研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Iron as Soul of Life on Earth Revisited: From Chemical Reaction, Ferroptosis to Therapeutics

Harigae Hideo, Hino Keisuke, Toyokuni Shinya

FREE RADICAL BIOLOGY AND MEDICINE 133 巻頁： 1-2 2019年3月

Effect of Non-Thermal Plasma on the Interface Between Skin and Surface Electrodes for Biological Signal Measurement 査読有り国際誌

Esaki T., Suzuki A., Shinozaki Y., Nomura K., Kagawa Y., Yamada M., Nakamura K., Tanaka H., Toyokuni S., Hori M., Mizuno M.

Plasma Processes and Polymers 22 巻 ( 12 ) 2025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：Plasma Processes and Polymers

Non-thermal plasma has potential applications in the medical field. In biological signal measurements using surface electrodes such as electrocardiograms and electroencephalograms, appropriate skin preparation is critical for acquiring high-quality signals. In this study, we demonstrated that the surface of porcine skin can be safely hydrophilized by irradiation with a plasma jet for only 5 s. We also investigated whether plasma treatment reduces skin-electrode contact impedance; however, no significant reduction was observed. Instead, the coefficient of variation of the impedance tended to decrease. This finding suggests the potential to improve measurement quality. Based on these results, further studies are warranted to explore the clinical application of plasma treatment.

DOI： 10.1002/ppap.70081

Scopus

Dual lipid modulation overcomes ferroptosis resistance in high-risk neuroblastoma. 査読有り国際誌 Open Access

Koeken I, Walravens M, Fernández-Acosta R, Van Hoyweghen R, Vintea I, Kong Y, Golba B, Dehairs J, Talebi A, Swinnen JV, Durinck K, Mañas A, Toyokuni S, Menschaert G, Fedorova M, De Geest BG, Hassannia B, Vanden Berghe T

Cell death and differentiation 2025年11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：Cell Death and Differentiation

Ferroptosis—an iron-dependent form of cell death triggered by phospholipid peroxidation—has emerged as a promising therapeutic avenue in cancer treatment. Although neuroblastoma (NB) has been identified as a ferroptosis susceptible cancer, our studies reveal striking heterogeneity in ferroptosis sensitivity across high-risk NB models. Through a targeted metabolic compound screen, we identified stearoyl-CoA desaturase 1 (SCD1)—a key enzyme in monounsaturated fatty acid (MUFA) synthesis—as a robust ferroptosis-sensitizing target. Genetic and pharmacological inhibition of SCD1 restored ferroptosis sensitivity in resistant NB cells. Notably, high SCD1 expression correlates with poor patient prognosis. Co-treatment with arachidonic acid (AA), a polyunsaturated fatty acid (PUFA), further enhanced ferroptotic cell death via increased PUFA/MUFA ratio. Nevertheless, neither baseline lipidomic profiles nor transcriptomes of key ferroptosis regulators reliably predicted ferroptosis sensitivity. To overcome AA’s poor solubility, we engineered AA-loaded lipid nanoparticles (AA-LNPs), which selectively accumulated in high-risk NB tumors and synergized with SCD1 inhibition. This dual-sensitization strategy, termed LipidSens, significantly suppressed tumor growth and induced ferroptosis in cell-derived xenograft mouse models without systemic toxicity. Together, these findings establish MUFA synthesis blockade and PUFA enrichment as a tumor-targeted, ferroptosis-enhancing strategy, and offer a nanomedicine-based therapeutic platform for high-risk NB.

DOI： 10.1038/s41418-025-01623-3

Open Access

Scopus

PubMed

Lunar life drives jawbone formation. 査読有り国際誌 Open Access

Sato K, Kouyama N, Akatsuka S, Motooka Y, Wang Q, Hibi H, Toyokuni S

Journal of dental sciences 20 巻 ( 4 ) 頁： 2399 - 2406 2025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：Journal of Dental Sciences

Background/purpose: The Japan Aerospace Exploration Agency bred mice in the “Kibo” module on the International Space Station to clarify the effects of gravity changes on the body. We determined the effects of lunar gravity (partial gravity, 1/6G) on the jawbone and elucidated its relationship with the oral cavity. Materials and methods: Mandibular bones of C57BL/6J male mice from the Kibo group (1/6G) and the Earth group (1G) were obtained. Ribonucleic acid was extracted from the samples; microarray and gene set enrichment analysis (GSEA) were performed; bone structure and histology were evaluated via micro-computed tomography, immunohistochemistry, and specific staining. Results: Microarray analysis revealed a significant increase in dentin matrix protein 1 (DMP1) expression in the 1/6G group. GSEA revealed enhanced Hedgehog signaling in this group. The weight and density of the cancellous bone were significantly greater in the 1/6G group than in the 1G group, as confirmed by histological analysis. Furthermore, the expression of insulin-like growth factor 1 (IGF-1), which is associated with mastication-induced bone formation, was increased in the 1/6G group. Although secreted phosphoprotein 1 (SPP1), which is associated with bone resorption under low mechanical stress, increased in the 1/6G group, receptor activator of nuclear factor kappa-B ligand (RANKL)-RANK signaling did not increase. No significant differences in the number or activity of osteoclasts were observed between the 1G and 1/6G groups. Conclusion: Bone formation, but not bone resorption, is promoted by lunar gravity and is associated with mastication. Proper oral management is necessary for extended lunar habitation.

