2024/03/22 更新

写真a

モトオカ ヤシロ
本岡 大社
MOTOOKA Yashiro
所属
大学院医学系研究科 附属医学教育研究支援センター 先端領域支援部門 助教
大学院担当
大学院医学系研究科
学部担当
医学部 医学科
職名
助教
外部リンク

学位 1

  1. 学士(医学) ( 2012年3月   熊本大学 ) 

研究キーワード 8

  1. 発がん

  2. 卵巣がん

  3. フェロトーシス

  4. BRCA1/2

  5. ナノ・マイクロマテリアルが生体に及ぼす影響

  6. 男性生殖能

  7. 女性生殖能

研究分野 2

  1. ライフサイエンス / 産婦人科学  / 婦人科腫瘍

  2. ライフサイエンス / 実験病理学  / 病理学

現在の研究課題とSDGs 4

  1. 細胞外微粒子への生体応答と発がん・動脈硬化症との関連の解析

  2. 環境中に存在するタルク、アスベストによる、卵巣がん形成機序の解明

  3. 新規ナノマテリアルのリスク評価

  4. アスベストおよびタルクが タンパク質を吸着することで惹起する、 卵巣におけるcancer initiating eventsの解明

受賞 3

  1. 学術奨励賞

    2022年5月   日本酸化ストレス学会  

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    受賞区分:国内学会・会議・シンポジウム等の賞  受賞国:日本国

  2. Young Innovator Award

    2022年4月   JST CREST「細胞外微粒子」  

  3. Discussant賞

    2021年2月   第141会東海産科婦人科学会  

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    受賞区分:国内学会・会議・シンポジウム等の賞 

 

論文 24

  1. Elaborate cooperation of poly(rC)-binding proteins 1/2 and glutathione in ferroptosis induced by plasma-activated Ringer's lactate 査読有り 国際誌

    Jiang L., Zheng H., Ishida M., Lyu Q., Akatsuka S., Motooka Y., Sato K., Sekido Y., Nakamura K., Tanaka H., Ishikawa K., Kajiyama H., Mizuno M., Hori M., Toyokuni S.

    Free Radical Biology and Medicine   214 巻   頁: 28 - 41   2024年3月

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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:Free Radical Biology and Medicine  

    Reactive species are involved in various aspects of neoplastic diseases, including carcinogenesis, cancer-specific metabolism and therapeutics. Non-thermal plasma (NTP) can directly provide reactive species, by integrating atmospheric and interjacent molecules as substrates, to represent a handy strategy to load oxidative stress in situ. NTP causes apoptosis and/or ferroptosis specifically in cancer cells of various types. Plasma-activated Ringer's lactate (PAL) is another modality at the preclinical stage as cancer therapeutics, based on more stable reactive species. PAL specifically kills malignant mesothelioma (MM) cells, employing lysosomal ·NO as a switch from autophagy to ferroptosis. However, the entire molecular mechanisms have not been elucidated yet. Here we studied cytosolic iron regulations in MM and other cancer cells in response to PAL exposure. We discovered that cells with higher catalytic Fe(II) are more susceptible to PAL-induced ferroptosis. PAL caused a cytosolic catalytic Fe(II)-associated pathology through iron chaperones, poly (rC)-binding proteins (PCBP)1/2, inducing a disturbance in glutathione-regulated iron homeostasis. PCBP1/NCOA4-mediated ferritinophagy started at a later phase, further increasing cytosolic catalytic Fe(II), ending in ferroptosis. In contrast, PCBP2 after PAL exposure contributed to iron loading to mitochondria, leading to mitochondrial dysfunction. Therapeutic effect of PAL was successfully applied to an orthotopic MM xenograft model in mice. In conclusion, PAL can selectively sensitize MM cells to ferroptosis by remodeling cytoplasmic iron homeostasis, where glutathione and PCBPs play distinct roles, resulting in lethal ferritinophagy and mitochondrial dysfunction. Our findings indicate the clinical application of PAL as a ferroptosis-inducer and the potential of PCBPs as novel targets in cancer therapeutics.

    DOI: 10.1016/j.freeradbiomed.2024.02.001

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  2. <i>Brca2<SUP>(p.T1942fs/+)</SUP></i> dissipates ovarian reserve in rats through oxidative stress in follicular granulosa cells 査読有り 国際誌

    Tanaka, H; Motooka, Y; Maeda, Y; Sonehara, R; Nakamura, T; Kajiyama, H; Mashimo, T; Toyokuni, S

    FREE RADICAL RESEARCH     頁: 1 - 14   2024年2月

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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:Free Radical Research  

    Pathogenic variants of BRCA1/2 constitute hereditary breast and ovarian cancer (HBOC) syndrome, and BRCA1/2 mutant is a risk for various cancers. Whereas the clinical guideline for HBOC patients has been organized for the therapy and prevention of cancer, there is no recommendation on the female reproductive discipline. Indeed, the role of BRCA1/2 pathogenic variants in ovarian reserve has not been established due to the deficiency of appropriate animal models. Here, we used a rat model of Brca2(p.T1942fs/+) mutant of Sprague-Dawley strain with CRISPR-Cas9 editing to evaluate ovarian reserve in females. Fertility and ovarian follicles were evaluated and anti-Müllerian hormone (AMH) was measured at 8–32 weeks of age with a comparison between the wild-type and the mutant rats (MUT). MUT revealed a significantly smaller number of deliveries with fewer total pups. Furthermore, MUT showed a significant decrease in primordial follicles at 20 weeks and a low AMH level at 28 weeks. RNA-sequencing of the ovary at 10 weeks detected acceleration of the DNA damage repair pathway, which was accompanied by oxidative stress-induced DNA double-strand breaks, a decrease in PTEN, and an increase in mTOR in follicular granulosa cells. In conclusion, Brca2(p.T1942fs/+) dissipates primordial follicles via early activation of granulosa cells through oxidative stress, leading to earlier termination of fertility.

