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Article ; Online: [Symposium of Division of Pharmaceutical Health Sciences and Environmental Toxicology-Diseases Caused by Food-nutrient Stress and Their Prevention Strategies].

Imai, Hirotaka / Matsuzawa, Atsushi

Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

2021 Volume 141, Issue 5, Page(s) 667–668

MeSH term(s)	Animals ; Biopharmaceutics ; Cadmium/metabolism ; Cation Transport Proteins ; Disease/etiology ; Ecotoxicology ; Fatty Acids, Omega-3 ; Food/adverse effects ; Food Analysis ; Glutathione/analogs & derivatives ; Humans ; Lysophospholipids ; Manganese/metabolism ; Mice ; Nutrients/adverse effects ; Nutritional Sciences ; Organoselenium Compounds ; Preventive Medicine ; Sphingosine/analogs & derivatives ; Trans Fatty Acids/adverse effects ; Vitamin K ; Vitamin K 2/analogs & derivatives
Chemical Substances	Cation Transport Proteins ; Fatty Acids, Omega-3 ; Lysophospholipids ; Organoselenium Compounds ; SLC39A8 protein, human ; Trans Fatty Acids ; Cadmium (00BH33GNGH) ; Vitamin K 2 (11032-49-8) ; Vitamin K (12001-79-5) ; sphingosine 1-phosphate (26993-30-6) ; menatetrenone (27Y876D139) ; selenodiglutathione (33944-90-0) ; Manganese (42Z2K6ZL8P) ; Glutathione (GAN16C9B8O) ; Sphingosine (NGZ37HRE42)
Language	Japanese
Publishing date	2021-05-05
Publishing country	Japan
Document type	Editorial
ZDB-ID	200514-1
ISSN	1347-5231 ; 0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
ISSN (online)	1347-5231
ISSN	0031-6903 ; 0372-7750 ; 0919-2085 ; 0919-2131
DOI	10.1248/yakushi.20-00243-F
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Article: Inhibition of lipid peroxidation during the reproductive period extends the lifespan of

Sakamoto, Taro / Maebayashi, Kana / Tsunoda, Yuka / Imai, Hirotaka

Journal of clinical biochemistry and nutrition

2020 Volume 66, Issue 2, Page(s) 116–123

Abstract: Glutathione peroxidase 4 (GPx4) is a unique antioxidant enzyme that directly reduces the phospholipid hydroperoxides (PLOOH) generated in biomembranes using glutathione as the reductant. We have previously reported that ... ...

Abstract	Glutathione peroxidase 4 (GPx4) is a unique antioxidant enzyme that directly reduces the phospholipid hydroperoxides (PLOOH) generated in biomembranes using glutathione as the reductant. We have previously reported that the
Language	English
Publishing date	2020-01-31
Publishing country	Japan
Document type	Journal Article
ZDB-ID	632945-7
ISSN	1880-5086 ; 0912-0009
ISSN (online)	1880-5086
ISSN	0912-0009
DOI	10.3164/jcbn.19-51
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Article: Slowly progressive cell death induced by GPx4-deficiency occurs via MEK1/ERK2 activation as a downstream signal after iron-independent lipid peroxidation.

Tsuruta, Kahori / Matsuoka, Masaki / Harada, Shinsaku / Enomoto, Ayaka / Kumagai, Takeshi / Yasuda, Shu / Koumura, Tomoko / Yamada, Ken-Ichi / Imai, Hirotaka

Journal of clinical biochemistry and nutrition

2023 Volume 74, Issue 2, Page(s) 97–107

Abstract: Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme that reduces phospholipid hydroperoxide. Studies have reported that the loss of GPx4 activity through anticancer drugs leads to ferroptosis, an iron-dependent lipid peroxidation-induced cell death. ...

