Updated on 2024/03/22

写真a

 
MOTOOKA Yashiro
 
Organization
Graduate School of Medicine Center for Research of Laboratory Animals and Medical Research Engineering Division for Advanced Medical Research Assistant Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Assistant Professor
External link

Degree 1

  1. 学士(医学) ( 2012.3   熊本大学 ) 

Research Interests 8

  1. Carcinogenesis

  2. Ovarian cancer

  3. フェロトーシス

  4. ナノ・マイクロマテリアルが生体に及ぼす影響

  5. BRCA1/2

  6. 女性生殖能

  7. 男性生殖能

Research Areas 2

  1. Life Science / Obstetrics and gynecology  / gynecological cancer

  2. Life Science / Experimental pathology  / Pathology

Current Research Project and 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

Awards 3

  1. 学術奨励賞

    2022.5   日本酸化ストレス学会  

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

  2. Young Innovator Award

    2022.4  

  3. Discussant賞

    2021.2   第141会東海産科婦人科学会  

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    Award type:Award from Japanese society, conference, symposium, etc. 

 

Papers 24

  1. Elaborate cooperation of poly(rC)-binding proteins 1/2 and glutathione in ferroptosis induced by plasma-activated Ringer's lactate Reviewed International journal

    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   Vol. 214   page: 28 - 41   2024.3

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed International journal

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

    FREE RADICAL RESEARCH     page: 1 - 14   2024.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed International journal

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

    PLOS PATHOGENS   Vol. 20 ( 2 ) page: e1011954   2024.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed International journal

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

    FREE RADICAL BIOLOGY AND MEDICINE   Vol. 208   page: S112 - S112   2023.11

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    Language:English   Publishing type:Research paper (scientific journal)  

    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 Invited Reviewed International journal

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

    ANTIOXIDANTS & REDOX SIGNALING   Vol. 39 ( 10-12 ) page: 807 - 815   2023.10

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    Authorship:Last author   Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed International journal

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

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS   Vol. 745   page: 109718   2023.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Invited Reviewed International journal

    Motooka, Y; Toyokuni, S

    ANTIOXIDANTS & REDOX SIGNALING   Vol. 39 ( 1-3 ) page: 206 - 223   2023.7

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed

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

    CANCER SCIENCE   Vol. 114 ( 4 ) page: 1423 - 1436   2023.4

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    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 Reviewed International journal

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

    NANOSCALE   Vol. 15 ( 9 ) page: 4570 - 4580   2023.3

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

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  10. DNA oxidative damage caused by the aromatic amine MOCA —Examination of 8-hydroxy-2’-deoxyguanosine levels in rat liver— Reviewed

    KOBAYASHI Saho, MOTOOKA Yashiro, KASHIWAGI Hiroki, TOYOKUNI Shinya

    Journal of Occupational Safety and Health   Vol. 16 ( 1 ) page: 45 - 49   2023.2

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:National Institute of Occupational Safety and Health, Japan  

    <p>MOCA (4,4’-methylenebis (2-chloroaniline)) , an aromatic amine, is industrially used as a curing agent for urethane resins; however, it is classified as a Group 1 compound (carcinogenic to humans) by the International Agency for Research on Cancer, and there is concern regarding its health effects on workers. The mechanism underlying MOCA-mediated carcinogenesis is thought to be related to DNA damage caused by reactive oxygen species (ROS) and DNA adducts, which are mainly generated during metabolism in the liver. 8-Oxoguanine (8-OHdG), a product of ROS-induced oxidation, occurs at high frequency and can induce G→T transversion mutations during DNA replication. However, to the best of our knowledge, no study has examined whether MOCA induces the formation of highly mutagenic 8-OHdG in experimental animals. Here, F344 rats were orally exposed to 0, 0.4, 2, 10, or 50 mg/kg/day MOCA three times a week for 2 weeks; this is expected to exert toxicity through the hepatic metabolism of MOCA. Livers obtained from these animals were examined for pathology and 8-OHdG levels. In pathological sections, vacuolar degeneration was observed with 50 mg/kg/day MOCA. Further, MOCA-induced 8-OHdG levels showed a slight increasing trend, except at 0.4 mg/kg/day. However, none of these differences were significant. Thus, 8-OHdG is unlikely the main cause of carcinogenesis.</p>

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

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  11. Environmental impact on carcinogenesis under BRCA1 haploinsufficiency Reviewed International journal

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

    GENES AND ENVIRONMENT   Vol. 45 ( 1 ) page: 2   2023.1

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

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

    REDOX BIOLOGY   Vol. 54   page: 102356   2022.8

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    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 Reviewed International journal

    Toyokuni Shinya, Kong Yingyi, Zheng Hao, Maeda Yuki, Motooka Yashiro, Akatsuka Shinya

    Journal of Clinical Biochemistry and Nutrition   Vol. 71 ( 2 ) page: 78 - 88   2022

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SOCIETY FOR FREE RADICAL RESEARCH JAPAN  

    <p>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(<i>rC</i>)-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 multi-system 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.</p>

    DOI: 10.3164/jcbn.22-43

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  14. Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles Reviewed International journal

