研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Effects of autophagy on the selective death of human breast cancer cells exposed to plasma-activated Ringer's lactate solution. 査読有り国際誌

Yamakawa T, Tanaka A, Miron C, Nakamura K, Kajiyama H, Toyokuni S, Mizuno M, Hori M, Tanaka H

Free radical research 58 巻 ( 11 ) 頁： 758 - 769 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：Free Radical Research

Plasma-activated Ringer’s lactate (PAL) solution prepared by irradiating an intravenous solution with a non-equilibrium atmospheric pressure plasma is a potential new cancer therapy having no side effects. However, the induction of autophagy to avoid cell death has been confirmed to occur following exposure to PAL solution. It is thought that the antitumor effect of PAL solution could be weakened by this process, which is meant to maintain homeostasis in cells and assists tumorigenesis. Thus, it would be helpful to devise PAL-based cancer therapies that inhibit autophagy. Unfortunately, it is not yet clear which substances in PAL solution promote autophagy. The present work examined the mechanism by which PAL solution induces autophagy when treating MCF-7 human breast cancer cells. Autophagy was found to be temporarily induced upon exposure to PAL solution, suggesting that this effect contributes to cell proliferation. Although autophagy is associated with reactive oxygen and nitrogen species and/or acidic environments, in this study, significant autophagy was observed using a PAL solution diluted 1/256x without these stressors. Acetate, glyoxylate and 2,3-dimethyltartrate in the PAL solution were determined to promote autophagy. Interestingly, 2,3-dimethyltartrate was found to either induce cell death or autophagy depending on the concentration.

DOI： 10.1080/10715762.2024.2433965

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.病理形態解析支援てんかん,神経変性症および慢性腎臓病モデル動物としてのTxn1遺伝子変異ラットの樹立査読有り国際誌

大守(川﨑) 伊織, 大内田守, 真下知士, 豊國伸哉

生体の科学 75 巻 ( 5 ) 頁： 454 - 455 2024年10月

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) 査読有り国際誌

豊國伸哉

生体の科学 75 巻 ( 5 ) 頁： 438 - 439 2024年10月

Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease. 国際誌

Peleman C, Hellemans S, Veeckmans G, Arras W, Zheng H, Koeken I, Van San E, Hassannia B, Walravens M, Kayirangwa E, Beyene NT, Van Herck MA, De Vos WH, Pintelon I, van Nassauw L, Oosterlinck B, Smet A, Vits L, Dirinck E, Verrijken A, De Man J, Van Eyck A, Kwanten WJ, Vonghia L, Driessen A, Augustyns K, Toyokuni S, De Winter B, Van Steenkiste C, Francque S, Vanden Berghe T

Cell death and differentiation 31 巻 ( 9 ) 頁： 1113 - 1126 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：Cell Death and Differentiation

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD. (Figure presented.)

DOI： 10.1038/s41418-024-01348-9

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Ferroptosis induced by plasma-activated Ringer's lactate solution prevents oral cancer progression. 国際誌 Open Access

Sato K, Yang M, Nakamura K, Tanaka H, Hori M, Nishio M, Suzuki A, Hibi H, Toyokuni S

Oral diseases 30 巻 ( 6 ) 頁： 3912 - 3924 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：Oral Diseases

Objective: This study aimed to investigate the effect of plasma-activated Ringer's lactate solution (PAL) on oral squamous cell carcinoma (OSCC) cells and carcinogenic processes with a particular focus on iron and collagenous matrix formation. Materials and Methods: We used three OSCC cell lines, one keratinocyte cell line, and two fibroblast lines, and cell viability assays, immunoblotting, flow cytometry, and transmission electron microscopy were performed to evaluate the effect and type of cell death. The effect of PAL treatment on lysyl oxidase (LOX) expression was investigated in vitro and in vivo. Tamoxifen-inducible Mob1a/b double-knockout mice were used for the in vivo experiment. Results: PAL killed OSCC cells more effectively than the control nontumorous cells and suppressed cell migration and invasion. Ferroptosis occurred and the protein level of LOX was downregulated in cancer cells in vitro and in vivo. Additionally, PAL improved the survival rate of mice and suppressed collagenous matrix formation. Conclusions: We demonstrated that PAL specifically kills OSCC cells and that ferroptosis occurs in vitro and in vivo. Furthermore, PAL can prevent carcinogenesis and improve the survival rate of oral cancer, especially tongue cancer, by changing collagenous matrix formation via LOX suppression.

