研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Mysterious link between iron overload and CDKN2A/2B. 国際誌 Open Access

Toyokuni S

Journal of clinical biochemistry and nutrition 48 巻 ( 1 ) 頁： 46 - 9 2011年1月

担当区分：最終著者,　責任著者記述言語：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

Persistent oxidative stress has been associated with carcinogenesis. Iron overload is considered one such condition that causes oxidative stress. Epidemiological studies support a close link between iron overload and carcinogenesis. Reportedly, regular semiannual phlebotomies reduced cancer risk in an otherwise normal population. More specifically, genetic hemochromatosis, chronic viral hepatitis, ovarian endometriosis and asbestosis induce iron overload, which can lead to hepatocellular carcinoma, ovarian carcinoma or mesothelioma in humans. Through a combination of animal experiments and microarray analyses, homozygous deletion of CDKN2A/2B has been recognized as one of the major target genes involved in iron overload-induced carcinogenesis. CDKN2A/2B are the second most frequently inactivated tumor suppressing genes in human cancers. Currently, when infection is becoming sufficiently controlled worldwide, iron regulation may be the next target for human longevity. ©2011 JCBN.

DOI： 10.3164/jcbn.11-001FR

Asbestos-induced Carcinogenesis is Oxidative Stress-dependent 査読有り国際誌

Toyokuni, S; Jiang, L; Nagai, H; Ohara, H; Okazaki, Y; Akatsuka, S; Yamashita, Y

FREE RADICAL BIOLOGY AND MEDICINE 49 巻頁： S72 - S72 2010年

Spaciotemporal alteration of 8-hydroxy-2'-deoxyguanosine levels in cardiomyocytes after myocardial infarction in rats. 査読有り国際誌 Open Access

Miwa S, Toyokuni S, Nishina T, Nomoto T, Hiroyasu M, Nishimura K, Komeda M

Free radical research 36 巻 ( 8 ) 頁： 853 - 8 2002年8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

Temporary or persistent heart failure is one of the major complications after myocardial infarction (MI). In order to elucidate the pathogenesis of MI, we studied the spaciotemporal alteration of 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in cardiomyocytes in a rat model of ligation of the left anterior descending branch of the coronary artery. The lethality in this model was 18%. Hearts were dissected at 0, 3, 6, 12, 24, 48h, and 1, 2, 4, 6 weeks after the operation. The cardiac level of 8-OHdG was evaluated biochemically as well as by immunohistochemistry with monoclonal antibody N45.1. Three to 6h after ligation, the 8-OHdG levels were increased in the cardiomyocytes of MI (six-fold) and peri-MI (four-fold) areas. After 24h, the myocardium in the MI area was necrotized, and thereafter the 8-OHdG level decreased. 8-OHdG levels in the myocardium of peri-MI areas returned once to a normal level, but were significantly increased at 2-4 weeks along with the appearance of apoptotic cardiomyocytes in this area. The heart after MI has been generally considered as clinically stable after four weeks. However, cardiomyocytes near the infarcted area were oxidatively stressed even after four weeks when the affected lesion was extensive. The present data support the use of supplementary antioxidant therapies to save functional myocardium after MI. (213 words).

DOI： 10.1081/1071576021000005285

Endogenous formation of protein adducts with carcinogenic aldehydes - Implications for oxidative stress 査読有り国際誌

Ichihashi K, Osawa T, Toyokuni S, Uchida K

JOURNAL OF BIOLOGICAL CHEMISTRY 276 巻 ( 26 ) 頁： 23903 - 23913 2001年6月

Antioxidant alpha-tocopherol improves glycemic control of GK rats, a model of type 2 diabetes 査読有り国際誌

Ihara Y, Yamada Y, Toyokuni S, Ban N, Kuroe A, Seino Y

DIABETES 49 巻頁： A429 - A429 2000年5月

4-hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress - Identification of proteasomes as target molecules 査読有り国際共著国際誌

