Publications (15)67.73 Total impact
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Article: Expression of promyelocytic leukemia protein and vascular endothelial growth factor in aqueous humor and vitreous fluid in patients with proliferative diabetic retinopathy.
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ABSTRACT: AIMS: To examine the expression of promyelocytic leukemia protein (PML) in the eye of proliferative diabetic retinopathy (PDR) patients. METHODS: PML mRNA levels were measured in proliferative membranes from 12 PDR patients and idiopathic epiretinal membranes from 5 control patients by quantitative RT-PCR. Protein levels of PML and vascular endothelial growth factor (VEGF) in aqueous humor and vitreous fluid samples from 34 PDR patients and 38 control patients were determined using ELISA. RESULTS: The PML mRNA expression levels in membrane samples, and the PML protein concentrations in aqueous humor and vitreous fluid samples were significantly lower in PDR patients than control patients. We observed a statistically significant inverse correlation between the concentrations of PML and VEGF in the aqueous humor and vitreous fluid of PDR patients. CONCLUSION: PML may be a good candidate as a diagnostic marker and a therapeutic agent for PDR.Diabetes research and clinical practice 10/2012; · 2.16 Impact Factor -
Article: Dock3 regulates BDNF-TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG.
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ABSTRACT: Dock3, a new member of the guanine nucleotide exchange factor family, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes neurite outgrowth through the formation of a protein complex with Fyn and WAVE downstream of brain-derived neurotrophic factor (BDNF) signaling. Here, we report a novel Dock3-mediated BDNF pathway for neurite outgrowth. We show that Dock3 forms a complex with Elmo and activated RhoG downstream of BDNF-TrkB signaling and induces neurite outgrowth via Rac1 activation in PC12 cells. We also show the importance of Dock3 phosphorylation in Rac1 activation and show two key events that are necessary for efficient Dock3 phosphorylation: membrane recruitment of Dock3 and interaction of Dock3 with Elmo. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the central nervous system where it stimulates actin polymerization by multiple pathways.Genes to Cells 06/2012; 17(8):688-97. · 2.68 Impact Factor -
Article: Dock3 stimulates axonal outgrowth via GSK-3β-mediated microtubule assembly.
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ABSTRACT: Dock3, a new member of the guanine nucleotide exchange factors, causes cellular morphological changes by activating the small GTPase Rac1. Overexpression of Dock3 in neural cells promotes axonal outgrowth downstream of brain-derived neurotrophic factor (BDNF) signaling. We previously showed that Dock3 forms a complex with Fyn and WASP (Wiskott-Aldrich syndrome protein) family verprolin-homologous (WAVE) proteins at the plasma membrane, and subsequent Rac1 activation promotes actin polymerization. Here we show that Dock3 binds to and inactivates glycogen synthase kinase-3β (GSK-3β) at the plasma membrane, thereby increasing the nonphosphorylated active form of collapsin response mediator protein-2 (CRMP-2), which promotes axon branching and microtubule assembly. Exogenously applied BDNF induced the phosphorylation of GSK-3β and dephosphorylation of CRMP-2 in hippocampal neurons. Moreover, increased phosphorylation of GSK-3β was detected in the regenerating axons of transgenic mice overexpressing Dock3 after optic nerve injury. These results suggest that Dock3 plays important roles downstream of BDNF signaling in the CNS, where it regulates cell polarity and promotes axonal outgrowth by stimulating dual pathways: actin polymerization and microtubule assembly.Journal of Neuroscience 01/2012; 32(1):264-74. · 7.11 Impact Factor -
Article: Glia- and neuron-specific functions of TrkB signalling during retinal degeneration and regeneration.
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ABSTRACT: Glia, the support cells of the central nervous system, have recently attracted considerable attention both as mediators of neural cell survival and as sources of neural regeneration. To further elucidate the role of glial and neural cells in neurodegeneration, we generated TrkB(GFAP) and TrkB(c-kit) knockout mice in which TrkB, a receptor for brain-derived neurotrophic factor (BDNF), is deleted in retinal glia or inner retinal neurons, respectively. Here, we show that the extent of glutamate-induced retinal degeneration was similar in these two mutant mice. Furthermore in TrkB(GFAP) knockout mice, BDNF did not prevent photoreceptor degeneration and failed to stimulate Müller glial cell proliferation and expression of neural markers in the degenerating retina. These results demonstrate that BDNF signalling in glia has important roles in neural protection and regeneration, particularly in conversion of Müller glia to photoreceptors. In addition, our genetic models provide a system in which glia- and neuron-specific gene functions can be tested in central nervous system tissues in vivo.Nature Communications 02/2011; 2:189. · 7.40 Impact Factor -
Article: Spermidine alleviates severity of murine experimental autoimmune encephalomyelitis.
