Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Field-effect transistor antigen/antibody-TMDs sensors for the detection of COVID-19 samples. Reviewed International journal Open Access

Ruben Canton-Vitoria, Kotaro Sato, Yashiro Motooka, Shinya Toyokuni, Zheng Liu, Ryo Kitaura

Nanoscale Vol. 15 ( 9 ) page： 4570 - 4580 2023.3

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

We fabricated sensors by modifying the surface of MoS2 and WS2 with COVID-19 antibodies and investigated their characteristics, including stability, reusability, sensitivity, and selectivity. Thiols and disulfanes in antibodies strongly interact with vacant Mo or W sites of MoS2 or WS2, yielding durable devices that are stable for several days in the air or water. More importantly, detachment of the antibodies is suppressed even during the aggressive cleaning process of the devices at pH 3, which allows reusing the same device in several experiments without appreciable loss of sensitivity. Therefore, the nanodevice may be employed in samples of different patients. Further, we found a limit of detection (LOD) of 1 fg ml-1 at room temperature, time responses of 1 second, and selectivity against interferences such as KLH protein or Albumin.

DOI： 10.1039/d2nr06630k

BRCA2生殖細胞系列変異が卵巣予備能低下へ及ぼす影響について 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. 112 ( 1 ) page： 370 - 370 2023.3

卵巣における細胞外小胞を介した鉄代謝と酸化ストレス応答の解析 Reviewed International journal

加藤大暉, 本岡大社, 豊國伸哉

日本病理学会会誌 Vol. 112 ( 1 ) page： 382 - 382 2023.3

タルクによる細胞外小胞を介した卵巣の鉄代謝の撹乱と発がん性 Reviewed International journal

本岡大社, 加藤大暉, 豊國伸哉

日本病理学会会誌 Vol. 112 ( 1 ) page： 256 - 256 2023.3

BRCA2変異は腎臓において鉄代謝を変化させ、フェロトーシス抵抗性を獲得する Reviewed International journal

前田勇貴, 真下知士, 豊國伸哉

日本病理学会会誌 Vol. 112 ( 1 ) page： 338 - 338 2023.3

DNA oxidative damage caused by the aromatic amine MOCA —Examination of 8-hydroxy-2’-deoxyguanosine levels in rat liver— International journal

KOBAYASHI Saho, MOTOOKA Yashiro, KASHIWAGI Hiroki, TOYOKUNI Shinya

Journal of Occupational Safety and Health Vol. 16 ( 1 ) page： 45 - 49 2023.2

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：National Institute of Occupational Safety and Health, Japan

<p>MOCA (4,4’-methylenebis (2-chloroaniline)) , an aromatic amine, is industrially used as a curing agent for urethane resins; however, it is classified as a Group 1 compound (carcinogenic to humans) by the International Agency for Research on Cancer, and there is concern regarding its health effects on workers. The mechanism underlying MOCA-mediated carcinogenesis is thought to be related to DNA damage caused by reactive oxygen species (ROS) and DNA adducts, which are mainly generated during metabolism in the liver. 8-Oxoguanine (8-OHdG), a product of ROS-induced oxidation, occurs at high frequency and can induce G→T transversion mutations during DNA replication. However, to the best of our knowledge, no study has examined whether MOCA induces the formation of highly mutagenic 8-OHdG in experimental animals. Here, F344 rats were orally exposed to 0, 0.4, 2, 10, or 50 mg/kg/day MOCA three times a week for 2 weeks; this is expected to exert toxicity through the hepatic metabolism of MOCA. Livers obtained from these animals were examined for pathology and 8-OHdG levels. In pathological sections, vacuolar degeneration was observed with 50 mg/kg/day MOCA. Further, MOCA-induced 8-OHdG levels showed a slight increasing trend, except at 0.4 mg/kg/day. However, none of these differences were significant. Thus, 8-OHdG is unlikely the main cause of carcinogenesis.</p>

