プロスタグランジン輸送体PGTを介したPGE2調節機構

13301甲第4076号博士（薬学）金沢大学博士論文要旨Abstract 要約Outlin

Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease

Iron has played an important role in energy production since the beginning of life, as iron-catalyzed redox reactions are required for energy production. Oxygen, a highly efficient electron acceptor with high reduction potential, facilitates highly efficient energy production in eukaryotic cells. However, the increasing atmospheric oxygen concentration produces new threats to the organism, as oxygen reacts with iron and produces reactive oxygen species unless its levels are strictly regulated. As the size of multicellular organisms increases, these organisms must transport oxygen to the peripheral tissues and begin to employ red blood cells containing hemoglobin. This system is potentially a double-edged sword, as hemoglobin autoxidation occurs at a certain speed and releases free iron into the cytoplasm. Nrf2 belongs to the CNC transcription factor family, in which NF-E2p45 is the founding member. NF-E2p45 was first identified as a transcription factor that binds to the erythroid gene regulatory element NF-E2 located in the promoter region of the heme biosynthetic porphobilinogen deaminase gene. Human Nrf2 was also identified as a transcription factor that binds to the regulatory region of the β-globin gene. Despite these original findings, NF-E2p45 and Nrf2 knockout mice exhibit few erythroid phenotypes. Nrf2 regulates the expression of a wide range of antioxidant and detoxification enzymes. In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen

ドウセイアイシャ LG エノ タイド ト ヒイシツシ フアン ケイコウ イシツ キョヒ ケイコウ トノ カンレン

同性愛者であるレズビアン・ゲイ（以下LGとする）に対する理解は深まっているが，差別・偏見等否定的態度は未だ存在している。LGへの否定的態度は当事者の心理的健康を低減させうるといわれており，偏見を強める要因を検討する必要があると考える。中学生頃に見られるチャムグループという関係性では，同質性を重視して維持され，自分と異質な存在を拒否する心性が生じる。本研究では，異質性拒否の心性である被異質視不安及び異質拒否傾向と，LGに対する態度の関連を検討することと、特に異質であるものに否定的な中学生の方が大学生より否定的であるかどうかを検討することを目的とした。その結果，被異質視不安・異質拒否傾向が高い場合，LGへの態度は否定的であった。異質拒否傾向がネガティブイメージに影響したことは，同性愛に対する知識の無さが外集団に対する偏見を増したためと考えられる。Recently, it seemed the understanding for homosexuality has been growing. However, prejudice and negative attitudes towards them have still existed. Many research showed that negative attitudes have negative effect on lesbians and gay men\u27s mental health. Therefore, we need to find the factor which strengthen these negative attitudes. Junior high school students tend to establish chum-group relationship which emphasize the sameness and heterogeneousness among the group and this kind of relationship tend to exclude the difference among group members. In this study, we focus on this tendency to find the relationship with the attitudes towards homosexuality. We compared this attitude with those of college students. Results showed that the high anxieties about being thought different from others and the tendency toward uniformity related with the negative attitude towards homosexuals. We concluded that the reason for this tendency was not having accurate and appropriate knowledge about homosexuality

Ribosome binding protein GCN1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice.