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ABSTRACT: Purpose. To assess the effects of spermidine on the severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), with a focus on optic neuritis often associated with MS and EAE. Methods. Myelin oligodendrocyte glycoprotein-induced EAE mice were administered with or without spermidine at 30 mM in drinking water for 25 days. Clinical signs of EAE were scored daily, and visual functions were measured by multifocal electroretinograms. Histopathology analysis of the spinal cord and optic nerve was performed after mice were killed on day 25. Hydrogen peroxide (H(2)O(2)) was detected using the probe 2'-7' dichlorofluorescein diacetate (DCFDA) in the optic nerve. The effect of spermidine on H(2)O(2)-induced retinal ganglion cell apoptosis was investigated by lactate dehydrogenase assay. Results. Daily clinical scoring revealed that the severity of EAE was significantly attenuated in the spermidine-treated group, which was confirmed by milder demyelination and improved axon survival in the spinal cord of spermidine-treated mice. Visual functions were significantly improved in spermidine-treated mice compared with vehicle-treated mice. Spermidine treatment ameliorated the extent of demyelination in the optic nerve and prevented cell loss in the retinal ganglion cell layer. Furthermore, fewer DCFDA-labeled cells were found in the optic nerve in the spermidine-treated EAE mice, and in vitro analysis revealed that spermidine reduced H(2)O(2)-induced retinal ganglion cell apoptosis, suggesting that spermidine alleviated the severities of EAE, particularly of optic neuritis, by acting as an antioxidant. Conclusions. The results from this study suggest that oral spermidine administration could be a useful treatment for MS.Investigative ophthalmology & visual science 01/2011; 52(5):2696-703. · 3.43 Impact Factor -
Article: Regulation of the severity of neuroinflammation and demyelination by TLR‐ASK1‐p38 pathway
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ABSTRACT: Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase which plays important roles in stress and immune responses. Here, we show that ASK1 deficiency attenuates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), without affecting the proliferation capability of T cells. Moreover, we found that EAE upregulates expression of Toll-like receptors (TLRs) in activated astrocytes and microglia, and that TLRs can synergize with ASK1-p38 MAPK signalling in the release of key chemokines from astrocytes. Consequently, oral treatment with a specific small molecular weight inhibitor of ASK1 suppressed EAE-induced autoimmune inflammation in both spinal cords and optic nerves. These results suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for autoimmune demyelinating disorders including multiple sclerosis.EMBO Molecular Medicine 11/2010; 2(12):504 - 515. · 10.33 Impact Factor -
Article: Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway.
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ABSTRACT: Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase which plays important roles in stress and immune responses. Here, we show that ASK1 deficiency attenuates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), without affecting the proliferation capability of T cells. Moreover, we found that EAE upregulates expression of Toll-like receptors (TLRs) in activated astrocytes and microglia, and that TLRs can synergize with ASK1-p38 MAPK signalling in the release of key chemokines from astrocytes. Consequently, oral treatment with a specific small molecular weight inhibitor of ASK1 suppressed EAE-induced autoimmune inflammation in both spinal cords and optic nerves. These results suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for autoimmune demyelinating disorders including multiple sclerosis.EMBO Molecular Medicine 10/2010; 2(12):504-15. · 10.33 Impact Factor -
Article: Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex.
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ABSTRACT: Atypical Rho-guanine nucleotide exchange factors (Rho-GEFs) that contain Dock homology regions (DHR-1 and DHR-2) are expressed in a variety of tissues; however, their functions and mechanisms of action remain unclear. We identify key conserved amino acids in the DHR-2 domain that are critical for the catalytic activity of Dock-GEFs (Dock1-4). We further demonstrate that Dock-GEFs directly associate with WASP family verprolin-homologous (WAVE) proteins through the DHR-1 domain. Brain-derived neurotrophic factor (BDNF)-TrkB signaling recruits the Dock3/WAVE1 complex to the plasma membrane, whereupon Dock3 activates Rac and dissociates from the WAVE complex in a phosphorylation-dependent manner. BDNF induces axonal sprouting through Dock-dependent Rac activation, and adult transgenic mice overexpressing Dock3 exhibit enhanced optic nerve regeneration after injury without affecting WAVE expression levels. Our results highlight a unique mechanism through which Dock-GEFs achieve spatial and temporal restriction of WAVE signaling, and identify Dock-GEF activity as a potential therapeutic target for axonal regeneration.Proceedings of the National Academy of Sciences 04/2010; 107(16):7586-91. · 9.68 Impact Factor -
Article: Delayed onset of experimental autoimmune encephalomyelitis in Olig1 deficient mice.