DOI： 10.1016/j.jds.2025.03.032

Open Access

Scopus

PubMed

Differential cytotoxicity of plasma-treated arginine in breast cancer and normal cell lines: time-dependent effects and media-driven modulation 査読有り国際誌

Liyin D., Camelia M., Xizhuo D., Masaaki M., Shinya T., Hiroaki K., Masaru H., Hiromasa T.

Japanese Journal of Applied Physics Part 1 Regular Papers and Short Notes and Review Papers 64 巻 ( 9 ) 2025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：Japanese Journal of Applied Physics Part 1 Regular Papers and Short Notes and Review Papers

This study evaluated the selective cytotoxicity of plasma-treated arginine (PTA) in breast cancer (MCF-7) and normal mammary epithelial (MCF-10A) cells. Reactive oxygen and nitrogen species generation in PTA correlated with initial arginine concentration. Under serum-free conditions, PTA induced acute cancer cell death, while serum-containing medium attenuated this effect. Notably, PTA suppressed MCF-7 viability for up to 72 h without harming MCF-10A, suggesting delayed oxidative stress-mediated cytotoxicity. These results underscore the therapeutic potential of PTA and highlight the importance of medium conditions and extended observation periods in plasma medicine.

DOI： 10.35848/1347-4065/adfef0

Scopus

LRP2 is a potential molecular target for nonsyndromic pathological myopia 査読有り国際誌

Delaunay, K; Picard, E; Lassiaz, P; Jonet, L; Cannaya, V; Ruiz-Moreno, JM; Kojima, K; Vorum, H; Honore, B; Medrano, JR; Cehofski, LJ; Pussard, E; Kozyraki, R; Torriglia, A; Cases, O; Behar-Cohen, F

JCI INSIGHT 10 巻 ( 15 ) 2025年8月

Terrestrial iron sulfide minerals induce distinct regulation of intracellular redox homeostasis and iron assimilation. 査読有り国際誌 Open Access

Lyu Q, Kouketsu Y, Tazaki A, Kato M, Motooka Y, Toyokuni S

Ecotoxicology and environmental safety 298 巻頁： 118327 2025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：Ecotoxicology and Environmental Safety

Repeated exposure to airborne terrestrial natural minerals may cause pneumoconiosis and lung cancer, among which iron sulfide is identified as an aggravating factor. In the biological system, iron-sulfur cluster is an inorganic cofactor that is evolutionarily conserved in all the living organisms. Whereas ferrous iron catalyzes the generation of hydroxyl radicals, sulfur is indispensable as a component of antioxidants, such as glutathione. Imbalanced redox homeostasis contributes to oxidative stress, causing ferroptosis, an iron-dependent regulated necrosis characterized by lipid peroxidation, resulting in various disorders. We undertook this study to understand the cellular regulatory mechanisms against major terrestrial minerals containing iron and sulfur from the viewpoint of cellular redox. We used fundamental iron sulfide minerals collected from natural sources to treat human macrophage and fibroblast cells and investigated the biological responses. Alterations in sulfane sulfur, glutathione and iron have been analyzed using either specific fluorescent probes or inductively coupled plasma mass spectrometry. Iron sulfide microparticles with high Fe/S ratio (pyrrhotite; Fe<inf>1-X</inf>S) induced more reactive sulfane species and glutathione, with less catalytic iron inside cells, whereas the mineral with low Fe/S ratio (pyrite; FeS<inf>2</inf>) exhibited the opposite effects. Notably both showed cytotoxicity, where pyrite caused ferroptosis but pyrrhotite led to non-ferroptotic disruption. Furthermore, assimilated cellular excess iron was secreted via CD63(+) exosome containing iron-loaded ferritin to the extracellular space with higher iron content in pyrrhotite. Our findings suggest that iron and sulfur work complementarily in maintaining intracellular redox homeostasis, which would be crucial to understand the associated pathology.