Amino acids exert many biological functions, serving as allosteric regulators and neurotransmitters, as constituents in proteins and as nutrients. GCN2-mediated phosphorylation of eukaryotic initiation factor 2 alpha (elF2α) restores homeostasis in response to amino acid starvation (AAS) through the inhibition of the general translation and upregulation of amino acid biosynthetic enzymes and transporters by activating the translation of Gcn4 and ATF4 in yeast and mammals, respectively. GCN1 is a GCN2-binding protein that possesses an RWD binding domain (RWDBD) in its C-terminus. In yeast, Gcn1 is essential for Gcn2 activation by AAS; however, the roles of GCN1 in mammals need to be established. Here, we revealed a novel role of GCN1 that does not depend on AAS by generating two Gcn1 mutant mouse lines: Gcn1-knockout mice (Gcn1 KO mice (Gcn1-/-)) and RWDBD-deleted mutant mice (Gcn1ΔRWDBD mice). Both mutant mice showed growth retardation, which was not observed in the Gcn2 KO mice, such that the Gcn1 KO mice died at the intermediate stage of embryonic development because of severe growth retardation, while the Gcn1ΔRWDBD embryos showed mild growth retardation and died soon after birth, most likely due to respiratory failure. Extension of pregnancy by 24 h through the administration of progesterone to the pregnant mothers rescued the expression of differentiation markers in the lungs and prevented lethality of the Gcn1ΔRWDBD pups, indicating that perinatal lethality of the Gcn1ΔRWDBD embryos was due to simple growth retardation. Similar to the yeast Gcn2/Gcn1 system, AAS- or UV irradiation-induced elF2α phosphorylation was diminished in the Gcn1ΔRWDBD mouse embryonic fibroblasts (MEFs), suggesting that GCN1 RWDBD is responsible for GCN2 activity. In addition, we found reduced cell proliferation and G2/M arrest accompanying a decrease in Cdk1 and Cyclin B1 in the Gcn1ΔRWDBD MEFs. Our results demonstrated, for the first time, that GCN1 is essential for both GCN2-dependent stress response and GCN2-independent cell cycle regulation

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae. VIII: The Eighth Year (2015-2016)

Continuing the project described by Kato et al. (2009, arXiv:0905.1757), we collected times of superhump maxima for 128 SU UMa-type dwarf novae observed mainly during the 2015-2016 season and characterized these objects. The data have improved the distribution of orbital periods, the relation between the orbital period and the variation of superhumps, the relation between period variations and the rebrightening type in WZ Sge-type objects. Coupled with new measurements of mass ratios using growing stages of superhumps, we now have a clearer and statistically greatly improved evolutionary path near the terminal stage of evolution of cataclysmic variables. Three objects (V452 Cas, KK Tel, ASASSN-15cl) appear to have slowly growing superhumps, which is proposed to reflect the slow growth of the 3:1 resonance near the stability border. ASASSN-15sl, ASASSN-15ux, SDSS J074859.55+312512.6 and CRTS J200331.3-284941 are newly identified eclipsing SU UMa-type (or WZ Sge-type) dwarf novae. ASASSN-15cy has a short (~0.050 d) superhump period and appears to belong to EI Psc-type objects with compact secondaries having an evolved core. ASASSN-15gn, ASASSN-15hn, ASASSN-15kh and ASASSN-16bu are candidate period bouncers with superhump periods longer than 0.06 d. We have newly obtained superhump periods for 79 objects and 13 orbital periods, including periods from early superhumps. In order that the future observations will be more astrophysically beneficial and rewarding to observers, we propose guidelines how to organize observations of various superoutbursts.Comment: 123 pages, 162 figures, 119 tables, accepted for publication in PASJ (including supplementary information

A Single Amino Acid Mutation in SNAP-25 Induces Anxiety-Related Behavior in Mouse

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a presynaptic protein essential for neurotransmitter release. Previously, we demonstrate that protein kinase C (PKC) phosphorylates Ser187 of SNAP-25, and enhances neurotransmitter release by recruiting secretory vesicles near to the plasma membrane. As PKC is abundant in the brain and SNAP-25 is essential for synaptic transmission, SNAP-25 phosphorylation is likely to play a crucial role in the central nervous system. We therefore generated a mutant mouse, substituting Ser187 of SNAP-25 with Ala using “knock-in” technology. The most striking effect of the mutation was observed in their behavior. The homozygous mutant mice froze readily in response to environmental change, and showed strong anxiety-related behavior in general activity and light and dark preference tests. In addition, the mutant mice sometimes exhibited spontaneously occurring convulsive seizures. Microdialysis measurements revealed that serotonin and dopamine release were markedly reduced in amygdala. These results clearly indicate that PKC-dependent SNAP-25 phosphorylation plays a critical role in the regulation of emotional behavior as well as the suppression of epileptic seizures, and the lack of enhancement of monoamine release is one of the possible mechanisms underlying these defects