Abstract	Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme that reduces phospholipid hydroperoxide. Studies have reported that the loss of GPx4 activity through anticancer drugs leads to ferroptosis, an iron-dependent lipid peroxidation-induced cell death. In this study, we established Tamoxifen-inducible GPx4-deficient Mouse embryonic fibroblast (MEF) cells (ETK1 cells) and found that Tamoxifen-inducible gene disruption of GPx4 induces slow cell death at ~72 h. In contrast, RSL3- or erastin-induced ferroptosis occurred quickly within 24 h. Therefore, we investigated the differences in these mechanisms between GPx4 gene disruption-induced cell death and RSL3- or erastin-induced ferroptosis. We found that GPx4-deficiency induced lipid peroxidation at 24 h in Tamoxifen-treated ETK1 cells, which was not suppressed by iron chelators, although lipid peroxidation in RSL3- or erastin-treated cells induced ferroptosis that was inhibited by iron chelators. We revealed that GPx4-deficient cell death was MEK1-dependent but RSL3- or erastin-induced ferroptosis was not, although MEK1/2 inhibitors suppressed both GPx4-deficient cell death and RSL3- or erastin-induced ferroptosis. In GPx4-deficient cell death, the phosphorylation of MEK1/2 and ERK2 was observed 39 h after lipid peroxidation, but ERK1 was not phosphorylated. Selective inhibitors of ERK2 inhibited GPx4-deficient cell death but not in RSL3- or erastin-induced cell death. These findings suggest that iron-independent lipid peroxidation due to GPx4 disruption induced cell death via the activation of MEK1/ERK2 as a downstream signal of lipid peroxidation in Tamoxifen-treated ETK1 cells. This indicates that GPx4 gene disruption induces slow cell death and involves a different pathway from RSL3- and erastin-induced ferroptosis in ETK1 cells.
Language	English
Publishing date	2023-11-01
Publishing country	Japan
Document type	Journal Article
ZDB-ID	632945-7
ISSN	1880-5086 ; 0912-0009
ISSN (online)	1880-5086
ISSN	0912-0009
DOI	10.3164/jcbn.23-101
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Article ; Online: Hydrogen peroxide produced by superoxide dismutase SOD-2 activates sperm in

Sakamoto, Taro / Imai, Hirotaka

The Journal of biological chemistry

2017 Volume 292, Issue 36, Page(s) 14804–14813

Abstract: Superoxide dismutase (SOD) is a ubiquitous antioxidant enzyme that catalytically converts the superoxide radical to hydrogen peroxide ( ... ...

Abstract	Superoxide dismutase (SOD) is a ubiquitous antioxidant enzyme that catalytically converts the superoxide radical to hydrogen peroxide (H
MeSH term(s)	Animals ; Caenorhabditis elegans/cytology ; Caenorhabditis elegans/enzymology ; Hydrogen Peroxide/metabolism ; Male ; Spermatozoa/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase/metabolism
Chemical Substances	Hydrogen Peroxide (BBX060AN9V) ; Superoxide Dismutase (EC 1.15.1.1) ; superoxide dismutase 2 (EC 1.15.1.1)
Language	English
Publishing date	2017-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M117.788901
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Article ; Online: New Strategy of Functional Analysis of PHGPx Knockout Mice Model Using Transgenic Rescue Method and Cre-LoxP System.

Imai, Hirotaka

Journal of clinical biochemistry and nutrition

2009 Volume 46, Issue 1, Page(s) 1–13

Abstract: Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is an intracellular antioxidant enzyme that directly reduces peroxidized phospholipids. PHGPx is transcribed from one gene into three types of mRNA, mitochondrial, non-mitochondrial and nucleolar ... ...

Abstract	Phospholipid hydroperoxide glutathione peroxidase (PHGPx) is an intracellular antioxidant enzyme that directly reduces peroxidized phospholipids. PHGPx is transcribed from one gene into three types of mRNA, mitochondrial, non-mitochondrial and nucleolar PHGPx by alternative transcription. In this review, we focus on our recent experiments on the regulation of promoter activity of the types of PHGPx and on the novel strategy of functional analysis of a PHGPx knockout mice model using the transgenic rescue method and Cre-LoxP system. PHGPx is especially high in testis and spermatozoa. A deficiency is implicated in human infertility. We established spermatocyte-specific PHGPx knockout (KO) mice using a Cre-loxP system. Targeted disruption of all exons of the PHGPx gene in mice by homologous recombination caused embryonic lethality at 7.5 days post coitum. The PHGPx-loxP transgene rescued PHGPx KO mice from embryonic lethality. These rescued floxed PHGPx mice were mated with spermatocyte specific Cre expressing mice. All the spermatocyte-specific PHGPx KO male mice were infertile and displayed a significant decrease in the number of spermatozoa and significant reductions in forward motility by mitochondrial dysfunction of spermatozoa. These results demonstrate that depletion of PHGPx in spermatozoa may be one of the causes of male infertility in mice and humans.
Language	English
Publishing date	2009-12-29
Publishing country	Japan
Document type	Journal Article
ZDB-ID	632945-7
ISSN	1880-5086 ; 0912-0009
ISSN (online)	1880-5086
ISSN	0912-0009
DOI	10.3164/jcbn.09-94R
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Article: Detection of material-derived differences in the stiffness of egg yolk phosphatidylcholine-containing liposomes using atomic force microscopy

Takechi-Haraya, Yuki / Matsuoka, Masaki / Imai, Hirotaka / Izutsu, Kenichi / Sakai-Kato, Kumiko

Chemistry and physics of lipids. 2020 Nov., v. 233

2020

Abstract: Naturally sourced phospholipids are used in many liposomal pharmaceuticals. The present report describes a method to detect the effects of different egg yolk phosphatidylcholines (EPCs) on liposomal physicochemical properties. Five EPC-containing ... ...

