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Dive into the research topics where Nagisa Arimitsu is active.

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Featured researches published by Nagisa Arimitsu.


Journal of Biological Chemistry | 2007

Mammalian Sec16/p250 plays a role in membrane traffic from the endoplasmic reticulum.

Takayuki Iinuma; Akiko Shiga; Koji Nakamoto; Matthew B. O'Brien; Meir Aridor; Nagisa Arimitsu; Mitsuo Tagaya; Katsuko Tani

Coat protein complex II (COPII)-coated vesicles/carriers, which mediate export of proteins from the endoplasmic reticulum (ER), are formed at special ER subdomains in mammals, termed ER exit sites or transitional ER. The COPII coat consists of a small GTPase, Sar1, and two protein complexes, Sec23-Sec24 and Sec13-Sec31. Sec23-Sec24 and Sec13-Sec31 appear to constitute the inner and the outermost layers of the COPII coat, respectively. We previously isolated two mammalian proteins (p125 and p250) that bind to Sec23. p125 was found to be a mammalian-specific, phospholipase A1-like protein that participates in the organization of ER exit sites. Here we show that p250 is encoded by the KIAA0310 clone and has sequence similarity to yeast Sec16 protein. Although KIAA0310p was found to be localized at ER exit sites, subcellular fractionation revealed its predominant presence in the cytosol. Cytosolic KIAA0310p was recruited to ER membranes in a manner dependent on Sar1. Depletion of KIAA0310p mildly caused disorganization of ER exit sites and delayed protein transport from the ER, suggesting its implication in membrane traffic out of the ER. Overexpression of KIAA0310p affected ER exit sites in a manner different from that of p125. Binding experiments suggested that KIAA0310p interacts with both the inner and the outermost layer coat complexes, whereas p125 binds principally to the inner layer complex. Our results suggest that KIAA0310p, a mammalian homologue of yeast Sec16, builds up ER exit sites in cooperation with p125 and plays a role in membrane traffic from the ER.


Clinical and Experimental Immunology | 2012

Excessive CD4+ T cells co-expressing interleukin-17 and interferon-γ in patients with Behçet's disease.

Jun Shimizu; Kenji Takai; Naruyoshi Fujiwara; Nagisa Arimitsu; Yuji Ueda; Sueshige Wakisaka; Hideshi Yoshikawa; F. Kaneko; Tomoko Suzuki; Noboru Suzuki

Excessive T helper type 1 (Th1) cell activity has been reported in Behçets disease (BD). Recently, association of Th17 cells with certain autoimmune diseases was reported, and we thus investigated circulating Th17 cells in BD. CD4+CD45RO– (naive) T cells were cultured with Th0‐, Th1‐, Th2‐ and Th17‐related cytokines and antibodies, and their mRNA was studied by real‐time polymerase chain reaction (PCR). When naive CD4+ T cells were cultured with Th1‐ and Th17‐related cytokines, interferon (IFN)‐γ mRNA and interleukin (IL)‐17 mRNA were up‐regulated, respectively, in BD patients. Naive CD4+ T cells cultured in a Th17 cell‐inducing condition expressed IL‐23 receptor (IL‐23R) mRNA excessively. IL‐17 mRNA expression was induced only when naive CD4+T cells were cultured in the presence of IL‐23. CD4+ T cells cultured with Th17 cytokines expressed excessive RAR‐related orphan receptor C (RORC) mRNA. Using intracellular cytokine staining, we found that CD45RO+(memory) CD4+ T cells producing IL‐17 and IFN‐γ simultaneously were increased significantly. Memory CD4+ T cells producing IFN‐γ but not IL‐17 decreased profoundly in BD patients. CD4+ T cells producing IL‐17 and IFN‐γ simultaneously were found in BD skin lesions. Collectively, we found excessive CD4+ T cells producing IL‐17 and IFN‐γ (Th1/Th17) cells in patients with BD, and possible involvement of IL‐23/IL‐23R pathway for the appearance of excessive Th1/Th17 cells.


