受賞国：日本国

受賞国：日本国

受賞区分：国内学会・会議・シンポジウム等の賞  受賞国：日本国

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受賞区分：国内学会・会議・シンポジウム等の賞 

本学医学系研究科 豊國伸哉 教授が、日本酸化ストレス学会 学会賞を受賞しました。本学会は本研究科（故）八木国夫名誉教授（生化学）が1977年に設立された過酸化脂質・フリーラジカル学会の流れを汲むものです。豊國教授は、京都大学医学部在学時から現在にいたるまで一貫して、実験病理学の立場から過剰鉄による発がん過程の解明という、酸化ストレス分野における主要な課題の一つに精力的に取組み、世界の酸化ストレス研究の発展に大きく貢献してきました。

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受賞国：日本国

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1002/path.4377.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.freeradbiomed.2019.01.042

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blood  

The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of messenger RNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we used selenocysteine transfer RNA (tRNASec) gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs’ self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. Although Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.

DOI： 10.1182/blood.2024025402

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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 Biology and Medicine  

Vitrectomy with silicone oil (SO) endotamponade is an effective treatment for vision-threatening retinal diseases. However, unexplained vision impairment has been reportedly critical side effects. Previously, we reported that the eyes with ocular toxoplasmosis showed retinal ferroptosis with the clinical sign of reduced intravitreal iron (Fe). We also found that total iron levels in sub-silicone oil fluid (SOF) in eyes with SO endotamponade were significantly reduced. We hypothesized that the cause of complications related to SO endotamponade is retinal ferroptosis and that low total iron in SOF is a secondary change that occurs similarly to the changes in ocular toxoplasmosis. In this study, we measured total iron levels in ocular fluid from patients, rabbits with SO endotamponade. Retinal iron taken up from the SOF was evaluated using laser ablation inductively coupled plasma mass spectrometry in human and rabbit eyes. Retinal ferroptosis was confirmed by immunohistochemistry of 4-hydrox-2-nonenal-modified proteins, FeRhoNox-1 staining, western blotting and RT-PCR. We found low total iron levels in the SOF, increased oxidative stress and Fe uptake from the SOF into the retinae of human and rabbit eyes, as well as decreased GPx4 expression, increased FeRhoNox-1 signals and altered Fe-related gene expression in SO-filled rabbit eyes. Of note, the target of ferroptosis was Müller cells. We generated an in vitro silicone oil-filled eye model using MIO-M1 cells (a human Müller cell line). The in vitro SO-filled eye model showed decreased GPx4 expression and increased intracellular catalytic Fe(II), an increase in ferroptosis, prevention of cell death by ferrostatin-1, a ferroptosis inhibitor, and altered Fe-related gene expression. These results indicate that the cause of complications related to SO endotamponade was the induction of retinal (Müller cell) ferroptosis, which can be prevented by ferrostatin-1.

DOI： 10.1016/j.freeradbiomed.2024.12.039

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/joccuh/uiae064

PubMed

担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Tumor suppressor BRCA2 executes homologous recombination to repair DNA double-strand breaks in collaboration with RAD51, involving exon 11 and 27. Exon 11 constitutes a region where pathogenic variants (PVs) accumulate, and mutations in this region are known to contribute to carcinogenesis. However, the impact of the heterozygous PVs of BRCA2 exon 11 on the life quality beyond cancer risk, including male fertility, remains unclear. Here, we established a rat model with a frameshift on the seventh BRC repeat in Brca2 exon 11 (Brca2+/p.T1942fs), which is homologous to human BRCA2+/p.T1974fs, using CRISPR/Cas9 system. Our analyses revealed that the heterozygous rats with the PV in the BRCA2 exon 11 showed increased DNA double-strand breaks and apoptosis in spermatogonia and spermatocytes, accelerated testicular germ cell loss, and deterioration in sperm quality according with aging, ultimately resulting in early male reproductive dysfunction. Of note, these alterations in testes and sperm, including DNA fragmentation in spermatozoa, were observed from completion of sexual maturation. The present findings suggest that it is crucial to consider not only cancer risk but also potential declines in reproductive capacity in men carrying BRCA2 exon 11 PVs. Further investigation is warranted to determine whether similar traits appear in humans.

DOI： 10.1038/s41598-024-84184-8

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担当区分：最終著者,　責任著者   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  

Plasma, which was coined by Irving Langmuir in 1928, is the fourth physical state after the solid/liquid/gas phases. Low-temperature plasma (LTP) is a contradictory condition that involves high energy with free radicals at near-body temperatures and was developed through engineering in the 1990’s. Research on LTP in engineering and medical fields has rapidly developed since the 2000’s. LTP can be applied through direct or indirect exposure, and there are advantages to both methods. In the medical field, LTP has been found to exert several effects, such as wound healing, hemostasis and anticancer effects, mainly based on different levels of oxidative stress. In the dental field, studies have been performed on LTP applications for general dental procedures, such as restorative, periodontal and prosthodontic procedures, and for oral cancer treatment. Many studies have demonstrated the effectiveness of LTP. Compared with other organs, the anatomical characteristic of the oral cavity is easy direct observation, which is highly advantageous for clinical applications. Due to its good accessibility and efficiency, plasma dentistry is expected to be applied to various dental applications in clinics in the near future.

DOI： 10.1080/10715762.2024.2446323

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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  

The human lens is composed of a monolayer of lens epithelial cells (LECs) and elongated fibers that align tightly but are separated by the plasma membrane. The integrity of the lens plasma membrane is crucial for maintaining lens cellular structure, homeostasis, and transparency. Glutathione peroxidase 4 (GPX4), a selenoenzyme, plays a critical role in protecting against lipid peroxidation. This study aims to elucidate the role of GPX4 in lens plasma membrane stability during lens development using in vitro, ex vivo, and in vivo systems. Our findings reveal that GPX4 deficiency triggers lens epithelial apoptosis-independent but ferroptosis-mediated cell death. Blocking lens GPX4 activity during ex vivo culture induces lens opacification, LEC death, and disruption of lens fiber cell arrangement. Deletion of lens-specific Gpx4 results in significant unsaturated phospholipid loss and an increase in oxidized phospholipids. Consequently, lenses with Gpx4 deficiency exhibit massive disruption of lens fiber cell structure, significant loss of LECs via ferroptosis, and formation of newborn cataracts. Remarkably, administering the lipid peroxidation inhibitor, liproxstatin-1, to pregnant mothers at embryonic days 9.5 significantly prevents lipid peroxidation, LEC death, and lens developmental defects. Our study unveils the crucial role of GPX4 in lens development and transparency, and also provides a successful intervention approach to prevent lens developmental defects through lipid peroxidation inhibition.

DOI： 10.1073/pnas.2407842121

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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  

Plasma-activated Ringer’s lactate (PAL) solution prepared by irradiating an intravenous solution with a non-equilibrium atmospheric pressure plasma is a potential new cancer therapy having no side effects. However, the induction of autophagy to avoid cell death has been confirmed to occur following exposure to PAL solution. It is thought that the antitumor effect of PAL solution could be weakened by this process, which is meant to maintain homeostasis in cells and assists tumorigenesis. Thus, it would be helpful to devise PAL-based cancer therapies that inhibit autophagy. Unfortunately, it is not yet clear which substances in PAL solution promote autophagy. The present work examined the mechanism by which PAL solution induces autophagy when treating MCF-7 human breast cancer cells. Autophagy was found to be temporarily induced upon exposure to PAL solution, suggesting that this effect contributes to cell proliferation. Although autophagy is associated with reactive oxygen and nitrogen species and/or acidic environments, in this study, significant autophagy was observed using a PAL solution diluted 1/256x without these stressors. Acetate, glyoxylate and 2,3-dimethyltartrate in the PAL solution were determined to promote autophagy. Interestingly, 2,3-dimethyltartrate was found to either induce cell death or autophagy depending on the concentration.

DOI： 10.1080/10715762.2024.2433965

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担当区分：最終著者,　責任著者   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  

DOI： 10.1080/10715762.2023.2297343

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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  

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD. (Figure presented.)

DOI： 10.1038/s41418-024-01348-9

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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  

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

DOI： 10.1016/j.redox.2024.103211

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oral Diseases  

Objective: This study aimed to investigate the effect of plasma-activated Ringer's lactate solution (PAL) on oral squamous cell carcinoma (OSCC) cells and carcinogenic processes with a particular focus on iron and collagenous matrix formation. Materials and Methods: We used three OSCC cell lines, one keratinocyte cell line, and two fibroblast lines, and cell viability assays, immunoblotting, flow cytometry, and transmission electron microscopy were performed to evaluate the effect and type of cell death. The effect of PAL treatment on lysyl oxidase (LOX) expression was investigated in vitro and in vivo. Tamoxifen-inducible Mob1a/b double-knockout mice were used for the in vivo experiment. Results: PAL killed OSCC cells more effectively than the control nontumorous cells and suppressed cell migration and invasion. Ferroptosis occurred and the protein level of LOX was downregulated in cancer cells in vitro and in vivo. Additionally, PAL improved the survival rate of mice and suppressed collagenous matrix formation. Conclusions: We demonstrated that PAL specifically kills OSCC cells and that ferroptosis occurs in vitro and in vivo. Furthermore, PAL can prevent carcinogenesis and improve the survival rate of oral cancer, especially tongue cancer, by changing collagenous matrix formation via LOX suppression.