DOI： 10.2486/josh.josh-2022-0022-ta

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Cancer-specific cytotoxicity of Ringer’s acetate solution irradiated by cold atmospheric pressure plasma Reviewed International journal Open Access

Camelia Miron, Kenji Ishikawa, Satoshi Kashiwagura, Yuki Suda, Hiromasa Tanaka, Kae Nakamura, Hiroaki Kajiyama, Shinya Toyokuni, Masaaki Mizuno, Masaru Hori

Free Radical Research Vol. 57 ( 2 ) page： 91 - 104 2023.2

Environmental impact on carcinogenesis under BRCA1 haploinsufficiency. Reviewed International journal Open Access

Shinya Toyokuni, Yingyi Kong, Yashiro Motooka, Shinya Akatsuka

Genes and environment : the official journal of the Japanese Environmental Mutagen Society Vol. 45 ( 1 ) page： 2 - 2 2023.1

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

Cancer is the primary cause of human mortality in Japan since 1981. Although numerous novel therapies have been developed and applied in clinics, the number of deaths from cancer is still increasing worldwide. It is time to consider the strategy of cancer prevention more seriously. Here we propose a hypothesis that cancer can be side effects of long time-use of iron and oxygen and that carcinogenesis is an evolution-like cellular events to obtain "iron addiction with ferroptosis-resistance" where genes and environment interact each other. Among the recognized genetic risk factors for carcinogenesis, we here focus on BRCA1 tumor suppressor gene and how environmental factors, including daily life exposure and diets, may impact toward carcinogenesis under BRCA1 haploinsufficiency. Although mice models of BRCA1 mutants have not been successful for decades in generating phenotype mimicking the human counterparts, a rat model of BRCA1 mutant was recently established that reasonably mimics the human phenotype. Two distinct categories of oxidative stress, one by radiation and one by iron-catalyzed Fenton reaction, promoted carcinogenesis in Brca1 rat mutants. Furthermore, mitochondrial damage followed by alteration of iron metabolism finally resulted in ferroptosis-resistance of target cells in carcinogenesis. These suggest a possibility that cancer prevention by active pharmacological intervention may be possible for BRCA1 mutants to increase the quality of their life rather than preventive mastectomy and/or oophorectomy.

DOI： 10.1186/s41021-023-00258-5

Exposure of low-temperature plasma after vaccination in tongue promotes systemic IgM induction against spike protein of SARS-CoV-2. Reviewed International journal Open Access

Kotaro Sato, Kouki Fujii, Hiromasa Tanaka, Masaru Hori, Hideharu Hibi, Shinya Toyokuni

Free radical research Vol. 57 ( 1 ) page： 30 - 37 2023.1

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

COVID-19 has been pandemic since 2020 with persistent generation of new variants. Cellular receptor for SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), where transmembrane serine protease-2 (TMPRSS2) is essential for viral internalization. We recently reported abundant expression of ACE2 and TMPRSS2 in the oral cavity of humans and mice. Therefore, oral cavity may work for COVID-19 infection gates. Here we undertook to evaluate whether vaccination in the tongue harbors any merit in comparison to subcutaneous injection. Low-temperature plasma (LTP) is the fourth physical state of matters with ionization above gas but at body temperature. LTP provides complex chemistry, eventually supplying oxidative and/or nitrosative stress on the interface. LTP-associated cellular death has been reported to cause apoptosis and/or ferroptosis. However, there is few data available on immunogenicity retention after LTP exposure. We therefore studied the effect of LTP exposure after the injection of keyhole limpet hemocyanin (KLH) or spike 2 protein of SARS-CoV-2 to the tongue of six-week-old male BALB/c mice, compared to subcutaneous vaccination. Whereas LTP did not change the expression of ACE2 and TMPRSS2 in the tongue, repeated LTP exposure after tongue vaccination significantly promoted systemic and specific IgM production at day 11. In contrast, repeated LTP exposure after subcutaneous vaccination of KLH decreased systemic IgM production. Of note, tongue injection produced significantly higher titer of IgM and IgG in the case of KLH. In conclusion, LTP significantly reinforced humoral immunity by IgM after tongue injection. Vaccination to the tongue can be a novel strategy to acquire immediate immunity.

