Language：English   Publishing type：Research paper (scientific journal)  

Signal peptides (SPs) and their fragments play important roles as biomarkers and substances with physiological functions in extracellular fluid. We previously reported that SP fragments were released into extracellular fluid via exosomes and bound to calmodulin (CaM), an exosomal component, in a cell-free system. However, it currently remains unclear whether CaM intracellularly interacts with SP fragments or is involved in the trafficking of these fragments to exosomes. Therefore, the present study examined the binding of CaM to SP fragments in T-REx AspALP cells, transformed HEK293 cells expressing amyloid precursor protein (APP) SP flanking a reporter protein, and their exosomes. APP SP fragments were detected in exosomes from T-REx AspALP cells in the absence of W13, a CaM inhibitor, but were present in lower amounts in exosomes from W13-treated cells. Cargo proteins, such as Alix, CD63, and CD81, were increased in W13-treated T-REx AspALP cells but were decreased in their exosomes. Furthermore, CaM interacted with heat shock protein 70 and CD81 in T-REx AspALP cells and this increased in the presence of W13. APP SP fragments were detected in intracellular CaM complexes in the absence of W13, but not in its presence. These results indicate that CaM functions as a key regulator of the transport of SP fragments into exosomes and plays novel roles in the sorting of contents during exosomal biogenesis.

DOI： 10.3390/cells12010158

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

In the course of screening lipopolysaccharide (LPS)-induced nitric oxide (NO) production inhibitors, two related benzodiazepine derivatives, cyclopenol and cyclopenin, were isolated from the extract of a deep marine-derived fungal strain, Aspergillus sp. SCSIOW2. Cyclopenol and cyclopenin inhibited the LPS-induced formation of NO and secretion of IL-6 in RAW264.7 cells at nontoxic concentrations. In terms of the mechanism underlying these effects, cyclopenol and cyclopenin were found to inhibit the upstream signal of NF-κB activation. These compounds also inhibited the expression of IL-1β, IL-6, and inducible nitric oxide synthase (iNOS) in mouse microglia cells, macrophages in the brain. In relation to the cause of Alzheimer’s disease, amyloid-β-peptide is known to induce inflammation in the brain. Therefore, the present study investigated the ameliorative effects of these inhibitors on an in vivo Alzheimer’s model using flies. Learning deficits were induced by the overexpression of amyloid-β42 in flies, and cyclopenin but not cyclopenol was found to rescue learning impairment. Therefore, novel anti-inflammatory activities of cyclopenin were identified, which may be useful as a candidate of anti-inflammatory agents for neurodegenerative diseases.

DOI： 10.1038/s41429-020-0302-9

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor-deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism-independent effects of anagliptin on NASH and HCC development.

DOI： 10.1038/s41598-020-57935-6

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Oxidative stress plays an important role in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The oxindole compound GIF-2165X-G1 is a hybrid molecule composed of the oxindole skeleton of the neuroprotective compound GIF-0726-r and the polyphenolic skeleton of the antioxidant curcumin. We previously reported that novel oxindole derivatives such as GIF-0726-r and GIF-2165X-G1 prevent endogenous oxidative stress-induced cell death in mouse hippocampal HT22 cells. In this study, we present a detailed investigation of the effect of GIF-2165X-G1 on endogenous oxidative stress in HT22 cells in comparison with GIF-0726-r and curcumin. GIF-2165X-G1 exhibited more potent neuroprotective activity than GIF-0726-r or curcumin and had less cytotoxicity than that observed with curcumin. Both GIF-0726-r and GIF-2165X-G1 were found to have ferrous ion chelating activity similar to that exhibited by curcumin. GIF-2165 X-G1 and curcumin induced comparable antioxidant response element transcriptional activity. Although the induction of heme oxygenase-1, an antioxidant response element-regulated gene product, was much stronger in curcumin-treated cells than in GIF-2165X-G1-treated cells, it turned out that the induction of heme oxygenase-1 is dispensable for neuroprotection. These results demonstrate that the introduction of the polyphenol skeleton of curcumin to the oxindole GIF-0726-r improves neuroprotective features. Furthermore, intrastriatal injection of GIF-2165X-G1 alleviated apomorphine-induced rotation and prevented dopaminergic neuronal loss in a 6-hydroxydopamine mouse model of Parkinson's diseases. Collectively, our novel findings indicate that the novel oxindole compound GIF-2165X-G1 serves to delay the progression of Parkinson's disease by suppressing oxidative stress.