DOI： 10.1111/odi.14827

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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 Cell Biology  

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

DOI： 10.1038/s41556-024-01360-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu290020174

CiNii Research

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

DOI： 10.1016/j.abb.2024.110027

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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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  

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

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担当区分：責任著者   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  

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. Although 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

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担当区分：最終著者,　責任著者   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 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

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担当区分：責任著者   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  

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

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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 Medicine  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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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  

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

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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

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Antioxidants and Redox Signaling  

Significance: 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. Recent Advances: 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 ferroptosisresistance, based on rodent animal studies. Critical Issues: 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. Future Directions: Whereas life attempts to prevent ferroptosis, ferroptotic cells eventually emit iron-loaded ferritin as extracellular vesicles to maintain monopoly of iron. Antioxid. Redox Signal. 39, 807–815.

DOI： 10.1089/ars.2022.0142

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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 Nanotechnology  

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

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担当区分：最終著者,　責任著者   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  

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

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担当区分：最終著者,　責任著者   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

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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  

Cold atmospheric pressure plasmas are promising medical tools that can assist in cancer treatment. While the medical pathology mechanism is substantially understood, knowledge of the contribution of reactive species formed in plasma and the mode of activation of biochemical pathways is insufficient. Herein, we present a concept involving antitumoral plasma-activated organics, which is envisaged to increase cytotoxicity levels against cancer cells. Ringer′s acetate solution was irradiated by low-temperature plasma at atmospheric pressure and possible reaction pathways of the compound generation are presented. The chemical compounds formed by plasma treatment and their effects on non-tumorigenic breast epithelial cells (MCF-10A) and breast cancer cells (MCF-7) were investigated. The cell viability results have shown that plasma-derived compounds have both, stimulatory and inhibitory effects on cell viability, depending on the concentration of the generated compounds in the irradiated liquids. Previous studies have shown that oxidative stresses involving reactive oxygen and nitrogen species (RONS) can be used to kill cancer cells. Hence, while RONS offers promising first-step killing effects, cell viability results have shown that plasma-derived compounds, such as acetic anhydride and ethyl acetate, have the potential to play important roles in plasma-based cancer therapy.

DOI： 10.1080/10715762.2023.2201390

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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担当区分：最終著者,　責任著者   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  

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

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担当区分：最終著者,　責任著者   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  

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 multisystem 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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担当区分：責任著者   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  

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 semiquantitation 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.

DOI： 10.3164/jcbn.21-172

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担当区分：最終著者,　責任著者   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

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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

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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 Reports  

Needle-like multi-walled carbon nanotubes (MWCNTs) are engulfed by macrophages, which cause inflammation and asbestosis-like pathogenesis in rodents; however, how macrophages recognize MWCNTs remains unclear. Omori et al. demonstrate that Tim4 recognizes MWCNTs through aromatic-aromatic interactions and mediates macrophage phagocytosis leading to granulomas.

DOI： 10.1016/j.celrep.2021.108734

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Autophagy  

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

DOI： 10.1080/15548627.2020.1797280

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

DOI： 10.1016/j.freeradbiomed.2016.10.344

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

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担当区分：最終著者,　責任著者   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  

Persistent oxidative stress has been associated with carcinogenesis. Iron overload is considered one such condition that causes oxidative stress. Epidemiological studies support a close link between iron overload and carcinogenesis. Reportedly, regular semiannual phlebotomies reduced cancer risk in an otherwise normal population. More specifically, genetic hemochromatosis, chronic viral hepatitis, ovarian endometriosis and asbestosis induce iron overload, which can lead to hepatocellular carcinoma, ovarian carcinoma or mesothelioma in humans. Through a combination of animal experiments and microarray analyses, homozygous deletion of CDKN2A/2B has been recognized as one of the major target genes involved in iron overload-induced carcinogenesis. CDKN2A/2B are the second most frequently inactivated tumor suppressing genes in human cancers. Currently, when infection is becoming sufficiently controlled worldwide, iron regulation may be the next target for human longevity. ©2011 JCBN.

DOI： 10.3164/jcbn.11-001FR

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（国際会議プロシーディングス）  

DOI： 10.1016/j.freeradbiomed.2010.10.179

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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  

Temporary or persistent heart failure is one of the major complications after myocardial infarction (MI). In order to elucidate the pathogenesis of MI, we studied the spaciotemporal alteration of 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels in cardiomyocytes in a rat model of ligation of the left anterior descending branch of the coronary artery. The lethality in this model was 18%. Hearts were dissected at 0, 3, 6, 12, 24, 48h, and 1, 2, 4, 6 weeks after the operation. The cardiac level of 8-OHdG was evaluated biochemically as well as by immunohistochemistry with monoclonal antibody N45.1. Three to 6h after ligation, the 8-OHdG levels were increased in the cardiomyocytes of MI (six-fold) and peri-MI (four-fold) areas. After 24h, the myocardium in the MI area was necrotized, and thereafter the 8-OHdG level decreased. 8-OHdG levels in the myocardium of peri-MI areas returned once to a normal level, but were significantly increased at 2-4 weeks along with the appearance of apoptotic cardiomyocytes in this area. The heart after MI has been generally considered as clinically stable after four weeks. However, cardiomyocytes near the infarcted area were oxidatively stressed even after four weeks when the affected lesion was extensive. The present data support the use of supplementary antioxidant therapies to save functional myocardium after MI. (213 words).

DOI： 10.1081/1071576021000005285

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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  

BRCA1 is one of the causative genes for hereditary breast and ovarian cancer syndrome with a high risk of early-onset breast cancer. Whereas olaparib (OLA), an inhibitor of poly-ADP-ribose polymerase, has been applied as adjuvant therapy to those cancer patients, its effect on ovarian reproductive function remains unelucidated. Recently, a rat model (MUT; Brca1(L63X/+) mutation) mimicking a human BRCA1 pathogenic variant has been established. Using this model, we evaluated the effects of OLA on ovarian reproductive function in comparison with the wild-type (WT) rats. MUT showed a significantly reduced number of primordial follicles and subfertility in accordance with aging. Oxidative stress was significantly elevated in the young MUT granulosa cells (GCs) accompanied by increased mTOR but decreased PTEN signals. OLA administration in MUT further decreased primordial follicles, with gene set enrichment analysis, indicating upregulated DNA repair pathways. Furthermore, a combination of OLA and cyclophosphamide (CPA) induced empty primordial follicles, recognized as CPA-induced severe ovarian toxicity. Whereas OLA + CPA caused greater reduction in primordial follicles both in MUT and WT in comparison with CPA alone, MUT ovaries were more susceptible to oxidative stress, potentially depleting primordial follicles via activation of GCs and inducing oocyte death due to accumulated DNA damage by OLA treatment. Our findings in this preclinical model underscore the importance of evaluating ovarian reserve prior to chemotherapy by performing reproductive consultation with female patients with BRCA1 pathogenic variants.

DOI： 10.1111/cas.16412

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(公社)大気環境学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Molecular Genetics and Metabolism Reports  

The SLC25A20 gene encodes carnitine-acylcarnitine translocase (CACT), facilitating the transport of long-chain acylcarnitine required for energy production via β-oxidation into the mitochondria. Loss-of-function mutations in this gene lead to CACT deficiency, a rare autosomal recessive disorder of fatty acid metabolism characterized by severe symptoms including cardiomyopathy, hepatic dysfunction, rhabdomyolysis, hypoketotic hypoglycemia, and hyperammonemia, often resulting in neonatal mortality. Here, we utilized CRISPR/Cas9 gene editing to isolate slc25a20 mutant zebrafish. Homozygous mutants displayed significant lethality, with the majority succumbing before reaching maturity. However, we identified a notably rare homozygous individual that survived into adulthood, prompting a histological examination. Firstly, we observed adipose tissue accumulation at various sites in the homozygous mutant. The mutant heart exhibited hypertrophy, along with degenerated myocardial and muscle cells containing numerous eosinophilic nuclei. Additionally, we found no large oil droplet vacuoles in the mutant liver; however, the hepatocytes displayed numerous small vacuoles resembling lipid droplets. Iron deposition was evident in the spleen and parts of the liver. Overall, our slc25a20 zebrafish mutant displayed tissue pathologies analogous to human CACT deficiency, suggesting its potential as a pathological model contributing to the elucidation of pathogenesis and the improvement/development of therapies for CACT deficiency.

