研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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BRCA1 haploinsufficiency promotes chromosomal amplification under Fenton reaction-based carcinogenesis through ferroptosis-resistance. 査読有り国際誌 Open Access

Kong Y, Akatsuka S, Motooka Y, Zheng H, Cheng Z, Shiraki Y, Mashimo T, Imaoka T, Toyokuni S

Redox biology 54 巻頁： 102356 - 102356 2022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：Redox Biology

Germline-mutation in BRCA1 tumor suppressor gene is an established risk for carcinogenesis not only in females but also in males. Deficiency in the repair of DNA double-strand breaks is hypothesized as a responsible mechanism for carcinogenesis. However, supporting data is insufficient both in the mutation spectra of cancers in the patients with BRCA1 germline-mutation and in murine knockout/knock-in models of Brca1 haploinsufficiency. Furthermore, information on the driving force toward carcinogenesis in BRCA1 mutation carriers is lacking. Here we applied Fenton reaction-based renal carcinogenesis to a rat heterozygously knockout model of BRCA1 haploinsufficiency (mutant [MUT] model; L63X/+). Rat MUT model revealed significant promotion of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Array-based comparative genome hybridization of the RCCs identified significant increase in chromosomal amplification, syntenic to those in breast cancers of BRCA1 mutation carriers, including c-Myc, in comparison to those in the wild-type. Subacute-phase analysis of the kidney after repeated Fe-NTA treatment in the MUT model revealed dysregulated iron metabolism with mitochondrial malfunction assessed by expression microarray and electron microscopy, leading to renal tubular proliferation with iron overload. In conclusion, we for the first time demonstrate that biallelic wild-type BRCA1 provides more robust protection for mitochondrial metabolism under iron-catalyzed oxidative stress, preventing the emergence of neoplastic cells with chromosomal amplification. Our results suggest that oxidative stress via excess iron is a major driving force for carcinogenesis in BRCA1 haploinsufficiency, which can be a target for cancer prevention and therapeutics.

DOI： 10.1016/j.redox.2022.102356

Hippo-TAZ signaling is the master regulator of the onset of triple-negative basal-like breast cancers. 査読有り国際誌 Open Access

Soyama H, Nishio M, Otani J, Sakuma T, Takao S, Hara S, Masuda T, Mimori K, Toyokuni S, Lydon JP, Nakao K, Nishina H, Fukumoto T, Maehama T, Suzuki A

Proceedings of the National Academy of Sciences of the United States of America 119 巻 ( 29 ) 頁： e2123134119 2022年7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：Proceedings of the National Academy of Sciences of the United States of America

Breast cancer is the most frequent malignancy in women worldwide. Basal-like breast cancer (BLBC) is the most aggressive form of this disease, and patients have a poor prognosis. Here, we present data suggesting that the Hippo-transcriptional coactivator with PDZ-binding motif (TAZ) pathway is a key driver of BLBC onset and progression. Deletion of Mob1a/b in mouse mammary luminal epithelium induced rapid and highly reproducible mammary tumorigenesis that was dependent on TAZ but not yes-associated protein 1 (YAP1). In situ early-stage BLBC-like malignancies developed in mutant animals by 2 wk of age, and invasive BLBC appeared by 4 wk. In a human estrogen receptor+ luminal breast cancer cell line, TAZ hyperactivation skewed the features of these luminal cells to the basal phenotype, consistent with the aberrant TAZ activation frequently observed in human precancerous BLBC lesions. TP53 mutation is rare in human precancerous BLBC but frequent in invasive BLBC. Addition of Trp53 deficiency to our Mob1a/b-deficient mouse model enhanced tumor grade and accelerated cancer progression. Our work justifies targeting the Hippo-TAZ pathway as a therapy for human BLBC, and our mouse model represents a powerful tool for evaluating candidate agents.