DOI： 10.1021/acschemneuro.9b00619.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Science Direct  

The current medical and surgical therapies for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease offer symptomatic relief but do not provide a cure. Thus, small synthetic compounds that protect neuronal cells from degeneration are critically needed to prevent and treat these. Oxidative stress has been implicated in various pathophysiological conditions, including neurodegenerative diseases. In a search for neuroprotective agents against oxidative stress using the murine hippocampal HT22 cell line, we found a novel oxindole compound, GIF-0726-r, which prevented oxidative stress-induced cell death, including glutamate-induced oxytosis and erastin-induced ferroptosis. This compound also exerted a protective effect on tunicamycin-induced ER stress to a lesser extent but had no effect on campthothecin-, etoposide- or staurosporine-induced apoptosis. In addition, GIF-0726-r was also found to be effective after the occurrence of oxidative stress. GIF-0726-r was capable of inhibiting reactive oxygen species accumulation and Ca2+ influx, a presumed executor in cell death, and was capable of activating the antioxidant response element, which is a cis-acting regulatory element in promoter regions of several genes encoding phase II detoxification enzymes and antioxidant proteins. These results suggest that GIF-0726-r is a low-molecular-weight compound that prevents neuronal cell death through attenuation of oxidative stress. Among the more than 200 derivatives of the GIF-0726-r synthesized, we identified the 11 most potent activators of the antioxidant response element and characterized their neuroprotective activity in HT22 cells.

DOI： 10.1016/j.neuropharm.2018.03.015

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Hypothermia is a significant sign of sepsis, which is associated with poor prognosis, but few mechanisms underlying the regulation of hypothermia are known. Inducible nitric oxide synthase (iNOS) is a key inflammatory mediator of sepsis. However, the therapeutic benefit of iNOS inhibition in sepsis is still controversial, and requires elucidation in an accurate model system. In this study, wild-type (WT) mice showed temperature drops in a biphasic manner at the early and late phase of sepsis, and all mice died within 48 h of sepsis. In contrast, iNOS-knockout (KO) mice never showed the second temperature drop and exhibited improved mortality. Plasma nitric oxide (NO) levels of WT mice increased in the late phase of sepsis and correlated to hypothermia. The results indicate that iNOS-derived NO during the late phase of sepsis caused vasodilation-induced hypothermia and a lethal hypodynamic state. The expression of the iNOS mRNA was high in the lung of WT mice with sepsis, which reflects the pathology of acute respiratory distress syndrome (ARDS). We obtained the results in a modified keyhole-type cecal ligation and puncture model of septic shock induced by minimally invasive surgery. In this accurate and reproducible model system, we transplanted the bone marrow cells of GFP transgenic mice into WT and iNOS-KO mice, and evaluated the role of increased pulmonary iNOS expression in cell migration during the late phase of sepsis. We also investigated the quantity and type of bone marrow-derived cells (BMDCs) in the lung. The number of BMDCs in the lung of iNOS-KO mice was less than that in the lung of WT mice. The major BMDCs populations were CD11b-positive, iNOS-negative cells in WT mice, and Gr-1-positive cells in iNOS-KO mice that expressed iNOS. These results suggest that sustained hypothermia may be a beneficial guide for future iNOS-targeted therapy of sepsis, and that iNOS modulated the migratory efficiency and cell type of BMDCs in septic ARDS.