Abstract	Naturally sourced phospholipids are used in many liposomal pharmaceuticals. The present report describes a method to detect the effects of different egg yolk phosphatidylcholines (EPCs) on liposomal physicochemical properties. Five EPC-containing liposomes were prepared using five different EPCs obtained from different suppliers. There was no significant difference in purity between each EPC. The stiffness of the liposomes was examined via atomic force microscopy (AFM) in relation to the liposomal membrane permeability coefficient of encapsulated calcein after gel filtration, which is indicative of liposomal stability including the release of a hydrophilic drug from a liposome. Although the size of the liposome and the encapsulation efficiency of calcein did not significantly change with the type of EPC used, the liposome stiffness was found to vary depending on the EPC used, and liposomes with a similar stiffness were found to show a similar membrane permeability to calcein. Our results indicate the usefulness of stiffness measurement, using AFM as the analytical method, to detect material-derived differences in EPC-containing liposomes that affect drug release from the liposomes. Because drug release is one of the most important liposomal functions, combining this method with other analytical methods could be useful in selecting material for the development and quality control of EPC-containing liposomes.
Keywords	atomic force microscopy ; drugs ; egg yolk ; encapsulation ; gel chromatography ; hydrophilicity ; membrane permeability ; phosphatidylcholines ; quality control
Language	English
Dates of publication	2020-11
Publishing place	Elsevier B.V.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	213869-4
ISSN	1873-2941 ; 0009-3084
ISSN (online)	1873-2941
ISSN	0009-3084
DOI	10.1016/j.chemphyslip.2020.104992
Database	NAL-Catalogue (AGRICOLA)

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Article: Redox reactions in mammalian spermatogenesis and the potential targets of reactive oxygen species under oxidative stress.

Fujii, Junichi / Imai, Hirotaka

Spermatogenesis

2014 Volume 4, Issue 2, Page(s) e979108

Abstract: Reduction-oxidation (Redox) reactions are ubiquitous mechanisms for vital activities in all organisms, and they play pivotal roles in the regulation of spermatogenesis as well. Here we focus on 3 redox-involved processes that have drawn much recent ... ...

Abstract	Reduction-oxidation (Redox) reactions are ubiquitous mechanisms for vital activities in all organisms, and they play pivotal roles in the regulation of spermatogenesis as well. Here we focus on 3 redox-involved processes that have drawn much recent attention: the regulation of signal transduction by reactive oxygen species (ROS) such as hydrogen peroxide, oxidative protein folding in the endoplasmic reticulum (ER), and sulfoxidation of protamines during sperm chromatin condensation. The first 2 of these processes are emerging topics in cell biology and are applicable to most living cells, which includes spermatogenic cells. The roles of ROS in signal transduction have been elucidated in the last 2 decades and have received broad attention, most notably from the viewpoint of the proper control of mitotic signals. Redox processes in the ER are important because this is the organelle where secretory and membrane proteins are synthesized and proceed toward their functional structure, so that malfunction of the ER affects not only the involved cells but also the accepting cells of the secreted proteins in multicellular organisms. Sulfoxidation is the third of these processes, and the sulfoxidation of chromatin is a unique process in sperm maturation. During recent sulfoxidase research, GPX4 has emerged as a promising enzyme that plays essential roles in the production of fertile sperm, but the involvement of other redox proteins is also becoming evident. Because the molecules involved in the redox reactions are prone to oxidation, they can be sensitive to oxidative damage, which makes them potential targets for antioxidant therapy.
Language	English
Publishing date	2014-12-31
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	2629571-4
ISSN	2156-5562 ; 2156-5554
ISSN (online)	2156-5562
ISSN	2156-5554
DOI	10.4161/21565562.2014.979108
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Article ; Online: Detection of material-derived differences in the stiffness of egg yolk phosphatidylcholine-containing liposomes using atomic force microscopy.