Okada K, Wangpoengtrakul C, Osawa T, Toyokuni S, Tanaka K, Uchida K

JOURNAL OF BIOLOGICAL CHEMISTRY 274 巻 ( 34 ) 頁： 23787 - 23793 1999年8月

8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure (vol 107, pg 733, 1996) 査読有り国際誌

Hattori, Y, Nishigori, C, Tanaka, T, Uchida, K, Nikaido, O, Osawa, T, Hiai, H, Imamura, S, Toyokuni, S

JOURNAL OF INVESTIGATIVE DERMATOLOGY 108 巻 ( 2 ) 頁： 237 - 237 1997年2月

ACUTE NEPHROTOXICITY OF A CARCINOGENIC IRON CHELATE - SELECTIVE-INHIBITION OF A PROTEOLYTIC CONVERSION OF ALPHA(2U)-GLOBULIN TO THE KIDNEY FATTY-ACID-BINDING PROTEIN 査読有り国際誌

UCHIDA K, FUKUDA A, KAWAKISHI S, TOYOKUNI S, HIAI H, IKEDA S, HORIO F

FEBS LETTERS 357 巻 ( 2 ) 頁： 165 - 167 1995年1月

L-ascorbate prevents non-alcoholic steatohepatitis-based hepatocarcinogenesis in Sod1/Prdx4 double-knockout mice. 査読有り国際誌 Open Access

Osaki T, Homma T, Maeda Y, Yamada KI, Yokoyama C, Toyokuni S, Fujii J

Scientific reports 15 巻 ( 1 ) 頁： 44312 - 44312 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：Scientific Reports

Superoxide dismutase 1 (Sod1) and peroxiredoxin 4 (Prdx4) double knockout (DKO) causes symptoms similar to non-alcoholic steatohepatitis (NASH) even at younger ages. This study revealed that DKO mice exhibited high mortality, and surviving DKO mice developed hepatocellular carcinoma within the first year of life. Administration of physiological doses of L-ascorbate (Asc; 1.5 mg/mL) in drinking water reduced mortality and effectively prevented tumor development. Oxidative stress due to SOD1 deficiency and endoplasmic reticulum stress due to PRDX4 deficiency may promote NASH, ultimately leading to hepatocarcinogenesis. Analyses of liver tissues from 8-month-old DKO mice revealed that Asc supplementation robustly suppressed upregulation of amino acid metabolic pathways observed in DKO mice. These findings suggest that upregulation of amino acid metabolic pathways may be important for the hepatocarcinogenesis. An iron-regulatory protein and aconitase activity were decreased in DKO mice regardless of Asc status. Furthermore, precancerous lesions were more reactive to a ferroptosis-specific antibody than tumor lesions. These results suggest that Asc supplementation and aberrant iron metabolism selectively induce the death of cells that lead to tumorigenic proliferation at the precancerous stage. Adequate intake of Asc in daily life may improve the tumorigenic process promoted by hepatic steatosis due to oxidative insult.

DOI： 10.1038/s41598-025-28982-8

Editorial note 査読有り国際誌

Dong A., Barat A., Toyokuni S.

International Journal of Biological Macromolecules 334 巻 2025年12月

Selective Killing of Human Breast Cancer Cells by Plasma-Treated L-Arginine Solution 査読有り国際誌 Open Access

Du L., Miron C., Kondo T., Kumagai J., Mizuno M., Toyokuni S., Kajiyama H., Hori M., Tanaka H.

Plasma Processes and Polymers 22 巻 ( 4 ) 2025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：Plasma Processes and Polymers

l-arginine is a nonessential amino acid that plays an important role in normal immune function and can be used as an adjuvant treatment for cancers. The antitumor effect of nonequilibrium atmospheric pressure plasma treated l-arginine solutions (PTA) was investigated in this research. The cancer-specific killing effect of PTA on human breast epithelial cells (MCF-10A) and human breast cancer cells (MCF-7) was proved. Liquid chromatography-tandem mass spectrometry was used to analyze the organic compounds formed in PTA, and their effects were individually evaluated by MTS assay, revealing that some compounds inhibited cell proliferation but lacked selectivity. PTA's selective cytotoxicity may result from a mixture of various compounds formed in plasma combined in a certain concentration.