DOI： 10.1038/s41374-018-0021-z

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

Visualization of direct neuronal activity to understand brain function is one of the most important challenges in neuroscience. We have previously demonstrated that in vivo and in vitro gene expression of the ferritin reporter system could be detected by magnetic resonance imaging (MRI). In addition, increased neuronal activity induces Arc, an immediate early gene, and insertion of a destabilized fluorescent reporter dVenus under Arc promoter control has been used for monitoring neuronal activities in the brain by optical imaging. In this study, to visualize Arc promoter-driven neuronal activities directly, we generated transgenic mice and cell lines that express a destabilized fusion reporter ferritin-mKate2 under Arc promoter control. When transgenic mice and cell lines were treated with pilocarpine, a non-selective muscarinic agonist, an increase in T2-weighted image signal was successfully found in neuronal cells. There was a difference in peak time between MRI and fluorescence imaging, which might result from the binding process of iron with ferritin. Visualization of Arc promoter-driven neuronal activity is essential to understand neural mechanisms underlying cognitive processes and complex behaviors, and could be a useful tool for therapeutic approaches in the brain by MRI.

DOI： 10.1016/j.neulet.2017.12.041

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neuint.2016.12.022.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12149-015-0948-8

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00702-014-1209-z.

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER WIEN  

Astrocytes modify and maintain neural activity and functions via gliotransmitter release such as, glutamate. They also change their properties and functions in response to alterations of ion environment resulting from neurotransmission; however, the direct evidence for whether intracellular ion alteration in astrocytes triggers gliotransmitter release is not indicated. Recent studies have reported that channelrhodopsin-2 (ChR2) is useful for alteration of intracellular ion environment in several types of cells with blue light exposure. Here, we show that ChR2-expressing GL261 (GLChR2) cells, clonal astrocytes, change their properties by photo-activation. Increased intracellular sodium and calcium ion concentrations and an altered membrane potential were observed in GLChR2 cells with blue light exposure. Alterations in the intracellular ion environment caused intracellular acidification and the inhibition of proliferation. In addition, it triggered glutamate release from GLChR2 cells. Glutamate from GLChR2 cells acted on N18 cells, clonal neuronal cells, as both a transmitter and neurotoxin depending on photo-activation. Our results show that the properties of ChR2-expressing astrocytes can be controlled by blue light exposure, and cation influx through photo-activated ChR2 might trigger functional cation influx via endogenous channels and result in the increase of glutamate release. Further, our results suggest that ChR2-expressing glial cells could become a useful tool in understanding the roles of glial cell activation and neural communication in the regulation of brain functions.

DOI： 10.1007/s00702-013-1096-8

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Web of Science

Language：English   Publishing type：Research paper (international conference proceedings)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER/PLENUM PUBLISHERS  

To evaluate the utility of new Translocator protein 18 kDa (TSPO)-targeted fluorescent probes for in vivo molecular imaging of activated microglia.
Compounds 2-4 were synthesized; their stability and affinity for TSPO were determined. Compounds 2-4 were incubated both with Ra2 cells in the presence of LPS, a potent activator of microglia, and with tissue sections of normal and chemically injured brains. Compounds 2-4 were injected into carotid artery or directly in striatum of mice. Cells and tissue sections from these in vitro and in vivo studies were observed by fluorescence microscopy after histochemical treatments.
Compounds 2-4 are stable in both buffer and physiological medium and showed high affinity for TSPO and were found to stain live Ra2 microglial cells effectively. Double staining with Mito Tracker Red suggested that binding sites of compounds 2 and 3 may exist on mitochondria. In vivo studies showed that compounds 2-4 may penetrate in part into brain; moreover, cells in mouse striatum were stained with compounds 2-4 and microglial marker CD11b.
Compounds 2-4 can fluorescently label activated microglia in vitro and in vivo.