DOI： 10.1016/j.ecoenv.2025.118327

Wavelength-dependency of the impact of light on proliferation and DNA damage of corneal cells in vitro 査読有り国際誌

Francon, A; Behar-Cohen, F; Torriglia, A

JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 264 巻 2025年3月

Repeated exposure to low doses of light induces retinal damage in vivo in a wavelength-dependent manner 査読有り国際誌

Françon, A; Jonet, L; Behar-Cohen, F; Torriglia, A

ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 290 巻 2025年1月

BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile-induced mesothelioma via ferroptosis resistance 査読有り国際誌

Luo, YG; Toyokuni, S

CANCER SCIENCE 116 巻頁： 193 - 193 2025年1月

Complementary Interplay of Iron and Sulfur: Implications for Cellular Redox Regulation 査読有り国際誌

Lyu, QY; Toyokuni, S; Kouketsu, Y

CANCER SCIENCE 116 巻頁： 1388 - 1388 2025年1月

BRCA1 haploinsufficiency interferes mitochondria under Fenton reaction-based carcinogenesis 査読有り国際誌

Kong, Y; Mashimo, T; Imaoka, T; Toyokuni, S

CANCER SCIENCE 116 巻頁： 648 - 648 2025年1月

Homozygous slc25a20 zebrafish mutant reveals insights into carnitine-acylcarnitine translocase deficiency pathogenesis. 査読有り国際誌 Open Access

Hishida R, Ishiguro K, Yamanaka T, Toyokuni S, Matsui H

Molecular genetics and metabolism reports 41 巻頁： 101165 2024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：Molecular Genetics and Metabolism Reports

The SLC25A20 gene encodes carnitine-acylcarnitine translocase (CACT), facilitating the transport of long-chain acylcarnitine required for energy production via β-oxidation into the mitochondria. Loss-of-function mutations in this gene lead to CACT deficiency, a rare autosomal recessive disorder of fatty acid metabolism characterized by severe symptoms including cardiomyopathy, hepatic dysfunction, rhabdomyolysis, hypoketotic hypoglycemia, and hyperammonemia, often resulting in neonatal mortality. Here, we utilized CRISPR/Cas9 gene editing to isolate slc25a20 mutant zebrafish. Homozygous mutants displayed significant lethality, with the majority succumbing before reaching maturity. However, we identified a notably rare homozygous individual that survived into adulthood, prompting a histological examination. Firstly, we observed adipose tissue accumulation at various sites in the homozygous mutant. The mutant heart exhibited hypertrophy, along with degenerated myocardial and muscle cells containing numerous eosinophilic nuclei. Additionally, we found no large oil droplet vacuoles in the mutant liver; however, the hepatocytes displayed numerous small vacuoles resembling lipid droplets. Iron deposition was evident in the spleen and parts of the liver. Overall, our slc25a20 zebrafish mutant displayed tissue pathologies analogous to human CACT deficiency, suggesting its potential as a pathological model contributing to the elucidation of pathogenesis and the improvement/development of therapies for CACT deficiency.

DOI： 10.1016/j.ymgmr.2024.101165

New era of plasma dentistry. 査読有り国際誌

Sato K, Tanaka H, Okazaki Y, Hori M, Hibi H, Toyokuni S

Free radical research 58 巻 ( 12 ) 頁： 868 - 874 2024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

Plasma, which was coined by Irving Langmuir in 1928, is the fourth physical state after the solid/liquid/gas phases. Low-temperature plasma (LTP) is a contradictory condition that involves high energy with free radicals at near-body temperatures and was developed through engineering in the 1990’s. Research on LTP in engineering and medical fields has rapidly developed since the 2000’s. LTP can be applied through direct or indirect exposure, and there are advantages to both methods. In the medical field, LTP has been found to exert several effects, such as wound healing, hemostasis and anticancer effects, mainly based on different levels of oxidative stress. In the dental field, studies have been performed on LTP applications for general dental procedures, such as restorative, periodontal and prosthodontic procedures, and for oral cancer treatment. Many studies have demonstrated the effectiveness of LTP. Compared with other organs, the anatomical characteristic of the oral cavity is easy direct observation, which is highly advantageous for clinical applications. Due to its good accessibility and efficiency, plasma dentistry is expected to be applied to various dental applications in clinics in the near future.

