Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Growth promotion and disease tolerance in strawberry plants with plasma-activated Ringer’s lactate solution Reviewed International journal

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

Acta Horticulturae Vol. 3 ( 1404 ) page： 917 - 922 2024.9

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

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 International journal

前田勇貴, 豊國伸哉

医学のあゆみ Vol. 290 ( 2 ) page： 174 - 177 2024.7

Special issue: Extracellular fine particles in life, death and disease. Reviewed International journal

Toyokuni S

Archives of biochemistry and biophysics Vol. 757 page： 110027 2024.7

International consensus guidelines for the definition, detection, and interpretation of autophagy-dependent ferroptosis. Reviewed International journal Open Access

Chen X, Tsvetkov AS, Shen HM, Isidoro C, Ktistakis NT, Linkermann A, Koopman WJH, Simon HU, Galluzzi L, Luo S, Xu D, Gu W, Peulen O, Cai Q, Rubinsztein DC, Chi JT, Zhang DD, Li C, Toyokuni S, Liu J, Roh JL, Dai E, Juhasz G, Liu W, Zhang J, Yang M, Liu J, Zhu LQ, Zou W, Piacentini M, Ding WX, Yue Z, Xie Y, Petersen M, Gewirtz DA, Mandell MA, Chu CT, Sinha D, Eftekharpour E, Zhivotovsky B, Besteiro S, Gabrilovich DI, Kim DH, Kagan VE, Bayir H, Chen GC, Ayton S, Lünemann JD, Komatsu M, Krautwald S, Loos B, Baehrecke EH, Wang J, Lane JD, Sadoshima J, Yang WS, Gao M, Münz C, Thumm M, Kampmann M, Yu D, Lipinski MM, Jones JW, Jiang X, Zeh HJ, Kang R, Klionsky DJ, Kroemer G, Tang D

Autophagy Vol. 20 ( 6 ) page： 1213 - 1246 2024.6

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

Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results. Abbreviation: 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.

DOI： 10.1080/15548627.2024.2319901

Fatal COVID-19 pulmonary disease involves ferroptosis. Reviewed International coauthorship International journal Open Access

Qiu B, Zandkarimi F, Saqi A, Castagna C, Tan H, Sekulic M, Miorin L, Hibshoosh H, Toyokuni S, Uchida K, Stockwell BR

Nature communications Vol. 15 ( 1 ) page： 3816 2024.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Nature Communications

Ferroptosis is a form of cell death that has been associated with different diseases. Here the authors describe an association of ferroptosis with COVID-19 pulmonary pathologies in both patient samples and hamster model and suggest that the dysregulation in iron and lipid metabolism could provide targets to reduce pathology.

DOI： 10.1038/s41467-024-48055-0

Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria. Reviewed International journal Open Access

Danyang Mi, Izumi Yanatori, Hao Zheng, Yingyi Kong, Tasuku Hirayama, Shinya Toyokuni

Free radical research Vol. 58 ( 4 ) page： 261 - 275 2024.3

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. Though 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

Elaborate cooperation of poly(rC)-binding proteins 1/2 and glutathione in ferroptosis induced by plasma-activated Ringer's lactate. Reviewed International journal Open Access

Jiang L, Zheng H, Ishida M, Lyu Q, Akatsuka S, Motooka Y, Sato K, Sekido Y, Nakamura K, Tanaka H, Ishikawa K, Kajiyama H, Mizuno M, Hori M, Toyokuni S

Free radical biology & medicine Vol. 214 page： 28 - 41 2024.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Free Radical Biology and Medicine