DOI： 10.1007/s11095-011-0552-0

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Osmotic demyelination syndrome (ODS) is a serious demyelinating disease in the central nervous system usually caused by rapid correction of hyponatremia. In an animal model of ODS, we previously reported microglial accumulation expressing proinflammatory cytokines. Microglia and astrocytes secreting proinflammatory cytokines and neurotrophic factors are reported to be involved in the pathogenesis of demyelinative diseases. Therefore, to clarify the role of microglial and astrocytic function in ODS, we examined the time-dependent changes in distribution, morphology, proliferation, and mRNA/protein expression of proinflammatory cytokines, neurotrophic factors, and matrix metalloproteinase (MMP) in microglia and astrocytes 2 days (early phase) and 5 days (late phase) after the rapid correction of hyponatremia in ODS rats. The number of microglia time dependently increased at demyelinative lesion sites, proliferated, and expressed tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6, inducible nitric oxide synthase, and MMP2, 9, and 12 at the early phase. Microglia also expressed leukemia inhibitory factor (a neurotrophic factor) and phagocytosed myelin debris at the late phase. The number of astrocytes time dependently increased around demyelinative lesions, extended processes to lesions, proliferated, and expressed nerve growth factor and glial cell line-derived neurotrophic factor at the late phase. Moreover, treatment with infliximab, a monoclonal antibody against TNF-alpha, significantly attenuated neurological impairments. Our results suggest that the role of microglia in ODS is time dependently shifted from detrimental to protective and that astrocytes play a protective role at the late phase. Modulation of excessive proinflammatory responses in microglia during the early phase after rapid correction may represent a therapeutic target for ODS. (C)2010 Wiley-Liss. Inc.

DOI： 10.1002/glia.21114

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PubMed

Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neures.2011.07.969

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Academy of Pharmaceutical Science and Technology, Japan  

DOI： 10.14843/jpstj.71.259

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2011.07.413

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Publishing type：Research paper (scientific journal)  

DOI： 10.1681/ASN.2010040438

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

Red blood cells (RBCs) are able to avoid filtration in the spleen to prolong their half-time in the body because of their flexibility and unique shape, or a concave disk with diameter of some 10 mu m. In addition, they can flow through capillary blood vessels, which are smaller than the diameter of RBCs, by morphing into a parachute-like shape. In this study, flexible RBC-like polymer particles are synthesized by electrospraying based on electrospinning. Furthermore, magnetite nanoparticles and fluorescent dye are encapsulated in the particles via in situ hydrolysis of an iron-organic compound in the presence of celluloses. The superparamagnetic behavior of the particles is confirmed by low-temperature magnetic measurements. The particles exhibited not only a dark contrast in magnetic resonance imaging (MRI), but also effective fluorescence. The RBC-like particles with flexibility are demonstrated to have a dual-modality for MRI and fluorescence imaging.

DOI： 10.1002/smll.201000399

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

DOI： 10.1016/j.neuroimage.2010.04.112

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Language：English   Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1021/cm100810g

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Most CNS diseases begin with inflammation with subsequent neural damage eventually occurring; however, the process leading from the onset of inflammation to neural damage remains obscure. We used an artificial brain injury mouse model and examined how neural damage occurred in the brain parenchyma. The damaged area in each mouse was clearly observed by magnetic resonance imaging (MRI), and the progression of damage was observed to occur in a biphasic manner (acute damage, within 1 week; delayed damage, after 2 weeks). We found that the delayed neural damage was absent in iNOS-deficient mice (iNOS-KO mice). Then, we analyzed brain tissues and determined that delayed neural damage was accompanied by an increase in the levels of NO end products and iNOS expression, with accumulation of iNOS-expressing microglia around the injured area. In addition, the expression of IL-1 beta mRNA was increased in areas affected by acute damage, but not in those affected by delayed damage. These findings suggest that delayed neural damage might arise from NO production by iNOS-expressing activated microglia and that such activated microglia might become a therapeutic target for many CNS diseases. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2010.02.041

