研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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Role of Iron, Oxygen and Ferroptosis in Tumor Evolutionary Biology 査読有り国際誌

Toyokuni, S; Kong, Y; Luo, Y; Zheng, H; Motooka, Y; Akatsuka, S

FREE RADICAL BIOLOGY AND MEDICINE 208 巻頁： S112 - S112 2023年11月

Retinal ferroptosis as a critical mechanism for the induction of retinochoroiditis during ocular toxoplasmosis. 査読有り国際誌 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 67 巻頁： 102890 2023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：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

Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression. 査読有り国際誌 Open Access

Van San E, Debruyne AC, Veeckmans G, Tyurina YY, Tyurin VA, Zheng H, Choi SM, Augustyns K, van Loo G, Michalke B, Venkataramani V, Toyokuni S, Bayir H, Vandenabeele P, Hassannia B, Vanden Berghe T

Cell death and differentiation 30 巻 ( 9 ) 頁： 2092 - 2103 2023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

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by central nervous (CNS) demyelination resulting in axonal injury and neurological deficits. Essentially, MS is driven by an auto-amplifying mechanism of inflammation and cell death. Current therapies mainly focus on disease modification by immunosuppression, while no treatment specifically focuses on controlling cell death injury. Here, we report that ferroptosis, an iron-catalyzed mode of regulated cell death (RCD), contributes to MS disease progression. Active and chronic MS lesions and cerebrospinal fluid (CSF) of MS patients revealed several signs of ferroptosis, reflected by the presence of elevated levels of (labile) iron, peroxidized phospholipids and lipid degradation products. Treatment with our candidate lead ferroptosis inhibitor, UAMC-3203, strongly delays relapse and ameliorates disease progression in a preclinical model of relapsing-remitting MS. In conclusion, the results identify ferroptosis as a detrimental and targetable factor in MS. These findings create novel treatment options for MS patients, along with current immunosuppressive strategies. [Figure not available: see fulltext.]

DOI： 10.1038/s41418-023-01195-0

Open Access

Scopus

PubMed

Organic decomposition and synthesis reactions in lactated solution exposed to nonequilibrium atmospheric pressure plasma 査読有り国際誌 Open Access

Liu, Y; Ishikawa, K; Tanaka, H; Miron, C; Kondo, T; Nakamura, K; Mizuno, M; Kajiyama, H; Toyokuni, S; Hori, M

PLASMA PROCESSES AND POLYMERS 20 巻 ( 5 ) 2023年5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

Lactate is used in the food and pharmaceutical industries and is a crucial intermediate for synthesis. Plasma-activated lactate (PAL) in Ringer's solution was recently shown to have effective antitumor action. Small molecule aldehydes, ketones, and organic acids were produced from lactate during plasma exposure, and five-membered conjugated lactone isomers of furanone (C<inf>5</inf>H<inf>6</inf>O<inf>2</inf>) were detected formed by interactions of lactate or its fragments with •OH, organic radicals, and H<inf>2</inf>O<inf>2</inf>. 2,3-Dimethyl-tartaric acid may be the effective component in PAL for the selective killing of cancer but not normal cells and possible pathways for its synthesis are provided. Aqueous reaction mechanisms are explained, including dehydration, esterification, hydrolysis, and dimerization. This study will help develop novel cancer therapies and further plasma organic chemistry.

DOI： 10.1002/ppap.202200193

Open Access

Web of Science

Scopus

Commentary on "Mechanisms of asbestos-induced carcinogenesis" published in 2009. 査読有り国際誌 Open Access

Toyokuni S

Nagoya journal of medical science 85 巻 ( 1 ) 頁： 13 - 15 2023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：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

Toward the next century of the Nagoya Journal of Medical Science: message from the Editor-in-chief. 査読有り国際誌 Open Access

Toyokuni S

Nagoya journal of medical science 85 巻 ( 1 ) 頁： 1 - 4 2023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：Nagoya Journal of Medical Science

It is my great pleasure and honor as the Editor-in-chief to congratulate the centennial anniversary of the Nagoya Journal of Medical Science in 2023 with all the editorial board members and the technical staffs as well as the authors and the readers. One hundred years are quite a long period, and the persistent publication from a medical school of national university in Japan has not been so easy. Especially, the publication was suspended from 1940 to 1950 due to the World War II.

DOI： 10.18999/nagjms.85.1.1

BRCA1 haploinsufficiency promotes chromosomal amplification under renal carcinogenesis through ferroptosis-resistance 査読有り国際誌

Kong, YY; Akatsuka, S; Motooka, Y; Zheng, H; Shiraki, Y; Mashimo, T; Imaoka, T; Toyokuni, S

CANCER SCIENCE 114 巻頁： 1534 - 1534 2023年2月

A/J mice exhibit a high susceptibility to ferric nitrilotriacetate-induced RCC through the resistance to ferroptosis 査読有り国際誌

Akatsuka, S; Cheng, Z; Toyokuni, S

CANCER SCIENCE 114 巻頁： 1315 - 1315 2023年2月

Carcinogenic genome toxicity of environmental factors, asbestos and talc in ovary 査読有り国際誌

Motooka, Y; Onimaru, K; Suzuki, HI; Katabuchi, M; Kondoh, E; Tashiro, H; Katabuchi, H; Toyokuni, S