DOI： 10.1002/ppap.202400192

Susceptibility of Brca1((L63X/+)) rat to ovarian reserve dissipation by chemotherapeutic agents to breast cancer. 査読有り国際誌 Open Access

Kaseki S, Sonehara R, Motooka Y, Tanaka H, Nakamura T, Osuka S, Akatsuka S, Kajiyama H, Mashimo T, Imaoka T, Toyokuni S

Cancer science 116 巻 ( 4 ) 頁： 1139 - 1152 2025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

BRCA1 is one of the causative genes for hereditary breast and ovarian cancer syndrome with a high risk of early-onset breast cancer. Whereas olaparib (OLA), an inhibitor of poly-ADP-ribose polymerase, has been applied as adjuvant therapy to those cancer patients, its effect on ovarian reproductive function remains unelucidated. Recently, a rat model (MUT; Brca1(L63X/+) mutation) mimicking a human BRCA1 pathogenic variant has been established. Using this model, we evaluated the effects of OLA on ovarian reproductive function in comparison with the wild-type (WT) rats. MUT showed a significantly reduced number of primordial follicles and subfertility in accordance with aging. Oxidative stress was significantly elevated in the young MUT granulosa cells (GCs) accompanied by increased mTOR but decreased PTEN signals. OLA administration in MUT further decreased primordial follicles, with gene set enrichment analysis, indicating upregulated DNA repair pathways. Furthermore, a combination of OLA and cyclophosphamide (CPA) induced empty primordial follicles, recognized as CPA-induced severe ovarian toxicity. Whereas OLA + CPA caused greater reduction in primordial follicles both in MUT and WT in comparison with CPA alone, MUT ovaries were more susceptible to oxidative stress, potentially depleting primordial follicles via activation of GCs and inducing oocyte death due to accumulated DNA damage by OLA treatment. Our findings in this preclinical model underscore the importance of evaluating ovarian reserve prior to chemotherapy by performing reproductive consultation with female patients with BRCA1 pathogenic variants.

DOI： 10.1111/cas.16412

Selenoprotein-mediated redox regulation shapes the cell fate of HSCs and mature lineages. 査読有り国際誌 Open Access

Aoyama Y, Yamazaki H, Nishimura K, Nomura M, Shigehiro T, Suzuki T, Zang W, Tatara Y, Ito H, Hayashi Y, Koike Y, Fukumoto M, Tanaka A, Zhang Y, Saika W, Hasegawa C, Kasai S, Kong Y, Minakuchi Y, Itoh K, Yamamoto M, Toyokuni S, Toyoda A, Ikawa T, Takaori-Kondo A, Inoue D

Blood 145 巻 ( 11 ) 頁： 1149 - 1163 2025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：Blood

The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of messenger RNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we used selenocysteine transfer RNA (tRNASec) gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs’ self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. Although Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.

DOI： 10.1182/blood.2024025402

BRCA2変異は酸化ストレス起因性の腎発癌を促進しないが鉄誘導性のCDKN2A欠失を促進する(BRCA2 mutation do not promote oxidative stress-induced renal carcinogenesis but CDKN2A deletion) 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 114 巻 ( 1 ) 頁： 379 - 379 2025年3月

Silicone oil, an intraocular surgical adjuvant, induces retinal ferroptosis. 査読有り国際誌 Open Access

Shimizu H, Tanaka H, Tazaki A, Yamada K, Suzumura A, Ota J, Ushio-Watanabe N, Zheng H, Kataoka K, Hara H, Nishikawa Y, Yasukawa T, Suzuma K, Terasaki H, Nishiguchi KM, Kato M, Toyokuni S, Kaneko H

Free radical biology & medicine 228 巻頁： 33 - 43 2025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 Biology and Medicine