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

    JOURNAL OF CANCER PREVENTION   Vol. 26 ( 4 ) page: 244 - 249   2021.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.15430/JCP.2021.26.4.244

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  15. Role of ferroptosis in nanofiber-induced carcinogenesis Reviewed International journal

    Toyokuni Shinya, Ito Fumiya, Motooka Yashiro

    Metallomics Research   Vol. 1 ( 1 ) page: rev-14 - rev-21   2021.10

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    Authorship:Last author   Language:English   Publishing type:Research paper (scientific journal)   Publisher: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

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  16. Plasma-activated Ringer's lactate solution inhibits the cellular respiratory system in HeLa cells Reviewed International journal

    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   Vol. 18 ( 10 )   2021.10

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

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  17. Role of ferroptosis in nanofiber-induced carcinogenesis Invited Reviewed

    Shinya Toyokuni, Fumiya Ito, Yashiro Motooka

    Metallomics Research   Vol. 1   page: 14 - 21   2021

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  18. Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice Reviewed International journal

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

    REDOX BIOLOGY   Vol. 37   page: 101726   2020.10

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

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  19. Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma Reviewed International journal

    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   Vol. 44 ( 3 ) page: 838 - 848   2020.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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 Reviewed International journal

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

    CANCER SCIENCE   Vol. 111 ( 8 ) page: 2665 - 2671   2020.8

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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. Reviewed

    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   Vol. 44 ( 3 ) page: 838 - 848   2020

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    Language:English  

  22. Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice. Invited Reviewed

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

    Redox Biology   Vol. 37   page: 101726   2020

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    Language:English   Publishing type:Research paper (scientific journal)  

  23. Ferroptosis at the crossroads of infection, aging and cancer Reviewed

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

    Cancer science   Vol. 111 ( 8 ) page: 2665 - 2671   2020

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    Language:English   Publishing type:Research paper (scientific journal)  

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

    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   Vol. 65 ( 1 ) page: 8 - 15   2019

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    Language:English  

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Books 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( Role: Contributor ,  第2章7節 使いたくなる病理解析新技術)

    羊土社  2021.4 

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    Total pages:317   Responsible for pages:147-160   Language:Japanese

  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( Role: Contributor ,  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  2020.7 

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    Language:Japanese Book type:Textbook, survey, introduction

Presentations 16

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

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

    CANCER SCIENCE  2023.2 

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    Event date: 2023.2

    Language:English   Presentation type:Symposium, workshop panel (nominated)  

  2. 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  2023.2 

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    Event date: 2023.2

    Language:English  

  3. Ferroptosis-resistance in rodent cancer models

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

    CANCER SCIENCE  2023.2 

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    Event date: 2023.2

    Language:English  

  4. 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  2023.2 

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    Event date: 2023.2

    Language:English   Presentation type:Poster presentation  

  5. 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  2023.2 

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    Event date: 2023.2

    Language:English   Presentation type:Poster presentation  

  6. 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  2023.2 

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    Event date: 2023.2

    Language:English   Presentation type:Poster presentation  

  7. Validation of reduced ovarian reserve in BRCA1 haploinsufficient rats

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

    CANCER SCIENCE  2023.2 

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    Event date: 2023.2

    Language:English   Presentation type:Poster presentation  

  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  2022.2 

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    Event date: 2022.2

    Language:English   Presentation type:Poster presentation  

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

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

    CANCER SCIENCE  2022.2 

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    Event date: 2022.2

    Language:English  

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

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

    CANCER SCIENCE  2022.2 

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    Event date: 2022.2

    Language:English   Presentation type:Oral presentation (general)  

  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  2021.11.8  熊本大学微生物学講座

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    Event date: 2021.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:web   Country:Japan  

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

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

    2021.10 

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    Event date: 2021.9 - 2021.10

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  13. Asbestos contributes to ovarian carcinogenesis Invited International conference

    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  2021.5.30  Taiwan Association of Obstetrics and Gynecology

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    Event date: 2021.5

    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:Taiwan   Country:Taiwan, Province of China  

  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  2022.2 

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

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

    CANCER SCIENCE  2022.2 

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

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

    CANCER SCIENCE  2022.2 

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Research Project for Joint Research, Competitive Funding, etc. 3

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

    2024.4 - 2025.3

    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

    2022.4 - 2023.3

    令和4年度 CREST「細胞外微粒子」若手チャレンジ  

    本岡 大社

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    Grant type:Competitive

    Grant amount:\500000

  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

    2021.4 - 2022.3

    令和3年度 CREST「細胞外微粒子」若手チャレンジ 

    本岡大社

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\1800000 ( Direct Cost: \1800000 )

KAKENHI (Grants-in-Aid for Scientific Research) 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

    Grant number:23K08883  2023.4 - 2026.3

    科学研究費助成事業  基盤研究(C)

    本岡 大社

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\4680000 ( Direct Cost: \3600000 、 Indirect Cost:\1080000 )

    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。

 

Teaching Experience (On-campus) 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

     詳細を見る

    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

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    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

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Teaching Experience (Off-campus) 1

  1. 母性

    2015.4 - 2015.3

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    Level:Undergraduate (specialized)