Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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増大特集学術研究支援の最先端 Ⅱ.先端モデル動物支援プラットフォーム(AdAMS) ⅱ.病理形態解析支援経験豊富な病理専門医が研究の方向性を指南する(総論) Reviewed International journal

豊國伸哉

生体の科学 Vol. 75 ( 5 ) page： 438 - 439 2024.10

Heat-treated and/or lysozyme-treated Enterococcus faecalis (FK-23) improves the progression of renal disease in a unilateral ischemia-reperfusion injury rat model Reviewed International journal Open Access

Takemura Shigekazu, Minamiyama Yukiko, Ito Norihiko, Yamamoto Atsushi, Ichikawa Hiroshi, Nakagawa Kanako, Toyokuni Shinya, Osada-Oka Mayuko, Yoshikawa Toshikazu

Journal of Clinical Biochemistry and Nutrition Vol. 75 ( 1 ) page： 78 - 89 2024.7

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

The prevalence of chronic kidney disease (CKD) is increasing owing to the elderly population. Here, we investigated the effects of heat-treated Enterococcus faecalis (FK-23) and lysozyme-treated FK-23 (LFK) on the progression of CKD in rats. A CKD model was established using male Wistar rats by subjecting them to right nephrectomy (1K), followed by ischemia and reperfusion (IR). FK-23 or LFK was fed ad libitum as a mixed diet after right nephrectomy. Animals subjected to renal ischemia-reperfusion injury (IRI) showed increased plasma creatinine and blood urea nitrogen levels. Furthermore, in the kidneys, collagen accumulation and α-smooth muscle actin, indicative of fibroblast activation and fibrosis-related gene and protein expression, increased 3 weeks after IRI. FK-23 and LFK suppressed the increase in the mRNA levels of some of these genes. The increase in oxidative stress markers, 4-hydroxy-2-nonenal, endothelial nitric oxide synthase, and nitrotyrosine in the kidney, as well as increased plasma uremic toxins after IRI, were also ameliorated by FK-23 and LFK. Metagenomic analysis of fecal samples revealed that gut microbial alteration caused by IRI was also ameliorated by LFK treatment. These results suggest that Enterococcus faecalis ingredients may improve CKD progression by suppressing oxidative stress and correcting the balance of the intestinal microflora.

DOI： 10.3164/jcbn.24-29

特集活性酸素と酸化ストレスがんとフェロトーシス International journal

豊國伸哉

医学のあゆみ Vol. 289 ( 4 ) page： 263 - 266 2024.4

Protocol for the isolation of GFP-expressing ferroptosis-dependent extracellular vesicles in in vitro cell culture models. Reviewed International journal Open Access

Fumiya Ito, Izumi Yanatori, Katsuhiro Kato, Shinya Toyokuni

STAR protocols Vol. 5 ( 1 ) page： 102892 - 102892 2024.3

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

Extracellular vesicles (EVs) are complex structures that transport various DNA, RNA, and protein. Recently, new EV secretion mechanisms have been identified through the iron regulatory system in mammalian cells. We revealed that ferroptosis increases EV secretion, which is named ferroptosis-dependent EVs (FedEVs). Here, we describe a step-by-step procedure to isolate GFP-expressing FedEVs for in vitro analysis. The FedEVs are further analyzed by imaging and flow cytometry analysis. For complete details on the use and execution of this protocol, please refer to Ito et al.1.