DOI： 10.1080/10715762.2024.2446323

Web of Science

Scopus

PubMed

Deficiency in glutathione peroxidase 4 (GPX4) results in abnormal lens development and newborn cataract. 査読有り国際誌 Open Access

Wei Z, Hao C, Radeen KR, Hao Z, Kettimuthu K, Maner-Smith K, Toyokuni S, Fan X

Proceedings of the National Academy of Sciences of the United States of America 121 巻 ( 48 ) 頁： e2407842121 2024年11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：Proceedings of the National Academy of Sciences of the United States of America

The human lens is composed of a monolayer of lens epithelial cells (LECs) and elongated fibers that align tightly but are separated by the plasma membrane. The integrity of the lens plasma membrane is crucial for maintaining lens cellular structure, homeostasis, and transparency. Glutathione peroxidase 4 (GPX4), a selenoenzyme, plays a critical role in protecting against lipid peroxidation. This study aims to elucidate the role of GPX4 in lens plasma membrane stability during lens development using in vitro, ex vivo, and in vivo systems. Our findings reveal that GPX4 deficiency triggers lens epithelial apoptosis-independent but ferroptosis-mediated cell death. Blocking lens GPX4 activity during ex vivo culture induces lens opacification, LEC death, and disruption of lens fiber cell arrangement. Deletion of lens-specific Gpx4 results in significant unsaturated phospholipid loss and an increase in oxidized phospholipids. Consequently, lenses with Gpx4 deficiency exhibit massive disruption of lens fiber cell structure, significant loss of LECs via ferroptosis, and formation of newborn cataracts. Remarkably, administering the lipid peroxidation inhibitor, liproxstatin-1, to pregnant mothers at embryonic days 9.5 significantly prevents lipid peroxidation, LEC death, and lens developmental defects. Our study unveils the crucial role of GPX4 in lens development and transparency, and also provides a successful intervention approach to prevent lens developmental defects through lipid peroxidation inhibition.

DOI： 10.1073/pnas.2407842121

Low-temperature plasma as a strategy to achieve SDGs. 査読有り国際誌

Tanaka H, Ishikawa K, Toyokuni S

Free radical research 58 巻 ( 10 ) 頁： 594 - 595 2024年10月

Glyburide confers neuroprotection against age-related macular degeneration (AMD) 査読有り国際誌

Picard, E; Youale, J; Hyman, MJ; Xie, ED; Achiedo, S; Kaufmann, GT; Moir, J; Daruich, A; Crisanti, P; Torriglia, A; Polak, M; Behar-Cohen, F; Skondra, D; Berdugo, M

TRANSLATIONAL RESEARCH 272 巻頁： 81 - 94 2024年10月

Growth promotion and disease tolerance in strawberry plants with plasma-activated Ringer’s lactate solution 査読有り国際誌

Sakai K., Matsubara Y., Hashizume H., Tanaka H., Toyokuni S., Hori M.

Acta Horticulturae 3 巻 ( 1404 ) 頁： 917 - 922 2024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：Acta Horticulturae

Recently, plasma-activated solutions have been attempted on biotic regulations mainly in medical aspects. In this study, effect of plasma-activated Ringer’s lactate solution (PAL) on disease (anthracnose, Fusarium wilt) tolerance and antifungal function in strawberry plants was investigated. Runner-derived strawberry (Fragaria × ananassa Duch. ‘Benihoppe’) plants were treated with Fuji-γ-PAL and Strong PAL (×100, ×300 dilution) to leaves or roots. Then, plants were inoculated with Colletotrichum fructicola (MAFF306788, 105 cfu mL-1); causable pathogen of anthracnose, or Fusarium oxysporum f. sp. fragariae (NRF0903, 106 cfu mL-1); pathogen of Fusarium wilt. Increase in dry weight of shoots occurred in Strong PAL 100-treated plants. Incidence and severity in symptoms of anthracnose and Fusarium wilt were alleviated in most of the PAL-treated plants in both diseases. In this case, Strong-PAL showed relatively higher suppression effect than Fuji-γ-PAL in both diseases. As for antifungal aspects in vitro using Czapek-Doc medium, both PALs suppressed Fusarium propagation; Strong PAL showed higher suppression effect compared to Fuji-γ-PAL. On the other hand, Strong PAL 100-treated plants showed higher DPPH radical scavenging activity in leaves among the treatments. These findings suggest that PAL induce growth promotion and disease tolerance in strawberry plants, and these effects differ with the method of PAL treatment.

DOI： 10.17660/ActaHortic.2024.1404.125

Scopus

特集フェロトーシス(鉄依存性細胞死)--そのメカニズムの解明と,治療への応用フェロトーシス抵抗性と発がん国際誌

前田勇貴, 豊國伸哉

医学のあゆみ 290 巻 ( 2 ) 頁： 174 - 177 2024年7月

Phototoxicity of low doses of light and influence of the spectral composition on human RPE cells 査読有り国際誌

Françon, A; Delaunay, K; Jaworski, T; Lebon, C; Picard, E; Youale, J; Behar-Cohen, F; Torriglia, A

SCIENTIFIC REPORTS 14 巻 ( 1 ) 2024年3月

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