    DOI: 10.1080/10715762.2024.2320405

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  3. Epstein-Barr virus lytic gene BNRF1 promotes B-cell lymphomagenesis via IFI27 upregulation 査読有り 国際誌

    Sagou, K; Sato, Y; Okuno, Y; Watanabe, T; Inagaki, T; Motooka, Y; Toyokuni, S; Murata, T; Kiyoi, H; Kimura, H

    PLOS PATHOGENS   20 巻 ( 2 ) 頁: e1011954   2024年2月

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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:PLoS Pathogens  

    Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus that is causally associated with several malignancies. In addition to latent factors, lytic replication contributes to cancer development. In this study, we examined whether the lytic gene BNRF1, which is conserved among gamma-herpesviruses, has an important role in lymphomagenesis. We found that lymphoblastoid cell lines (LCLs) established by BNRF1-knockout EBV exhibited remarkably lower pathogenicity in a mice xenograft model than LCLs produced by wild-type EBV (LCLs-WT). RNA-seq analyses revealed that BNRF1 elicited the expression of interferon-inducible protein 27 (IFI27), which promotes cell proliferation. IFI27 knockdown in LCLs-WT resulted in excessive production of reactive oxygen species, leading to cell death and significantly decreased their pathogenicity in vivo. We also confirmed that IFI27 was upregulated during primary infection in B-cells. Our findings revealed that BNRF1 promoted robust proliferation of the B-cells that were transformed by EBV latent infection via IFI27 upregulation both in vitro and in vivo.

    DOI: 10.1371/journal.ppat.1011954

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  4. Role of Iron, Oxygen and Ferroptosis in Tumor Evolutionary Biology 査読有り 国際誌

    Toyokuni, S; Kong, Y; Luo, Y; Zheng, H; Motooka, Y; Akatsuka, S

    FREE RADICAL BIOLOGY AND MEDICINE   208 巻   頁: S112 - S112   2023年11月

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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.freeradbiomed.2023.10.254

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  5. Three-Dimensional Regulation of Ferroptosis at the Intersection of Iron, Sulfur, and Oxygen Executing Scrap and Build Toward Evolution 招待有り 査読有り 国際誌

    Toyokuni, S; Kong, YY; Zheng, H; Maeda, Y; Katabuchi, M; Motooka, Y

    ANTIOXIDANTS & REDOX SIGNALING   39 巻 ( 10-12 ) 頁: 807 - 815   2023年10月

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    担当区分:最終著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Antioxidants and Redox Signaling  

    Significance: Iron is an essential element for every life on earth as a primary media for electron flow. Sulfur compounds as sulfhydryls counteract catalytic activity of iron whereas sulfur overdose is also toxic. In aerobic organisms, oxygen is the major media for electron transfer with higher intracellular mobility, which cooperates with the iron system. Based on the importance of iron, there is no active pathway to excrete iron outside the body in higher species. Whereas bacterial infection causes a scramble for iron in situ, cancer can be the outcome of the side effects of long use of iron and oxygen. Recent Advances: Ferroptosis is a recently coined cell death, defined as catalytic Fe(II)-dependent regulated necrosis accompanied by lipid peroxidation. Researchers recently recognized that ferroptosis is involved in a variety of physiological and pathological contexts, including embryonic erythropoiesis, aging, neurodegeneration and cancer cell death. Alternatively, carcinogenesis is a process to obtain iron addiction with ferroptosisresistance, based on rodent animal studies. Critical Issues: Here we propose that ferroptosis is three-dimensionally regulated by iron, sulfur and oxygen, which correspond to oxidants, antioxidants and membrane fluidity with susceptibility to lipid peroxidation, respectively. Future Directions: Whereas life attempts to prevent ferroptosis, ferroptotic cells eventually emit iron-loaded ferritin as extracellular vesicles to maintain monopoly of iron. Antioxid. Redox Signal. 39, 807–815.

    DOI: 10.1089/ars.2022.0142

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  6. Iron links endogenous and exogenous nanoparticles 査読有り 国際誌

    Toyokuni, S; Kong, YY; Katabuchi, M; Maeda, Y; Motooka, Y; Ito, F; Yanatori, I

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   745 巻   頁: 109718   2023年9月

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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:Archives of Biochemistry and Biophysics  

    Current progress in biology and medical science is based on the observation at the level of nanometers via electron microscopy and computation. Of note, the size of most cells in higher species exists in a limited range from 5 to 50 μm. Recently, it was demonstrated that endogenous extracellular nanoparticles play a role in communication among various cellular types in a variety of contexts. Among them, exosomes in serum have been established as biomarkers for human diseases by analyzing the cargo molecules. No life on the earth can survive without iron. However, excess iron can be a risk for carcinogenesis in rodents and humans. Nano-sized molecules may cause unexpected bioeffects, including carcinogenesis, which is a process to establish cellular iron addiction with ferroptosis-resistance. Asbestos and carbon nanotubes are the typical examples, leading to carcinogenesis by the alteration of iron metabolism. Recently, we found that CD63, one of the representative markers of exosomes, is under the regulation of iron-responsive element/iron-regulatory protein system. This is a safe strategy to share excess iron in the form of holo-ferritin between iron-sufficient and -deficient cells. On the other hand, damaged cells may secrete holo-ferritin-loaded exosomes as in the case of macrophages in ferroptosis after asbestos exposure. These holo-ferritin-loaded exosomes can cause mutagenic DNA damage in the recipient mesothelial cells. Thus, there is an iron link between exogenous and endogenous nanoparticles, which requires further investigation for better understanding and the future applications.