DOI： 10.1080/10715762.2023.2190486

Low-temperature plasma as magic wand to differentiate between the good and the evil. Reviewed International journal Open Access

Shinya Toyokuni, Hao Zheng, Yingyi Kong, Kotaro Sato, Kae Nakamura, Hiromasa Tanaka, Yasumasa Okazaki

Free radical research Vol. 57 ( 1 ) page： 38 - 46 2023.1

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

Plasma is the fourth physical state of matter, characterized by an ionized gaseous mixture, after solid, liquid, and gas phases, and contains a wide array of components such as ions, electrons, radicals, and ultraviolet ray. Whereas the sun and thunder are typical natural plasma, recent progress in the electronics enabled the generation of body-temperature plasma, designated as low-temperature plasma (LTP) or non-thermal plasma since the 1990s. LTP has attracted the attention of researchers for possible biological and medical applications. All the living species on earth utilize water as essential media for solvents and molecular transport. Thus, biological application of LTP naturally intervenes water whether LTP is exposed directly or indirectly, where plasma-activated lactate (PAL) is a standard, containing H2O2, NO2- and other identified molecules. Electron spin resonance and immunohistochemical studies demonstrated that LTP exposure is a handy method to load local oxidative stress. Cancer cells are characterized by persistent self-replication and high cytosolic catalytic Fe(II). Therefore, both direct exposure of LTP and PAL can provide higher damage to cancer cells in comparison to non-tumorous cells, which has been demonstrated in a variety of cancer types. The cell death mode is either apoptosis or ferroptosis, depending on the cancer-type. Thus, LTP and PAL are expected to work as an additional cancer therapy to the established guideline protocols, especially for use in somatic cavities or surgical margins.

DOI： 10.1080/10715762.2023.2190860

Extracellular fine particles and carcinogenesis Reviewed International journal

Toyokuni Shinya

Vol. 95 ( 2 ) page： 177 - 183 2023

Thioredoxin deficiency increases oxidative stress and causes bilateral symmetrical degeneration in rat midbrain. Reviewed International journal Open Access

Iori Ohmori, Mamoru Ouchida, Hirohiko Imai, Saeko Ishida, Shinya Toyokuni, Tomoji Mashimo

Neurobiology of disease Vol. 175 page： 105921 - 105921 2022.12

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

Thioredoxin, encoded by Txn1, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of thioredoxin in the central nervous system (CNS) is largely unknown. A phenotype-driven study of N-ethyl-N-nitrosourea-mutated rats with wild-running seizures revealed the importance of Txn1 mutations in CNS degeneration. Genetic mapping identified Txn1-F54L in the epileptic rats. The insulin-reducing activity of Txn1-F54L was approximately one-third of that of the wild-type (WT). Bilateral symmetrical vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the Txn1-F54L rats. The lesions displayed neuronal and oligodendrocytic cell death. Neurons in Txn1-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration peaked at five weeks of age, and spontaneous repair began at seven weeks. The TUNEL assay showed that fibroblasts derived from homozygotes were susceptible to cell death under oxidative stress. In five-week-old WT rats, energy metabolism in the thalamus was significantly higher than that in the cerebral cortex. In conclusion, in juvenile rats, Txn1 seems to play an essential role in reducing oxidative stress in the midbrains with high energy metabolism.