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The transition of microglia from the normal resting state to the activated state is associated with an increased expression of peripheral benzodiazepine receptors (PBR). The extent of PBR expression is dependent on the level of microglial activation. A PBR ligand, [(11)C]PK11195, has been used for imaging of the activation of microglia in vivo. We evaluated whether [(11)C]PK11195 PET can indicate differences of microglial activation between no treatment and lipopolysaccharide (LPS) treatment in a rat artificial injury model of brain inflammation. METHODS: On day 1, a small aliquot of absolute ethanol was injected into the rat right striatum (ST) to produce artificial brain injury. On day 3, MRI scans were performed to evaluate and select rats showing a similar degree of brain injury. Then LPS or vehicle was administered intraperitoneally. On day 4, PET scans were performed after a bolus injection of [(11)C]PK11195. Eleven rats (7 LPS administered rats, 4 LPS non-administered rats) were evaluated. We used uptake ratios of the integral of right and left striatum from 0 to 60 min as an estimate of PBR distribution volume (V (60)). The number of activated microglia and mRNA expression of inflammatory cytokines (TNFalpha, IL-1beta) were assessed by isolectin-B4 staining and RT-PCR, respectively. RESULTS: Right/left ST V (60) ratios of LPS group were significantly higher than those of non-LPS group (P < 0.03). Although there were no significant differences in the number of activated microglia between the two groups, LPS group showed higher expression of inflammatory cytokines (TNFalpha, IL-1beta) than the non-treated group indicating that further activation was induced by LPS treatment. CONCLUSION: The results suggest that intensity of PBR signals in [(11)C]PK11195 PET may be related to the level of microglial activation rather than the number in activated microglia at least in an artificial brain injury model.

DOI： 10.1007/s12149-009-0339-0

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Web of Science

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.020

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Activated microglia play important roles in the inflammatory process and progression in Parkinson's disease. These cells produce various cytokines, nitric oxide, and neurotrophins, which are pleiotropic in their action, i.e., neuroprotective or neurotoxic. In an in vivo study on a mouse model with nigrostriatal lesions produced by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), microglia activated by systemic lipopolysaccharide (LPS) were neurotoxic toward dopamine neurons in aged mice, but unexpectedly, neuroprotective in neonatal mice. In contrast to microglia in the MPTP model, LPS-activated microglia in neonatal mice in a model made by the stereotaxic injection of ethanol into the striatum were neurotoxic, and systemic LPS administration in the ethanol-injury model caused marked increases both in the volume of necrotic lesions and in the number of degenerative neurons in the striatum. Thus, activated microglia in the neonatal mouse brain play either a neuroprotective or neurotoxic role depending on the type of brain injury. Copyright (C) 2010 S. Karger AG, Basel

DOI： 10.1159/000285508

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.2453

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

CiNii Research

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/978-1-60761-292-6_13

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neures.2009.09.055

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2009.09.551

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Glutamate released by activated microglia induces excito-neurotoxicity and may contribute to neurodegeneration in numerous neurological diseases including ischemia, inflammation, epilepsy, and neurodegenerative diseases. We observed that the gap junction blocker carbenoxolone (CBX) or the glutaminase inhibitor 6-diazo-5-oxo-i-norleucine (DON) decreased glutamate release from activated microglia and rescued neuronal death in a dose-dependent manner in vitro. In gerbils, treatment with CBX or DON also prevented the delayed death of hippocampal neurons following transient global ischemia. Thus, blockade of microglial glutamate release may be an effective therapeutic strategy against neurodegeneration after ischemic injury. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.expneurol.2008.08.001