DOI： 10.1073/pnas.2123134119

Hepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells. 査読有り国際誌 Open Access

Igarashi N, Miyata K, Loo TM, Chiba M, Hanyu A, Nishio M, Kawasaki H, Zheng H, Toyokuni S, Kon S, Moriyama K, Fujita Y, Takahashi A

Nature communications 13 巻 ( 1 ) 頁： 4157 - 4157 2022年7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：Nature Communications

Cellular senescence and cell competition are important tumor suppression mechanisms that restrain cells with oncogenic mutations at the initial stage of cancer development. However, the link between cellular senescence and cell competition remains unclear. Senescent cells accumulated during the in vivo aging process contribute toward age-related cancers via the development of senescence-associated secretory phenotype (SASP). Here, we report that hepatocyte growth factor (HGF), a SASP factor, inhibits apical extrusion and promotes basal protrusion of Ras-mutated cells in the cell competition assay. Additionally, cellular senescence induced by a high-fat diet promotes the survival of cells with oncogenic mutations, whereas crizotinib, an inhibitor of HGF signaling, provokes the removal of mutated cells from mouse livers and intestines. Our study provides evidence that cellular senescence inhibits cell competition-mediated elimination of oncogenic cells through HGF signaling, suggesting that it may lead to cancer incidence during aging.

DOI： 10.1038/s41467-022-31642-4

Diluted aqueous extract of heat-not-burn tobacco product smoke causes less oxidative damage in fibroblasts than conventional cigarette. 国際誌 Open Access

Lyu Q, Jiang L, Zheng H, Hayashi S, Sato K, Toyokuni S

Journal of clinical biochemistry and nutrition 71 巻 ( 1 ) 頁： 55 - 63 2022年7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 Clinical Biochemistry and Nutrition

Smoke from conventional cigarettes (C-cigarettes) contains various reactive oxygen species and toxic chemicals, which potentially cause oxidative damage not only to airways but also to the whole body, leading eventually to diseases, including emphysema, advanced atherosclerosis, and cancer. Many heat-not-burn tobacco products (HTPs) have been commercialized recently in Japan to maintain the smoking population by advertising that HTPs are less toxic. However, there were few studies reported from neutral organizations whether HTPs are indeed less damaging. To evaluate the potential capacity of HTPs to induce oxidative stress, we here compared two different HTPs with two types of C-cigarettes, using human fibroblast IMR90SV cells and 5% aqueous extracts in 10-ml phosphate-buffered saline (50-ml smoke/10 s). HTPs exhibited significantly lower oxidative toxicity in comparison to C-cigarettes. Whereas C-cigarettes induced ferroptosis in fibroblasts, the effects of HTPs were significantly reduced by measuring the levels of peroxides, pro-inflammatory cytokine expression, autophagy, catalytic Fe(II) and 8-hydroxy-2'-deoxyguanosine. Notably, major portions of C-cigarettes-induced pathogenic responses were inhibited by catalase. However, HTPs still induced p62 autophagy-adaptor at 5%-dilution and caused lethal effects to fibroblasts with undiluted solution. In conclusion, HTPs smoke per se can be toxic despite less toxicity in comparison to C-cigarettes, which warrants further investigation.

DOI： 10.3164/jcbn.21-134

Cytotoxicity of plasma-irradiated lactate solution produced under atmospheric airtight conditions and generation of the methyl amino group 査読有り国際誌

Ito D., Iwata N., Ishikawa K., Nakamura K., Hashizume H., Miron C., Tanaka H., Kajiyama H., Toyokuni S., Mizuno M., Hori M.

Applied Physics Express 15 巻 ( 5 ) 2022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：Applied Physics Express

Ringer's lactate solution was irradiated with non-equilibrium plasma under airtight conditions. The plasma-activated lactate (PAL) was produced with argon, oxygen, and nitrogen gases following purging of Ar. Cytotoxicity could be controlled by diluting PAL, and a killing effect was selectively obtained on cancer cells compared to normal cells for Ar+O2+N2 PALs. Nonetheless, cytotoxicity was partly reproduced by similar concentrations of H2O2 and NO2- in the PALs. The organics produced by plasma irradiation to lactate were investigated using nuclear magnetic resonance, and the generation of methyl amino species was confirmed.