Takechi-Haraya, Yuki / Matsuoka, Masaki / Imai, Hirotaka / Izutsu, Kenichi / Sakai-Kato, Kumiko

Chemistry and physics of lipids

2020 Volume 233, Page(s) 104992

Abstract	Naturally sourced phospholipids are used in many liposomal pharmaceuticals. The present report describes a method to detect the effects of different egg yolk phosphatidylcholines (EPCs) on liposomal physicochemical properties. Five EPC-containing liposomes were prepared using five different EPCs obtained from different suppliers. There was no significant difference in purity between each EPC. The stiffness of the liposomes was examined via atomic force microscopy (AFM) in relation to the liposomal membrane permeability coefficient of encapsulated calcein after gel filtration, which is indicative of liposomal stability including the release of a hydrophilic drug from a liposome. Although the size of the liposome and the encapsulation efficiency of calcein did not significantly change with the type of EPC used, the liposome stiffness was found to vary depending on the EPC used, and liposomes with a similar stiffness were found to show a similar membrane permeability to calcein. Our results indicate the usefulness of stiffness measurement, using AFM as the analytical method, to detect material-derived differences in EPC-containing liposomes that affect drug release from the liposomes. Because drug release is one of the most important liposomal functions, combining this method with other analytical methods could be useful in selecting material for the development and quality control of EPC-containing liposomes.
MeSH term(s)	Animals ; Egg Yolk/chemistry ; Hydrodynamics ; Hydrophobic and Hydrophilic Interactions ; Liposomes/chemistry ; Microscopy, Atomic Force ; Phosphatidylcholines/analysis
Chemical Substances	Liposomes ; Phosphatidylcholines
Language	English
Publishing date	2020-10-12
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	213869-4
ISSN	1873-2941 ; 0009-3084
ISSN (online)	1873-2941
ISSN	0009-3084
DOI	10.1016/j.chemphyslip.2020.104992
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Article ; Online: Regulated Necrosis in Pulmonary Disease. A Focus on Necroptosis and Ferroptosis.

Minagawa, Shunsuke / Yoshida, Masahiro / Araya, Jun / Hara, Hiromichi / Imai, Hirotaka / Kuwano, Kazuyoshi

American journal of respiratory cell and molecular biology

2020 Volume 62, Issue 5, Page(s) 554–562

Abstract: To date, increasing evidence suggests the possible involvement of various types of cell death in lung diseases. The recognized regulated cell death includes necrotic cell death that is immunogenic, releasing damage-associated molecular patterns and ... ...

Abstract	To date, increasing evidence suggests the possible involvement of various types of cell death in lung diseases. The recognized regulated cell death includes necrotic cell death that is immunogenic, releasing damage-associated molecular patterns and driving tissue inflammation. Necroptosis is a well-understood form of regulated necrosis that is executed by RIPK3 (receptor-interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase domain-like protein). Ferroptosis is a newly described caspase-independent form of regulated necrosis that is characterized by the increase of detrimental lipid reactive oxygen species produced via iron-dependent lipid peroxidation. The role of these two cell death pathways differs depending on the disease, cell type, and microenvironment. Moreover, some experimental cell death models have demonstrated shared ferroptotic and necroptotic cell death and the synergistic effect of simultaneous inhibition. This review examines the role of regulated necrotic cell death, particularly necroptosis and ferroptosis, in lung disease pathogenesis in the context of recent insights into the roles of the key effector molecules of these two cell death pathways.
MeSH term(s)	Alarmins/metabolism ; Animals ; Autophagy ; Ferroptosis ; Humans ; Lung Diseases/pathology ; Necroptosis ; Necrosis
Chemical Substances	Alarmins
Language	English
Publishing date	2020-02-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2019-0337TR
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Article ; Online: Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity.

Tadokoro, Tomonori / Ikeda, Masataka / Ide, Tomomi / Deguchi, Hiroko / Ikeda, Soichiro / Okabe, Kosuke / Ishikita, Akihito / Matsushima, Shouji / Koumura, Tomoko / Yamada, Ken-Ichi / Imai, Hirotaka / Tsutsui, Hiroyuki

JCI insight

2023 Volume 8, Issue 6

MeSH term(s)	Humans ; Cardiotoxicity/etiology ; Ferroptosis ; Doxorubicin/adverse effects ; Mitochondria
Chemical Substances	Doxorubicin (80168379AG)
Language	English
Publishing date	2023-03-22
Publishing country	United States
Document type	Journal Article ; Published Erratum
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.169756
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