Vitrectomy with silicone oil (SO) endotamponade is an effective treatment for vision-threatening retinal diseases. However, unexplained vision impairment has been reportedly critical side effects. Previously, we reported that the eyes with ocular toxoplasmosis showed retinal ferroptosis with the clinical sign of reduced intravitreal iron (Fe). We also found that total iron levels in sub-silicone oil fluid (SOF) in eyes with SO endotamponade were significantly reduced. We hypothesized that the cause of complications related to SO endotamponade is retinal ferroptosis and that low total iron in SOF is a secondary change that occurs similarly to the changes in ocular toxoplasmosis. In this study, we measured total iron levels in ocular fluid from patients, rabbits with SO endotamponade. Retinal iron taken up from the SOF was evaluated using laser ablation inductively coupled plasma mass spectrometry in human and rabbit eyes. Retinal ferroptosis was confirmed by immunohistochemistry of 4-hydrox-2-nonenal-modified proteins, FeRhoNox-1 staining, western blotting and RT-PCR. We found low total iron levels in the SOF, increased oxidative stress and Fe uptake from the SOF into the retinae of human and rabbit eyes, as well as decreased GPx4 expression, increased FeRhoNox-1 signals and altered Fe-related gene expression in SO-filled rabbit eyes. Of note, the target of ferroptosis was Müller cells. We generated an in vitro silicone oil-filled eye model using MIO-M1 cells (a human Müller cell line). The in vitro SO-filled eye model showed decreased GPx4 expression and increased intracellular catalytic Fe(II), an increase in ferroptosis, prevention of cell death by ferrostatin-1, a ferroptosis inhibitor, and altered Fe-related gene expression. These results indicate that the cause of complications related to SO endotamponade was the induction of retinal (Müller cell) ferroptosis, which can be prevented by ferrostatin-1.

DOI： 10.1016/j.freeradbiomed.2024.12.039

Decoding the molecular enigma behind asbestos and fibrous nanomaterial-induced carcinogenesis. 国際誌 Open Access

Toyokuni S, Kong Y

Journal of occupational health 67 巻 ( 1 ) 頁： n/a 2025年1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 Occupational Health

Objectives: The natural fibrous mineral, asbestos, has been useful in industry for many centuries. In the 1960s, epidemiology recognized the association between asbestos exposure and mesothelioma, and in 1987 the International Agency for Research on Cancer designated all kinds of asbestos as Group 1 carcinogens. However, various scientific enigmas remained regarding the molecular mechanisms of asbestos-induced mesothelial carcinogenesis. This review article was undertaken to reveal and summarize recent discoveries to resolve those enigmas. Methods: We collected recent important findings from our own laboratory and others to explain why mesothelial cells are the target for asbestos-induced carcinogenesis and what are the key molecular mechanisms. Results: The long incubation period of 30-40 years for mesothelial carcinogenesis after asbestos exposure allows the asbestos fibers to go through the pulmonary parenchyma from the central to peripheral portions and ultimately reach the parietal mesothelium by piercing visceral pleura. Asbestos fibers have affinity for hemoglobin and histones, thus accumulating iron on the surface while traveling through the lung. Mesothelial cells are phagocytic cells, engulfing iron-coated asbestos fibers. Accordingly, homozygous deletion of the p16INK4a tumor suppressor gene, a signature of excess iron-induced carcinogenesis, is acquired through oxidative DNA damage. Recently, exosome-dependent iron transfer from asbestos-fed macrophages to mesothelial cells was reported. Similar molecular mechanisms are observed with multiwalled carbon nanotubes of ∼50-nm diameter. Conclusions: Physical dimensions, biopersistence, and affinity to iron/histones are essential for fibrous material to be carcinogenic to mesothelial cells. Therefore, local iron reduction may be a strategy to prevent mesothelial carcinogenesis.