DOI： 10.1016/j.nbd.2022.105921

RhoA and vigilin are candidates for immunohistochemical markers for epithelioid malignant mesothelioma. International journal Open Access

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

Scientific reports Vol. 12 ( 1 ) page： 18519 2022.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

Diagnostic markers of malignant mesothelioma (MM) have been extensively investigated. Immunohistochemistry (IHC) markers, such as calretinin, have been used for pathologic diagnosis. However, more diagnostic markers are required to improve the specificity and sensitivity of pathologic diagnosis. This study proposed two proteins as diagnostic markers for epithelioid MM. One is RhoA, an MM mutation-susceptible locus-derived protein, and another is vigilin, a lung small cell carcinoma marker. IHC was performed using 93 MM (epithelioid, 71 cases; sarcomatoid, 13 cases; and biphasic, 9 cases), 64 lung adenocarcinoma (LAC), 60 lung squamous cell carcinoma (LSC), and 14 normal mesothelial (NM) tissues. The majority of epithelioid MM cases were positive for both RhoA and vigilin, whereas both IHCs showed lower stainability in biphasic and sarcomatoid MM. Besides, both IHCs showed significantly higher stainability for RhoA and vigilin in epithelioid MM than in LAC and LSC (p < 0.05). Chi-square tests showed that both RhoA and vigilin IHC positive rate in epithelioid MM was not significantly different from that of calretinin (p > 0.05). In the differential diagnosis of MM from lung cancer, the accuracy and specificity of RhoA, vigilin, and calretinin staining were almost equivalent. Further, H-score test showed that there was no significant difference between RhoA versus calretinin and vigilin versus calretinin in IHC positivity in epithelioid MM (p > 0.05). In conclusion, RhoA and vigilin may be candidates for immunohistochemical markers for epithelioid MM.

DOI： 10.1038/s41598-022-20334-0

Molecular hydrogen has a positive impact on pregnancy maintenance through enhancement of mitochondrial function and immunomodulatory effects on T cells. Reviewed International journal

Chieko Aoki, Kenji Imai, Teruyuki Mizutani, Daisuke Sugiyama, Rika Miki, Yoshihiro Koya, Tomoko Kobayashi, Takafumi Ushida, Yukako Iitani, Noriyuki Nakamura, Taro Owaki, Hiroyoshi Nishikawa, Shinya Toyokuni, Hiroaki Kajiyama, Tomomi Kotani

Life sciences Vol. 308 page： 120955 - 120955 2022.11

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

AIMS: Molecular hydrogen (H2) has attracted growing interest because of its implications in various diseases. However, the molecular mechanisms underlying the remarkable effect of a small amount of H2 remain elusive. No knowledge has been available on the role of H2 in the etiology of pregnancy disorders or its direct influence on human immune cells. Since maternal immunity, T cells in particular, plays a critical role in pregnancy maintenance. We investigated the effects of H2 on T cells and its relation to preterm birth (PTB). MAIN METHODS: Exhaled H2 concentrations in pregnant women were measured and correlated with cytokine concentrations in maternal and umbilical cord blood. H2 was added to T cells collected from healthy donors, and differentiation and proliferation were examined. Energy metabolism was also examined. H2 was administered to mice and cytokine expression was compared. KEY FINDINGS: Our prospective observational study revealed that maternal production of H2 is significantly lower in pregnant women with PTB, suggesting its potential as a biomarker for predicting PTB. We found that H2 has clear associations with several maternal cytokines, and acts as an immunomodulator by exerting mitochondrial function in human T cells. Moreover, in vivo administration of H2 to pregnant mice regulated inflammatory responses and reduced PTB caused by T cell activation, which further supports the notion that H2 may contribute to prolonged gestation through its immunomodulatory effect. SIGNIFICANCE: Measuring maternal H2-production could be a potential clinical tool in the management of PTB, and H2 may have positive impact on pregnancy maintenance.

DOI： 10.1016/j.lfs.2022.120955

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PubMed

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Commentary for an article on photooxidation in isolated chloroplasts. Reviewed International journal

Shinya Toyokuni, Yingyi Kong, Danyang Mi

Archives of biochemistry and biophysics Vol. 726 page： 109133 - 109133 2022.9

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

This commentary concerns a highly cited paper by Robert L Heath and Lester Packer in Archives of Biochemistry and Biophysics published in 1968. Chloroplasts are organelles in algae and plants that use light energy for carbon fixation and oxygen production. These authors discovered that isolated chloroplasts exposed to visible light undergo a cyclic peroxidation of tri-unsaturated fatty acids, contributing to the double-edged sword concept of electron transfer reactions.