CANCER SCIENCE 114 巻頁： 1085 - 1085 2023年2月

Validation of reduced ovarian reserve in BRCA1 haploinsufficient rats 査読有り国際誌

Sonehara, R; Motooka, Y; Kajiyama, H; Mashimo, T; Imaoka, T; Toyokuni, S

CANCER SCIENCE 114 巻頁： 2041 - 2041 2023年2月

Precision cancer prevention 査読有り国際誌

Toyokuni, S; Takayama, T

CANCER SCIENCE 114 巻頁： 1528 - 1528 2023年2月

Ferroptosis-resistance in rodent cancer models 査読有り国際誌

Toyokuni, S; Kong, Y; Akatsuka, S; Motooka, Y; Zheng, H; Mashimo, T; Imaoka, T

CANCER SCIENCE 114 巻頁： 912 - 912 2023年2月

Ferroptosis resistance is induced by BRCA1 deficiency in asbestos-induced mesothelioma 査読有り国際誌

Luo, YG; Motooka, Y; Akatsuka, S; Mashimo, T; Imaoka, T; Toyokuni, S

CANCER SCIENCE 114 巻頁： 1308 - 1308 2023年2月

Cooperation of Poly(rC)-binding Proteins 1/2 and Glutathione in Ferroptosis Induced by Plasmaactivated Ringer's Lactate 査読有り国際誌

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

CANCER SCIENCE 114 巻頁： 1340 - 1340 2023年2月

Cooperation of Poly(rC)-binding Proteins 1/2 and Glutathione in Ferroptosis Induced by Plasma-activated Ringer's Lactate 査読有り国際誌

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

CANCER SCIENCE 114 巻頁： 749 - 749 2023年2月

Plasma activated Ringer's lactate solution. 査読有り国際誌 Open Access

Tanaka H, Mizuno M, Ishikawa K, Miron C, Okazaki Y, Toyokuni S, Nakamura K, Kajiyama H, Hori M

Free radical research 57 巻 ( 1 ) 頁： 14 - 20 2023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：Free Radical Research

Low-temperature plasma (LTP) has been widely used in life science. Plasma-activated solutions were defined as solutions irradiated with LTP, and water, medium, and Ringer’s solutions have been irradiated with LTP to produce plasma-activated solutions. They contain chemical compounds produced by reactions among LTP, air, and solutions. Reactive oxygen and nitrogen species (RONS) are major components in plasma-activated solutions and recent studies revealed that plasma-activated organic compounds are produced in plasma-activated Ringer’s lactate solution (PAL). Many in vitro and in vivo studies demonstrated that PAL exhibits anti-tumor effects on cancers, and biochemical analyses revealed intracellular molecular mechanisms of cancer cell death by PAL.

DOI： 10.1080/10715762.2023.2182663

Non-thermal plasma elicits ferrous chloride-catalyzed DMPO-OH. 査読有り国際誌

Okazaki Y, Ito N, Tanaka H, Hori M, Toyokuni S

Free radical research 56 巻 ( 9-10 ) 頁： 595 - 606 2022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：Free Radical Research

Non-thermal plasma (NTP) induces the generation of reactive oxygen species (ROS) and reactive nitrogen species, such as hydroxyl radicals (•OH), hydrogen peroxide (H<inf>2</inf>O<inf>2</inf>), singlet oxygen, superoxide, ozone, and nitric oxide, at near-physiological temperatures. These molecules promote blood coagulation, wound healing, disinfection, and selective cancer cell death. Based on these evidences, clinical trials of NTP have been conducted for treating chronic wounds and head and neck cancers. Although clinical applications have progressed, the stoichiometric quantification of NTP-induced ROS remains unclear in the liquid phase in the presence of FeCl<inf>2</inf> or FeCl<inf>3</inf> in combination with biocompatible reducing agents, which may modulate the final biological effects of NTP. In this study, we employed electron paramagnetic resonance spectroscopy to quantify ROS using spin-trapping probe, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and H<inf>2</inf>O<inf>2</inf>, using luminescent probe in the presence of FeCl<inf>2</inf> or FeCl<inf>3</inf>. NTP-induced DMPO-OH levels were elevated 10–100 µM FeCl<inf>2</inf> or 500 and 1000 µM FeCl<inf>3</inf>. NTP-induced DMPO-OH with 10 µM FeCl<inf>2</inf> or FeCl<inf>3</inf> was significantly scavenged by ascorbate, α-tocopherol, dithiothreitol, reduced glutathione, or oxidized glutathione, whereas dehydroascorbate was ineffective in 2 mM DMPO. NTP-induced H<inf>2</inf>O<inf>2</inf> was significantly degraded by 100 µM FeCl<inf>2</inf> and FeCl<inf>3</inf> in an iron-dependent manner. Meanwhile, decomposition of H<inf>2</inf>O<inf>2</inf> by catalase decayed DMPO-OH efficiently in the presence of iron, indicating iron causes DMPO-OH production and degradation simultaneously. These results suggest that NTP-induced DMPO-OH is generated by the H<inf>2</inf>O<inf>2</inf>-consuming, iron-dependent Fenton reaction and ferryl intermediates. The potential iron-mediated ROS production by NTP is also discussed to clarify the interaction between NTP-induced ROS and biomolecules.

DOI： 10.1080/10715762.2022.2157272

Web of Science

Scopus

PubMed

Editorial: Centennial anniversary of vitamin E discovery. 査読有り国際誌

Toyokuni S, Noguchi N, Niki E

Free radical biology & medicine 183 巻頁： 125 - 126 2022年4月

BRCA1 deficiency regulates the metabolism of iron and oxidative stress-induced carcinogenesis in the kidney 査読有り国際誌

Kong, YY; Motooka, Y; Akatsuka, S; Mashimo, T; Imaoka, T; Toyokuni, S

CANCER SCIENCE 113 巻頁： 336 - 336 2022年2月

Visualization of physiological ferroptosis 査読有り国際誌

Zheng, H; Toyokuni, S

CANCER SCIENCE 113 巻頁： 1547 - 1547 2022年2月

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論文 - 豊國　伸哉