DOI： 10.1093/joccuh/uiae064

Heterozygous mutation in BRCA2 induces accelerated age-dependent decline in sperm quality with male subfertility in rats. 査読有り国際誌 Open Access

Motooka Y, Tanaka H, Maeda Y, Katabuchi M, Mashimo T, Toyokuni S

Scientific reports 15 巻 ( 1 ) 頁： 447 - 447 2025年1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：Scientific Reports

Tumor suppressor BRCA2 executes homologous recombination to repair DNA double-strand breaks in collaboration with RAD51, involving exon 11 and 27. Exon 11 constitutes a region where pathogenic variants (PVs) accumulate, and mutations in this region are known to contribute to carcinogenesis. However, the impact of the heterozygous PVs of BRCA2 exon 11 on the life quality beyond cancer risk, including male fertility, remains unclear. Here, we established a rat model with a frameshift on the seventh BRC repeat in Brca2 exon 11 (Brca2+/p.T1942fs), which is homologous to human BRCA2+/p.T1974fs, using CRISPR/Cas9 system. Our analyses revealed that the heterozygous rats with the PV in the BRCA2 exon 11 showed increased DNA double-strand breaks and apoptosis in spermatogonia and spermatocytes, accelerated testicular germ cell loss, and deterioration in sperm quality according with aging, ultimately resulting in early male reproductive dysfunction. Of note, these alterations in testes and sperm, including DNA fragmentation in spermatozoa, were observed from completion of sexual maturation. The present findings suggest that it is crucial to consider not only cancer risk but also potential declines in reproductive capacity in men carrying BRCA2 exon 11 PVs. Further investigation is warranted to determine whether similar traits appear in humans.

DOI： 10.1038/s41598-024-84184-8

細胞外微粒子が鉄代謝と酸化ストレスに及ぼす影響と発がんへの関与査読有り国際誌

本岡大社, 豊國伸哉

大気環境学会誌 60 巻 ( 1 ) 頁： A32 - A38 2025年1月

BRCA2 mutant induce ferroptosis resistance via AKT and promote cell cycle under Fenton reaction-based carcinogenesis 査読有り国際誌

Maeda, Y; Mashimo, T; Toyokuni, S

CANCER SCIENCE 116 巻頁： 875 - 875 2025年1月

Cold plasma irradiation of chitosan: A straight pathway to selective antitumor therapy. 査読有り国際誌 Open Access

Miron C, Andreica B, Iftime MM, Fifere A, Yamakawa T, Toyokuni S, Mizuno M, Tartau LM, Bejan A, Motooka Y, Kondo T, Sava I, Harabagiu V, Kumagai J, Tanaka A, Tanaka H, Marin L, Hori M

International journal of biological macromolecules 281 巻 ( Pt 4 ) 頁： 136513 - 136513 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：International Journal of Biological Macromolecules

Plasma-activated chitosan (PAC) colloids for cancer treatment were obtained by using the cold atmospheric plasma technique. Chitosan solutions were irradiated by plasma ignited in argon gas and in a mixture of argon with nitrogen and oxygen gases in certain ratios. The structural modifications of chitosan and the chemical species generated in plasma were investigated by EPR, LC-MS/MS, XRD, DLS, and TGA methods. The cell viability test showed a selective cytotoxic effect on human breast carcinoma cells (MCF-7), while the human mammary epithelial cells (MCF-10A) were left unharmed. The cytotoxic effect was attributed mainly to chitooligosaccharides, but also to a synergistic effect with other compounds generated in very low concentrations in plasma, such as glyceric acid, ethyl acetate, or tricarballylic acid. The plasma irradiation improved the antioxidant activity and mucoadhesivity, while not affecting the hemocompatibility investigated by a standard hemolysis ex vivo test on mice blood. Moreover, the in vivo biocompatibility investigation at intraperitoneal administration of PAC in mice showed no statistically significant changes in the hematologic, biochemical, and immune system parameters, and no morphologic alterations of the liver and kidney. All these data indicate the cold plasma activation of chitosan as a straight method to produce biocompatible, antitumor systems.

DOI： 10.1016/j.ijbiomac.2024.136513

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論文 - 豊國　伸哉