DOI： 10.1016/j.ymgmr.2024.101165

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Biological Macromolecules  

Plasma-activated chitosan (PAC) colloids for cancer treatment were obtained by using the cold atmospheric plasma technique. Chitosan solutions were irradiated by plasma ignited in argon gas and in a mixture of argon with nitrogen and oxygen gases in certain ratios. The structural modifications of chitosan and the chemical species generated in plasma were investigated by EPR, LC-MS/MS, XRD, DLS, and TGA methods. The cell viability test showed a selective cytotoxic effect on human breast carcinoma cells (MCF-7), while the human mammary epithelial cells (MCF-10A) were left unharmed. The cytotoxic effect was attributed mainly to chitooligosaccharides, but also to a synergistic effect with other compounds generated in very low concentrations in plasma, such as glyceric acid, ethyl acetate, or tricarballylic acid. The plasma irradiation improved the antioxidant activity and mucoadhesivity, while not affecting the hemocompatibility investigated by a standard hemolysis ex vivo test on mice blood. Moreover, the in vivo biocompatibility investigation at intraperitoneal administration of PAC in mice showed no statistically significant changes in the hematologic, biochemical, and immune system parameters, and no morphologic alterations of the liver and kidney. All these data indicate the cold plasma activation of chitosan as a straight method to produce biocompatible, antitumor systems.

DOI： 10.1016/j.ijbiomac.2024.136513

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.2425201925

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.2425201917

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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  

The prevalence of chronic kidney disease (CKD) is increasing owing to the elderly population. Here, we investigated the effects of heat-treated Enterococcus faecalis (FK-23) and lysozyme-treated FK-23 (LFK) on the progression of CKD in rats. A CKD model was established using male Wistar rats by subjecting them to right nephrectomy (1K), followed by ischemia and reperfusion (IR). FK-23 or LFK was fed ad libitum as a mixed diet after right nephrectomy. Animals subjected to renal ischemia-reperfusion injury (IRI) showed increased plasma creatinine and blood urea nitrogen levels. Furthermore, in the kidneys, collagen accumulation and α-smooth muscle actin, indicative of fibroblast activation and fibrosis-related gene and protein expression, increased 3 weeks after IRI. FK-23 and LFK suppressed the increase in the mRNA levels of some of these genes. The increase in oxidative stress markers, 4-hydroxy-2-nonenal, endothelial nitric oxide synthase, and nitrotyrosine in the kidney, as well as increased plasma uremic toxins after IRI, were also ameliorated by FK-23 and LFK. Metagenomic analysis of fecal samples revealed that gut microbial alteration caused by IRI was also ameliorated by LFK treatment. These results suggest that Enterococcus faecalis ingredients may improve CKD progression by suppressing oxidative stress and correcting the balance of the intestinal microflora.

DOI： 10.3164/jcbn.24-29

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu28904263

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：STAR Protocols  

Extracellular vesicles (EVs) are complex structures that transport various DNA, RNA, and protein. Recently, new EV secretion mechanisms have been identified through the iron regulatory system in mammalian cells. We revealed that ferroptosis increases EV secretion, which is named ferroptosis-dependent EVs (FedEVs). Here, we describe a step-by-step procedure to isolate GFP-expressing FedEVs for in vitro analysis. The FedEVs are further analyzed by imaging and flow cytometry analysis. For complete details on the use and execution of this protocol, please refer to Ito et al.1

DOI： 10.1016/j.xpro.2024.102892

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PLoS Pathogens  

Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus that is causally associated with several malignancies. In addition to latent factors, lytic replication contributes to cancer development. In this study, we examined whether the lytic gene BNRF1, which is conserved among gamma-herpesviruses, has an important role in lymphomagenesis. We found that lymphoblastoid cell lines (LCLs) established by BNRF1-knockout EBV exhibited remarkably lower pathogenicity in a mice xenograft model than LCLs produced by wild-type EBV (LCLs-WT). RNA-seq analyses revealed that BNRF1 elicited the expression of interferon-inducible protein 27 (IFI27), which promotes cell proliferation. IFI27 knockdown in LCLs-WT resulted in excessive production of reactive oxygen species, leading to cell death and significantly decreased their pathogenicity in vivo. We also confirmed that IFI27 was upregulated during primary infection in B-cells. Our findings revealed that BNRF1 promoted robust proliferation of the B-cells that were transformed by EBV latent infection via IFI27 upregulation both in vitro and in vivo.

DOI： 10.1371/journal.ppat.1011954

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Laboratory Investigation  

The pathogenesis of malignant mesothelioma (MM) has been extensively investigated, focusing on stress derived from reactive oxygen species. We aimed to identify diagnostic biomarkers of MM by analyzing proteins in formalin-fixed paraffin-embedded specimens using liquid chromatography-mass spectrometry. We extracted proteins from formalin-fixed paraffin-embedded sections of MM tissues (n = 7) and compared their profiles with those of benign mesothelial tissues (n = 4) and alveolar tissue (n = 1). Proteomic data were statistically assessed and profiled using principal component analysis. We were successful in the classification of MM and healthy tissue. The levels of superoxide dismutase 2 (SOD2), an enzyme that converts superoxide anion into oxygen and hydrogen peroxide, and thioredoxin (TXN), which plays a crucial role in reducing disulfide bonds in proteins, primarily contributed to the classification. Other redox-related proteins, such as pyruvate dehydrogenase subunit X, and ceruloplasmin also contributed to the classification. Protein-protein interaction analysis demonstrated that these proteins play essential roles in MM pathogenesis. Immunohistochemistry revealed that TXN levels were significantly lower, whereas SOD2 levels were significantly higher in MM and lung cancer tissues than in controls. Proteomic profiling suggested that MM tissues experienced increased exposure to hydrogen peroxide and other reactive oxygen species. Combining immunohistochemistry for TXN and SOD2 allows for differentiation among MM, lung cancer, and control tissues; hence, TXN and SOD2 may be promising MM biomarkers and therapeutic targets.

DOI： 10.1016/j.labinv.2023.100299

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Advances in Redox Research  

Research on nonthermal plasma (NTP) devices first began almost five decades ago. NTP devices discharge electrons, positive ions, ultraviolet light, reactive oxygen species (ROS) and reactive nitrogen species (RNS) at near-physiological temperatures. Advances in plasma science have enabled the manipulation of ROS/RNS irradiation for medical applications. During preclinical stages and in human clinical trials, NTP promotes blood coagulation, eradication of bacterial, viral, and biofilm-related infections, wound healing, and cancer therapy. Previously, tetrachloroaurate (III) increased NTP-induced oxidative stress that was attenuated by reduced and oxidized glutathione, indicating that the presence of interactions between metal ions and biomolecules may modulate biological effects. In this study, using 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) as a spin probe in electron paramagnetic resonance (EPR), we observed that the tetrachloroaurate-induced M4PO-X spin adduct was significantly suppressed by ascorbate and α-tocopherol, while dehydroascorbate (DHA) and Trolox were ineffective. Tetrachloroaurate-induced lipid peroxidation, which was measured by 2-thiobarbituric acid-reactive substances (TBARS) in combination with NTP exposure, was suppressed by ascorbate, α-tocopherol and Trolox, while DHA was ineffective. Furthermore, N-acetyl-L-cysteine and dithiothreitol efficiently suppressed tetrachloroaurate-induced M4PO-X spin adduct and lipid peroxidation. LC‒MS/MS analyzes identified hexanal that was significantly elevated by NTP exposure and/or tetrachloroaurate. However, 25 and 250 μM ascorbate did not significantly suppress the formation of aldehydes, such as acetaldehyde, hexanal, nonanal, nonenal, and 4‑hydroxy-2-nonenal. Further studies are warranted to elucidate the redox reactions between metal ions, including gold (III), and biomolecules to expand the possibility of NTP application in medicine and agriculture.

DOI： 10.1016/j.arres.2023.100074

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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  

This review provides a description of the historical background of the development of biological applications of low-temperature plasmas. The generation of plasma, methods and devices, plasma sources, and measurements of plasma properties, such as electron dynamics and chemical species generation in both gaseous and aqueous phases, were assessed. Currently, direct irradiation methods for plasma discharges contacting biological surfaces, such as the skin and teeth, are related to plasma biological interactions. Indirect methods using plasma-treated liquids are based on plasma–liquid interactions. The use of these two methods is rapidly increasing in preclinical studies and cancer therapy. The authors address the prospects for further developments in cancer therapeutic applications by understanding the interactions between the plasma and living organisms.

DOI： 10.1080/10715762.2023.2230351

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

Ferritin is a spherical nanocage protein for iron storage, composed of 24 light- or heavy-polypeptide chain subunits. A single ferritin molecule can carry up to 4500 iron atoms in its core, which plays an important role in suppressing intracellular iron toxicity. Serum ferritin levels are used as a marker for the total amount of iron stored in the body. Most serum ferritin is iron-free (apo-ferritin) and it is unclear how ferritin is released from cells. Ferritin is secreted into serum via extracellular vesicles (EVs) or the secretory autophagy pathway but not via the classical endoplasmic reticulum (ER)-to-Golgi secretion pathway. We recently discovered that the level of tetraspanin CD63, a common EV marker, is post-transcriptionally regulated by the intracellular iron level and both CD63 and ferritin expression is induced by iron loading. Ferritin is incorporated into CD63(+)-EVs through the ferritin-specific autophagy adapter molecule, NCOA4, and then secreted from cells. EV production differs drastically depending on cell type and physiological conditions. Extracellular matrix detached cells express pentaspanin prominin 2 and prominin 2(+)-EVs secrete ferritin independently of NCOA4 trafficking. Ferritin is tightly bound to iron in EVs and functions as an iron-carrier protein in the extracellular environment. Cells can suppress ferroptosis by secreting holo-ferritin, which reduces intracellular iron concentration. However, this exposes the neighboring cells receiving the secreted holo-ferritin to a large excess of iron. This results in cellular toxicity through increased generation of reactive oxygen species (ROS). Here we review the machinery by which ferritin is incorporated into EVs and its role as an intercellular communication molecule.