    DOI: 10.1016/j.abb.2023.109718

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  7. Ferroptosis As Ultimate Target of Cancer Therapy 招待有り 査読有り 国際誌

    Motooka, Y; Toyokuni, S

    ANTIOXIDANTS & REDOX SIGNALING   39 巻 ( 1-3 ) 頁: 206 - 223   2023年7月

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    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:Antioxidants and Redox Signaling  

    Significance: The significance of ferroptosis in cancer therapeutics has now been unveiled. Specific ferroptosis inducers are expected as a promising strategy for cancer treatment, especially in cancers with epithelial mesenchymal transition and possibly in cancers with activated Hippo signaling pathways, both of which cause resistance to traditional chemotherapy but tend to show ferroptosis susceptibility. Recent Advances: Ferroptosis is a new form of regulated non-apoptotic cell death, which is characterized by iron-dependent lipid peroxidation, leading eventually to plasma membrane rupture. Its core mechanisms have been elucidated, consisting of a driving force as catalytic Fe(II)-dependent Fenton reaction and an incorporation of polyunsaturated fatty acids to membrane phospholipids via peroxisome-dependent and -independent pathways, and suppressing factors as prevention of lipid peroxidation with glutathione peroxidase 4 and direct membrane repair via coenzyme Q10 and ESCRT-III pathways. Critical Issues: Developments of ferroptosis inducers are in progress by nanotechnology-based drugs or by innovative engineering devices. Especially, low-temperature (non-thermal) plasma is a novel technology at the preclinical stage. The exposure can induce ferroptosis selectively in cancer cells rich in catalytic Fe(II). Future Directions: We also summarize and discuss the recently uncovered responsible molecular mechanisms in association with iron metabolism, ferroptosis and cancer therapeutics. Targeting ferroptosis in addition to the current therapeutic modalities would be important to cure advanced-stage cancer. Antioxid. Redox Signal. 39, 206-223.

    DOI: 10.1089/ars.2022.0048

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  8. BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile-induced mesothelioma via ferroptosis resistance 査読有り

    Luo, YG; Akatsuka, S; Motooka, Y; Kong, YY; Zheng, H; Mashimo, T; Imaoka, T; Toyokuni, S

    CANCER SCIENCE   114 巻 ( 4 ) 頁: 1423 - 1436   2023年4月

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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:Cancer Science  

    Malignant mesothelioma (MM) is still a social burden associated with asbestos exposure. Local iron accumulation thereby represents the major pathogenesis, followed by oxidative DNA strand breaks and genomic alterations in the mesothelium. BRCA1 is a critical component of homologous recombination repair directed to DNA double-stranded breaks, whereas BRCA1 germline mutation is an established risk for breast/ovarian cancer, its role in MM development remains to be elucidated. Murine Brca1 mutant models so far have not reproduced human phenotypes. However, a rat Brca1 mutant model (Mut; L63X/+) recently reproduced them at least partially. Here we describe the differential induction of MM in Brca1 mutant rats by intraperitoneal injection of chrysotile or crocidolite. Only Mut males injected with chrysotile revealed a promotional effect on mesothelial carcinogenesis in comparison with wild-type and/or females, with all the MMs Brca1 haploinsufficient. Array-based comparative genomic hybridization of MMs disclosed a greater extent of chromosomal deletions in Brca1 mutants, including Cdkn2a/2b accompanied by Tfr2 amplification, in comparison with wild-type tumors. Mutant MMs indicated iron metabolism dysregulation, such as an increase in catalytic Fe(II) and Ki67-index as well as a decrease in Fe(III) and ferritin expression. Simultaneously, mutant MMs revealed ferroptosis resistance by upregulation of Slc7A11 and Gpx4. At an early carcinogenic stage of 4 weeks, induced Brca1 expression in mesothelial cells was significantly suppressed in chrysotile/Mut in comparison with crocidolite/Mut, whereas significant preference to iron with a decrease in Fe(III) has been already established. In conclusion, chrysotile exposure can be a higher risk for MM in BRCA1 mutant males, considering the rat results.

    DOI: 10.1111/cas.15705

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  9. Field-effect transistor antigen/antibody-TMDs sensors for the detection of COVID-19 samples 査読有り 国際誌

    Canton-Vitoria, R; Sato, K; Motooka, Y; Toyokuni, S; Liu, Z; Kitaura, R

    NANOSCALE   15 巻 ( 9 ) 頁: 4570 - 4580   2023年3月

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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:Nanoscale  

    We fabricated sensors by modifying the surface of MoS2 and WS2 with COVID-19 antibodies and investigated their characteristics, including stability, reusability, sensitivity, and selectivity. Thiols and disulfanes in antibodies strongly interact with vacant Mo or W sites of MoS2 or WS2, yielding durable devices that are stable for several days in the air or water. More importantly, detachment of the antibodies is suppressed even during the aggressive cleaning process of the devices at pH 3, which allows reusing the same device in several experiments without appreciable loss of sensitivity. Therefore, the nanodevice may be employed in samples of different patients. Further, we found a limit of detection (LOD) of 1 fg ml−1 at room temperature, time responses of 1 second, and selectivity against interferences such as KLH protein or Albumin.