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ABSTRACT: Olig1 is a basic helix-loop-helix (bHLH) transcription factor that is essential for oligodendrogenesis and efficient remyelination. However, its role in neurodegenerative disorders has not been well-elucidated. Here we investigated the effects of Olig1 deficiency on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We show that the mean disease onset of myelin oligodendrocyte glycoprotein (MOG)-induced EAE in Olig1(-/-) mice is significantly slower than wide-type (WT) mice (19.8 ± 2.2 in Olig1(-/-) mice and 9.5 ± 0.3 days in WT mice). In addition, 10% of Olig1(-/-) mice did not develop EAE by the end of the observation periods (60 days). The severity of EAE, the extent of demyelination, and the activation of microglial cells and astrocytes in spinal cords, were significantly milder in Olig1(-/-) mice compared with WT mice in the early stage. Moreover, the visual function, as assessed by the second-kernel of multifocal electroretinograms, was better preserved, and the number of degenerating axons in the optic nerve was significantly reduced in Olig1(-/-) mice. Interestingly, Olig1 deficiency had no effect on T cell response capability, however, it reduced the expression of myelin proteins such as MOG, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG). The expression of Olig2 remained unchanged in the optic nerve and brain, and it was reduced in the spinal cord of Olig1(-/-) mice. Our results suggest that the Olig1 signaling pathways may be involved in the incidence rate and the severity of neurological symptoms in MS.PLoS ONE 01/2010; 5(9). · 4.09 Impact Factor -
Article: Expression of Epiplakin1 in the developing and adult mouse retina.
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ABSTRACT: To assess the expression of Epiplakin1 (Eppk1) in the developing and adult mouse retina. Eppk1 expression was examined using reverse transcription-polymerase chain reaction (RTPCR) analysis and immunoblot analysis. The Eppk1 expression pattern was examined by immunohistochemical analysis in embryonic and adult C57BL/6J mice. Both Eppk1 mRNA and protein were detected in adult mouse retina. Eppk1 was expressed in nestin-positive neural progenitor cells in the embryonic retina. In adults, Eppk1 was expressed in retinal ganglion cells, bipolar cells, and Müller glial cells. These results suggest that Eppk1 is expressed both in embryonic and adult retina and may be involved in retinal development.Japanese Journal of Ophthalmology 01/2010; 54(1):85-8. · 0.92 Impact Factor -
Article: Expression of NG2-positive cells during optic neuritis.
Japanese Journal of Ophthalmology 01/2010; 54(1):100-2. · 0.92 Impact Factor -
Article: Effect of geranylgeranylacetone on optic neuritis in experimental autoimmune encephalomyelitis.
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ABSTRACT: Optic neuritis is an acute inflammatory demyelinating syndrome of the central nervous system (CNS) that often occurs in multiple sclerosis (MS). Since it can cause irreversible visual loss, especially in the optic-spinal form of MS or neuromyelitis optica (NMO), the present study was conducted to assess the effects of geranylgeranylacetone (GGA) on optic neuritis in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Myelin oligodendrocyte glycoprotein-induced EAE mice received oral administration of GGA at 500 mg/kg or vehicle once daily for 22 days. The effects of GGA on the severity of optic neuritis were examined by morphological analysis on day 22. Visual functions were measured by the multifocal electroretinograms (mfERG). In addition, the effects of GGA on severity of myelitis were monitored both on clinical signs and morphological aspects. The visual function, as assessed by the second-kernel of mfERG, was significantly improved in GGA-treated mice compared with vehicle-treated mice. GGA treatment decreased the number of degenerating axons in the optic nerve and prevented cell loss in the retinal ganglion cell layer. However, the severity of demyelination in the spinal cord remained unaffected with the treatment of GGA. These results suggest that oral GGA administration has beneficial effect on the treatment for optic neuritis in the EAE mouse model of MS.Neuroscience Letters 11/2009; 462(3):281-5. · 2.11 Impact Factor -
Article: Interleukin-1 attenuates normal tension glaucoma-like retinal degeneration in EAAC1-deficient mice.