DOI： 10.1016/j.abb.2023.109737

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

Current progress in biology and medical science is based on the observation at the level of nanometers via electron microscopy and computation. Of note, the size of most cells in higher species exists in a limited range from 5 to 50 μm. Recently, it was demonstrated that endogenous extracellular nanoparticles play a role in communication among various cellular types in a variety of contexts. Among them, exosomes in serum have been established as biomarkers for human diseases by analyzing the cargo molecules. No life on the earth can survive without iron. However, excess iron can be a risk for carcinogenesis in rodents and humans. Nano-sized molecules may cause unexpected bioeffects, including carcinogenesis, which is a process to establish cellular iron addiction with ferroptosis-resistance. Asbestos and carbon nanotubes are the typical examples, leading to carcinogenesis by the alteration of iron metabolism. Recently, we found that CD63, one of the representative markers of exosomes, is under the regulation of iron-responsive element/iron-regulatory protein system. This is a safe strategy to share excess iron in the form of holo-ferritin between iron-sufficient and -deficient cells. On the other hand, damaged cells may secrete holo-ferritin-loaded exosomes as in the case of macrophages in ferroptosis after asbestos exposure. These holo-ferritin-loaded exosomes can cause mutagenic DNA damage in the recipient mesothelial cells. Thus, there is an iron link between exogenous and endogenous nanoparticles, which requires further investigation for better understanding and the future applications.

DOI： 10.1016/j.abb.2023.109718

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1101/2023.08.14.553187

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Antioxidants and Redox Signaling  

Significance: The significance of ferroptosis in cancer therapeutics has now been unveiled. Specific ferroptosis inducers are expected as a promising strategy for cancer treatment, especially in cancers with epithelial mesenchymal transition and possibly in cancers with activated Hippo signaling pathways, both of which cause resistance to traditional chemotherapy but tend to show ferroptosis susceptibility. Recent Advances: Ferroptosis is a new form of regulated non-apoptotic cell death, which is characterized by iron-dependent lipid peroxidation, leading eventually to plasma membrane rupture. Its core mechanisms have been elucidated, consisting of a driving force as catalytic Fe(II)-dependent Fenton reaction and an incorporation of polyunsaturated fatty acids to membrane phospholipids via peroxisome-dependent and -independent pathways, and suppressing factors as prevention of lipid peroxidation with glutathione peroxidase 4 and direct membrane repair via coenzyme Q10 and ESCRT-III pathways. Critical Issues: Developments of ferroptosis inducers are in progress by nanotechnology-based drugs or by innovative engineering devices. Especially, low-temperature (non-thermal) plasma is a novel technology at the preclinical stage. The exposure can induce ferroptosis selectively in cancer cells rich in catalytic Fe(II). Future Directions: We also summarize and discuss the recently uncovered responsible molecular mechanisms in association with iron metabolism, ferroptosis and cancer therapeutics. Targeting ferroptosis in addition to the current therapeutic modalities would be important to cure advanced-stage cancer. Antioxid. Redox Signal. 39, 206-223.

DOI： 10.1089/ars.2022.0048

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Life Science Alliance  

Old animals display significant alterations in sleep–wake patterns such as increases in sleep fragmentation and sleep propensity. Here, we demonstrated that PR-domain containing protein 13 (Prdm13)+ neurons in the dorsomedial hypothalamus (DMH) are activated during sleep deprivation (SD) in young mice but not in old mice. Chemogenetic inhibition of Prdm13+ neurons in the DMH in young mice promotes increase in sleep attempts during SD, suggesting its involvement in sleep control. Furthermore, DMH-specific Prdm13-knockout (DMH-Prdm13-KO) mice recapitulated age-associated sleep alterations such as sleep fragmentation and increased sleep attempts during SD. These phenotypes were further exacerbated during aging, with increased adiposity and decreased physical activity, resulting in shortened lifespan. Dietary restriction (DR), a well-known anti-aging intervention in diverse organisms, ameliorated age-associated sleep fragmentation and increased sleep attempts during SD, whereas these effects of DR were abrogated in DMHPrdm13-KO mice. Moreover, overexpression of Prdm13 in the DMH ameliorated increased sleep attempts during SD in old mice. Therefore, maintaining Prdm13 signaling in the DMH might play an important role to control sleep–wake patterns during aging.

DOI： 10.26508/lsa.202301992

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMC Cancer  

Organoids are a three-dimensional (3D) culture system that simulate actual organs. Therefore, tumor organoids are expected to predict precise response to chemotherapy in patients. However, to date, few studies have studied the drug responses in organoids of malignant mesothelioma (MM). The poor prognosis of MM emphasizes the importance of establishing a protocol for generating MM-organoid for research and clinical use. Here, we established murine MM organoids from p53 +/- or wild-type C57BL/6 strain by intraperitoneal injection either with crocidolite or carbon nanotube. Established MM-organoids proliferated in Matrigel as spheroids. Subcutaneous injection assays revealed that the MM-organoids mimicked actual tissue architecture and maintained the original histological features of the primary MM. RNA sequencing and pathway analyses revealed that the significant expressional differences between the 2D- and 3D-culture systems were observed in receptor tyrosine kinases, including IGF1R and EGFR, glycosylation and cholesterol/steroid metabolism. MM-organoids exhibited a more sensitive response to cisplatin through stable plasma membrane localization of a major cisplatin transporter, copper transporter 1/Slc31A1 (Ctr1) in comparison to 2D-cultures, presumably through glycosylation and lipidation. The Matrigel culture system facilitated the localization of CTR1 on the plasma membrane, which simulated the original MMs and the subcutaneous xenografts. These results suggest that the newly developed protocol for MM-organoids is useful to study strategies to overcome chemotherapy resistance to cisplatin.

DOI： 10.1186/s12885-023-10966-4

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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 (C5H6O2) were detected formed by interactions of lactate or its fragments with •OH, organic radicals, and H2O2. 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

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nanoscale  

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

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：独立行政法人 労働者健康安全機構 労働安全衛生総合研究所  

<p>芳香族アミン類の一種である3,3’-ジクロロ-4,4’-ジアミノジフェニルメタン（MOCA）は，ウレタン樹脂の硬化剤等に産業利用される一方，国際がん研究機関 によりグループ1（ヒトに発がん性あり）に分類され，労働者の健康影響が懸念されている．MOCAの発がん過程には，肝臓をはじめとした各臓器で代謝される際に生じる活性酸素種（ROS）やDNA付加体によるDNA損傷が関係すると考えられているが，その中でもROSによって引き起こされるDNA酸化的損傷である8-ヒドロキシ-2’ -デオキシグアノシン（8-オキソグアニン：8-OHdG）は，高頻度に発生し，DNA複製時のG→Tの点突然変異を惹起する．しかし，実験動物においてMOCAばく露が実際に変異原性の高い8-OHdGを引き 起こすか調べた研究は我々の知る限り存在しない．</p> <p>そこで本研究では，ラットを用い，肝臓におけるMOCAばく露が十分に期待できる経口投与法により，0（対照）, 0.4, 2, 10, 50mg/kg/日の用量で 週3回2週間の反復ばく露を実施し，その標的臓器である肝臓について，病理解析及び8-OHdGの生成レベルを検討した．その結果，病理所見では，50mg/kg/日投与群において空胞変性が認められた一方， 8-OHdGは，0.4mg/kg/日投与群を除いて用量依存的な若干の増加傾向がみられたが，いずれも有意な差は認められなかった．以上から，少なくとも8-OHdGはMOCAにより引き起こされる発がんメカニズムの主原因ではないと推察される．</p>

DOI： 10.2486/josh.josh-2022-0022-ta

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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

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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

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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  

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

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担当区分：最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Seikagaku  

外因性微粒子や感染に伴う炎症反応は体内の鉄分布を大きく変え，細胞外の鉄を減らすように作用するため，細胞内鉄過剰が発生する．過剰鉄は発がんリスクである．鉄は細胞増殖に必須な酵素の補因子であるが，過剰鉄はフェントン反応により変異性DNA傷害を起こし，発がんの基盤となるフェロトーシス抵抗性を持った細胞の進化・選択を促進する．血清フェリチン値は体内鉄貯蔵の指標だがその分泌機構は不明であった．我々は最近，ヒト細胞において細胞外小胞（EV）のマーカーCD63が鉄代謝に固有なIRP/IREを介して転写後制御を受け，鉄が十分あるときには鉄充填フェリチンをEVとして分泌することを明らかにした．一方，アスベストに曝露されたマクロファージはフェロトーシスに陥るが，そのとき同様の鉄充填フェリチンをEVとして放出し，それを受け取った中皮細胞に変異性傷害を与えることを見いだした．