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/bjp.2008.301

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12149-008-0136-1

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PubMed

CiNii Books

CiNii Research

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Web of Science

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Web of Science

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

CiNii Research

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neuroimage.2008.04.063

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

Microglia play an important role in the inflammatory process that occurs in Parkinson's disease (PD). Activated microglia produce cytokines and neurotrophins and may have neurotoxic or neurotrophic effects. Because microglia are most proliferative and easily activated during the neonatal period, we examined the effects of neonatal microglia activated with lipopolysaccharide (LPS) on the nigro-striatal dopamine neurons in mice treated with 1-methyl-4-phenyl-1 2,3,6-tetrahyd ropyridine (MPTP), in comparison with activated microglia from the aged mice. By MPTP administration to neonatal mice, the number of dopamine neurons in the substantia nigra (SN) was decreased significantly, whereas that in the mice treated with LPS and MPTP was recovered to normal, along with significant microglial activation. Tyrosine hydroxylase (TH) activity, the levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), and the levels of pro-inflammatory cytokines IL-1 beta and IL-6 in the midbrain were elevated in the neonates treated with LPS and MPTR On the contrary, although the number of dopamine neurons in the 60-week-old mice treated with MPTP was also decreased significantly, the microglial activation by LPS treatment caused a further decrease in their number. These results suggest that the activated microglia in neonatal mice are different from those in aged mice, with the former having neurotrophic potential toward the dopamine neurons in the SN, in contrast to the neurotoxic effect of the latter. (c) 2007 Wiley-Liss, Inc.

DOI： 10.1002/jnr.21241

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PubMed

J-GLOBAL

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/sj.jcbfm.9600362

PubMed

Publishing type：Research paper (scientific journal)  

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The aim of this work was to develop new fluorescent probes for the localization and function of the peripheral benzodiazepine receptor (PBR). This receptor is primarily expressed on the mitochondria, and it is overexpressed in a variety of different states including glioma, breast cancer, Alzeheimer's disease, and activated microglia. For the mentioned purpose, imidazopyridine and imidazopyrimidine compounds 5-20 were synthesized, and their affinity for PBR was determined. Although some intrinsically fluorescent imidazopyrimidine compounds 12-20 possess good binding affinity, they cannot be used for visualizing PBR due to their unfavorable fluorescence characteristics. Among the imidazopyridine-7-nitrofurazan conjugates 5-11, compound 10 was the most active, and it was found to stain live Ra2 microglial cells effectively. An in vivo biodistribution study carried out on compound 10 showed that this imidazopyridine derivative, injected in the carotid artery, is able to penetrate to liver parenchyma, whereas fluorescein isothiocyanate labeled dextran (FITC-dextran), used as a control dye, hardly penetrated from blood vessels to tissues. On the other hand, as for the distribution to brain, the patterns of staining with 10 and FITC-dextran are similar, indicating that both of them hardly penetrate into the brain because of the existence of the blood-brain barrier. The obtained results indicate that compound 10 represents a new useful fluorescent probe for visualization of activated microglia and PBR.

DOI： 10.1021/bc060393c

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PubMed

Publishing type：Research paper (scientific journal)   Publisher：日本組織細胞化学会  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

In the present study, we have attempted to elucidate the effects of the intra-arterial injection of microglia on the global ischemia-induced functional and morphological deficits of hippocampal CA1 neurons. When PKH26-labeled immortalized microglial cells, GMIR1, were injected into the subclavian artery, these exogenous microglia were found to accumulate in the hippocampus at 24 h after ischemia. In hippocampal slices prepared from medium-injected rats subjected to ischemia 48 h earlier, synaptic dysfunctions including a significant reduction of synaptic responses and a marked reduction of long-term potentiation (LTP) of the CA3-CA1 Schaffer collateral synapses were observed. At this stage, however, neither significant neuronal degeneration nor gliosis was observed in the hippocampus. At 96 h after ischemia, there was a total loss of the synaptic activity and a marked neuronal death in the CA1 subfield. In contrast, the basal synaptic transmission and LTP of the CA3-CA1 synapses were well preserved after ischemia in the slices prepared from the microglia-injected animals. We also found the microglial-conditioned medium (MCM) to significantly increase the frequency of the spontaneous postsynaptic currents of CA1 neurons without affecting the amplitude, thus indicating that MCM increased the provability of the neurotransmitter release. The protective effect of the intra-arterial injected microglia against the ischemia-induced neuronal degeneration in the hippocampus was substantiated by immunohistochemical and immunoblot analyses. Furthermore, the arterial-injected microglia prevented the ischemia-induced decline of the brain-derived neurotrophic factor (BDNF) levels in CA1 neurons. These observations strongly suggest that the arterial-injection of microglia protected CA1 neurons against the ischemia-induced neuronal degeneration. The restoration of the ischemia-induced synaptic deficits and the resultant reduction of the BDNF levels in CA1 neurons, possibly by the release of diffusible factor(s), might thus contribute to the protective effect of the arterial-injection of microglia against ischemia-induced neuronal degeneration. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuroscience.2006.06.003

