Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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マイクロプラスチック曝露によるラット子宮内膜症の増悪(Growth of rat endometriosis is accelerated by microplastics exposure) Reviewed International journal

片渕充沙子, 本岡大社, 田代浩徳, 近藤英治, 豊國伸哉

日本病理学会会誌 Vol. 113 ( 1 ) page： 429 - 429 2024.2

シクロホスファミドとオラパリブによる卵巣毒性はBRCA1変異で増強される(Ovarian follicle toxicity of Cyclophosphamide and Olaparib in BRCA1 mutant rats) Reviewed International journal

可世木聡, 本岡大社, 中村智子, 梶山広明, 豊國伸哉

日本病理学会会誌 Vol. 113 ( 1 ) page： 428 - 428 2024.2

BRCA2変異はラットモデルにおいて精子の質の低下と精巣の退行性変化をきたし男性不妊を惹起する Reviewed International journal

界外誠, 本岡大社, 豊國伸哉

日本病理学会会誌 Vol. 113 ( 1 ) page： 479 - 479 2024.2

BRCA2変異のフェロトーシス抵抗性獲得因子の探索 Reviewed International journal

前田勇貴, 真下知士, 豊國伸哉

日本病理学会会誌 Vol. 113 ( 1 ) page： 292 - 292 2024.2

Science and Applications of Plasma-Activated Solutions: Current Trends and Future Directions Reviewed International journal

Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Camelia Miron, Yasumasa Okazaki, Shinya Toyokuni, Kae Nakamura, Hiroaki Kajiyama, Masafumi Ito, Masaru Hori

Plasma Medicine Vol. 14 ( 1 ) page： 67 - 76 2024

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

Recent research into plasma-activated solutions has unveiled their considerable potential across a range of applications, including cancer treatment, industrial processes, and environmental management. This review summarizes key findings from recent studies on the effects of plasma-activated solutions, focusing on their ability to induce cell death in glioblastoma cells, enhance ethanol production in yeast, and convert organic compounds into environmentally friendly substances. The review highlights the mechanisms by which plasma-activated solutions exert their effects, such as oxidative stress induction and cellular metabolic alterations. Addition-ally, it discusses the implications of these findings for overcoming challenges in cancer therapy, improving agricultural practices, and developing novel environmental technologies. The ongoing advancements in plasma technology offer promising avenues for future research and applications, underscoring its transformative potential in both scientific and practical domains.

DOI： 10.1615/PlasmaMed.v14.i1.50

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Tetrachloroaurate (III)–induced oxidation increases nonthermal plasma-induced aldehydes Reviewed International journal Open Access

Yasumasa Okazaki, Jun Yoshitake, Nanami Ito, Kanako Sasaki, Hiromasa Tanaka, Masaru Hori, Takahiro Shibata, Shinya Toyokuni

Advances in Redox Research Vol. 9 page： 100074 - 100074 2023.12

Generation and measurement of low-temperature plasma for cancer therapy: a historical review Reviewed International journal Open Access

Kenji Ishikawa, Keigo Takeda, Shinji Yoshimura, Takashi Kondo, Hiromasa Tanaka, Shinya Toyokuni, Kae Nakamura, Hiroaki Kajiyama, Masaaki Mizuno, Masaru Hori

Free Radical Research Vol. 57 ( 3 ) page： 239 - 270 2023.12

Three-dimensional regulation of ferroptosis at the intersection of iron, sulfur and oxygen executing scrap and build toward evolution. Reviewed International journal

Shinya Toyokuni, Yingyi Kong, Hao Zheng, Yuki Maeda, Misako Katabuchi, Yashiro Motooka

Antioxidants & redox signaling Vol. 39 ( 10-12 ) page： 807 - 815 2023.10

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

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. 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 ferroptosis-resistance, based on rodent animal studies. 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. Whereas life attempts to prevent ferroptosis, ferroptotic cells eventually emit iron-loaded ferritin as extracellular vesicles to maintain monopoly of iron.

DOI： 10.1089/ars.2022.0142

New iron export pathways acting via holo-ferritin secretion. Reviewed International journal