DOI： 10.14952/SEIKAGAKU.2023.950177

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neurobiology of Disease  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Life Sciences  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

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

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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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 (H2O2), 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 FeCl2 or FeCl3 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 H2O2, using luminescent probe in the presence of FeCl2 or FeCl3. NTP-induced DMPO-OH levels were elevated 10–100 µM FeCl2 or 500 and 1000 µM FeCl3. NTP-induced DMPO-OH with 10 µM FeCl2 or FeCl3 was significantly scavenged by ascorbate, α-tocopherol, dithiothreitol, reduced glutathione, or oxidized glutathione, whereas dehydroascorbate was ineffective in 2 mM DMPO. NTP-induced H2O2 was significantly degraded by 100 µM FeCl2 and FeCl3 in an iron-dependent manner. Meanwhile, decomposition of H2O2 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 H2O2-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

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本微量元素学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本微量元素学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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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

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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

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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 Metabolism  

Multiple roles of reactive oxygen species (ROS) and their consequences for health and disease are emerging throughout biological sciences. This development has led researchers unfamiliar with the complexities of ROS and their reactions to employ commercial kits and probes to measure ROS and oxidative damage inappropriately, treating ROS (a generic abbreviation) as if it were a discrete molecular entity. Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims entering the literature and impeding progress, despite a well-established body of knowledge on how best to assess individual ROS, their reactions, role as signalling molecules and the oxidative damage that they can cause. In this consensus statement we illuminate problems that can arise with many commonly used approaches for measurement of ROS and oxidative damage, and propose guidelines for best practice. We hope that these strategies will be useful to those who find their research requiring assessment of ROS, oxidative damage and redox signalling in cells and in vivo.

DOI： 10.1038/s42255-022-00591-z

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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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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

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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 Biology and Medicine  

DOI： 10.1016/j.freeradbiomed.2022.03.018

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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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.

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

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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.

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

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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 (1O2), superoxide (O2•-), hydrogen peroxide (H2O2), 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

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.15430/JCP.2021.26.4.244

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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  

Asbestos-associated diseases remain a social burden worldwide. Our previous studies identified asbestos-induced iron-rich milieu for mesothelial cells with ceaseless macrophage ferroptosis. However, molecular mechanisms how this mutagenic milieu influences mesothelial cells have not been elucidated yet. Here, we propose a novel mechanism that extracellular vesicles (EVs) mediate asbestos-associated mutagenic factors to mesothelial cells. In a mice model of intraperitoneal crocidolite injection, mutagenic milieu highly expressed CD63, an exosomal marker. We then used a GFP-CD63 labeled THP-1 macrophage model exposed to crocidolite/iron, which generated EVs under ferroptotic process. We observed that MeT-5A mesothelial cells can receive and internalize these EVs. Furthermore, we comprehensively analyzed the ferroptosis-dependent EVs (FedEVs) for transported proteins and identified ferritin heavy/light chains as major components. Therefore, we inferred that FedEVs transport iron from ferroptotic macrophages to mesothelial cells. RNA sequencing revealed that the mesothelial cells receiving higher amounts of the FedEVs were mitotic, especially at the S and G2/M phases, by the use of Fucci mesothelial cells. Nuclear 8-hydroxy-2′-deoxyguanosine and γ-H2AX were significantly increased in the recipient mesothelial cells after exposure to FedEVs. Collectively, we here demonstrate a novel mechanism that FedEVs act as a key mutagenic mediator by transporting iron, which contribute to asbestos-induced mesothelial carcinogenesis.

DOI： 10.1016/j.redox.2021.102174

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

DOI： 10.1016/j.abb.2021.109006

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担当区分：最終著者,　責任著者   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  

Ferroptosis is a form of regulated cell necrosis, as a consequence of Fe(II)-dependent lipid peroxidation. Although ferroptosis has been linked to cancer cell death, neurodegeneration and reperfusion injury, physiological roles of ferroptosis have not been elucidated to date mostly due to the lack of appropriate methodologies. Here, we show that 4-hydroxy-2-nonenal (HNE)-modified proteins detected by a HNEJ-1 mouse monoclonal antibody is a robust immunohistochemical technology to locate ferroptosis in tissues in combination with morphological nuclear information, based on various models of ferroptosis, including erastin-induced cysteine-deprivation, conditional Gpx4 knockout and Fe(II)-dependent renal tubular injury, as well as other types of regulated cell death. Specificity of HNEJ-1 with ferroptosis was endorsed by non-selective identification of HNE-modified proteins in an Fe(II)-dependent renal tubular injury model. We further comprehensively searched for signs of ferroptosis in different developmental stages of Fischer-344 rats from E9.5–2.5 years of age. We observed that there was a significant age-dependent increase in ferroptosis in the kidney, spleen, liver, ovary, uterus, cerebellum and bone marrow, which was accompanied by iron accumulation. Not only phagocytic cells but also parenchymal cells were affected. Epidermal ferroptosis in ageing SAMP8 mice was significantly promoted by high-fat or carbohydrate-restricted diets. During embryogenesis of Fischer-344 rats, we found ferroptosis in nucleated erythrocytes at E13.5, which disappeared in enucleated erythrocytes at E18.5. Administration of a ferroptosis inhibitor, liproxstatin-1, significantly delayed erythrocyte enucleation. Therefore, our results demonstrate for the first time the involvement of ferroptosis in physiological processes, such as embryonic erythropoiesis and aging, suggesting the evolutionally acquired mechanism and the inevitable side effects, respectively.

DOI： 10.1016/j.redox.2021.102175

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blood  

Extracellular vesicles (EVs) transfer functional molecules between cells. CD63 is a widely recognized EV marker that contributes to EV secretion from cells. However, the regulation of its expression remains largely unknown. Ferritin is a cellular iron storage protein that can also be secreted by the exosome pathway, and serum ferritin levels classically reflect body iron stores. Iron metabolism–associated proteins such as ferritin are intricately regulated by cellular iron levels via the iron responsive element-iron regulatory protein (IRE-IRP) system. Herein, we present a novel mechanism demonstrating that the expression of the EV-associated protein CD63 is under the regulation of the IRE-IRP system. We discovered a canonical IRE in the 5′ untranslated region of CD63 messenger RNA that is responsible for regulating its expression in response to increased iron. Cellular iron loading caused a marked increase in CD63 expression and the secretion of CD63+ EVs from cells, which were shown to contain ferritin-H and ferritin-L. Our results demonstrate that under iron loading, intracellular ferritin is transferred via nuclear receptor coactivator 4 (NCOA4) to CD63+ EVs that are then secreted. Such iron-regulated secretion of the major iron storage protein ferritin via CD63+ EVs, is significant for understanding the local cell-to-cell exchange of ferritin and iron.

DOI： 10.1182/blood.2021010995

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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

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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  

<p>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 <i>in situ</i> 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. </p>

DOI： 10.11299/metallomicsresearch.mr202102

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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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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-H2O2 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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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Low-temperature plasma is being widely used in the various fields of life science, such as medicine and agriculture. Plasma-activated solutions have been proposed as potential cancer therapeutic reagents. We previously reported that plasma-activated Ringer’s lactate solution exhibited selective cancer-killing effects, and that the plasma-treated L-sodium lactate in the solution was an anti-tumor factor; however, the components that are generated through the interactions between plasma and L-sodium lactate and the components responsible for the selective killing of cancer cells remain unidentified. In this study, we quantified several major chemical products, such as pyruvate, formate, and acetate, in plasma-activated L-sodium lactate solution by nuclear magnetic resonance analysis. We further identified novel chemical products, such as glyoxylate and 2,3-dimethyltartrate, in the solution by direct infusion-electrospray ionization with tandem mass spectrometry analysis. We found that 2,3-dimethyltartrate exhibited cytotoxic effects in glioblastoma cells, but not in normal astrocytes. These findings shed light on the identities of the components that are responsible for the selective cytotoxic effect of plasma-activated solutions on cancer cells, and provide useful data for the potential development of cancer treatments using plasma-activated L-sodium lactate solution.

DOI： 10.1038/s41598-021-98020-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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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  

Cellular senescence causes a dramatic alteration of chromatin organization and changes the gene expression profile of proinflammatory factors, thereby contributing to various age-related pathologies through the senescence-associated secretory phenotype (SASP). Chromatin organization and global gene expression are maintained by the CCCTC-binding factor (CTCF); however, the molecular mechanism underlying CTCF regulation and its association with SASP gene expression remains unclear. We discovered that noncoding RNA (ncRNA) derived from normally silenced pericentromeric repetitive sequences directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of SASP-like inflammatory genes, promoting malignant transformation. Notably, pericentromeric ncRNA was transferred into surrounding cells via small extracellular vesicles acting as a tumorigenic SASP factor. Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the down-regulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression. In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non-cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.