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jn/136.1.234S

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.neuroimage.2006.04.131

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Dementia is a frequent complication of Parkinson's disease (PD) and usually occurs late in the protracted course of the illness. We have already reported numerous MHC class II-positive microglia in the hippocampus in PD patients, and that this phenomenon may be responsible for functional changes in the neurons and the cognitive decline in PD patients. In this study, we have investigated the distribution of activated microglia and the immunohistochemical and the mRNA expression of several cytokines and neurotrophic factors of the hippocampus in PD and dementia with Lewy bodies (DLB). The brains from five cases of PD and five cases of DLB that were clinically and neuropathologically diagnosed, and those from four normal controls (NC) were evaluated by immunohistochemistry using anti-HLA-DP, -DQ, -DR (CR3/43), anti-alpha-synuclein, anti-brain-derived neurotrophic factor (BDNF), and anti-glial fibrillary acidic protein antibodies. In addition, the mRNA expressions of cytokines (IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, TGF-beta) and neurotrophic factors (BDNF, GDNF, NGF, NT-3) of these brains were evaluated by the reverse transcription-PCR method. MHC class II-positive microglia were distributed diffusely in the hippocampus of PD and DLB brains. Although the cytoplasm of pyramidal and granular cells of the hippocampus in NC brains was strongly stained by anti-BDNF antibodies, it was only weakly stained in PD and DLB brains. The mRNA expression of IL-6 was significantly increased in the hippocampus of PD and DLB brains, and that of BDNF was significantly decreased in the hippocampus of DLB brains. The increased number of activated microglia and the production of neurotrophic cytokines such as IL-6, together with the decreased expression of the neurotrophic factors of neurons in the hippocampus of PD and DLB brains, may be related to functional cellular changes associated with dementia.

DOI： 10.1007/s00401-004-0919-y

Web of Science

Publishing type：Research paper (scientific journal)  

Web of Science

Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jnr.10588

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-LISS  

We examined the expression and function of beta-adrenergic receptor (beta-AR) subtypes in both isolated primary rat microglia and a rat microglial cell line. RTPCR analyses revealed that microglia expressed beta(1)- and beta(2)-ARs but not beta(3)-ARs, whereas rat primary peritoneal macrophages expressed only beta(2)-ARs. Stimulation of beta-ARs on microglia by norepinephrine (NE) resulted in an increase in the level of intracellular cAMP and the subsequent expression of interleukin-1beta mRNA. These effects were prevented by propranolol. Similar results were obtained with other selective beta(1)-AR agonists and antagonists. beta(2)-ARs on microglia were also functional. It is possible that noradrenergic innervations participate in the control of microglial functions via beta(1)-ARs on microglia in the brain, because NE has high affinity for beta(1)- and beta(3)-ARs but little or no affinity for beta(2)-ARs. It seems physiologically significant that microglia can be controlled by NE, which predominates over epinephrine in the brain, whereas macrophages in peripheral tissues can be controlled by epinephrine, which is at higher levels in peripheral tissues. (C) 2002 Wiley-Liss, inc.