DOI： 10.35848/1882-0786/ac6360

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PCBP2 knockdown promotes ferroptosis in malignant mesothelioma. 査読有り国際誌 Open Access

Yue L, Luo Y, Jiang L, Sekido Y, Toyokuni S

Pathology international 72 巻 ( 4 ) 頁： 242 - 251 2022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：Pathology International

Malignant mesothelioma (MM) is still increasing worldwide. The pathogenesis depends on asbestos-induced iron accumulation, which eventually leads to ferroptosis-resistance of mesothelial cells via somatic mutations. Poly (rC)-binding proteins 1 and 2 (PCBP1/2) are recently recognized cytosolic Fe(II) chaperones. Here we studied the role of PCBP1/2 in rat/human mesothelial and MM cells as well as rat/human MM specimens. Normal peritoneal mesothelial cells in rats exhibited PCBP1 but not PCBP2 immunopositivity whereas primary/immortalized mesothelial cells showed PCBP1/2 immunopositivity. Rat MM specimens induced by intraperitoneal injection of chrysotile, including in situ lesion, revealed PCBP1/2 immunopositivity (90% for both) in the nucleus and cytoplasm with a tendency of higher expression in epithelioid subtype. Knockdown of PCBP2 but not PCBP1 significantly decreased both TfR1 and FTH expression in MM cells with inhibition of proliferation, indicating stagnation of intracellular iron transport. Erastin, a cysteine-deprivation type ferroptosis inducer, decreased the expression of both PCBP1/2 in MM cells. Furthermore, PCBP2 knockdown significantly increased the sensitivity of MM cells to erastin-induced ferroptosis with increased catalytic Fe(II). In conclusion, PCBP2 works for ferroptosis-resistance not only during mesothelial carcinogenesis but also in MM, which warrants further investigation as a novel therapeutic target.

DOI： 10.1111/pin.13209

タルクは曝露卵巣に鉄過剰状態とフェロトーシス抵抗性を誘導し発がんに関わる

井上陽太, 本岡大社, 豊國伸哉

日本病理学会会誌 111 巻 ( 1 ) 頁： 353 - 353 2022年3月

アスベストはヘモグロビンを吸着し卵巣表層上皮に鉄過剰状態を形成することで卵巣がん形成に関わる

本岡大社, 豊國伸哉

日本病理学会会誌 111 巻 ( 1 ) 頁： 249 - 249 2022年3月

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury

Sato Yuki, Oguchi Akiko, Fukushima Yuji, Masuda Kyoko, Toriu Naoya, Taniguchi Keisuke, Yoshikawa Takahisa, Cui Xiaotong, Kondo Makiko, Hosoi Takeshi, Komidori Shota, Shimizu Yoko, Fujita Harumi, Jiang Li, Kong Yingyi, Yamanashi Takashi, Seita Jun, Yamamoto Takuya, Toyokuni Shinya, Hamazaki Yoko, Hattori Masakazu, Yoshikai Yasunobu, Boor Peter, Floege Jürgen, Kawamoto Hiroshi, Murakawa Yasuhiro, Minato Nagahiro, Yanagita Motoko

Journal of Clinical Investigation 132 巻 ( 2 ) 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Tertiary lymphoid tissues (TLTs) facilitate local T- and B-cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here we identify TNF superfamily CD153-CD30 signaling between two unique age-dependent lymphocyte subpopulations, CD153⁺PD-1⁺CD4⁺ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL21 and IFNγ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153-CD30 signaling in TLT formation and propose targeting CD153-CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

DOI： 10.1172/JCI146071

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CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury. 国際誌 Open Access

Sato Y, Oguchi A, Fukushima Y, Masuda K, Toriu N, Taniguchi K, Yoshikawa T, Cui X, Kondo M, Hosoi T, Komidori S, Shimizu Y, Fujita H, Jiang L, Kong Y, Yamanashi T, Seita J, Yamamoto T, Toyokuni S, Hamazaki Y, Hattori M, Yoshikai Y, Boor P, Floege J, Kawamoto H, Murakawa Y, Minato N, Yanagita M

The Journal of clinical investigation 132 巻 ( 2 ) 2022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 Clinical Investigation

Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

DOI： 10.1172/JCI146071

CD153/CD30 signaling promotes age-dependent tertiary lymphoid tissue expansion and kidney injury

Journal of Clinical Investigation 132 巻 ( 2 ) 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

DOI： 10.1172/JCI146071

Ferroptosis resistance determines high susceptibility of murine A/J strain to iron-induced renal carcinogenesis. 査読有り国際誌 Open Access

Cheng Z, Akatsuka S, Li GH, Mori K, Takahashi T, Toyokuni S

Cancer science 113 巻 ( 1 ) 頁： 65 - 78 2022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：Cancer Science

Cancer susceptibility is a critical factor in the understanding of carcinogenesis. Intraperitoneal (i.p.) injection of an iron chelate, ferric nitrilotriacetate (Fe-NTA), produces hydroxyl radicals via Fenton reaction to induce ferroptosis in renal proximal tubules. Rats or mice subjected to repeated i.p. injections of Fe-NTA develop renal cell carcinoma (RCC). To elucidate the molecular mechanisms that cause susceptibility to renal carcinogenesis, we first established an inter-strain difference in the susceptibility to Fe-NTA-induced renal carcinogenesis in mice. Based on a previous observation of a low incidence of RCC with this model in C57BL/6J strain mice, we investigated A/J strain mice here, which demonstrated significantly higher susceptibility to Fe-NTA-induced renal carcinogenesis. Homozygous deletion of the Cdkn2a/2b tumor suppressor locus was detected for the first time in A/J strain mice. Focusing on ferroptosis and iron metabolism, we explored the mechanisms involved that lead to the difference in RCC development. We compared the protective responses in the kidney of A/J and C57BL/6J strains after Fe-NTA treatment. After 3-week Fe-NTA treatment, A/J mice maintained higher levels of expression of glutathione peroxidase 4 and xCT (SLC7A11), leading to a lower level of lipid peroxidation. Simultaneously, A/J mice had decreased expression of transferrin receptor and increased expression of ferritin to greater degrees than C57BL/6 mice. After a single Fe-NTA injection, higher levels of oxidative cell damage and cytosolic catalytic Fe(II) were observed in C57BL/6J mice, accompanied by a greater increase in lipocalin-2. Lipocalin-2 deficiency significantly decreased oxidative renal damage. Our results suggest that a genetic trait favoring ferroptosis resistance contributes to high susceptibility to Fe-NTA-induced RCC in A/J strain.

DOI： 10.1111/cas.15175

Tetrachloroaurate (III)-induced oxidation increases non-thermal plasma-induced oxidative stress. 査読有り国際誌 Open Access

Okazaki Y, Sasaki K, Ito N, Tanaka H, Matsumoto KI, Hori M, Toyokuni S

Free radical research 56 巻 ( 1 ) 頁： 17 - 27 2022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

Non-thermal plasma (NTP) devices have been explored for medical applications. NTP devices discharge electrons, positive ions, ultraviolet (UV), reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as the hydroxyl radical (•OH), singlet oxygen (1O<inf>2</inf>), superoxide (O<inf>2</inf>•-), hydrogen peroxide (H<inf>2</inf>O<inf>2</inf>), ozone, and nitric oxide, at near-physiological temperature. At preclinical stages or in human clinical trials, NTP promotes blood coagulation, eradication of bacterial, viral, and biofilm-related infections, wound healing, and cancer cell death. Here, we observed that ferric, vanadium, and gold(III) ions significantly elevated lipid peroxidation, which was measured by 2-thiobarbituric acid-reactive substances (TBARS) in combination with NTP exposure. Using 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) as a spin probe in electron paramagnetic resonance (EPR), we observed that tetrachloroaurate (III) yielded an M4PO-X spin adduct. Tetrachloroaurate-induced oxidation was attenuated efficiently by reduced (GSH) and oxidized glutathione (GSSG), while glycine (Gly), and L-glutamate (Glu), components of GSH, were ineffective. Furthermore, GSH and GSSG efficiently suppressed tetrachloroaurate-induced lipid peroxidation, while Gly and Glu were ineffective in suppressing TBARS elevation. These results indicate that tetrachloroaurate-induced oxidation is attenuated by GSH as well as GSSG. Further studies are warranted to elucidate the redox reactions between metal ions and biomolecules to advance the clinical application of NTP.