Reactive species are involved in various aspects of neoplastic diseases, including carcinogenesis, cancer-specific metabolism and therapeutics. Non-thermal plasma (NTP) can directly provide reactive species, by integrating atmospheric and interjacent molecules as substrates, to represent a handy strategy to load oxidative stress in situ. NTP causes apoptosis and/or ferroptosis specifically in cancer cells of various types. Plasma-activated Ringer's lactate (PAL) is another modality at the preclinical stage as cancer therapeutics, based on more stable reactive species. PAL specifically kills malignant mesothelioma (MM) cells, employing lysosomal ·NO as a switch from autophagy to ferroptosis. However, the entire molecular mechanisms have not been elucidated yet. Here we studied cytosolic iron regulations in MM and other cancer cells in response to PAL exposure. We discovered that cells with higher catalytic Fe(II) are more susceptible to PAL-induced ferroptosis. PAL caused a cytosolic catalytic Fe(II)-associated pathology through iron chaperones, poly (rC)-binding proteins (PCBP)1/2, inducing a disturbance in glutathione-regulated iron homeostasis. PCBP1/NCOA4-mediated ferritinophagy started at a later phase, further increasing cytosolic catalytic Fe(II), ending in ferroptosis. In contrast, PCBP2 after PAL exposure contributed to iron loading to mitochondria, leading to mitochondrial dysfunction. Therapeutic effect of PAL was successfully applied to an orthotopic MM xenograft model in mice. In conclusion, PAL can selectively sensitize MM cells to ferroptosis by remodeling cytoplasmic iron homeostasis, where glutathione and PCBPs play distinct roles, resulting in lethal ferritinophagy and mitochondrial dysfunction. Our findings indicate the clinical application of PAL as a ferroptosis-inducer and the potential of PCBPs as novel targets in cancer therapeutics.

DOI： 10.1016/j.freeradbiomed.2024.02.001

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

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

Free radical research Vol. 58 ( 2 ) page： 130 - 143 2024.2

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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

Science and Applications of Plasma-Activated Solutions: Current Trends and Future Directions Reviewed International coauthorship International journal

Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Camelia Miron, Yasumasa Okazaki, Shinya Toyokuni, Kae Nakamura, Hiroaki Kajiyama, Masafumi Ito, Masaru Hori

Plasma Medicine Vol. 14 ( 1 ) page： 67 - 76 2024

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

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

Cold Atmospheric Pressure Plasma-Activated Liquids for Cancer Treatment Reviewed International coauthorship International journal

Miron C., Hiromasa T., Britun N., Hashizume H., Ishikawa K., Du L., Yamakawa T., Kurebayashi Y., Kondo T., Kondo H., Kajiyama H., Toyokuni S., Mizuno M., Hori M.

IFMBE Proceedings Vol. 111 IFMBE page： 150 - 162 2024

Language：English Publishing type：Research paper (scientific journal) Publisher：IFMBE Proceedings

Low-temperature plasma (LTP) is a promising tool that can assist in cancer treatment. Plasma-treated liquids have shown a selective cytotoxic effect on cancer cells attributed to reactive species formed in discharge, but this mechanism is not completely understood. In this study, the chemical compounds formed by plasma irradiation of Ringer’s lactate solutions and their effects on non-tumorigenic breast epithelial cells (MCF-10A) and breast cancer cells (MCF-7) were investigated. Among these compounds, glyceric acid increased the cell viability by more than two-fold compared to the control samples for MCF-10A and MCF-7 cells, whereas the tricarballylic acid had a pronounced cytotoxic effect on the cells when incubated with solutions of 0.6 mM to 50 mM concentrations. A good selectivity in killing the cancer cells was observed when the chemical compounds identified in plasma-treated liquids (such as ethyl acetate, glyceric acid, and tricarballylic acid) were used in a mixture solution of a certain concentration. The results show that the LTP-generated chemical compounds have both, stimulatory and inhibitory effects on cell viability, and the best selectivity is achieved only when these compounds are combined in a certain amount and have a synergistic effect, completely killing only the cancer cells.

DOI： 10.1007/978-3-031-62523-7_17

Selective Killing of Human Breast Cancer Cells by Plasma-Treated L-Arginine Solution Reviewed International coauthorship International journal Open Access

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

Plasma Processes and Polymers 2024

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

Retinal ferroptosis as a critical mechanism for the induction of retinochoroiditis during ocular toxoplasmosis. Reviewed International journal Open Access

Yamada K, Tazaki A, Ushio-Watanabe N, Usui Y, Takeda A, Matsunaga M, Suzumura A, Shimizu H, Zheng H, Ariefta NR, Yamamoto M, Hara H, Goto H, Sonoda KH, Nishiguchi KM, Kato M, Nishikawa Y, Toyokuni S, Kaneko H

Redox biology Vol. 67 page： 102890 2023.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Redox Biology