    DOI: 10.1039/d2nr06630k

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  10. 芳香族アミン類MOCAのDNA酸化損傷に関する研究 -ラット肝臓における8 -ヒドロキシ-2’-デオキシグアノシンの検討- 査読有り

    小林 沙穂, 本岡 大社, 柏木 裕呂樹, 豊國 伸哉

    労働安全衛生研究   16 巻 ( 1 ) 頁: 45 - 49   2023年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:独立行政法人 労働者健康安全機構 労働安全衛生総合研究所  

    <p>芳香族アミン類の一種である3,3’-ジクロロ-4,4’-ジアミノジフェニルメタン(MOCA)は,ウレタン樹脂の硬化剤等に産業利用される一方,国際がん研究機関 によりグループ1(ヒトに発がん性あり)に分類され,労働者の健康影響が懸念されている.MOCAの発がん過程には,肝臓をはじめとした各臓器で代謝される際に生じる活性酸素種(ROS)やDNA付加体によるDNA損傷が関係すると考えられているが,その中でもROSによって引き起こされるDNA酸化的損傷である8-ヒドロキシ-2’ -デオキシグアノシン(8-オキソグアニン:8-OHdG)は,高頻度に発生し,DNA複製時のG→Tの点突然変異を惹起する.しかし,実験動物においてMOCAばく露が実際に変異原性の高い8-OHdGを引き 起こすか調べた研究は我々の知る限り存在しない.</p> <p>そこで本研究では,ラットを用い,肝臓におけるMOCAばく露が十分に期待できる経口投与法により,0(対照), 0.4, 2, 10, 50mg/kg/日の用量で 週3回2週間の反復ばく露を実施し,その標的臓器である肝臓について,病理解析及び8-OHdGの生成レベルを検討した.その結果,病理所見では,50mg/kg/日投与群において空胞変性が認められた一方, 8-OHdGは,0.4mg/kg/日投与群を除いて用量依存的な若干の増加傾向がみられたが,いずれも有意な差は認められなかった.以上から,少なくとも8-OHdGはMOCAにより引き起こされる発がんメカニズムの主原因ではないと推察される.</p>

    DOI: 10.2486/josh.josh-2022-0022-ta

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  11. Environmental impact on carcinogenesis under BRCA1 haploinsufficiency 査読有り 国際誌

    Toyokuni, S; Kong, YY; Motooka, Y; Akatsuka, S

    GENES AND ENVIRONMENT   45 巻 ( 1 ) 頁: 2   2023年1月

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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:Genes and Environment  

    Cancer is the primary cause of human mortality in Japan since 1981. Although numerous novel therapies have been developed and applied in clinics, the number of deaths from cancer is still increasing worldwide. It is time to consider the strategy of cancer prevention more seriously. Here we propose a hypothesis that cancer can be side effects of long time-use of iron and oxygen and that carcinogenesis is an evolution-like cellular events to obtain “iron addiction with ferroptosis-resistance” where genes and environment interact each other. Among the recognized genetic risk factors for carcinogenesis, we here focus on BRCA1 tumor suppressor gene and how environmental factors, including daily life exposure and diets, may impact toward carcinogenesis under BRCA1 haploinsufficiency. Although mice models of BRCA1 mutants have not been successful for decades in generating phenotype mimicking the human counterparts, a rat model of BRCA1 mutant was recently established that reasonably mimics the human phenotype. Two distinct categories of oxidative stress, one by radiation and one by iron-catalyzed Fenton reaction, promoted carcinogenesis in Brca1 rat mutants. Furthermore, mitochondrial damage followed by alteration of iron metabolism finally resulted in ferroptosis-resistance of target cells in carcinogenesis. These suggest a possibility that cancer prevention by active pharmacological intervention may be possible for BRCA1 mutants to increase the quality of their life rather than preventive mastectomy and/or oophorectomy.

    DOI: 10.1186/s41021-023-00258-5

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  12. <i>BRCA1 </i>haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance 査読有り

    Kong, YY; Akatsuka, S; Motooka, Y; Zheng, H; Cheng, Z; Shiraki, Y; Mashimo, T; Imaoka, T; Toyokuni, S

    REDOX BIOLOGY   54 巻   頁: 102356   2022年8月

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    記述言語:英語   出版者・発行元:Redox Biology  

    Germline-mutation in BRCA1 tumor suppressor gene is an established risk for carcinogenesis not only in females but also in males. Deficiency in the repair of DNA double-strand breaks is hypothesized as a responsible mechanism for carcinogenesis. However, supporting data is insufficient both in the mutation spectra of cancers in the patients with BRCA1 germline-mutation and in murine knockout/knock-in models of Brca1 haploinsufficiency. Furthermore, information on the driving force toward carcinogenesis in BRCA1 mutation carriers is lacking. Here we applied Fenton reaction-based renal carcinogenesis to a rat heterozygously knockout model of BRCA1 haploinsufficiency (mutant [MUT] model; L63X/+). Rat MUT model revealed significant promotion of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Array-based comparative genome hybridization of the RCCs identified significant increase in chromosomal amplification, syntenic to those in breast cancers of BRCA1 mutation carriers, including c-Myc, in comparison to those in the wild-type. Subacute-phase analysis of the kidney after repeated Fe-NTA treatment in the MUT model revealed dysregulated iron metabolism with mitochondrial malfunction assessed by expression microarray and electron microscopy, leading to renal tubular proliferation with iron overload. In conclusion, we for the first time demonstrate that biallelic wild-type BRCA1 provides more robust protection for mitochondrial metabolism under iron-catalyzed oxidative stress, preventing the emergence of neoplastic cells with chromosomal amplification. Our results suggest that oxidative stress via excess iron is a major driving force for carcinogenesis in BRCA1 haploinsufficiency, which can be a target for cancer prevention and therapeutics.

