Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Visualization of physiological ferroptosis Reviewed International journal

Zheng, H; Toyokuni, S

CANCER SCIENCE Vol. 113 page： 1547 - 1547 2022.2

The differences between cigarette smoke and electronic cigarette smoke in inducing oxidative stress Reviewed International journal

Lyu, QY; Toyokuni, S

CANCER SCIENCE Vol. 113 page： 1652 - 1652 2022.2

Pathologic findings toward the concept of cancer as ferroptosis-resistance Reviewed International journal

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

CANCER SCIENCE Vol. 113 page： 661 - 661 2022.2

Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation. Reviewed International journal Open Access

Satoshi Omori, Misato Tsugita, Yasuto Hoshikawa, Masanobu Morita, Fumiya Ito, Shin-Ichiro Yamaguchi, Qilin Xie, Osamu Noyori, Tomoya Yamaguchi, Ayato Takada, Tatsuya Saitoh, Shinya Toyokuni, Hisaya Akiba, Shigekazu Nagata, Kengo Kinoshita, Masafumi Nakayama

Cell reports Vol. 34 ( 6 ) page： 108734 - 108734 2021.2

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

Macrophage recognition and phagocytosis of crystals is critical for the associated fibrosis and cancer. Of note, multi-walled carbon nanotubes (MWCNTs), the highly representative products of nanotechnology, induce macrophage NLRP3 inflammasome activation and cause asbestosis-like pathogenesis. However, it remains largely unknown how macrophages efficiently recognize MWCNTs on their cell surfaces. Here, we identify by a targeted screening of phagocyte receptors the phosphatidylserine receptors T cell immunoglobulin mucin 4 (Tim4) and Tim1 as the pattern-recognition receptors for carbon crystals. Docking simulation studies reveal spatiotemporally stable interfaces between aromatic residues in the extracellular IgV domain of Tim4 and one-dimensional carbon crystals. Further, CRISPR-Cas9-mediated deletion of Tim4 and Tim1 reveals that Tim4, but not Tim1, critically contributes to the recognition of MWCNTs by peritoneal macrophages and to granuloma development in a mouse model of direct mesothelium exposure to MWCNTs. These results suggest that Tim4 recognizes MWCNTs through aromatic interactions and mediates phagocytosis leading to granulomas.

DOI： 10.1016/j.celrep.2021.108734

Ferroptosis and Oxidative DNA Damage Reviewed International journal

Toyokuni, S; Yanatori, I

DNA DAMAGE, DNA REPAIR AND DISEASE, VOL. 1 Vol. 14 page： 140 - 153 2021

Induction of cancer cell-specific ferroptosis by non-thermal plasma exposure Reviewed International journal

Okazaki, Y; Toyokuni, S

JAPANESE JOURNAL OF APPLIED PHYSICS Vol. 59 ( 11 ) 2020.11

Chemical reaction mechanism in non-thermal plasma from the viewpoint of oxidative stress toward clinical cancer applications Reviewed International coauthorship International journal

Toyokuni, S; Shi, L; Okazaki, Y; Richardson, DR

FREE RADICAL BIOLOGY AND MEDICINE Vol. 100 page： S131 - S131 2016.11

CANCER AS A FERROTOXIC DISEASE: WHAT WE HAVE LEARNED FROM ANIMAL STUDIES TOWARD ITS PREVENTION Reviewed International journal

Toyokuni, S, Jiang, L, Okazaki, Y, Akatsuka, S

AMERICAN JOURNAL OF HEMATOLOGY Vol. 88 ( 5 ) page： E168 - E169 2013.5

Mysterious link between iron overload and CDKN2A/2B International journal Open Access

Toyokuni Shinya

Journal of Clinical Biochemistry and Nutrition Vol. 48 ( 1 ) page： 46 - 9 2011.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：SOCIETY FOR FREE RADICAL RESEARCH JAPAN

Persistent oxidative stress has been associated with carcinogenesis. Iron overload is considered one such condition that causes oxidative stress. Epidemiological studies support a close link between iron overload and carcinogenesis. Reportedly, regular semiannual phlebotomies reduced cancer risk in an otherwise normal population. More specifically, genetic hemochromatosis, chronic viral hepatitis, ovarian endometriosis and asbestosis induce iron overload, which can lead to hepatocellular carcinoma, ovarian carcinoma or mesothelioma in humans. Through a combination of animal experiments and microarray analyses, homozygous deletion of CDKN2A/2B has been recognized as one of the major target genes involved in iron overload-induced carcinogenesis. CDKN2A/2B are the second most frequently inactivated tumor suppressing genes in human cancers. Currently, when infection is becoming sufficiently controlled worldwide, iron regulation may be the next target for human longevity.