Potential Health-modulating Effects of Isoflavones and Metabolites via Activation of PPAR and AhR

Isoflavones have multiple actions on cell functions. The most prominent one is the activation of estrogen receptors. Other functions are often overlooked, but are equally important and explain the beneficial health effects of isoflavones. Isoflavones are potent dual PPARα/γ agonists and exert anti-inflammatory activity, which may contribute to the prevention of metabolic syndrome, atherosclerosis and various other inflammatory diseases. Some isoflavones are potent aryl hydrocarbon receptor (AhR) agonists and induce cell cycle arrest, chemoprevention and modulate xenobiotic metabolism. This review discusses effects mediated by the activation of AhR and PPARs and casts a light on the concerted action of isoflavones

Calpain-1 C2L domain peptide protects mouse hippocampus-derived neuronal HT22 cells against glutamate-induced oxytosis

Calpains are Ca2+-dependent cysteine proteases; their aberrant activation is associated with several neurodegenerative diseases. The μ-calpain catalytic subunit, calpain-1, is located in the cytoplasm as well as in the mitochondria. Mitochondrial calpain-1 cleaves apoptosis-inducing factor (AIF), leading to apoptotic cell death. We have previously reported that short peptides of calpain-1 C2-like domain conjugated with cell penetrating peptide HIV-Tat (Tat-μCL) selectively inhibit mitochondrial calpain-1 and effectively prevent neurodegenerative diseases of the eye. In this study, we determined whether mitochondrial calpain-1 mediates oxytosis (oxidative glutamate toxicity) in hippocampal HT22 cells using Tat-μCL and newly generated polyhistidine-conjugated μCL peptide and compared their efficacies in preventing oxytosis. TUNEL assay and single strand DNA staining revealed that both μCL peptides inhibited glutamate-induced oxytosis. Additionally, both the peptides suppressed the mitochondrial AIF translocation into the nucleus. All polyhistidine-μCL peptides (containing 4–16 histidine residues) showed higher cell permeability than Tat-μCL. Notably, tetrahistidine (H4)-μCL exerted the highest cytoprotective activity. Thus, H4-μCL may be a potential peptide drug for calpain-1-mediated neurodegenerative diseases such as Alzheimer's disease

Identification of an Essential Cytoplasmic Region of Interleukin-7 Receptor α Subunit in B-Cell Development

Interleukin-7 (IL-7) is essential for lymphocyte development. To identify the functional subdomains in the cytoplasmic tail of the IL-7 receptor (IL-7R) α chain, here, we constructed a series of IL-7Rα deletion mutants. We found that IL-7Rα-deficient hematopoietic progenitor cells (HPCs) gave rise to B cells both in vitro and in vivo when a wild-type (WT) IL-7Rα chain was introduced; however, no B cells were observed under the same conditions from IL-7Rα-deficient HPCs with introduction of the exogenous IL-7Rα subunit, which lacked the amino acid region at positions 414–441 (d414–441 mutant). Signal transducer and activator of transcription 5 (STAT5) was phosphorylated in cells with the d414–441 mutant, similar to that in WT cells, in response to IL-7 stimulation. In contrast, more truncated STAT5 (tSTAT5) was generated in cells with the d414–441 mutant than in WT cells. Additionally, the introduction of exogenous tSTAT5 blocked B lymphopoiesis but not myeloid cell development from WT HPCs in vivo. These results suggested that amino acids 414–441 in the IL-7Rα chain formed a critical subdomain necessary for the supportive roles of IL-7 in B-cell development