DOI： 10.1111/odi.14827

BRCA2変異は酸化ストレス発がん環境下でAKTを介したフェロトーシス抵抗性を誘導し細胞周期を促進する(BRCA2 mutant induce ferroptosis resistance via AKT and promote cell cycle under Fenton reaction-based carcinogenesis) 査読有り国際誌

前田勇貴, 真下知士, 豊國伸哉, 豊國伸哉

日本癌学会総会記事 83回巻頁： P - 2013 2024年9月

Special issue: Extracellular fine particles in life, death and disease. 国際誌

Toyokuni S

Archives of biochemistry and biophysics 757 巻頁： 110027 2024年7月

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

Takemura S, Minamiyama Y, Ito N, Yamamoto A, Ichikawa H, Nakagawa K, Toyokuni S, Osada-Oka M, Yoshikawa T

Journal of clinical biochemistry and nutrition 75 巻 ( 1 ) 頁： 78 - 89 2024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：Journal of Clinical Biochemistry and Nutrition

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国際誌

豊國伸哉

医学のあゆみ 289 巻 ( 4 ) 頁： 263 - 266 2024年4月

Protocol for the isolation of GFP-expressing ferroptosis-dependent extracellular vesicles in in vitro cell culture models. 査読有り国際誌 Open Access

Ito F, Yanatori I, Kato K, Toyokuni S

STAR protocols 5 巻 ( 1 ) 頁： 102892 - 102892 2024年3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：STAR Protocols

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

Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria. 査読有り国際誌 Open Access

Mi D, Yanatori I, Zheng H, Kong Y, Hirayama T, Toyokuni S

Free radical research 58 巻 ( 4 ) 頁： 261 - 275 2024年3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

Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here, we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S-transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC–MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Although direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.

DOI： 10.1080/10715762.2024.2340711

BRCA2 mutation promotes ferroptosis resistance via suppression of p53 査読有り国際誌

Maeda, Y; Mashimo, T; Toyokuni, S

CANCER SCIENCE 115 巻頁： 504 - 504 2024年3月

Formalin-Fixed Paraffin-Embedded Proteomics of Malignant Mesothelioma and New Candidate Biomarkers Thioredoxin and Superoxide Dismutase 2 for Immunohistochemistry. 国際誌 Open Access

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

Laboratory investigation; a journal of technical methods and pathology 104 巻 ( 2 ) 頁： 100299 2024年2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：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

Brca2((p.T1942fs/+)) dissipates ovarian reserve in rats through oxidative stress in follicular granulosa cells. 国際誌 Open Access

Tanaka H, Motooka Y, Maeda Y, Sonehara R, Nakamura T, Kajiyama H, Mashimo T, Toyokuni S

Free radical research 58 巻 ( 2 ) 頁： 130 - 143 2024年2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

Pathogenic variants of BRCA1/2 constitute hereditary breast and ovarian cancer (HBOC) syndrome, and BRCA1/2 mutant is a risk for various cancers. Whereas the clinical guideline for HBOC patients has been organized for the therapy and prevention of cancer, there is no recommendation on the female reproductive discipline. Indeed, the role of BRCA1/2 pathogenic variants in ovarian reserve has not been established due to the deficiency of appropriate animal models. Here, we used a rat model of Brca2(p.T1942fs/+) mutant of Sprague-Dawley strain with CRISPR-Cas9 editing to evaluate ovarian reserve in females. Fertility and ovarian follicles were evaluated and anti-Müllerian hormone (AMH) was measured at 8–32 weeks of age with a comparison between the wild-type and the mutant rats (MUT). MUT revealed a significantly smaller number of deliveries with fewer total pups. Furthermore, MUT showed a significant decrease in primordial follicles at 20 weeks and a low AMH level at 28 weeks. RNA-sequencing of the ovary at 10 weeks detected acceleration of the DNA damage repair pathway, which was accompanied by oxidative stress-induced DNA double-strand breaks, a decrease in PTEN, and an increase in mTOR in follicular granulosa cells. In conclusion, Brca2(p.T1942fs/+) dissipates primordial follicles via early activation of granulosa cells through oxidative stress, leading to earlier termination of fertility.

DOI： 10.1080/10715762.2024.2320405

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) 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

日本病理学会会誌 113 巻 ( 1 ) 頁： 428 - 429 2024年2月

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) 査読有り国際誌

本岡大社, 豊國伸哉

日本病理学会会誌 113 巻 ( 1 ) 頁： 194 - 194 2024年2月

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

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