Journal of Cell Science | 2009

Role of syntaxin 18 in the organization of endoplasmic reticulum subdomains

Takayuki Iinuma; Takehiro Aoki; Kohei Arasaki; Hidenori Hirose; Akitsugu Yamamoto; Rie Samata; Hans-Peter Hauri; Nagisa Arimitsu; Mitsuo Tagaya; Katsuko Tani

The presence of subdomains in the endoplasmic reticulum (ER) enables this organelle to perform a variety of functions, yet the mechanisms underlying their organization are poorly understood. In the present study, we show that syntaxin 18, a SNAP (soluble NSF attachment protein) receptor localized in the ER, is important for the organization of two ER subdomains, smooth/rough ER membranes and ER exit sites. Knockdown of syntaxin 18 caused a global change in ER membrane architecture, leading to the segregation of the smooth and rough ER. Furthermore, the organization of ER exit sites was markedly changed concomitantly with dispersion of the ER-Golgi intermediate compartment and the Golgi complex. These morphological changes in the ER were substantially recovered by treatment of syntaxin-18-depleted cells with brefeldin A, a reagent that stimulates retrograde membrane flow to the ER. These results suggest that syntaxin 18 has an important role in ER subdomain organization by mediating the fusion of retrograde membrane carriers with the ER membrane.


Molecular and Cellular Biology | 2006

Transcription Elongation Factor S-II Is Required for Definitive Hematopoiesis

Takahiro Ito; Nagisa Arimitsu; Masaki Takeuchi; Nobuyuki Kawamura; Makiko Nagata; Kayoko Saso; Nobuyoshi Akimitsu; Hiroshi Hamamoto; Shunji Natori; Atsushi Miyajima; Kazuhisa Sekimizu

ABSTRACT Transcription elongation factor S-II/TFIIS promotes readthrough of transcriptional blocks by stimulating nascent RNA cleavage activity of RNA polymerase II in vitro. The biologic significance of S-II function in higher eukaryotes, however, remains unclear. To determine its role in mammalian development, we generated S-II-deficient mice through targeted gene disruption. Homozygous null mutants died at midgestation with marked pallor, suggesting severe anemia. S-II−/− embryos had a decreased number of definitive erythrocytes in the peripheral blood and disturbed erythroblast differentiation in fetal liver. There was a dramatic increase in apoptotic cells in S-II −/− fetal liver, which was consistent with a reduction in Bcl-xL gene expression. The presence of phenotypically defined hematopoietic stem cells and in vitro colony-forming hematopoietic progenitors in S-II −/− fetal liver indicates that S-II is dispensable for the generation and differentiation of hematopoietic stem cells. S-II-deficient fetal liver cells, however, exhibited a loss of long-term repopulating potential when transplanted into lethally irradiated adult mice, indicating that S-II deficiency causes an intrinsic defect in the self-renewal of hematopoietic stem cells. Thus, S-II has critical and nonredundant roles in definitive hematopoiesis.


Neuroscience Letters | 2013

Restoration of spatial memory dysfunction of human APP transgenic mice by transplantation of neuronal precursors derived from human iPS cells.

Naruyoshi Fujiwara; Jun Shimizu; Kenji Takai; Nagisa Arimitsu; Asako Saito; Takao Kono; Tasuku Umehara; Yuji Ueda; Sueshige Wakisaka; Tomoko Suzuki; Noboru Suzuki

PDGF promoter driven amyloid precursor protein (PDAPP) transgenic mice were accompanied by age dependent amyloid β deposition and progressive spatial memory dysfunction which emerges within a few months of age. We conducted transplantation of neuronal precursors of cholinergic neuron phenotype which were derived from human iPS (hiPS) cells into bilateral hippocampus of PDAPP mice. We first generated neuronal precursors with cholinergic neuron phenotype from hiPS cells by culturing them with retinoic acid (RA), sonic hedgehog (SHH) and noggin-Fc (NOG). Spatial memory function of PDAPP mice was significantly impaired compared to that of nontransgenic littermates at age 8 weeks. After neuronal precursor transplantation, subsequent memory dysfunction of PDAPP mice was significantly improved, compared to that of vehicle injected PDAPP mice. We observed choline acetyltransferase (ChAT) positive cholinergic human neurons and vesicle GABA transporter (VGAT) positive GABAergic human neurons in PDAPP mouse hippocampus 45 days after the transplantation. Neuronal precursors with cholinergic neuron phenotype derived from hiPS cells survived in PDAPP mouse hippocampus and their spatial memory loss was improved. hiPS cells may become applicable for the treatment of patients with dementia.