DOI： 10.1073/pnas.2025647118

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Molecular Sciences  

Oxidative stress plays a pathological role in pulmonary hypoplasia and pulmonary hypertension in congenital diaphragmatic hernia (CDH). This study investigated the effect of molecular hydrogen (H2), an antioxidant, on CDH pathology induced by nitrofen. Sprague-Dawley rats were divided into three groups: control, CDH, and CDH + hydrogen-rich water (HW). Pregnant dams of CDH + HW pups were orally administered HW from embryonic day 10 until parturition. Gasometric evaluation and histological, immunohistochemical, and real-time polymerase chain re-action analyses were performed. Gasometric results (pH, pO2, and pCO2 levels) were better in the CDH + HW group than in the CDH group. The CDH + HW group showed amelioration of alveo-larization and pulmonary artery remodeling compared with the CDH group. Oxidative stress (8-hydroxy-2′-deoxyguanosine-positive-cell score) in the pulmonary arteries and mRNA levels of pro-tein-containing pulmonary surfactant that protects against pulmonary collapse (surfactant protein A) were significantly attenuated in the CDH + HW group compared with the CDH group. Overall, prenatal H2 administration improved respiratory function by attenuating lung morphology and pulmonary artery thickening in CDH rat models. Thus, H2 administration in pregnant women with diagnosed fetal CDH might be a novel antenatal intervention strategy to reduce newborn mortality due to CDH.

DOI： 10.3390/ijms22179500

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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  

DOI： 10.1080/10715762.2021.1991083

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

Recent developments in electronics have enabled the medical applications of non-thermal plasma (NTP), which elicits reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as hydroxyl radical (●OH), hydrogen peroxide (H2O2), singlet oxygen (1O2), superoxide (O2●-), ozone, and nitric oxide at near-physiological temperatures. In preclinical studies or human clinical trials, NTP promotes blood coagulation, eradication of bacterial, viral and biofilm-related infections, wound healing, and cancer cell death. To elucidate the solution-phase biological effects of NTP in the presence of biocompatible reducing agents, we employed electron paramagnetic resonance (EPR) spectroscopy to quantify ●OH using a spin-trapping probe, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO); 1O2 using a fluorescent probe; and O2●- and H2O2 using luminescent probes in the presence of thiols or tempol. NTP-induced ●OH was significantly scavenged by dithiothreitol (DTT), reduced glutathione (GSH), and oxidized glutathione (GSSG) in 2 or 5 mM DMPO. NTP-induced O2●- was significantly scavenged by 10 μM DTT and GSH, while 1O2 was not efficiently scavenged by these compounds. GSSG degraded H2O2 more effectively than GSH and DTT, suggesting that the disulfide bonds reacted with H2O2. In the presence of 1–50 mM DMPO, NTP-induced H2O2 quantities were unchanged. The inhibitory effect of tempol concentration (50 and 100 μM) on H2O2 production was observed in 1 and 10 mM DMPO, whereas it became ineffective in 50 mM DMPO. Furthermore, DMPO-OH did not interact with tempol. These results suggest that DMPO and tempol react competitively with O2●-. Further studies are warranted to elucidate the interaction between NTP-induced ROS and biomolecules.

DOI： 10.1016/j.abb.2021.108901

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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  

Non-thermal plasma (NTP), an engineered technology to generate reactive species, induces ferroptosis and/or apoptosis specifically in various-type cancer cells. NTP-activated Ringer's lactate (PAL) is another modality for cancer therapy at preclinical stage. Here we found that PAL induces selective ferroptosis of malignant mesothelioma (MM) cells, where non-targeted metabolome screening identified upregulated citrulline-nitric oxide (.NO) cycle as a PAL target .NO probe detected biphasic peaks transiently at PAL exposure with time-dependent increase, which was responsible for inducible .NO synthase (iNOS) overexpression through NF-κB activation. .NO and lipid peroxidation occupied lysosomes as a major compartment with increased TFEB expression. Not only ferrostatin-1 but inhibitors for .NO and/or iNOS could suppress this ferroptosis. PAL-induced ferroptosis accompanied autophagic process in the early phase, as demonstrated by an increase in essential amino acids, LC3B-II, p62 and LAMP1, transforming into the later phase with boosted lipid peroxidation. Therefore, .NO-mediated lysosomal impairment is central in PAL-induced ferroptosis.

DOI： 10.1016/j.redox.2021.101989

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

DOI： 10.1016/j.abb.2021.108762

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancers  

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The major cause of EOC’s lethality is that intraperitoneal recurrence occurs with high frequency due to occult metastasis. We had demonstrated that plasma-activated medium (PAM) exerts a metastasis-inhibitory effect on ovarian cancer in vitro and in vivo. Here we investigated how PAM inhibits intraperitoneal metastasis. We studied PAM’s inhibition of micro-dissemination onto the omentum by performing in vivo imaging in combination with a sequential histological analysis. The results revealed that PAM induced macrophage infiltration into the disseminated lesion. The iNOS-positive signal was co-localized at the macrophages in the existing lesion, indicating that PAM might induce M1-type macrophages. This may be another mechanism of the antitumor effect through a PAM-evoked immune response. Intraperitoneal lavage with plasma-activated lactate Ringer’s solution (PAL) significantly improved the overall survival rate in an ovarian cancer mouse model. Our results demonstrated the efficiency and practicality of aqueous plasma for clinical applications.

DOI： 10.3390/cancers13051141

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.freeradbiomed.2020.12.249

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Free Radical Biology and Medicine  

DOI： 10.1016/j.freeradbiomed.2020.10.023

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Genes Chromosomes and Cancer  

DOI： 10.1002/gcc.22899

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Current Medicinal Chemistry  

Low-temperature plasma (LTP) is a partially ionized gas that contains elec-trons, 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 ex-periments 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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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本毒性学会  

<p>カーボンナノチューブ（CNTs）は次世代ナノ材料として期待されているものの、その毒性の懸念から国際化学物質事務局ChemSecがCNTsをSIN (Substitute It Now)リストに加えたため、今後のCNTsの使用継続について国際的に大きく議論されている。多層CNTs（MWCNTs）は生体内に入ると主にマクロファージに取り込まれ、そのマクロファージ細胞死およびNLRP3インフラマソーム活性化によるIL-1β分泌が毒性発現に関与すると考えられているが、マクロファージがどのように細胞表面上でMWCNTsを認識するのかはよく分かっていない。本研究で我々は貪食受容体スクリーニングによりT cell immunoglobulin mucin 4（Tim4）およびTim1がMWCNTsを認識することを見出した。CRISPR/Cas9システムによって作製した<i>Tim4^-/-Tim1^-/- </i>マウスや<i>Tim4^-/-</i> マウス由来腹腔マクロファージを用いた解析から、Tim4はマクロファージによるMWCNTsの貪食、およびその結果起きるIL-1β分泌に関与することが判明した。さらに<i>Tim4^-/-</i>マウス、あるいは抗Tim4モノクローナル抗体を全投与した野生型マウスにおいて、MWCNTs腹腔投与による横隔膜中皮細胞層の肉芽種形成が有意に抑制されていたことから、Tim4はMWCNTs曝露によるin vivo炎症応答に関与することが示唆された。一方、Tim1はヒト肺細胞株によるMWCNTsの認識に関与することが判明した。以上の結果は、Tim4およびTim1はMWCNTs受容体として機能することを示す。</p>

DOI： 10.14869/toxpt.48.1.0_o-4

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

DOI： 10.1016/j.abb.2020.108678

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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  

DOI： 10.1080/10715762.2020.1774177

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JCI Insight  

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 (ItpacKO 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

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancers  

Evolution from the first life on earth to humans took ~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

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Applied Physics  

DOI： 10.35848/1347-4065/abbc56

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Biochimica et Biophysica Acta - General Subjects  

DOI： 10.1016/j.bbagen.2020.129685

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Plasma Processes and Polymers  

DOI： 10.1002/ppap.201900259

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

DOI： 10.1111/cas.14581

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Redox Biology  

DOI： 10.1016/j.redox.2020.101726

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Redox Biology  

DOI： 10.1016/j.redox.2020.101616

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oncology Reports  

DOI： 10.3892/or.2020.7669

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

DOI： 10.1016/j.abb.2020.108440

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

DOI： 10.1111/cas.14496

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

DOI： 10.1016/j.abb.2020.108414

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

DOI： 10.1111/cas.14405

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancer Science  

DOI： 10.1111/cas.14358

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Free Radical Research  

DOI： 10.1080/10715762.2020.1743285

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

DOI： 10.1038/s41598-020-58667-3

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Free Radical Research  

DOI： 10.1080/10715762.2020.1733548

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

DOI： 10.1038/s41598-019-50136-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

DOI： 10.1016/j.abb.2019.108071

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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  

DOI： 10.1016/j.redox.2019.101297

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

DOI： 10.1016/j.abb.2019.05.019

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.tox.2019.01.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Archives of Biochemistry and Biophysics  

DOI： 10.1016/j.abb.2018.12.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1293/tox.2018-0029

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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  

DOI： 10.3164/jcbn.18-91

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Ferroptosis in Health and Disease  

