研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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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) 査読有り国際誌

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 113 巻 ( 1 ) 頁： 429 - 429 2024年2月

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) 査読有り国際誌

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 113 巻 ( 1 ) 頁： 428 - 428 2024年2月

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査読有り国際誌

界外誠, 本岡大社, 豊國伸哉

日本病理学会会誌 113 巻 ( 1 ) 頁： 479 - 479 2024年2月

BRCA2変異のフェロトーシス抵抗性獲得因子の探索査読有り国際誌

前田勇貴, 真下知士, 豊國伸哉

日本病理学会会誌 113 巻 ( 1 ) 頁： 292 - 292 2024年2月

Science and Applications of Plasma-Activated Solutions: Current Trends and Future Directions 査読有り国際誌

Tanaka H., Mizuno M., Ishikawa K., Miron C., Okazaki Y., Toyokuni S., Nakamura K., Kajiyama H., Ito M., Hori M.

Plasma Medicine 14 巻 ( 1 ) 頁： 67 - 76 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Plasma Medicine

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 査読有り国際誌 Open Access

Okazaki, Y; Yoshitake, J; Ito, N; Sasaki, K; Tanaka, H; Hori, M; Shibata, T; Toyokuni, S

ADVANCES IN REDOX RESEARCH 9 巻頁： 100074 - 100074 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Advances in Redox Research

Research on nonthermal plasma (NTP) devices first began almost five decades ago. NTP devices discharge electrons, positive ions, ultraviolet light, reactive oxygen species (ROS) and reactive nitrogen species (RNS) at near-physiological temperatures. Advances in plasma science have enabled the manipulation of ROS/RNS irradiation for medical applications. During preclinical stages and in human clinical trials, NTP promotes blood coagulation, eradication of bacterial, viral, and biofilm-related infections, wound healing, and cancer therapy. Previously, tetrachloroaurate (III) increased NTP-induced oxidative stress that was attenuated by reduced and oxidized glutathione, indicating that the presence of interactions between metal ions and biomolecules may modulate biological effects. In this study, using 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) as a spin probe in electron paramagnetic resonance (EPR), we observed that the tetrachloroaurate-induced M4PO-X spin adduct was significantly suppressed by ascorbate and α-tocopherol, while dehydroascorbate (DHA) and Trolox were ineffective. Tetrachloroaurate-induced lipid peroxidation, which was measured by 2-thiobarbituric acid-reactive substances (TBARS) in combination with NTP exposure, was suppressed by ascorbate, α-tocopherol and Trolox, while DHA was ineffective. Furthermore, N-acetyl-L-cysteine and dithiothreitol efficiently suppressed tetrachloroaurate-induced M4PO-X spin adduct and lipid peroxidation. LC‒MS/MS analyzes identified hexanal that was significantly elevated by NTP exposure and/or tetrachloroaurate. However, 25 and 250 μM ascorbate did not significantly suppress the formation of aldehydes, such as acetaldehyde, hexanal, nonanal, nonenal, and 4‑hydroxy-2-nonenal. Further studies are warranted to elucidate the redox reactions between metal ions, including gold (III), and biomolecules to expand the possibility of NTP application in medicine and agriculture.

DOI： 10.1016/j.arres.2023.100074

Generation and measurement of low-temperature plasma for cancer therapy: a historical review. 査読有り国際誌 Open Access

Ishikawa K, Takeda K, Yoshimura S, Kondo T, Tanaka H, Toyokuni S, Nakamura K, Kajiyama H, Mizuno M, Hori M

Free radical research 57 巻 ( 3 ) 頁： 239 - 270 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Free Radical Research

This review provides a description of the historical background of the development of biological applications of low-temperature plasmas. The generation of plasma, methods and devices, plasma sources, and measurements of plasma properties, such as electron dynamics and chemical species generation in both gaseous and aqueous phases, were assessed. Currently, direct irradiation methods for plasma discharges contacting biological surfaces, such as the skin and teeth, are related to plasma biological interactions. Indirect methods using plasma-treated liquids are based on plasma–liquid interactions. The use of these two methods is rapidly increasing in preclinical studies and cancer therapy. The authors address the prospects for further developments in cancer therapeutic applications by understanding the interactions between the plasma and living organisms.

DOI： 10.1080/10715762.2023.2230351

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

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

Antioxidants & redox signaling 39 巻 ( 10-12 ) 頁： 807 - 815 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Antioxidants and Redox Signaling

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

DOI： 10.1089/ars.2022.0142

New iron export pathways acting via holo-ferritin secretion. 査読有り国際誌

Yanatori I, Kishi F, Toyokuni S

Archives of biochemistry and biophysics 746 巻頁： 109737 - 109737 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Archives of Biochemistry and Biophysics

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. 査読有り国際誌 Open Access

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

Archives of biochemistry and biophysics 745 巻頁： 109718 - 109718 2023年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Archives of Biochemistry and Biophysics

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

DOI： 10.1016/j.abb.2023.109718

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) 査読有り国際誌

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 82回巻頁： 170 - 170 2023年9月

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) 査読有り国際誌

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 82回巻頁： 907 - 907 2023年9月

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) 査読有り国際誌

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 82回巻頁： 172 - 172 2023年9月

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) 査読有り国際誌

前田勇貴, 真下知士, 豊國伸哉

日本癌学会総会記事 82回巻頁： 504 - 504 2023年9月

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年8月

Ferroptosis As Ultimate Target of Cancer Therapy. 査読有り国際誌

Motooka Y, Toyokuni S

Antioxidants & redox signaling 39 巻 ( 1-3 ) 頁： 206 - 223 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Antioxidants and Redox Signaling

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

DOI： 10.1089/ars.2022.0048

Carbon nanotube recognition by human Siglec-14 provokes inflammation. 査読有り国際誌

Yamaguchi SI, Xie Q, Ito F, Terao K, Kato Y, Kuroiwa M, Omori S, Taniura H, Kinoshita K, Takahashi T, Toyokuni S, Kasahara K, Nakayama M

Nature nanotechnology 18 巻 ( 6 ) 頁： 628 - 636 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Nanotechnology

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. 査読有り国際誌 Open Access

Tsuji S, Brace CS, Yao R, Tanie Y, Tada H, Rensing N, Mizuno S, Almunia J, Kong Y, Nakamura K, Furukawa T, Ogiso N, Toyokuni S, Takahashi S, Wong M, Imai SI, Satoh A

Life science alliance 6 巻 ( 6 ) 2023年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Life Science Alliance

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 DMHPrdm13-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. 査読有り国際誌 Open Access

Ito F, Kato K, Yanatori I, Maeda Y, Murohara T, Toyokuni S

BMC cancer 23 巻 ( 1 ) 頁： 487 - 487 2023年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BMC Cancer

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 <sup>+/-</sup> 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. 査読有り国際誌 Open Access

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

Cancer science 114 巻 ( 4 ) 頁： 1423 - 1436 2023年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Science

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

DOI： 10.1111/cas.15705

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