    DOI: 10.1016/j.redox.2022.102356

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  13. Iron as spirit of life to share under monopoly 査読有り 国際誌

    Toyokuni, S; Kong, YY; Zheng, H; Maeda, Y; Motooka, Y; Akatsuka, S

    Journal of Clinical Biochemistry and Nutrition   71 巻 ( 2 ) 頁: 78 - 88   2022年

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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:一般社団法人 日本酸化ストレス学会  

    Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multisystem organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.

    DOI: 10.3164/jcbn.22-43

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  14. Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles 査読有り 国際誌

    Toyokuni, S; Kong, YY; Zheng, H; Mi, DY; Katabuchi, M; Motooka, Y; Ito, F

    JOURNAL OF CANCER PREVENTION   26 巻 ( 4 ) 頁: 244 - 249   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.15430/JCP.2021.26.4.244

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  15. Role of ferroptosis in nanofiber-induced carcinogenesis 査読有り 国際誌

    Toyokuni Shinya, Ito Fumiya, Motooka Yashiro

    Metallomics Research   1 巻 ( 1 ) 頁: rev-14 - rev-21   2021年10月

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    担当区分:最終著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japan Society for Biomedical Research on Trace Elements  

    <p>Biopersistent nanofibers with specified physical dimension are unexpected human carcinogens whether they are natural or synthetic. Asbestos, a natural fibrous mineral, is classified as a definite human carcinogen (IARC Group 1) to cause malignant mesothelioma (MM) and lung cancer. Multi-walled carbon nanotube of 50 nm-diameter was defined in 2014 as a possible carcinogen (IARC Group 2B) toward MM, fortunately with no authorized patients thus far. Carcinogenic mechanism of asbestos has been a mystery for a long time. It is now recognized that asbestos goes through lung parenchyma by collecting hemoglobin-derived iron to reach pleural cavity, which takes several decades. Iron-loaded asbestos can induce oxidative damage directly to mesothelial cells, carcinogenesis-target cells lining somatic cavities. Recently, it was clarified that surrounding stromal environment are as important for mesothelial carcinogenesis. The novel concept here is ceaseless ferroptosis of macrophages, which forms a Fe(II)-dependent stromal mutagenic milieu indirectly for mesothelial cells and indeed is a revised understanding of frustrated phagocytosis. Deposition of foreign materials eventually causes iron accumulation <i>in situ</i> due to the innate characteristic of preserving iron inside cells. Nanofiber-induced carcinogenesis may be involved in other human carcinogenesis, including ovarian cancer. Alternatively, iron excess can be an optimal target of cancer prevention and cancer treatment. </p>

    DOI: 10.11299/metallomicsresearch.mr202102

    CiNii Research

  16. Plasma-activated Ringer's lactate solution inhibits the cellular respiratory system in HeLa cells 査読有り 国際誌

    Tanaka, H; Maeda, S; Nakamura, K; Hashizume, H; Ishikawa, K; Ito, M; Ohno, K; Mizuno, M; Motooka, Y; Okazaki, Y; Toyokuni, S; Kajiyama, H; Kikkawa, F; Hori, M

    PLASMA PROCESSES AND POLYMERS   18 巻 ( 10 )   2021年10月

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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:Plasma Processes and Polymers  

    Nonequilibrium atmospheric pressure plasma has enabled a variety of new applications in medicine, agriculture, and other industries. It is particularly noteworthy that plasma itself and/or plasma-activated culture medium have been shown to preferentially kill various cancer cells. We have previously developed a plasma-activated Ringer's lactate solution (PAL) for use as a new cancer treatment. In this study, behaviors of extracellular and intracellular reactive oxygen and nitrogen species in the cellular respiratory system of PAL-treated HeLa cells were investigated using an extracellular flux analyzer and a probe to measure mitochondrial membrane potential. In PAL-treated HeLa cells, extracellular hydrogen peroxide in PAL was found to be responsible for the induction of intracellular hydrogen peroxide and apoptosis, while other components in PAL are responsible for the induction of non-H2O2 intracellular ROS and non-apoptotic cell death, which should be clarified by further experiments. We believe that these are long-lived species derived from plasma-activated lactates. Furthermore, we found that the plasma-activated lactates inhibited glycolysis and the tricarboxylic acid (TCA) cycle, but not the electron transport chain in HeLa cells. These results suggest that PAL induces multiple modes of cell death, including apoptosis through hydrogen peroxide, and non-apoptotic cell death associated with the impairment of mitochondrial functions (glycolysis and TCA cycle). These findings shed light on the novel mechanism underlying plasma-activated lactate-induced cell death.

    DOI: 10.1002/ppap.202100056

    Web of Science

    Scopus

  17. Role of ferroptosis in nanofiber-induced carcinogenesis 招待有り 査読有り

    Shinya Toyokuni, Fumiya Ito, Yashiro Motooka

    Metallomics Research   1 巻   頁: 14 - 21   2021年

     詳細を見る

    担当区分:最終著者   記述言語:英語  

  18. Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice 査読有り 国際誌

    Hayashi, S; Nakamura, T; Motooka, Y; Ito, F; Jiang, L; Akatsuka, S; Iwase, A; Kajiyama, H; Kikkawa, F; Toyokuni, S

    REDOX BIOLOGY   37 巻   頁: 101726   2020年10月

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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:Redox Biology  