Izumi Yanatori, Fumio Kishi, Shinya Toyokuni

Archives of biochemistry and biophysics Vol. 746 page： 109737 - 109737 2023.9

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

Ferritin is a spherical nanocage protein for iron storage, composed of 24 light- or heavy-polypeptide chain subunits. A single ferritin molecule can carry up to 4500 iron atoms in its core, which plays an important role in suppressing intracellular iron toxicity. Serum ferritin levels are used as a marker for the total amount of iron stored in the body. Most serum ferritin is iron-free (apo-ferritin) and it is unclear how ferritin is released from cells. Ferritin is secreted into serum via extracellular vesicles (EVs) or the secretory autophagy pathway but not via the classical endoplasmic reticulum (ER)-to-Golgi secretion pathway. We recently discovered that the level of tetraspanin CD63, a common EV marker, is post-transcriptionally regulated by the intracellular iron level and both CD63 and ferritin expression is induced by iron loading. Ferritin is incorporated into CD63(+)-EVs through the ferritin-specific autophagy adapter molecule, NCOA4, and then secreted from cells. EV production differs drastically depending on cell type and physiological conditions. Extracellular matrix detached cells express pentaspanin prominin 2 and prominin 2(+)-EVs secrete ferritin independently of NCOA4 trafficking. Ferritin is tightly bound to iron in EVs and functions as an iron-carrier protein in the extracellular environment. Cells can suppress ferroptosis by secreting holo-ferritin, which reduces intracellular iron concentration. However, this exposes the neighboring cells receiving the secreted holo-ferritin to a large excess of iron. This results in cellular toxicity through increased generation of reactive oxygen species (ROS). Here we review the machinery by which ferritin is incorporated into EVs and its role as an intercellular communication molecule.

DOI： 10.1016/j.abb.2023.109737

Iron links endogenous and exogenous nanoparticles. Reviewed International journal Open Access

Shinya Toyokuni, Yingyi Kong, Misako Katabuchi, Yuki Maeda, Yashiro Motooka, Fumiya Ito, Izumi Yanatori

Archives of biochemistry and biophysics Vol. 745 page： 109718 - 109718 2023.9

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

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

BRCA1変異モデルラットの卵巣機能に対する加齢とPARP阻害剤オラパリブの影響(Effect of aging and PARP inhibitor, olaparib on ovarian function with BRCA1 mutant model rats) Reviewed International journal

曽根原玲菜, 本岡大社, 真下知士, 今岡達彦, 梶山広明, 豊國伸哉

日本癌学会総会記事 Vol. 82回 page： 170 - 170 2023.9

腫瘍進化生物学における鉄、酸素、フェロトーシスの役割(Role of iron, oxygen and ferroptosis in tumor evolutionary biology) Reviewed International journal

豊國伸哉, 孔穎怡, 羅亜光, 鄭好, 本岡大社, 今岡達彦, 赤塚慎也

日本癌学会総会記事 Vol. 82回 page： 907 - 907 2023.9

BRCA2の生殖細胞変異は卵胞発育を促進し卵巣予備能の低下を惹起する(BRCA2 germline mutation promotes follicle development and induces diminished ovarian reserve) Reviewed International journal

田中秀明, 本岡大社, 前田勇貴, 真下知士, 梶山広明, 豊國伸哉

日本癌学会総会記事 Vol. 82回 page： 172 - 172 2023.9

BRCA2変異はp53活性を抑制しフェロトーシス抵抗性を獲得する(BRCA2 mutation promotes ferroptosis resistance via suppression of p53) Reviewed International journal

前田勇貴, 真下知士, 豊國伸哉

日本癌学会総会記事 Vol. 82回 page： 504 - 504 2023.9

Txn1 mutation is a monogenic cause of chronic kidney disease associated with mitochondrial dysfunction in rats

Iori Ohmori, Mamoru Ouchida, Yoshiko Hada, Haruhito, A. Uchida, Shinya Toyokuni, Tomoji Mashimo

BioRxiv 2023.8

Ferroptosis as ultimate target of cancer therapy. Reviewed International journal

Yashiro Motooka, Shinya Toyokuni

Antioxidants & redox signaling Vol. 39 ( 1-3 ) page： 206 - 223 2023.7

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

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, whereas suppressing factors are the prevention of lipid peroxidation by glutathione peroxidase 4 to protect lipid peroxidation and direct membrane repair via coenzyme Q10 and ESCRT-III pathways. 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. 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 which are generally rich in catalytic Fe(II). Here we summarize and discuss the recently uncovered responsible molecular mechanisms in association with iron metabolism, ferroptosis and cancer therapeutics. Finally, we also highlight the current classification of ferroptosis inducers.