DOI： 10.1016/j.abb.2022.109133

Iron as spirit of life to share under monopoly. Open Access

Shinya Toyokuni, Yingyi Kong, Hao Zheng, Yuki Maeda, Yashiro Motooka, Shinya Akatsuka

Journal of clinical biochemistry and nutrition Vol. 71 ( 2 ) page： 78 - 88 2022.9

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

Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multi-system organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.

DOI： 10.3164/jcbn.22-43

Association of alcohol intake and female gender with high expression of TMPRSS2 in tongue as potential risk for SARS-CoV-2 infection International journal Open Access

Kotaro Sato, Koki Fujii, Noriyuki Yamamoto, Norihisa Ichimura, Satoshi Yamaguchi, Hirohisa Yamada, Hideharu Hibi, Shinya Toyokuni

Journal of Clinical Biochemistry and Nutrition Vol. 71 ( 2 ) page： 129 - 135 2022.9

Language：English Publishing type：Research paper (scientific journal) Publisher：The Society for Free Radical Research Japan

<p>COVID-19 is pandemic since 2020 and further information is necessary on the risk factors associated with the infection of SARS-CoV-2. As an entry mechanism, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as receptor and transmembrane serine protease 2 (TMPRSS2) to activate fusion with host plasma membrane. Because dysgeusia is an early symptom of COVID-19, we here studied the expression of ACE2 and TMPRSS2 in the tongue and the associated tissues of mice and humans with immunohistochemistry and immunoblot analysis. ACE2 expression was low in the human tongue but was observed in the squamous epithelium, perineurium, arterial wall, salivary glands as well as taste buds. In contrast, mice showed high expression. In sharp contrast, TMPRSS2 expression was high in all the cells mentioned above in humans but relatively low in mice except for salivary glands. We then performed semi-quantitation of immunohistochemistry data of human ACE2 and TMPRSS2 and analyzed for age, sex, alcohol intake, and smoking habit with logistic regression analysis. We found that alcohol intake and female gender were the significant risk factors for increasing TMPRSS2 expression. In conclusion, TMPRSS2 is an important factor to be considered regarding SARS-CoV-2 entry and amplification in the oral cavity, which is promoted through drinking habit.</p>

DOI： 10.3164/jcbn.21-172

環境因子であるタルクおよびアスベストの卵巣発がん性とゲノム毒性の検討(Carcinogenic genome toxicity of environmental factors, asbestos and talc in ovary)

本岡大社, 鬼丸洸, 鈴木洋, 片渕充沙子, 近藤英治, 田代浩徳, 片渕秀隆, 豊國伸哉

日本癌学会総会記事 Vol. 81回 page： P - 2007 2022.9

プラズマ活性化された乳酸リンゲルに誘導されたフェロトーシスにおけるpcbp1/2とグルタチオンとの協同作用(Cooperation of Poly(rC)-binding Proteins 1/2 and Glutathione in Ferroptosis Induced by Plasma-activated Ringer's Lactate)

鄭好, 蒋麗, 呂沁穎, 赤塚慎也, 本岡大社, 関戸好孝, 中村香江, 田中宏昌, 石川健治, 梶山広明, 水野正明, 堀勝, 豊國伸哉

日本癌学会総会記事 Vol. 81回 page： E - 2004 2022.9

個別化予防医療・先制医療 BRCA1のハプロ不全は、腎臓発がん過程において、フェロトーシス抵抗性を獲得することにより染色体増幅を促進する(BRCA1 haploinsufficiency promotes chromosomal amplification under renal carcinogenesis through ferroptosis-resistance)

孔穎怡, 赤塚慎也, 本岡大社, 鄭好, 白木之浩, 真下知士, 今岡達彦, 豊國伸哉

日本癌学会総会記事 Vol. 81回 page： S20 - 7 2022.9

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Papers - TOYOKUNI Shinya