    Ovarian endometriosis (OE) provides women of reproductive age with not only severe menstrual pain but also infertility and an increased risk for ovarian carcinogenesis. Whereas peritoneal endometriosis models have been developed with syngeneic implantation of minced uterine tissue and oncogenic K-ras allele with conditional Pten deletion within ovarian surface epithelium generated preneoplastic endometrial glandular morphology, followed by endometrioid adenocarcinoma, there has been no mouse model of OE similar to human counterparts, applicable to preclinical studies. Here we for the first time established a murine OE model that reveals infertility, and evaluated the involvement of iron catalyzed oxidative stress in the pathogenesis. Minced uterine tissue from female mice was implanted on ovarian surface of syngeneic mice after bursectomy to induce OE. Ectopic growth of endometrium was observed in association with ovary 4 weeks after implantation in 85.7% (12/14) of the operated mice with our protocol. Endometriotic lesions involved intestine, pancreas and peritoneal wall. Fibrosis around the ovary was prominent and increased time-dependently in the OE group. Iron accumulation was significantly increased in the OE group, leading to oxidative stress in each stage of the follicles as evaluated by 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2′-deoxyguanosine. Expression of follicle stimulating hormone receptor in the follicles revealed a significant decrease during pre-antral, antral and pre-ovulatory phases in the OE group. Finally, the number of pups was significantly reduced in the OE group in comparison to the controls. This model affords an opportunity to evaluate agents or procedures to counteract ovarian endometriosis in the preclinical settings.

    DOI: 10.1016/j.redox.2020.101726

    Web of Science

    Scopus

    PubMed

  19. Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma 査読有り 国際誌

    Ohara, Y; Enomoto, A; Tsuyuki, Y; Sato, K; Iida, T; Kobayashi, H; Mizutani, Y; Miyai, Y; Hara, A; Mii, S; Suzuki, J; Yamashita, K; Ito, F; Motooka, Y; Misawa, N; Fukui, T; Kawaguchi, K; Yokoi, K; Toyokuni, S

    ONCOLOGY REPORTS   44 巻 ( 3 ) 頁: 838 - 848   2020年9月

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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:Oncology Reports  

    Malignant mesothelioma is an aggressive neoplasm for which effective treatments are lacking. We often encounter mesothelioma cases with a profound desmoplastic reaction, suggesting the involvement of cancer.associated fibroblasts (CAFs) in mesothelioma progression. While the roles of CAFs have been extensively studied in other tumors and have led to the view that the cancer stroma contains heterogeneous populations of CAFs, their roles in mesothelioma remain unknown. We previously showed that connective tissue growth factor (CTGF), a secreted protein, is produced by both mesothelioma cells and fibroblasts and promotes the invasion of mesothelioma cells in vitro. In this study, we examined the clinical relevance of CAFs in mesothelioma. Using surgical specimens of epithelioid malignant pleural mesothelioma, we evaluated the clinicopathological significance of the expression of α-smooth muscle actin (αSMA), the most widely used marker of CAFs, the expression of CTGF, and the extent of fibrosis by immunohistochemistry and Elastica.Masson staining. We also analyzed the expression of mesenchymal stromal cell. and fibroblast.expressing Linx paralogue (Meflin; ISLR), a recently reported CAF marker that labels cancer.restraining CAFs and differ from αSMA-positive CAFs, by in situ hybridization. The extent of fibrosis and CTGF expression in mesothelioma cells did not correlate with patient prognosis. However, the expression of αSMA and CTGF, but not Meflin, in CAFs correlated with poor prognosis. The data suggest that CTGF+ CAFs are involved in mesothelioma progression and represent a potential molecular target for mesothelioma therapy.

    DOI: 10.3892/or.2020.7669

    Web of Science

    Scopus

    PubMed

  20. Ferroptosis at the crossroads of infection, aging and cancer 査読有り 国際誌

    Toyokuni, S; Yanatori, I; Kong, YY; Zheng, H; Motooka, Y; Jiang, L

    CANCER SCIENCE   111 巻 ( 8 ) 頁: 2665 - 2671   2020年8月

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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:Cancer Science  

    Despite significant developments and persistent efforts by scientists, cancer is one of the primary causes of human death worldwide. No form of life on Earth can survive without iron, although some species can live without oxygen. Iron presents a double-edged sword. Excess iron is a risk for carcinogenesis, while its deficiency causes anemia, leading to oxygen shortage. Every cell is eventually destined to death, either through apoptosis or necrosis. Regulated necrosis is recognized in distinct forms. Ferroptosis is defined as catalytic Fe(II)-dependent regulated necrosis accompanied by lipid peroxidation. The main observation was necrosis of fibrosarcoma cells through inhibition of cystine/glutamate antiporter with erastin, which reduced intracellular cysteine and, thus, glutathione levels. Our current understanding of ferroptosis is relative abundance of iron (catalytic Fe[II]) in comparison with sulfur (sulfhydryls). Thus, either excess iron or sulfur deficiency causes ferroptosis. Cell proliferation inevitably requires iron for DNA synthesis and energy production. Carcinogenesis is a process toward iron addiction with ferroptosis resistance. Conversely, ferroptosis is associated with aging and neurodegeneration. Ferroptosis of immune cells during infection is advantageous for infectious agents, whereas ferroptosis resistance incubates carcinogenic soil as excess iron. Cancer cells are rich in catalytic Fe(II). Directing established cancer cells to ferroptosis is a novel strategy for discovering cancer therapies. Appropriate iron regulation could be a tactic to reduce and delay carcinogenesis.