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ABSTRACT: Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of retinal ganglion cells (RGCs) and optic nerves. Although glaucoma is often associated with elevated intraocular pressure, recent studies have shown a relatively high prevalence of normal tension glaucoma (NTG) in glaucoma patient populations. In the mammalian retina, glutamate/aspartate transporter (GLAST) is localized to Müller glial cells, whereas excitatory amino acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs. Since the loss of GLAST or EAAC1 leads to retinal degeneration similar to that seen in NTG, we examined the effects of interleukin-1 (IL-1) on RGC death in GLAST- and EAAC1-deficient mice. IL-1 promoted increased glutamate uptake in Müller cells by suppressing intracellular Na(+) accumulation, which is necessary to counteract Na(+)-glutamate cotransport. The observed trends for the glutamate uptake increase in the wild-type (WT), GLAST- and EAAC1-deficient mice were similar; however, the baseline glutamate uptake and intracellular Na(+) concentration in the GLAST-deficient mice were significantly lower than those in the wild-type mice. Consistently, pretreatment with IL-1 exhibited no beneficial effects on glutamate-induced RGC degeneration in the GLAST-deficient mice. In contrast, IL-1 significantly increased glutamate uptake by Müller cells and the number of surviving RGCs in the wild-type and EAAC1-deficient mice. Our findings suggest that the use of IL-1 for enhancing the function of glutamate transporters may be useful for neuroprotection in retinal degenerative disorders including NTG.Neuroscience Letters 09/2009; 465(2):160-4. · 2.11 Impact Factor -
Article: Inhibition of glial cell activation ameliorates the severity of experimental autoimmune encephalomyelitis.
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ABSTRACT: Activated microglia and astrocytes have been implicated in the course of multiple sclerosis (MS) and its animal model: experimental autoimmune encephalomyelitis (EAE). MW01-5-188WH is a novel drug that selectively inhibits glial activation in the central nervous system (CNS). We report here that MW01-5-188WH is effective to ameliorate the severity of myelin oligodendrocyte glycoprotein (MOG)-induced EAE. Daily oral administration of MW01-5-188WH at 5mg/kg body weight reduced the clinical scores of EAE mice while having no influence on the disease incidence or animal mortality. Pathological examination revealed reduced numbers of microglia and astrocytes in the spinal cord of MW01-5-188WH-treated EAE mice. Moreover, MW01-5-188WH suppressed the release of key chemokines, which are involved in MS pathology, from cultured microglia and astrocytes. Taken together, our results indicate that treatments that suppress the activation of microglia and astrocytes should be pursued in future research for their potential as avenues for the treatment of MS.Neuroscience Research 01/2008; 59(4):457-66. · 2.25 Impact Factor -
Article: Neuroprotective effect of geranylgeranylacetone against ischemia-induced retinal injury.
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ABSTRACT: This study was conducted to assess the effects of geranylgeranylacetone (GGA) on ischemia-induced retinal injury. Adult C57BL/6J mice were given oral treatments of GGA at 200 mg/kg daily for seven days. Ischemic retinal injury was carried out, and the extent of retinal cell death was quantitatively examined after 7 days. Immunohistochemistry for single-stranded DNA, phosphorylated form of p38 mitogen-activated protein kinase (p38 MAPK), and cleaved caspase-3 were performed one day after ischemic injury. In GGA-treated mice, we found the number of surviving retinal neurons was significantly increased compared with vehicle-treated mice. Ischemia-induced phosphorylation of p38 MAPK, which mediates apoptosis of retinal ganglion cells, was suppressed by GGA treatment. In such retinas, cleaved caspase-3- and single-stranded DNA-positive cells were also decreased compared with vehicle-treated mice. Oral GGA is a useful treatment for various retinal degenerative diseases that involve ischemic injury.Molecular vision 02/2007; 13:1601-7. · 2.20 Impact Factor
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2012
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Tokyo Metropolitan Institute of Medical Science
Tokyo, Tokyo-to, Japan
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2007–2011
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Tokyo Metropolitan Institute
Tokyo, Tokyo-to, Japan
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