PLOS ONE | 2016

Bifidobacteria Abundance-Featured Gut Microbiota Compositional Change in Patients with Behcet’s Disease

Jun Shimizu; Takao Kubota; Erika Takada; Kenji Takai; Naruyoshi Fujiwara; Nagisa Arimitsu; Yuji Ueda; Sueshige Wakisaka; Tomoko Suzuki; Noboru Suzuki

Gut microbiota compositional alteration may have an association with immune dysfunction in patients with Behcet’s disease (BD). We conducted a fecal metagenomic analysis of BD patients. We analyzed fecal microbiota obtained from 12 patients with BD and 12 normal individuals by sequencing of 16S ribosomal RNA gene. We compared the relative abundance of bacterial taxa. Direct comparison of the relative abundance of bacterial taxa demonstrated that the genera Bifidobacterium and Eggerthella increased significantly and the genera Megamonas and Prevotella decreased significantly in BD patients compared with normal individuals. A linear discriminant analysis of bacterial taxa showed that the phylum Actinobacteria, including Bifidobacterium, and the family Lactobacillaceae exhibited larger positive effect sizes than other bacteria in patients with BD. The phylum Firmicutes and the class Clostridia had large effect sizes in normal individuals. There was no significant difference in annotated species numbers (as numbers of operational taxonomic unit; OTU) and bacterial diversity of each sample (alpha diversity) between BD patients and normal individuals. We next assigned each sample to a position using three axes by principal coordinates analysis of the OTU table. The two groups had a significant distance as beta diversity in the 3-axis space. Fecal sIgA concentrations increased significantly in BD patients but did not correlate with any bacterial taxonomic abundance. These data suggest that the compositional changes of gut microbes may be one type of dysbiosis (unfavorable microbiota alteration) in patients with BD. The dysbiosis may have an association with the pathophysiology of BD.


International Journal of Molecular Sciences | 2012

Role of SDF1/CXCR4 Interaction in Experimental Hemiplegic Models with Neural Cell Transplantation

Nagisa Arimitsu; Jun Shimizu; Naruyoshi Fujiwara; Kenji Takai; Erika Takada; Takao Kono; Yuji Ueda; Tomoko Suzuki; Noboru Suzuki

Much attention has been focused on neural cell transplantation because of its promising clinical applications. We have reported that embryonic stem (ES) cell derived neural stem/progenitor cell transplantation significantly improved motor functions in a hemiplegic mouse model. It is important to understand the molecular mechanisms governing neural regeneration of the damaged motor cortex after the transplantation. Recent investigations disclosed that chemokines participated in the regulation of migration and maturation of neural cell grafts. In this review, we summarize the involvement of inflammatory chemokines including stromal cell derived factor 1 (SDF1) in neural regeneration after ES cell derived neural stem/progenitor cell transplantation in mouse stroke models.


Experimental Neurology | 2015

Cellular and molecular mechanisms of the restoration of human APP transgenic mouse cognitive dysfunction after transplant of human iPS cell-derived neural cells

Naruyoshi Fujiwara; Jun Shimizu; Kenji Takai; Nagisa Arimitsu; Yuji Ueda; Sueshige Wakisaka; Tomoko Suzuki; Noboru Suzuki

Cholinergic neuronal loss is a common finding in patients with Alzheimers disease (AD) and AD model mice. We previously transplanted neurons derived from human induced pluripotent stem (iPS) cells into the hippocampus of human amyloid precursor protein transgenic AD model mice. In the present study, we examined the cellular and molecular mechanisms involved in the alleviation of cognitive dysfunction in transplanted mice. After transplant, mice showed improvement in cognitive function, confirming our previous findings. Human choline acetyltransferase (ChAT)-positive cholinergic neurons were distributed throughout the cortex of the grafted mice. Human and mouse ChAT-positive neurons and alpha7 nicotinic acetylcholine receptor (α7nAChR)-positive neurons were significantly increased in the cortex and hippocampus of the grafted mice compared with the vehicle-injected mice. In addition, human and mouse vesicular GABA transporter (VGAT)-positive neurons were located mainly in the hippocampus and, though the number was small, human VGAT-positive neurons were observed in the cortex. In the grafted mouse cortex, the number of GABA receptor (GABAR)-positive neurons of both human origin and mouse origin were significantly increased compared with those in the vehicle-injected mouse cortex. The α7nAChR-positive and GABAR-positive neurons expressed phosphorylated Akt and c-fos in the cortex, suggesting that these receptor-expressing neurons were possibly activated by the neurotransmitters secreted from the grafted neurons. Collectively, the grafted and host neurons may form positive feedback loops via neurotransmitter secretion in both the cerebral cortex and hippocampus, leading to alleviation of cognitive dysfunction in dementia model mice.