    DOI: 10.1111/cas.14496

    Web of Science

    Scopus

    PubMed

  21. Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma. 査読有り

    Yuuki Ohara, Atsushi Enomoto, Yuta Tsuyuki, Kotaro Sato, Tadashi Iida, Hiroki Kobayashi, Yasuyuki Mizutani, Yuki Miyai, Akitoshi Hara, Shinji Mii, Jun Suzuki, Kyoko Yamashita, Fumiya Ito, Yashiro Motooka, Nobuaki Misawa, Takayuki Fukui, Koji Kawaguchi, Kohei Yokoi, Shinya Toyokuni

    Oncology Report   44 巻 ( 3 ) 頁: 838 - 848   2020年

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    記述言語:英語  

  22. Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice. 招待有り 査読有り

    Shotaro Hayashi, Tomoko Nakamura, Yashiro Motooka, Fumiya Ito, Li Jiang, Shinya Akatsuka, Akira Iwase, Hiroaki Kajiyama, Fumitaka Kikkawa, Shinya Toyokuni.

    Redox Biology   37 巻   頁: 101726   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  23. Ferroptosis at the crossroads of infection, aging and cancer 査読有り

    Shinya Toyokuni, Izumi Yanatori, Yingyi Kong, Hao Zheng, Yashiro Motooka, Li Jiang

    Cancer science   111 巻 ( 8 ) 頁: 2665 - 2671   2020年

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  24. Non-thermal plasma specifically kills oral squamous cell carcinoma cells in a catalytic Fe(II)-dependent manner. 査読有り

    Kotaro Sato, Lei Shi, Fumiya Ito, Yuuki Ohara, Yashiro Motooka, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Tasuku Hirayama, Hideharu Hibi, Shinya Toyokuni

    Journal of Clinical Biochemistry and Nutrition   65 巻 ( 1 ) 頁: 8 - 15   2019年

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    記述言語:英語  

▼全件表示

書籍等出版物 2

  1. マウス・ラット モデル作成・解析プロフェッショナル

    豊國伸哉, 伊藤文哉, 本岡 大社, 蒋麗( 担当: 分担執筆 ,  範囲: 第2章7節 使いたくなる病理解析新技術)

    羊土社  2021年4月 

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    総ページ数:317   担当ページ:147-160   記述言語:日本語

  2. 図解腫瘍薬学

    本原剛志、本岡大社、三宅俊介、片渕秀隆、城野博史( 担当: 分担執筆 ,  範囲: 13章臓器別がん薬物療法 7)生殖器がん①(卵巣がん、子宮頸がん、子宮体がん))

    南山堂  2020年7月 

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    記述言語:日本語 著書種別:教科書・概説・概論

講演・口頭発表等 16

  1. <i>BRCA1</i> haploinsufficiency promotes chromosomal amplification under renal carcinogenesis through ferroptosis-resistance 招待有り

    Kong, YY; Akatsuka, S; Motooka, Y; Zheng, H; Shiraki, Y; Mashimo, T; Imaoka, T; Toyokuni, S

    CANCER SCIENCE  2023年2月 

     詳細を見る

    開催年月日: 2023年2月

    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

  2. Carcinogenic genome toxicity of environmental factors, asbestos and talc in ovary

    Motooka, Y; Onimaru, K; Suzuki, HI; Katabuchi, M; Kondoh, E; Tashiro, H; Katabuchi, H; Toyokuni, S

    CANCER SCIENCE  2023年2月 

     詳細を見る

    開催年月日: 2023年2月

    記述言語:英語   会議種別:ポスター発表  

  3. Validation of reduced ovarian reserve in BRCA1 haploinsufficient rats

    Sonehara, R; Motooka, Y; Kajiyama, H; Mashimo, T; Imaoka, T; Toyokuni, S

    CANCER SCIENCE  2023年2月 

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    開催年月日: 2023年2月

    記述言語:英語   会議種別:ポスター発表  

  4. Cooperation of Poly(rC)-binding Proteins 1/2 and Glutathione in Ferroptosis Induced by Plasmaactivated Ringer's Lactate

    Zheng, H; Jiang, L; Lyu, QY; Akatsuka, S; Motooka, Y; Sekido, Y; Nakamura, K; Tanaka, H; Ishikawa, K; Kajiyama, H; Mizuno, M; Hori, M; Toyokuni, S

    CANCER SCIENCE  2023年2月 

     詳細を見る

    開催年月日: 2023年2月

    記述言語:英語  

  5. Ferroptosis-resistance in rodent cancer models

    Toyokuni, S; Kong, Y; Akatsuka, S; Motooka, Y; Zheng, H; Mashimo, T; Imaoka, T

    CANCER SCIENCE  2023年2月 

     詳細を見る

    開催年月日: 2023年2月

    記述言語:英語  

  6. Ferroptosis resistance is induced by BRCA1 deficiency in asbestos-induced mesothelioma

    Luo, YG; Motooka, Y; Akatsuka, S; Mashimo, T; Imaoka, T; Toyokuni, S

    CANCER SCIENCE  2023年2月 

     詳細を見る

    開催年月日: 2023年2月

    記述言語:英語   会議種別:ポスター発表  

  7. Cooperation of Poly(rC)-binding Proteins 1/2 and Glutathione in Ferroptosis Induced by Plasma-activated Ringer's Lactate

    Zheng, H; Jiang, L; Lyu, QY; Akatsuka, S; Motooka, Y; Sekido, Y; Nakamura, K; Tanaka, H; Ishikawa, K; Kajiyama, H; Mizuno, M; Hori, M; Toyokuni, S

    CANCER SCIENCE  2023年2月 

     詳細を見る

    開催年月日: 2023年2月

    記述言語:英語   会議種別:ポスター発表  

  8. BRCA1 deficiency regulates the metabolism of iron and oxidative stress-induced carcinogenesis in the kidney

    Kong, YY; Motooka, Y; Akatsuka, S; Mashimo, T; Imaoka, T; Toyokuni, S

    CANCER SCIENCE  2022年2月 

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    開催年月日: 2022年2月

    記述言語:英語   会議種別:ポスター発表  

  9. Iron overload led by genital talc exposure contributes to ovarian carcinogenesis

    Motooka, Y; Ito, F; Tashiro, H; Katabuchi, H; Toyokuni, S

    CANCER SCIENCE  2022年2月 

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    開催年月日: 2022年2月

    記述言語:英語   会議種別:口頭発表(一般)  