Toxoplasmosis is a major infectious disease, affecting approximately one-third of the world's population; its main clinical manifestation, ocular toxoplasmosis (OT), is a severe sight-threatening disease. Nevertheless, the diagnosis of OT is based on clinical findings, which needs improvement, even with biochemical tests, such as polymerase chain reaction and antibody detections. Furthermore, the efficacy of OT-targeted treatment is limited; thus, additional measures for diagnosis and treatments are needed. Here, we for the first time report a significantly reduced iron concentration in the vitreous humor (VH) of human patients infected with OT. To obtain further insights into molecular mechanisms, we established a mouse model of T. gondii infection, in which intravitreally injected tracer 57Fe, was accumulated in the neurosensory retina. T. gondii-infected eyes showed increased lipid peroxidation, reduction of glutathione peroxidase-4 expression and mitochondrial deformity in the photoreceptor as cristae loss. These findings strongly suggest the involvement of ferroptotic process in the photoreceptor of OT. In addition, deferiprone, an FDA-approved iron chelator, reduced the iron uptake but also ameliorated toxoplasma-induced retinochoroiditis by reducing retinal inflammation. In conclusion, the iron levels in the VH could serve as diagnostic markers and iron chelators as potential treatments for OT.

DOI： 10.1016/j.redox.2023.102890

Three-dimensional regulation of ferroptosis at the intersection of iron, sulfur and oxygen executing scrap and build toward evolution. Reviewed International journal

Shinya Toyokuni, Yingyi Kong, Hao Zheng, Yuki Maeda, Misako Katabuchi, Yashiro Motooka

Antioxidants & redox signaling Vol. 39 ( 10-12 ) page： 807 - 815 2023.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. 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 ferroptosis-resistance, based on rodent animal studies. 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. Whereas life attempts to prevent ferroptosis, ferroptotic cells eventually emit iron-loaded ferritin as extracellular vesicles to maintain monopoly of iron.

DOI： 10.1089/ars.2022.0142

Carbon nanotube recognition by human Siglec-14 provokes inflammation. Reviewed International journal

Shin-Ichiro Yamaguchi, Qilin Xie, Fumiya Ito, Kazuki Terao, Yoshinobu Kato, Miki Kuroiwa, Satoshi Omori, Hideo Taniura, Kengo Kinoshita, Takuya Takahashi, Shinya Toyokuni, Kota Kasahara, Masafumi Nakayama

Nature nanotechnology Vol. 18 ( 6 ) page： 628 - 636 2023.6

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

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

BRCA1 haploinsufficiency impairs iron metabolism to promote chrysotile-induced mesothelioma via ferroptosis-resistance. Reviewed International journal Open Access

Yaguang Luo, Shinya Akatsuka, Yashiro Motooka, Yingyi Kong, Hao Zheng, Tomoji Mashimo, Tatsuhiko Imaoka, Shinya Toyokuni

Cancer science Vol. 114 ( 4 ) page： 1423 - 1436 2023.4

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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-strand 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 thus 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 to 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 to wild-type tumors. Mutant MMs indicated iron metabolism dysregulation, such as increase in catalytic Fe(II) and Ki67-index as well as 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 to crocidolite/Mut whereas significant preference to iron with 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

Commentary on "Mechanisms of asbestos-induced carcinogenesis" published in 2009. Reviewed International journal

Toyokuni S

Nagoya journal of medical science Vol. 85 ( 1 ) page： 13 - 15 2023.2

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Nagoya Journal of Medical Science

Respiratory exposure to asbestos fibers has been associated with diffuse malignant mesothelioma (DMM) in humans. Despite advancements in the molecular analyses of human DMM and the development of animal models, the carcinogenic mechanisms of the disease remain unclear. There are basically three hypotheses regarding the pathogenesis of asbestos-induced DMM, which may be summarized as follows: (1) the “oxidative stress theory” is based on the fact that phagocytic cells that engulf asbestos fibers produce large amounts of free radicals due to their inability to digest the fibers, and epidemiological studies indicating that iron-containing asbestos fibers appear more carcinogenic; (2) the “chromosome tangling theory” postulates that asbestos fibers damage chromosomes when cells divide; and (3) the “theory of adsorption of many specific proteins as well as carcinogenic molecules” states that asbestos fibers in vivo concentrate proteins or chemicals including the components of cigarette smoke. Elucidation of the major mechanisms underlying DMM would be helpful for the development of novel strategies to prevent DMM induction in people who have already been exposed to asbestos

DOI： 10.18999/nagjms.85.1.13

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

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

Toyokuni S, Kong Y, Motooka Y, Akatsuka S

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

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Genes and Environment

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

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

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

Authorship：Last author,　Corresponding author 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

Iron as spirit of life to share under monopoly. Reviewed 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

Authorship：Last author,　Corresponding author 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

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