DOI： 10.1007/978-3-030-26780-3_2

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掲載種別：研究論文（学術雑誌）   出版者・発行元：日本毒性学会  

<p><b>[Introduction]</b> Drug-induced acute kidney injury (AKI) is a frequent cause of adverse drug reaction. Serum creatinine (CRE) and blood urea nitrogen (BUN) are widely used as standard biomarkers for kidney injury; however, the sensitivity and specificity are considered to be low. In recent years, circulating microRNA (miRNAs) have been attracting considerable attention as novel biomarkers for organ injury, but there are currently no established miRNA biomarkers for drug-induced AKI. The present study aimed to identify plasma miRNAs that may enable early and specific detection of drug-induced tubular and glomerular injury through next-generation sequencing analysis. <b>[Methods]</b> Six-week old male Sprague-Dawley rats were administered cisplatin and gentamicin to induce tubular injury. To create glomerular injury models, puromycin and doxorubicin were administered, and these models were always accompanied by tubular damage. Small RNA-sequencing was performed to analyze time-dependent changes in the plasma miRNA profiles. <b>[Results and Discussion]</b> In the differential analysis, miR-3473 was specifically up-regulated in the glomerular injury models. miR-143-3p and miR-122-5p were commonly down-regulated in all models, and the changes were earlier than the traditional biomarkers, such as plasma CRE and BUN. These data indicated that changes in the specific miRNAs in plasma may enable the early and sensitive detection of tubular and glomerular injuries. The present study suggests the potential utility of plasma miRNAs in the early and type-specific detection of drug-induced AKI.</p>

DOI： 10.14869/toxpt.46.1.0_P-233

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/10715762.2018.1500019

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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  

Carbon nanotubes (CNTs) have attracted much business interest in industrial applications due to their high electrical and heat conductivities while being both durable and versatile. However, multiwall CNTs (MWCNTs) of ~ 50 nm diameter (NT50) have been shown to cause mesothelioma in rodents after direct exposure to mesothelial cells, and thus were classified as a Group 2B carcinogen to humans, which requires considerable regulations for use. In contrast, tangled MWCNTs of ~ 15 nm diameter (NTtngl) are not carcinogenic to rats, indicating that the physical dimension linked with mesothelial cellular uptake is an important factor for human environmental risk. In the present study, hypothesizing that dustability is another distinct risk factor, for the first time, we evaluated the toxicity of CNT granules (Durobeads) that were generated with a polymer coating to mesothelial cells. Polymer coating induced prominent agglomeration and significantly suppressed the dustability of CNTs in a dose-dependent manner, with a 10% polymer coating resulting in 730 times less dustability. These CNT granules revealed significantly lower mesothelial uptake and cytotoxicity in comparison to NT50 in in vitro assays. Similarly, in in vivo analyses, CNT granules induced limited peritoneal inflammation 4 weeks after intraperitoneal injection, whereas NT50 caused severe fibrosing inflammation. Previously, we demonstrated that the severity of inflammation by intraperitoneal injection in the subacute studies are in agreement with the mesothelial carcinogenicity by CNTs. Therefore, we suggest that adding a polymer coating to CNTs provides another smart strategy for the safe use of CNTs.

DOI： 10.18999/nagjms.80.4.597

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/10715762.2018.1514604

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.freeradbiomed.2018.10.401

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1515/hsz-2018-0199

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/10715762.2018.1528501

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：公益社団法人 応用物理学会  

DOI： 10.11470/jsapmeeting.2018.2.0_37

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本癌学会  

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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 Biology and Medicine  

Non-enzymatic peroxidation of polyunsaturated fatty acids (PUFA) results in the formation of various α,β-unsaturated aldehydes, of which 4-hydroxyalkenals are abundant. The propensity of n-6 PUFA, such as linoleic acid, γ-linolenic acid and arachidonic acid, to undergo radical-induced peroxidation and generate 4-hydroxy-2E-nonenal (4-HNE) has been widely demonstrated. The ability of the latter to form covalent adducts with macromolecules and modify cellular functions has been linked to numerous pathological processes. Concomitantly, evidence has accumulated on specific signaling properties of low concentrations of 4-HNE that may induce hormetic and protective responses to peroxidation stress in cells. It has long been known that peroxidation of PUFA, and particularly arachidonic acid, also give rise to 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), which is more chemically reactive than 4-HNE. Few studies on 4-HDDE revealed its ability to avidly interact covalently with electronegative moieties in macromolecules and to its ability to selectively activate the transcriptional regulator Peroxisome Proliferator-Activated Receptor (PPAR)-β/δ. The research on 4-HDDE has been impeded due to the lack of available pure 4-HDDE and antibodies that recognize 4-HDDE-modified epitopes in proteins. The purpose of this study was to employ an established procedure to synthesize 4-HDDE and use it to create and characterize a monoclonal antibody against 4-HDDE-modified proteins and establish its application for ELISA and immunohistochemical analysis of cells and tissues and further expand lipid peroxidation research.

DOI： 10.1016/j.freeradbiomed.2018.05.079

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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  

DOI： 10.1111/pin.12665

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H2) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H2 attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Short-term memory, sociability and social novelty, and sensorimotor gating were evaluated using the Y-maze, three-chamber, and prepulse inhibition (PPI) tests, respectively, at postnatal 3 or 4 weeks. The number of neurons and oligodendrocytes was also analyzed at postnatal 5 weeks by immunohistochemical analysis. Offspring of the LPS-exposed dams showed deficits in short-term memory and social interaction, following neuronal and oligodendrocytic loss in the amygdala and cortex. Maternal H2 administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H2 on LPS-induced astrocytic activation, both in vivo and in vitro. The number of activated astrocytes with hypertrophic morphology was increased in LPS-exposed offspring, but decreased in the offspring of H2-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H2 administration. Overall, these findings indicate that maternal H2 administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life.

DOI： 10.1038/s41598-018-27626-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Medical Mycology Case Reports  

A 62-year-old previously healthy male who was a welder/smoker/drinker was admitted to Kani Tono Hospital for severe hypoxemia (Day 0). Initial physical and radiological examinations suggested an acute exacerbation of chronic obstructive pulmonary disease. However, respiratory failure developed rapidly, and he died on Day + 4. Aspergillus fumigatus was identified after his death, and he was diagnosed with invasive pulmonary aspergillosis. The clinical and pathological features are precisely described with pathogenetic considerations.

DOI： 10.1016/j.mmcr.2018.02.002

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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  

p16 activation caused by oncogenic mutations may represent oncogene-induced senescence (OIS), a protective mechanism against oncogenic events. However, OIS can contribute to tumor development via tissue remodeling in some tumors. Erdheim–Chester disease (ECD), a rare non-Langerhans cell histiocytosis, is one such tumor. Its clinical and histological features vary, making it difficult to diagnose. Herein, we describe an autopsy of an ECD patient. The patient underwent radiological examinations, including 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), bone scintigraphy and CT. A biopsy from the lesion with the highest FDG accumulation confirmed the presence of foamy macrophages, a diagnostic clue for ECD. Based on this finding and the clinical features, ECD was diagnosed. However, the patient died from heart dysfunction. After the autopsy, each radiologically different site showed various histological findings regarding the morphology of macrophages, fibrosis, inflammation, and p16 expression. OIS-induced histological progression can cause certain changes observed in radiological images. In addition, in order to evaluate the increase in glucose metabolism, which can affect FDG accumulation, the expression of glucose transporter 1 and hexokinase II was also analyzed. Summarizing the radio-histological correlation can help further both the understanding and diagnosis of ECD.

DOI： 10.1111/pin.12663

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本微量元素学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.freeradbiomed.2018.04.081

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oncotarget  

P-REX2a is a PTEN inhibitor that also activates Rac 1. No associations with P-REX2a and human endometrial cancers have been reported to date. In this study, we immunohistochemically analyzed 155 uterine endometrial malignancies for P-REX2a expression. The P-REX2a-positive tumors displayed worse prognosis independent of PTEN expression. Then, we transduced either P-REX2a expression vector or short hairpin RNAs targeting P-REX2a into 2 uterine endometrioid carcinoma cell lines, OMC-2 and JHUEM-14. Ectopic expression of P-REX2a led to increased cell proliferation only in the PTEN-expressing OMC-2 cells but did not show any change in the PTEN-negative JHUEM-14 cells or the P-REX2a-knockdown cells. Induction of P-REX2a increased and knockdown of P-REX2a decreased cell migration in both cell lines. Then, we performed expression microarray analysis using these cells, and pathway analysis revealed that the expression of members of the GPCR downstream pathway displayed the most significant changes induced by the knockdown of P-REX2a. Immunohistochemical analysis revealed that Vav1, a member of the GPCR downstream pathway, was expressed in 139 of the 155 endometrial tumors, and the expression levels of Vav1 and P-REX2a showed a positive correlation (r = 0.44, p < 0.001). In conclusion, P-REX2a enhanced cell motility via the GPCR downstream pathway independently of PTEN leading to progression of uterine endometrioid malignancies and poor prognosis of the patients.