  10. Pathologic findings toward the concept of cancer as ferroptosis-resistance

    Toyokuni, S; Zheng, H; Kong, YY; Luo, YG; Motooka, Y

    CANCER SCIENCE  2022年2月 

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    開催年月日: 2022年2月

    記述言語:英語  

  11. アスベストとタルクは鉄代謝異常による 酸化ストレスの増加から卵巣発がんに関与する

    本岡 大社、豊國 伸哉

    レドックスR&D戦略委員会 第1回若手シンポジウム  2021年11月8日  熊本大学微生物学講座

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    開催年月日: 2021年11月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:web   国名:日本国  

  12. Iron overload led by genital talc exposure contributes to ovarian carcinogenesis

    Yashiro Motooka, Fumiya Ito, Hironori Tashiro, Hidetaka Katabuchi, Shinya Toyokunii

    2021年10月 

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    開催年月日: 2021年9月 - 2021年10月

    記述言語:英語   会議種別:口頭発表(一般)  

    国名:日本国  

  13. Asbestos contributes to ovarian carcinogenesis 招待有り 国際会議

    Yashiro Motooka, Hironori Tashiro, Shinya Toyokuni, Hidetaka Katabuchi

    The 60th Annual Congress and The 9th International Symposium of the Taiwan Association of Obstetrics and Gynecology  2021年5月30日  Taiwan Association of Obstetrics and Gynecology

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    開催年月日: 2021年5月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

    開催地:Taiwan   国名:台湾  

  14. BRCA1 deficiency regulates the metabolism of iron and oxidative stress-induced carcinogenesis in the kidney

    Kong Yingyi, Motooka Yashiro, Akatsuka Shinya, Mashimo Tomoji, Imaoka Tatsuhiko, Toyokuni Shinya

    CANCER SCIENCE  2022年2月 

  15. Pathologic findings toward the concept of cancer as ferroptosis-resistance

    Toyokuni Shinya, Zheng Hao, Kong Yingyi, Luo Yaguang, Motooka Yashiro

    CANCER SCIENCE  2022年2月 

  16. Iron overload led by genital talc exposure contributes to ovarian carcinogenesis

    Motooka Yashiro, Ito Fumiya, Tashiro Hironori, Katabuchi Hidetaka, Toyokuni Shinya

    CANCER SCIENCE  2022年2月 

▼全件表示

共同研究・競争的資金等の研究課題 3

  1. 二次元ナノマテリアルMXene (Ti3C2Tx) の創傷治癒への応用

    2024年4月 - 2025年3月

    令和6年度 CREST「細胞外微粒子」若手チャレンジ  

    本岡 大社

  2. タルクによるEVs伝達阻害:卵巣における評価と応用

    2022年4月 - 2023年3月

    令和4年度 CREST「細胞外微粒子」若手チャレンジ  

    本岡 大社

      詳細を見る

    資金種別:競争的資金

    配分額:500000円

  3. アスベストおよびタルクがタンパク質を吸着することで惹起する、卵巣におけるcancer initiating eventsの解明

    2021年4月 - 2022年3月

    令和3年度 CREST「細胞外微粒子」若手チャレンジ 

    本岡大社

      詳細を見る

    担当区分:研究代表者  資金種別:競争的資金

    配分額:1800000円 ( 直接経費:1800000円 )

科研費 1

  1. 環境中微粒子によるタンパク質や細胞外小胞の吸着が鉄代謝と卵巣がん形成に及ぼす影響

    研究課題/研究課題番号:23K08883  2023年4月 - 2026年3月

    科学研究費助成事業  基盤研究(C)

    本岡 大社

      詳細を見る

    担当区分:研究代表者  資金種別:競争的資金

    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    環境中の微粒子であるアスベスト、タルクと卵巣がんの関連性は疫学調査によって指摘されてきたものの、実験動物による実証はなされておらず、これらの物質が生体内で引き起こす発がんメカニズムも不明であった。このような背景の中、研究代表者は齧歯類を用いた発がん実験によってアスベスト、タルクの卵巣における発がん性をこれまでに示してきた。
    本検討ではこれらの物質による卵巣発がんの分子細胞学的なメカニズムをタンパク質等の「吸着性」に着目して明らかにする。今回着目する「吸着性」は多くのナノマテリアルが持つ性質であるため、その生体への影響を明らかにすることは安全なナノマテリアルの開発・運用に貢献するものと考えている。

 

担当経験のある科目 (本学) 12

  1. 臨床病理学実習

    2023

  2. 基礎セミナー

    2023

  3. 病理病態学

    2023

  4. 基礎医学セミナー

    2023

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    10月から3月上旬の学内発表会まで学部3年生の基礎研究、実験、発表にかんする指導をおこなう。

  5. 病理病態学

    2022

  6. 基礎セミナー

    2022

  7. 基礎医学セミナー

    2022

  8. 臨床病理学実習

    2022

  9. 基礎セミナー

    2021

     詳細を見る

    医学英語

  10. 病理学実習

    2021

  11. 基礎医学セミナー

    2021

  12. 臨床病理学実習

    2021

▼全件表示

担当経験のある科目 (本学以外) 1

  1. 母性

    2015年4月 - 2015年3月

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    科目区分:学部専門科目