Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Cancer Treatments Using Low-Temperature Plasma. International journal

Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Shinya Toyokuni, Hiroaki Kajiyama, Fumitaka Kikkawa, Masaru Hori

Current medicinal chemistry Vol. 28 ( 41 ) page： 8549 - 8558 2021

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

Low-temperature plasma (LTP) is a partially ionized gas that contains electrons, ions, radicals, light, etc. Recently, the bio-medical application of LTP has become a hot topic in plasma science and biological science. Cancer treatment with plasma is the most challenging topic in plasma bio-medical applications. Many in vitro and in vivo experiments have been conducted to investigate the anti-tumor effects of LTP. Extracellular reactive oxygen and nitrogen species (RONS) in plasma-activated solutions are key factors for the anti-tumor effects, and amino acid modifications by LTP may affect cellular responses. Intracellular RONS are also key factors for the anti-tumor effects. Various signaling pathways, such as p53 signaling pathways, survival and proliferation signaling pathways, and oxidative stress-dependent signaling pathways are activated by LTP.

DOI： 10.2174/0929867328666210629121731

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Mechanisms of toxicity caused by carbon nanotubes

YAMAGUCHI Shin-Ichiro, MORITA Masanobu, ITO Fumiya, XIE Qilin, TOYOKUNI Shinya, NAKAYAMA Masafumi

Annual Meeting of the Japanese Society of Toxicology Vol. 48.1 ( 0 ) page： O-4 - 4 2021

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Toxicology

Multi-walled carbon nanotubes (MWCNTs), the highly representative products of nanotechnology, induce macrophage cell death and NLRP3 inflammasome activation leading to granuloma and mesothelioma in rodents; however, it remains unknown how macrophages recognize MWCNTs. By a target screening of phagocyte receptors, we here demonstrated that T cell immunoglobulin mucin 4 (Tim4) and Tim1 recognize MWCNTs. Using Tim4-/- Tim1-/- mice, we revealed that Tim4 is involved in MWCNT-associated pathogenesis. Taken together, these results indicate that Tim4 and Tim1 are receptors for MWCNTs.

DOI： 10.14869/toxpt.48.1.0_o-4

CiNii Research

The new era for research on polyphenols and food factors International journal

Oteiza P.I.

Archives of Biochemistry and Biophysics Vol. 696 2020.12

The new era for redox research. International journal

Yuji Naito, Koji Uchida, Shinya Toyokuni

Free radical research Vol. 54 ( 11-12 ) page： 787 - 789 2020.12

Neural stem cell-specific ITPA deficiency causes neural depolarization and epilepsy. International journal

Yuichiro Koga, Daisuke Tsuchimoto, Yoshinori Hayashi, Nona Abolhassani, Yasuto Yoneshima, Kunihiko Sakumi, Hiroshi Nakanishi, Shinya Toyokuni, Yusaku Nakabeppu

JCI insight Vol. 5 ( 22 ) 2020.11

Language：English Publishing type：Research paper (scientific journal) Publisher：American Society for Clinical Investigation

Inosine triphosphate pyrophosphatase (ITPA) hydrolyzes inosine triphosphate (ITP) and other deaminated purine nucleotides to the corresponding nucleoside monophosphates. In humans, ITPA deficiency causes severe encephalopathy with epileptic seizure, microcephaly, and developmental retardation. In this study, we established neural stem cell-specific Itpa-conditional KO mice (Itpa-cKO mice) to clarify the effects of ITPA deficiency on the neural system. The Itpa-cKO mice showed growth retardation and died within 3 weeks of birth. We did not observe any microcephaly in the Itpa-cKO mice, although the female Itpa-cKO mice did show adrenal hypoplasia. The Itpa-cKO mice showed limb-clasping upon tail suspension and spontaneous and/or audiogenic seizure. Whole-cell patch-clamp recordings from entorhinal cortex neurons in brain slices revealed a depolarized resting membrane potential, increased firing, and frequent spontaneous miniature excitatory postsynaptic current and miniature inhibitory postsynaptic current in the Itpa-cKO mice compared with ITPA-proficient controls. Accumulated ITP or its metabolites, such as cyclic inosine monophosphates, or RNA containing inosines may cause membrane depolarization and hyperexcitability in neurons and induce the phenotype of ITPA-deficient mice, including seizure.

DOI： 10.1172/jci.insight.140229

Carcinogenesis as Side Effects of Iron and Oxygen Utilization: From the Unveiled Truth toward Ultimate Bioengineering. International journal

Shinya Toyokuni, Yingyi Kong, Zhen Cheng, Kotaro Sato, Shotaro Hayashi, Fumiya Ito, Li Jiang, Izumi Yanatori, Yasumasa Okazaki, Shinya Akatsuka

Cancers Vol. 12 ( 11 ) page： 1 - 20 2020.11

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

Simple Summary: Cancer is a major cause of human mortality worldwide. No life on earth can live without iron. Persistent oxidative stress resulting from continuous use of iron and oxygen may be a fundamental cause of carcinogenesis. Many animal models demonstrated that excess iron may lead to carcinogenesis. This is supported by a variety of human epidemiological data on cancer risk and prognosis. Cancer is basically a disease of the genome with persistently activated oncogenes and inactivated tumor suppressor genes through which iron addiction with ferroptosis-resistance is established. We predict that fine use of nanomaterials and non-thermal plasma may be able to reverse this situation.Evolution from the first life on earth to humans took similar to 3.8 billion years. During the time there have been countless struggles among the species. Mycobacterium tuberculosis was the last major uncontrollable species against the human public health worldwide. After the victory with antibiotics, cancer has become the leading cause of death since 1981 in Japan. Considering that life inevitably depends on ceaseless electron transfers through iron and oxygen, we believe that carcinogenesis is intrinsically unavoidable side effects of using iron and oxygen. Many animal models unequivocally revealed that excess iron is a risk for carcinogenesis. This is supported by a variety of human epidemiological data on cancer risk and prognosis. Cancer is basically a disease of the genome with persistently activated oncogenes and inactivated tumor suppressor genes through which iron addiction with ferroptosis-resistance is maintained. Engineering has made a great advance in the past 50 years. In particular, nanotechnology is distinct in that the size of the engineered molecules is similar to that of our biomolecules. While some nano-molecules are found carcinogenic, there are principles to avoid such carcinogenicity with a smart possibility to use nano-molecules to specifically kill cancer cells. Non-thermal plasma is another modality to fight against cancer.