DOI： 10.1016/j.xpro.2024.102892

Epstein-Barr virus lytic gene BNRF1 promotes B-cell lymphomagenesis via IFI27 upregulation. Reviewed International journal Open Access

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

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

Open Access

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PubMed

Formalin-Fixed Paraffin-Embedded Proteomics of Malignant Mesothelioma and New Candidate Biomarkers Thioredoxin and Superoxide Dismutase 2 for Immunohistochemistry. Reviewed International journal

Hiratsuka T, Yoshizawa A, Endo T, Yamamoto T, Toyokuni S, Tsuruyama T

Laboratory investigation; a journal of technical methods and pathology Vol. 104 ( 2 ) page： 100299 2024.2

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

The pathogenesis of malignant mesothelioma (MM) has been extensively investigated, focusing on stress derived from reactive oxygen species. We aimed to identify diagnostic biomarkers of MM by analyzing proteins in formalin-fixed paraffin-embedded specimens using liquid chromatography-mass spectrometry. We extracted proteins from formalin-fixed paraffin-embedded sections of MM tissues (n = 7) and compared their profiles with those of benign mesothelial tissues (n = 4) and alveolar tissue (n = 1). Proteomic data were statistically assessed and profiled using principal component analysis. We were successful in the classification of MM and healthy tissue. The levels of superoxide dismutase 2 (SOD2), an enzyme that converts superoxide anion into oxygen and hydrogen peroxide, and thioredoxin (TXN), which plays a crucial role in reducing disulfide bonds in proteins, primarily contributed to the classification. Other redox-related proteins, such as pyruvate dehydrogenase subunit X, and ceruloplasmin also contributed to the classification. Protein-protein interaction analysis demonstrated that these proteins play essential roles in MM pathogenesis. Immunohistochemistry revealed that TXN levels were significantly lower, whereas SOD2 levels were significantly higher in MM and lung cancer tissues than in controls. Proteomic profiling suggested that MM tissues experienced increased exposure to hydrogen peroxide and other reactive oxygen species. Combining immunohistochemistry for TXN and SOD2 allows for differentiation among MM, lung cancer, and control tissues; hence, TXN and SOD2 may be promising MM biomarkers and therapeutic targets.

DOI： 10.1016/j.labinv.2023.100299

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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 accelerates follicle maturation, leading to reduced 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

日本病理学会会誌 Vol. 113 ( 1 ) page： 428 - 429 2024.2

病理形態学から発がんメカニズムの本質に迫る環境中の微粒子であるアスベストやタルクによる卵巣発がん(Mechanisms of carcinogenesis revealed by pathomorphology Ovarian carcinogenesis induced by environmental particulates: asbestos and talc) Reviewed International journal

本岡大社, 豊國伸哉

日本病理学会会誌 Vol. 113 ( 1 ) page： 194 - 194 2024.2

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

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

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

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

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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

Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression. Reviewed International journal Open Access

Van San E, Debruyne AC, Veeckmans G, Tyurina YY, Tyurin VA, Zheng H, Choi SM, Augustyns K, van Loo G, Michalke B, Venkataramani V, Toyokuni S, Bayir H, Vandenabeele P, Hassannia B, Vanden Berghe T

Cell death and differentiation Vol. 30 ( 9 ) page： 2092 - 2103 2023.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Cell Death and Differentiation

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by central nervous (CNS) demyelination resulting in axonal injury and neurological deficits. Essentially, MS is driven by an auto-amplifying mechanism of inflammation and cell death. Current therapies mainly focus on disease modification by immunosuppression, while no treatment specifically focuses on controlling cell death injury. Here, we report that ferroptosis, an iron-catalyzed mode of regulated cell death (RCD), contributes to MS disease progression. Active and chronic MS lesions and cerebrospinal fluid (CSF) of MS patients revealed several signs of ferroptosis, reflected by the presence of elevated levels of (labile) iron, peroxidized phospholipids and lipid degradation products. Treatment with our candidate lead ferroptosis inhibitor, UAMC-3203, strongly delays relapse and ameliorates disease progression in a preclinical model of relapsing-remitting MS. In conclusion, the results identify ferroptosis as a detrimental and targetable factor in MS. These findings create novel treatment options for MS patients, along with current immunosuppressive strategies. [Figure not available: see fulltext.]

DOI： 10.1038/s41418-023-01195-0

Open Access

Scopus

PubMed

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

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

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Papers - TOYOKUNI Shinya