DOI： 10.1080/10715762.2022.2026348

Enhancement of ethanol production and cell growth in budding yeast by direct irradiation of low-temperature plasma 査読有り国際誌 Open Access

Tanaka H., Matsumura S., Ishikawa K., Hashizume H., Ito M., Nakamura K., Kajiyama H., Kikkawa F., Ito M., Ohno K., Okazaki Y., Toyokuni S., Mizuno M., Hori M.

Japanese Journal of Applied Physics 61 巻 ( SA ) 2022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：Japanese Journal of Applied Physics

Ethanol production by budding yeast was compared between direct and indirect plasma irradiation. We observed enhancement of ethanol production and cell growth not by indirect plasma irradiation but by direct plasma irradiation. Glucose consumption was increased in budding yeast by direct plasma irradiation. Extracellular flux analysis revealed that glycolytic activity in the budding yeast was elevated by direct plasma irradiation. These results suggest that direct plasma irradiation enhances ethanol production in budding yeast by elevating the glycolytic activity.

DOI： 10.35848/1347-4065/ac2037

Double-edged Sword Role of Iron-loaded Ferritin in Extracellular Vesicles. 査読有り国際誌 Open Access

Toyokuni S, Kong Y, Zheng H, Mi D, Katabuchi M, Motooka Y, Ito F

Journal of cancer prevention 26 巻 ( 4 ) 頁： 244 - 249 2021年12月

Mitochondrial involvement in the development and progression of diseases. 査読有り国際誌

Valacchi G, Pecorelli A, Toyokuni S

Archives of biochemistry and biophysics 711 巻頁： 109006 - 109006 2021年10月

Mice lacking DYRK2 exhibit congenital malformations with lung hypoplasia and altered Foxf1 expression gradient. 査読有り国際誌 Open Access

Yogosawa S, Ohkido M, Horii T, Okazaki Y, Nakayama J, Yoshida S, Toyokuni S, Hatada I, Morimoto M, Yoshida K

Communications biology 4 巻 ( 1 ) 頁： 1204 - 1204 2021年10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：Communications Biology

Congenital malformations cause life-threatening diseases in pediatrics, yet the molecular mechanism of organogenesis is poorly understood. Here we show that Dyrk2-deficient mice display congenital malformations in multiple organs. Transcriptome analysis reveals molecular pathology of Dyrk2-deficient mice, particularly with respect to Foxf1 reduction. Mutant pups exhibit sudden death soon after birth due to respiratory failure. Detailed analyses of primordial lungs at the early developmental stage demonstrate that Dyrk2 deficiency leads to altered airway branching and insufficient alveolar development. Furthermore, the Foxf1 expression gradient in mutant lung mesenchyme is disrupted, reducing Foxf1 target genes, which are necessary for proper airway and alveolar development. In ex vivo lung culture system, we rescue the expression of Foxf1 and its target genes in Dyrk2-deficient lung by restoring Shh signaling activity. Taken together, we demonstrate that Dyrk2 is essential for embryogenesis and its disruption results in congenital malformation.

DOI： 10.1038/s42003-021-02734-6

Role of ferroptosis in nanofiber-induced carcinogenesis 国際誌

Toyokuni Shinya, Ito Fumiya, Motooka Yashiro

Metallomics Research 1 巻 ( 1 ) 頁： rev-14 - rev-21 2021年10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：Japan Society for Biomedical Research on Trace Elements