DOI： 10.18632/oncotarget.25349

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/10715762.2018.1467562

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biomedical Reports  

Intrauterine inflammation causes preterm birth and is associated with complications in preterm neonates. Thus, strategies aimed at suppressing inflammation are expected to be effective for reducing the risk of preterm birth and associated complications. Our previous studies demonstrated that molecular hydrogen (H2), an anti-inflammatory agent, prevented inflammation-induced impairment in foetal brain and lung tissues in lipopolysaccharide (LPS)-induced rodent models. However, it remains unclear whether H2 is capable of inhibiting preterm labour. The aim of the current study was therefore to investigate the effect of H2 on inflammation-induced preterm labour. Pregnant ICR (CD-1) mice were divided into three groups: Control, LPS and H2 water (HW) + LPS. In the control and LPS groups, vehicle and LPS, respectively, were intraperitoneally injected on embryonic day 15.5. In the HW + LPS group, HW was administered 24 h prior to LPS injection. The time from LPS administration to parturition was compared between the LPS and HW + LPS groups. Maternal uterus was collected 6 h after LPS injection and the transcript levels of pro-inflammatory cytokines, contractile-associated proteins (CAPs), matrix metalloproteinase-3 (Mmp3) and endothelin-1 (Et1) were assessed by reverse transcription-quantitative polymerase chain reaction. The protein levels of cyclooxygenase-2 (Cox2) were also evaluated by immunohistochemistry. The time from LPS administration to parturition in the HW + LPS group was significantly increased compared with that in the LPS group (33.5±3.4 vs. 18.3±8.8 h, respectively, P=0.020). H2 administration also resulted in significantly higher progesterone levels compared with LPS treatment alone (P=0.002). The transcript levels of pro-inflammatory cytokines, CAPs, Mmp3 and Et1 in the uteri of the LPS group were significantly higher than those in the control group (all P<0.05). In turn, all these levels with the exception of interleukin-8 and Mmp3 were significantly lower in the HW + LPS group compared with those in the LPS group (all P<0.05). The protein levels of Cox2 in the LPS group were also significantly increased compared with those in the control (P<0.001) and HW + LPS (P=0.003) groups. These results suggest that inflammation-induced changes in the uterus may be ameliorated through maternal H2 administration. Preventive H2 administration may therefore represent an effective strategy for the suppression of inflammation during preterm labour.

DOI： 10.3892/br.2018.1082

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oncotarget  

Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo. We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro, which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.

DOI： 10.18632/oncotarget.24892

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Histopathology  

Aims: Ossification is found occasionally in dedifferentiated liposarcoma (DDLPS). The aims of this study were to elucidate whether the formed bone tissue is usually produced by tumour cells or by reactive non-neoplastic cells, and to reveal the clinicopathological characteristics of DDLPS with ossification. Methods and results: We examined 36 cases of ossified DDLPS by comparing them to 31 cases of non-ossified DDLPS. MDM2 amplification was confirmed in osteocytes and/or osteoblastic cells in all but one ossified DDLPS cases (27 of 28) using fluorescence in-situ hybridisation, although the morphological impression of ossification appeared to be mainly metaplastic (27 of 36) or high-grade osteosarcoma-like (six of 36). The bone tissue was often formed predominantly at the periphery of the DDLPS area near the well-differentiated liposarcoma component (18 of 36), and an organised structure such as bone marrow-like differentiation was not uncommon (12 of 36). According to a modified French Fédération Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, ossified DDLPS tended to be lower grade than non-ossified DDLPS (mean grade: 1.88 and 2.15, respectively). Ossification in DDLPS was associated significantly with shorter local recurrence-free survival by multivariate analysis (P = 0.02347), but metaplastic-appearing ossification tended to be associated with longer overall survival (P = 0.1400). Conclusions: The bone tissue formed in DDLPS was mainly neoplastic regardless of its morphology and maturity, which highlighted the osteogenic differentiation of the tumour cells. DDLPS patients with osteogenic differentiation tended to suffer from earlier local recurrences, which did not necessarily lead to poor life outcomes.

DOI： 10.1111/his.13421

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病理学会  

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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  

Malignant mesothelioma (MM) is a rare but socially important neoplasm due to its association with asbestos exposure. Malignant mesothelioma is difficult to diagnose at an early stage, yet there are no particularly effective treatments available at the advanced stage, thus necessitating efficient strategies to prevent MM in individuals already exposed to asbestos. We previously showed that persistent oxidative damage caused by foreign body reaction and affinity of asbestos both to hemoglobin and histones is one of the major pathogeneses. Accordingly, as an effective strategy to prevent asbestos-induced MM, we undertook the use of an iron chelator, deferasirox, which decreased the epithelial–mesenchymal transition in a crocidolite-induced rat MM model. However, this agent may show adverse effects. Here, we studied the effects of iron removal by phlebotomy as a realistic measure on the same rat model. We injected a total of 5 mg crocidolite i.p. to F1 hybrid rats between the Fischer-344 and Brown-Norway strains at the age of 6 weeks. We repeated weekly or biweekly phlebotomy of 6-8 mL/kg/time from 10 to 60 weeks of age. The animals were observed until 120 weeks. In male rats, phlebotomy significantly decreased the weight and nuclear grade of MM, and modestly reduced the associated ascites and the fraction of more malignant sarcomatoid subtype. Weekly phlebotomy prolonged long-term survival. Our results indicate that appropriate phlebotomy may be a practical preventive measure to attenuate the initiation and promotion capacity of asbestos towards MM by reducing iron in individuals exposed to asbestos.

DOI： 10.1111/cas.13460

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：IEEE Transactions on Radiation and Plasma Medical Sciences  

Plasma-activated medium (PAM) is a novel chemotherapy that induces reactive oxygen species (ROS) and cell death in a wide range of cancer cell types, suggesting that PAM may be a promising therapeutic option for cancer treatment. However, dose response experiments suggest that PAM sensitivity is cell line specific. We examined the sensitivities of three glioblastoma cell lines to PAM, and found a wide variation in cell killing that was linked to differences in PAM induced ROS and apoptosis. These results indicate that the PAM sensitivity of glioblastoma cells, and potentially cancer cells more generally, is heterogeneous and likely to be dependent on the regulation of apoptosis and antioxidant pathways in target cells.

DOI： 10.1109/trpms.2017.2721973

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Reviews of Modern Plasma Physics  

Plasma medical science is a novel interdisciplinary field that combines studies on plasma science and medical science, with the anticipation that understanding the scientific principles governing plasma medical science will lead to innovations in the field. Non-thermal atmospheric pressure plasma has been used for medical treatments, such as for cancer, blood coagulation, and wound healing. The interactions that occur between plasma and cells/tissues have been analyzed extensively. Direct and indirect treatment of cells with plasma has broadened the applications of non-thermal atmospheric pressure plasma in medicine. Examples of indirect treatment include plasma-assisted immune-therapy and plasma-activated medium. Controlling intracellular redox balance may be key in plasma cancer treatment. Animal studies are required to test the effectiveness and safety of these treatments for future clinical applications.

DOI： 10.1007/s41614-017-0004-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/cas.13460.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1111/pin.12598.

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：一般社団法人　日本酸化ストレス学会  

Congenital diaphragmatic hernia (CDH) is a life-threatening neonatal disease that leads to lung hypoplasia and pulmonary hypertension. We recently found that maternal prenatal administration of Saireito (TJ-114) ameliorates fetal CDH in a nitrofen-induced rat model. Here, we studied the role of iron and oxidative stress in neonates of this model and in lung fibroblasts IMR90-SV in asso-ciation with nitrofen and Saireito. We observed increased immuno- staining of 8-hydroxy-2'-deoxyguanosine in the lungs of neonates with CDH, which was ameliorated by maternal Saireito intake. Pulmonary transferrin receptor expression was significantly decreased in both CDH and CDH after Saireito in comparison to normal controls, indicating functional lung immaturity, whereas catalytic Fe(ll) and pulmonaiy DMT1/ferroportin expression remained constant among the three groups. Saireito revealed a dose-dependent scavenging capacity with electron spin resonance spin trapping in vitro against hydroxyl radicals but not against superoxide. Finally, nitrofen revealed dose-dependent cytotoxicity to IMR90-SV cells, accompanied by an increase in oxidative stress, as seen by 5(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and catalytic Fe(ll). Saireito ameliorated all of these in IMR90-SV cells. In conclusion, catalytic Fe(ll)-dependent oxidative stress by nitrofen may be the pathogenic cause of CDH, and the antioxidative activity of Saireito is at least partially responsible for improving nitrof en-induced CDH.

DOI： 10.3164/jcbn.17-17

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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  

Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh-deficient mice in comparison to wild-type mice (7.1%). Fe-NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe-NTA treatment in both the genotypes. Renal tumor-free survival after Fe-NTA treatment was marginally different (P = 0.157) between the two genotypes. Array-based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16INKA inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe-NTA-induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.

DOI： 10.1111/pin.12598

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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  

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death. Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

DOI： 10.1016/j.cell.2017.09.021

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： doi: 10.1111/his.13421.

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/his.13421.