DOI： 10.3164/jcbn.11-001FR

Asbestos-induced Carcinogenesis is Oxidative Stress-dependent Reviewed International journal

Shinya Toyokuni, Li Jiang, Hirotaka Nagai, Hiroki Ohara, Yasumasa Okazaki, Shinya Akatsuka, Yoriko Yamashita

FREE RADICAL BIOLOGY AND MEDICINE Vol. 49 page： S72 - S72 2010

Spaciotemporal alteration of 8-hydroxy-2'-deoxyguanosine levels in cardiomyocytes after myocardial infarction in rats. Reviewed International journal Open Access

Senri Miwa, Shinya Toyokuni, Takeshi Nishina, Takuya Nomoto, Makoto Hiroyasu, Kazunobu Nishimura, Masashi Komeda

Free radical research Vol. 36 ( 8 ) page： 853 - 8 2002.8

Language：English Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS LTD

Temporary or persistent heart failure is one of the major complications after myocardial infarction (MI). In order to elucidate the pathogenesis of MI, we studied the spaciotemporal alteration of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in cardiomyocytes in a rat model of ligation of the left anterior descending branch of the coronary artery The lethality in this model was 18%. Hearts were dissected at 0, 3, 6, 12, 24, 48 h, and 1, 2, 4, 6 weeks after the operation. The cardiac level of 8-OHdG was evaluated biochemically as well as by immunohistochemistry with monoclonal antibody N45.1. Three to 6h after ligation, the 8-OHdG levels were increased in the cardiomyocytes of MI (six-fold) and peri-MI (four-fold) areas. After 24h, the myocardium in the MI area was necrotized, and thereafter the 8-OHdG level decreased. 8-OHdG levels in the myocardium of peri-MI areas returned once to a normal level, but were significantly increased at 2-4 weeks along with the appearance of apoptotic cardiomyocytes in this area. The heart after MI has been generally considered as clinically stable after four weeks. However, cardiomyocytes near the infarcted area were oxidatively stressed even after four weeks when the affected lesion was extensive. The present data support the use of supplementary antioxidant therapies to save functional myocardium after MI. (213 words).

DOI： 10.1081/1071576021000005285

Endogenous formation of protein adducts with carcinogenic aldehydes - Implications for oxidative stress Reviewed International journal

Ichihashi K, Osawa T, Toyokuni S, Uchida K

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 276 ( 26 ) page： 23903 - 23913 2001.6

Antioxidant alpha-tocopherol improves glycemic control of GK rats, a model of type 2 diabetes Reviewed International journal

Ihara Y, Yamada Y, Toyokuni S, Ban N, Kuroe A, Seino Y

DIABETES Vol. 49 page： A429 - A429 2000.5

4-hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress - Identification of proteasomes as target molecules Reviewed International coauthorship International journal

Okada K, Wangpoengtrakul C, Osawa T, Toyokuni S, Tanaka K, Uchida K

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 274 ( 34 ) page： 23787 - 23793 1999.8

8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure (vol 107, pg 733, 1996) Reviewed International journal

Hattori, Y, Nishigori, C, Tanaka, T, Uchida, K, Nikaido, O, Osawa, T, Hiai, H, Imamura, S, Toyokuni, S

JOURNAL OF INVESTIGATIVE DERMATOLOGY Vol. 108 ( 2 ) page： 237 - 237 1997.2

ACUTE NEPHROTOXICITY OF A CARCINOGENIC IRON CHELATE - SELECTIVE-INHIBITION OF A PROTEOLYTIC CONVERSION OF ALPHA(2U)-GLOBULIN TO THE KIDNEY FATTY-ACID-BINDING PROTEIN Reviewed International journal

UCHIDA K, FUKUDA A, KAWAKISHI S, TOYOKUNI S, HIAI H, IKEDA S, HORIO F

FEBS LETTERS Vol. 357 ( 2 ) page： 165 - 167 1995.1

Susceptibility of Brca1(L63X/+) rat to ovarian reserve dissipation by chemotherapeutic agents to breast cancer. Reviewed International journal Open Access