Biopersistent nanofibers with specified physical dimension are unexpected human carcinogens whether they are natural or synthetic. Asbestos, a natural fibrous mineral, is classified as a definite human carcinogen (IARC Group 1) to cause malignant mesothelioma (MM) and lung cancer. Multi-walled carbon nanotube of 50 nm-diameter was defined in 2014 as a possible carcinogen (IARC Group 2B) toward MM, fortunately with no authorized patients thus far. Carcinogenic mechanism of asbestos has been a mystery for a long time. It is now recognized that asbestos goes through lung parenchyma by collecting hemoglobin-derived iron to reach pleural cavity, which takes several decades. Iron-loaded asbestos can induce oxidative damage directly to mesothelial cells, carcinogenesis-target cells lining somatic cavities. Recently, it was clarified that surrounding stromal environment are as important for mesothelial carcinogenesis. The novel concept here is ceaseless ferroptosis of macrophages, which forms a Fe(II)-dependent stromal mutagenic milieu indirectly for mesothelial cells and indeed is a revised understanding of frustrated phagocytosis. Deposition of foreign materials eventually causes iron accumulation in situ due to the innate characteristic of preserving iron inside cells. Nanofiber-induced carcinogenesis may be involved in other human carcinogenesis, including ovarian cancer. Alternatively, iron excess can be an optimal target of cancer prevention and cancer treatment.

DOI： 10.11299/metallomicsresearch.mr202102

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Txn1 mutation causes epilepsy associated with vacuolar degeneration in the midbrain

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

bioRxiv 2021年10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：Cold Spring Harbor Laboratory

<title>Abstract</title>Thioredoxin (TXN), encoded by <italic>Txn1</italic>, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of TXN in the central nervous system (CNS) is largely unknown. A phenotype-driven study of <italic>N</italic>-ethyl-<italic>N</italic>-nitrosourea-mutated rats with running seizures at around five-week of age revealed the relevance of <italic>Txn1</italic> mutations to CNS disorders. Genetic mapping identified <italic>Txn1</italic>-F54L in epileptic rats. The insulin-reducing activity of <italic>Txn1</italic>-F54L rats was approximately one-third that of the wild-type. Vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the <italic>Txn1</italic>-F54L rats. The lesions displayed neuronal and oligodendrocyte cell death. Neurons in <italic>Txn1</italic>-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration began at three weeks of age, and spontaneous repair began at seven weeks; a dramatic change from cell death to repair occurred in the midbrain during a restricted period. In conclusion, <italic>Txn1</italic> is essential for the development of the midbrain in juvenile rats.

DOI： 10.1101/2021.10.07.463470

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Plasma-activated Ringer's lactate solution inhibits the cellular respiratory system in HeLa cells 査読有り国際誌

Tanaka H., Maeda S., Nakamura K., Hashizume H., Ishikawa K., Ito M., Ohno K., Mizuno M., Motooka Y., Okazaki Y., Toyokuni S., Kajiyama H., Kikkawa F., Hori M.

Plasma Processes and Polymers 18 巻 ( 10 ) 2021年10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

Nonequilibrium atmospheric pressure plasma has enabled a variety of new applications in medicine, agriculture, and other industries. It is particularly noteworthy that plasma itself and/or plasma-activated culture medium have been shown to preferentially kill various cancer cells. We have previously developed a plasma-activated Ringer's lactate solution (PAL) for use as a new cancer treatment. In this study, behaviors of extracellular and intracellular reactive oxygen and nitrogen species in the cellular respiratory system of PAL-treated HeLa cells were investigated using an extracellular flux analyzer and a probe to measure mitochondrial membrane potential. In PAL-treated HeLa cells, extracellular hydrogen peroxide in PAL was found to be responsible for the induction of intracellular hydrogen peroxide and apoptosis, while other components in PAL are responsible for the induction of non-H<inf>2</inf>O<inf>2</inf> intracellular ROS and non-apoptotic cell death, which should be clarified by further experiments. We believe that these are long-lived species derived from plasma-activated lactates. Furthermore, we found that the plasma-activated lactates inhibited glycolysis and the tricarboxylic acid (TCA) cycle, but not the electron transport chain in HeLa cells. These results suggest that PAL induces multiple modes of cell death, including apoptosis through hydrogen peroxide, and non-apoptotic cell death associated with the impairment of mitochondrial functions (glycolysis and TCA cycle). These findings shed light on the novel mechanism underlying plasma-activated lactate-induced cell death.

DOI： 10.1002/ppap.202100056

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論文 - 豊國　伸哉