DOI： 10.1002/jnr.10399

Web of Science

Publishing type：Research paper (scientific journal)  

Web of Science

Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：KLUWER ACADEMIC/PLENUM PUBL  

Web of Science

Language：English   Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Web of Science

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1242/jcs.113.4.635

PubMed

Publishing type：Research paper (scientific journal)  

Web of Science

Publishing type：Research paper (scientific journal)  

Web of Science

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

We compared migration of systemically injected microglia into normal brain vs. ischaemic brain using a model of ischaemic hippocampal lesion. Microglia were labeled by a fluorescent dye using our standard phagocytosis procedure of microscopic particles and then injected intra-arterially into Mongolian gerbils subjected to ischaemia reperfusion neuronal injury. Delayed death of pyramidal neurons was confirmed by conventional histological analysis and dUTP nick end labeling (TUNEL) method. Clusters of dye-tagged cells migrating into the hippocampal ischaemic lesions were confirmed histochemically to be microglia. Since peripherally injected microglia exhibit specific affinity for ischaemic brain lesions and does not exacerbate ischaemic neuronal injury in the present model, we suggest that microglia may have a potential to be used as a piggy-back ride to deliver therapeutic genes and/or drugs for CNS repair following transitory global ischaemic insult. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3940(99)00592-3

Web of Science

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese

Language：English

Language：English   Publishing type：Research paper, summary (international conference)  

DOI： doi.org/10.1016/j.neures.2010.07.020

Language：English   Publishing type：Research paper, summary (international conference)  

DOI： doi.org/10.1016/j.neures.2010.07.2453

Authorship：Corresponding author   Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1016/j.neulet.2010.02.04

Language：Japanese  

CiNii Books

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

本論文では、脳選択的移行能を有するミクログリアや一部の骨髄細胞を用いた脳の標的化技術と近赤外波長域蛍光色素を組み合わせたin vivo imagingについて述べている。

Language：Japanese  

CiNii Books

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

The DA subgroup strains of Theiler&#039;s murine encephalomyelitis virus (TMEV) synthesize L* protein, which is translated out of frame with the polyprotein from an alternative AUG, 13 nucleotides downstream from the authentic polyprotein AUG. By a &#039;loss of function&#039; experiment using a mutant virus, DAL*-1, in which the L* AUG is mutated to an ACG, L* protein is shown to play an important role in virus persistence, TMEV-induced demyelination, and virus growth in macrophages. In the present study, we established an L* protein-expressed macrophage-like cell line and confirmed the importance of L* protein in virus growth in this cell line.

Language：Japanese  

CiNii Books

Language：Japanese   Publisher：医歯薬出版  

CiNii Books

Other Link： http://search.jamas.or.jp/link/ui/2005023766

Language：Japanese  

CiNii Books

Language：Japanese   Publisher：日本神経化学会  

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：INT SOC NEUROPATHOLOGY  

Web of Science

Language：English   Publisher：ELSEVIER SCIENCE BV  

The intra-arterial injection of immortalized microglia transfected with the lacZ gene, resulted in the expression of beta-galactosidase in the rat brain at 48 h and the activity of beta-galactosidase was detected for up to 3 weeks post-injection. More than 30-fold higher activity of beta-galactosidase was detected in the brain than in the liver, lung or spleen at 48 h post-injection. This method allows us to easily deliver the gene of interest to the brain without influencing other organs. Our brain-targeting gene delivery system can facilitate gene therapy of several brain disorders, including brain tumor, metabolic disorders, and degenerative disorders, as well as investigation into the roles of particular genes in brain function and development. (C) 1998 Federation of European Biochemical Societies.

DOI： 10.1016/S0014-5793(98)00879-5

Web of Science

PubMed

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Language：English   Presentation type：Poster presentation  

Venue：パシフィコ横浜  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名城大学薬学部  

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Venue：神戸国際会議場(神戸)  

Language：English   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名鉄ニューグランドホテル  

Language：Japanese   Presentation type：Oral presentation (general)  

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Country of applicant：Domestic  

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