Satoshi Kaseki, Reina Sonehara, Yashiro Motooka, Hideaki Tanaka, Tomoko Nakamura, Satoko Osuka, Shinya Akatsuka, Hiroaki Kajiyama, Tomoji Mashimo, Tatsuhiko Imaoka, Shinya Toyokuni

Cancer science Vol. 116 ( 4 ) page： 1139 - 1152 2025.4

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

BRCA1 is one of the causative genes for hereditary breast and ovarian cancer syndrome with a high risk of early-onset breast cancer. Whereas olaparib (OLA), an inhibitor of poly-ADP-ribose polymerase, has been applied as adjuvant therapy to those cancer patients, its effect on ovarian reproductive function remains unelucidated. Recently, a rat model (MUT; Brca1(L63X/+) mutation) mimicking a human BRCA1 pathogenic variant has been established. Using this model, we evaluated the effects of OLA on ovarian reproductive function in comparison with the wild-type (WT) rats. MUT showed a significantly reduced number of primordial follicles and subfertility in accordance with aging. Oxidative stress was significantly elevated in the young MUT granulosa cells (GCs) accompanied by increased mTOR but decreased PTEN signals. OLA administration in MUT further decreased primordial follicles, with gene set enrichment analysis, indicating upregulated DNA repair pathways. Furthermore, a combination of OLA and cyclophosphamide (CPA) induced empty primordial follicles, recognized as CPA-induced severe ovarian toxicity. Whereas OLA + CPA caused greater reduction in primordial follicles both in MUT and WT in comparison with CPA alone, MUT ovaries were more susceptible to oxidative stress, potentially depleting primordial follicles via activation of GCs and inducing oocyte death due to accumulated DNA damage by OLA treatment. Our findings in this preclinical model underscore the importance of evaluating ovarian reserve prior to chemotherapy by performing reproductive consultation with female patients with BRCA1 pathogenic variants.

DOI： 10.1111/cas.16412

Heterozygous mutation in BRCA2 induces accelerated age-dependent decline in sperm quality with male subfertility in rats. Reviewed International journal Open Access

Yashiro Motooka, Hideaki Tanaka, Yuki Maeda, Misako Katabuchi, Tomoji Mashimo, Shinya Toyokuni

Scientific reports Vol. 15 ( 1 ) page： 447 - 447 2025.1

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

Tumor suppressor BRCA2 executes homologous recombination to repair DNA double-strand breaks in collaboration with RAD51, involving exon 11 and 27. Exon 11 constitutes a region where pathogenic variants (PVs) accumulate, and mutations in this region are known to contribute to carcinogenesis. However, the impact of the heterozygous PVs of BRCA2 exon 11 on the life quality beyond cancer risk, including male fertility, remains unclear. Here, we established a rat model with a frameshift on the seventh BRC repeat in Brca2 exon 11 (Brca2+/p.T1942fs), which is homologous to human BRCA2+/p.T1974fs, using CRISPR/Cas9 system. Our analyses revealed that the heterozygous rats with the PV in the BRCA2 exon 11 showed increased DNA double-strand breaks and apoptosis in spermatogonia and spermatocytes, accelerated testicular germ cell loss, and deterioration in sperm quality according with aging, ultimately resulting in early male reproductive dysfunction. Of note, these alterations in testes and sperm, including DNA fragmentation in spermatozoa, were observed from completion of sexual maturation. The present findings suggest that it is crucial to consider not only cancer risk but also potential declines in reproductive capacity in men carrying BRCA2 exon 11 PVs. Further investigation is warranted to determine whether similar traits appear in humans.

DOI： 10.1038/s41598-024-84184-8

細胞外微粒子が鉄代謝と酸化ストレスに及ぼす影響と発がんへの関与 Reviewed International journal

本岡大社, 豊國伸哉

大気環境学会誌 Vol. 60 ( 1 ) page： A32 - A38 2025.1

BRCA2 mutant induce ferroptosis resistance via AKT and promote cell cycle under Fenton reaction-based carcinogenesis Reviewed International journal

Yuki Maeda, Tomoji Mashimo, Shinya Toyokuni

CANCER SCIENCE Vol. 116 page： 875 - 875 2025.1

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Papers - TOYOKUNI Shinya