DOI： 10.1089/ars.2022.0048

Carbon nanotube recognition by human Siglec-14 provokes inflammation. Reviewed International journal

Shin-Ichiro Yamaguchi, Qilin Xie, Fumiya Ito, Kazuki Terao, Yoshinobu Kato, Miki Kuroiwa, Satoshi Omori, Hideo Taniura, Kengo Kinoshita, Takuya Takahashi, Shinya Toyokuni, Kota Kasahara, Masafumi Nakayama

Nature nanotechnology Vol. 18 ( 6 ) page： 628 - 636 2023.6

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

For the design and development of innovative carbon nanotube (CNT)-based tools and applications, an understanding of the molecular interactions between CNTs and biological systems is essential. In this study, a three-dimensional protein-structure-based in silico screen identified the paired immune receptors, sialic acid immunoglobulin-like binding lectin-5 (Siglec-5) and Siglec-14, as CNT-recognizing receptors. Molecular dynamics simulations showed the spatiotemporally stable association of aromatic residues on the extracellular loop of Siglec-5 with CNTs. Siglec-14 mediated spleen tyrosine kinase (Syk)-dependent phagocytosis of multiwalled CNTs and the subsequent secretion of interleukin-1β from human monocytes. Ectopic in vivo expression of human Siglec-14 on mouse alveolar macrophages resulted in enhanced recognition of multiwalled CNTs and exacerbated pulmonary inflammation. Furthermore, fostamatinib, a Syk inhibitor, blocked Siglec-14-mediated proinflammatory responses. These results indicate that Siglec-14 is a human activating receptor recognizing CNTs and that blockade of Siglec-14 and the Syk pathway may overcome CNT-induced inflammation.

DOI： 10.1038/s41565-023-01363-w

Sleep-wake patterns are altered with age, Prdm13 signaling in the DMH, and diet restriction in mice. Reviewed International journal Open Access

Shogo Tsuji, Cynthia S Brace, Ruiqing Yao, Yoshitaka Tanie, Hirobumi Tada, Nicholas Rensing, Seiya Mizuno, Julio Almunia, Yingyi Kong, Kazuhiro Nakamura, Takahisa Furukawa, Noboru Ogiso, Shinya Toyokuni, Satoru Takahashi, Michael Wong, Shin-Ichiro Imai, Akiko Satoh

Life science alliance Vol. 6 ( 6 ) 2023.6

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

Old animals display significant alterations in sleep-wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control. Furthermore, DMH-specific Prdm13-knockout (DMH-Prdm13-KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during SD. These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep fragmentation and increased sleep attempts during SD, whereas these effects of DR were abrogated in DMH-Prdm13-KO mice. Moreover, overexpression of Prdm13 in the DMH ameliorated increased sleep attempts during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep-wake patterns during aging.

DOI： 10.26508/lsa.202301992

Matrigel-based organoid culture of malignant mesothelioma reproduces cisplatin sensitivity through CTR1. Reviewed International journal Open Access

Fumiya Ito, Katsuhiro Kato, Izumi Yanatori, Yuki Maeda, Toyoaki Murohara, Shinya Toyokuni

BMC cancer Vol. 23 ( 1 ) page： 487 - 487 2023.5

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

Organoids are a three-dimensional (3D) culture system that simulate actual organs. Therefore, tumor organoids are expected to predict precise response to chemotherapy in patients. However, to date, few studies have studied the drug responses in organoids of malignant mesothelioma (MM). The poor prognosis of MM emphasizes the importance of establishing a protocol for generating MM-organoid for research and clinical use. Here, we established murine MM organoids from p53+/- or wild-type C57BL/6 strain by intraperitoneal injection either with crocidolite or carbon nanotube. Established MM-organoids proliferated in Matrigel as spheroids. Subcutaneous injection assays revealed that the MM-organoids mimicked actual tissue architecture and maintained the original histological features of the primary MM. RNA sequencing and pathway analyses revealed that the significant expressional differences between the 2D- and 3D-culture systems were observed in receptor tyrosine kinases, including IGF1R and EGFR, glycosylation and cholesterol/steroid metabolism. MM-organoids exhibited a more sensitive response to cisplatin through stable plasma membrane localization of a major cisplatin transporter, copper transporter 1/Slc31A1 (Ctr1) in comparison to 2D-cultures, presumably through glycosylation and lipidation. The Matrigel culture system facilitated the localization of CTR1 on the plasma membrane, which simulated the original MMs and the subcutaneous xenografts. These results suggest that the newly developed protocol for MM-organoids is useful to study strategies to overcome chemotherapy resistance to cisplatin.

DOI： 10.1186/s12885-023-10966-4

BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile-induced mesothelioma via ferroptosis-resistance. Reviewed International journal Open Access

Yaguang Luo, Shinya Akatsuka, Yashiro Motooka, Yingyi Kong, Hao Zheng, Tomoji Mashimo, Tatsuhiko Imaoka, Shinya Toyokuni

Cancer science Vol. 114 ( 4 ) page： 1423 - 1436 2023.4

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

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-strand 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 thus 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 to 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 to wild-type tumors. Mutant MMs indicated iron metabolism dysregulation, such as increase in catalytic Fe(II) and Ki67-index as well as 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 to crocidolite/Mut whereas significant preference to iron with 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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Papers - TOYOKUNI Shinya