DOI： 10.3390/cancers12113320

Induction of cancer cell-specific ferroptosis by non-thermal plasma exposure

Okazaki Yasumasa, Toyokuni Shinya

JAPANESE JOURNAL OF APPLIED PHYSICS Vol. 59 ( 11 ) 2020.11

Induction of cancer cell-specific ferroptosis by non-thermal plasma exposure International journal

Okazaki Y.

Japanese Journal of Applied Physics Vol. 59 ( 11 ) 2020.11

The new role of poly (rC)-binding proteins as iron transport chaperones: Proteins that could couple with inter-organelle interactions to safely traffic iron International journal

Yanatori I.

Biochimica et Biophysica Acta - General Subjects Vol. 1864 ( 11 ) 2020.11

Adjusted multiple gases in the plasma flow induce differential antitumor potentials of plasma-activated solutions International journal

Nakamura K.

Plasma Processes and Polymers Vol. 17 ( 10 ) 2020.10

Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice International journal

Nishio M.

Cancer Science Vol. 111 ( 10 ) page： 3576 - 3587 2020.10

Novel ovarian endometriosis model causes infertility via iron-mediated oxidative stress in mice International journal

Hayashi S.

Redox Biology Vol. 37 2020.10

アスベストとタルクは鉄過剰環境を形成し卵巣がんの発がんに関わる

本岡大社, 伊藤文哉, 田代浩徳, 片渕秀隆, 豊國伸哉

日本癌学会総会記事 Vol. 79回 page： OJ1 - 1 2020.10

Asbestos conceives Fe(II)-dependent mutagenic stromal milieu through ceaseless macrophage ferroptosis and β-catenin induction in mesothelium International journal

Ito F.

Redox Biology Vol. 36 2020.9

Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma International journal

Ohara Y.

Oncology Reports Vol. 44 ( 3 ) page： 838 - 848 2020.9

Role of carbonic anhydrases in ferroptosis-resistance International journal

Li Z.

Archives of Biochemistry and Biophysics Vol. 689 2020.8

Ferroptosis at the crossroads of infection, aging and cancer International journal

Toyokuni S.

Cancer Science Vol. 111 ( 8 ) page： 2665 - 2671 2020.8

Non-thermal plasma-activated lactate solution kills U251SP glioblastoma cells in an innate reductive manner with altered metabolism International journal

Ishikawa Kenji, Hosoi Yugo, Tanaka Hiromasa, Jiang Li, Toyokuni Shinya, Nakamura Kae, Kajiyama Hiroaki, Kikkawa Fumitaka, Mizuno Masaaki, Hori Masaru

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS Vol. 688 2020.7

Overexpression of miR-199/214 is a distinctive feature of iron-induced and asbestos-induced sarcomatoid mesothelioma in rats International journal

Okazaki Y.

Cancer Science Vol. 111 ( 6 ) page： 2016 - 2027 2020.6

Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats. Reviewed International journal

Yasumasa Okazaki, Nobuaki Misawa, Shinya Akatsuka, Norihiko Kohyama, Yoshitaka Sekido, Takashi Takahashi, Shinya Toyokuni

Cancer science Vol. 111 ( 4 ) page： 1180 - 1192 2020.4

Publishing type：Research paper (scientific journal)

The onset of malignant mesothelioma (MM) is linked to exposure to asbestos fibers. Asbestos fibers are classified as serpentine (chrysotile) or amphibole, which includes the crocidolite, amosite, anthophyllite, tremolite, and actinolite types. Although few studies have been undertaken, anthophyllite has been shown to be associated with mesothelioma, and tremolite, a contaminant in talc and chrysotile, is a risk factor for carcinogenicity. Here, after characterizing the length and width of these fibers by scanning electron microscopy, we explored the cytotoxicity induced by tremolite and anthophyllite in cells from an immortalized human mesothelial cell line (MeT5A), murine macrophages (RAW264.7), and in a rat model. Tremolite and short anthophyllite fibers were phagocytosed and localized to vacuoles, whereas the long anthophyllite fibers were caught on the pseudopod of the MeT5A and Raw 264.7 cells, according to transmission electron microscopy. The results from a 2-day time-lapse study revealed that tremolite was engulfed and damaged the MeT5A and RAW264.7 cells, but anthophyllite was not cytotoxic to these cells. Intraperitoneal injection of tremolite in rats induced diffuse serosal thickening, whereas anthophyllite formed focal fibrosis and granulomas on peritoneal serosal surfaces. Furthermore, the loss of Cdkn2a/2b, which are the most frequently lost foci in human MM, were observed in 8 cases of rat MM (homozygous deletion [5/8] and loss of heterozygosity [3/8]) by array-based comparative genomic hybridization techniques. These results indicate that tremolite initiates mesothelial injury and persistently frustrates phagocytes, causing subsequent peritoneal fibrosis and MM. The possible mechanisms of carcinogenicity based on fiber diameter/length are discussed.

DOI： 10.1111/cas.14358

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Papers - TOYOKUNI Shinya