05493-5

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biochemical and Biophysical Research Communications  

DOI： 10.1016/j.bbrc.2019.08.117

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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 Mg²⁺-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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications Inc.  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Tumor Biology  

DOI： 10.1177/1010428318799250

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.envpol.2016.11.050

PubMed

記述言語：日本語   出版者・発行元：放射線生物研究会  

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)

開催年月日： 2019年10月

記述言語：英語   会議種別：ポスター発表  

開催年月日： 2019年9月

記述言語：日本語   会議種別：ポスター発表  

開催年月日： 2019年3月

記述言語：英語   会議種別：ポスター発表  

開催年月日： 2018年11月

記述言語：日本語   会議種別：ポスター発表  

会議種別：ポスター発表  

<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>

<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 (H₂O₂) and plasma membrane state in CRR cells. </p><p>　CRR cells showed resistance to H₂O₂, but catalase enzyme activity was down-regulated. Plasma membrane potential were low, no internal H₂O₂increase and no lipid peroxidation were seen even after 2 hours of H₂O₂treatment in CRR cells. Administration of oxidized lipid led to further cell death after H₂O₂ treatment in CRR cells. The lipoxygenase (ALOX) gene and protein expressions were down-regulated in CRR cells. We also established stress-sensitive ρ⁰ cells that lack mitochondrial DNA. Gene and protein expressions of ALOX were up-regulated in ρ⁰ 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>

会議種別：ポスター発表  

記述言語：日本語  

記述言語：英語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語