Neuroscience Letters | 2012

Establishment of retinal progenitor cell clones by transfection with Pax6 gene of mouse induced pluripotent stem (iPS) cells.

Noboru Suzuki; Jun Shimizu; Kenji Takai; Nagisa Arimitsu; Yuji Ueda; Erika Takada; Chieko Hirotsu; Tomoko Suzuki; Naruyoshi Fujiwara; Mamoru Tadokoro

We previously reported that transfection of Pax6 gene which regulated early events in eye development into mouse ES cells brought about their differentiation into retinal progenitors. Here, we attempted to establish cloned retinal progenitors which had ability to further differentiate into photoreceptor like cells by transfecting mouse induced pluripotent stem (iPS) cells with Pax6 gene. Undifferentiated iPS cells were transfected with Pax6 cDNA, followed by selection with G418. After limiting dilution culture, we selected cloned Pax6-transfected cells, which simultaneously expressed mRNAs of Nestin, Musashi1, Six3 and Chx10 for further characterization. We obtained totally 8 clonally expanding Pax6-transfected cells. They started to express mRNAs of Brn3b, Cone-rod homeobox (Crx), pkc, CD73, rhodopsin and the γ-subunit of rod cGMP phosphodiesterase (PDEγ). Flow cytometric analysis revealed that almost half of the cells were CD73+, a marker of photoreceptor precursors. Western blotting confirmed cytoplasmic protein expression of rhodopsin. High KCl stimulation increased free Ca influx into the cells on Ca(2+) imaging. iPS cells transfected with Pax6 gene, followed by subsequent limiting dilution culture became retinal progenitors including photoreceptor like cells. The cloned cell lines may be useful for analyzing differentiation requirement of retinal progenitors.


Journal of Alzheimers Disease & Parkinsonism | 2016

Cellular Transplantation as the Treatment of Alzheimers Diseas e inMouse Models

Noboru Suzuki; Jun Shimizu; Naruyoshi Fujiwara; Nagisa Arimitsu

Acetylcholine (Ach) and N-methyl-D-aspartate (NMDA) have been two major therapeutic targets of Alzheimer’s disease (AD) for decade. However, truly effective remedy for AD has not been successfully developed. We previously transplanted neurons derived from human induced pluripotent stem (hiPS) cells into the hippocampus of human amyloid precursor protein transgenic AD model mice. The cell transplantation significantly improved cognitive dysfunction in the dementia model mice. Human choline acetyl transferase (ChAT) positive cholinergic neurons located throughout the cortex of the grafted mice. Human and mouse ChAT positive neurons and alpha7 nicotinic acetylcholine receptor (α7nAChR) positive neurons significantly increased in the cortex and hippocampus of the grafted dementia mice compared with the vehicle injected dementia mice. Human and mouse vesicular GABA transporter (VGAT) positive neurons distributed mainly in the hippocampus and, though the number was small, human VGAT positive neurons located in the cortex. In the grafted mouse cortex, the number of GABA receptor (GABAR) positive neurons of both hiPS origin and mouse origin increased significantly compared with those in the vehicle injected mouse cortex. We suggested that positive feedback loops of neurotransmitter secretion of the cortex and hippocampus induced the characteristic distribution of the transplanted neurons. In this review, we summarized current advances in stem cell therapy for dementia model mice, especially to highlight the relationships between major neurotransmitters and host/transplanted neurons.

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Jun Shimizu

St. Marianna University School of Medicine

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Naruyoshi Fujiwara

St. Marianna University School of Medicine

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Kenji Takai

St. Marianna University School of Medicine

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Noboru Suzuki

St. Marianna University School of Medicine

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Tomoko Suzuki

St. Marianna University School of Medicine

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Yuji Ueda

St. Marianna University School of Medicine

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Sueshige Wakisaka

St. Marianna University School of Medicine

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Erika Takada

St. Marianna University School of Medicine

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Chieko Hirotsu

St. Marianna University School of Medicine

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Masahiro Iinuma

St. Marianna University School of Medicine

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