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Dive into the research topics where Masachika Shudou is active.

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Featured researches published by Masachika Shudou.


Journal of Cell Biology | 2008

Membrane-anchored growth factor, HB-EGF, on the cell surface targeted to the inner nuclear membrane

Miki Hieda; Mayumi Isokane; Michiko Koizumi; Chiduru Higashi; Taro Tachibana; Masachika Shudou; Tomohiko Taguchi; Yohki Hieda; Shigeki Higashiyama

Heparin-binding EGF-like growth factor (HB-EGF) is synthesized as a type I transmembrane protein (proHB-EGF) and expressed on the cell surface. The ectodomain shedding of proHB-EGF at the extracellular region on the plasma membrane yields a soluble EGF receptor ligand and a transmembrane-cytoplasmic fragment (HB-EGF-CTF). The cytoplasmic domain of proHB-EGF (HB-EGF-cyto) interacts with transcriptional repressors to reverse their repressive activities. However, how HB-EGF-cyto accesses transcriptional repressors is yet unknown. The present study demonstrates that, after exposure to shedding stimuli, both HB-EGF-CTF and unshed proHB-EGF translocate to the nuclear envelope. Immunoelectron microscopy and digitonin-permeabilized cells showed that HB-EGF-cyto signals are at the inner nuclear membrane. A short sequence element within the HB-EGF-cyto allows a transmembrane protein to localize to the nuclear envelope. The dominant-active form of Rab5 and Rab11 suppressed nuclear envelope targeting. Collectively, these data demonstrate that membrane-anchored HB-EGF is targeted to the inner nuclear membrane via a retrograde membrane trafficking pathway.


Hypertension | 2012

Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice

Li-Juan Min; Masaki Mogi; Masachika Shudou; Fei Jing; Kana Tsukuda; Kousei Ohshima; Jun Iwanami; Masatsugu Horiuchi

We reported previously that an angiotensin II type 1 receptor blocker, telmisartan, improved cognitive decline with peroxisome proliferator-activated receptor-&ggr; activation; however, the detailed mechanisms are unclear. Enhanced blood-brain barrier (BBB) permeability with alteration of tight junctions is suggested to be related to diabetes mellitus. Therefore, we examined the possibility that telmisartan could attenuate BBB impairment with peroxisome proliferator-activated receptor-&ggr; activation to improve diabetes mellitus–induced cognitive decline. Type 2 diabetic mice KKAy exhibited impairment of cognitive function, and telmisartan treatment attenuated this. Cotreatment with GW9662, a peroxisome proliferator-activated receptor-&ggr; antagonist, interfered with these protective effects of telmisartan against cognitive function. BBB permeability was increased in both the cortex and hippocampus in KKAy mice. Administration of telmisartan attenuated this increased BBB permeability. Coadministration of GW9662 reduced this effect of telmisartan. Significant decreases in expression of tight junction proteins and increases in matrix metalloproteinase expression, oxidative stress, and proinflammatory cytokine production were observed in the brain, and treatment with telmisartan restored these changes. Swollen astroglial end-feet in BBB were observed in KKAy mice, and this change in BBB ultrastructure was decreased in telmisartan. These effects of telmisartan were weakened by cotreatment with GW9662. In contrast, administration of another angiotensin II type 1 receptor blocker, losartan, was less effective compared with telmisartan in terms of preventing BBB permeability and astroglial end-foot swelling, and coadministration of GW9662 did not affect the effects of losartan. These findings are consistent with the possibility that, in type 2 diabetic mice, angiotensin II type 1 receptor blockade with peroxisome proliferator-activated receptor-&ggr; activation by telmisartan may help with protection against cognitive decline by preserving the integrity of the BBB.


Journal of Cerebral Blood Flow and Metabolism | 2008

Accumulation of macrophage-like cells expressing NG2 proteoglycan and Iba1 in ischemic core of rat brain after transient middle cerebral artery occlusion.

Hiroaki Matsumoto; Yoshiaki Kumon; Hideaki Watanabe; Takanori Ohnishi; Masachika Shudou; Miao Chuai; Yoshinori Imai; Hisaaki Takahashi; Junya Tanaka

Although neurons and glia inevitably undergo degeneration in the core of ischemic lesions, many cells, particularly immune cells, infiltrate the core and survive in it. Such infiltrating cells may play certain roles in the regeneration and repair of damaged brain tissues. In this study, we characterized macrophage-like cells that accumulated in the ischemic core of a rat brain whose right middle cerebral artery was transiently occluded for 90 mins. Many of the accumulated macrophage-like cells expressed Iba1, a marker of macrophages/microglia, as well as NG2 chondroitin sulfate proteoglycan (NG2), which has been recognized as a marker of oligodendrocyte progenitor cells. Such macrophage-like cells were termed BINCs (brain Iba1+/NG2+ cells) to distinguish them from NG2/Iba1+ or NG2+/Iba1− cells that were also present in the perilesion and the contralateral hemisphere. Electron microscopy showed the localization of NG2 along the plasma membrane of cells that had many phagosomes and irregular-shaped or reniform heterochromatin-rich nuclei, which are characteristics of monocytes/macrophages. Brain Iba1+/NG2+ cells were highly proliferative and their number peaked at 7 days post-reperfusion. An immunoblot analysis of NG2 revealed the presence of two NG2s: one expressed by BINCs with a molecular weight of 300 kDa, and the other found in the contralateral hemisphere with a molecular weight of 290 kDa. Taken the various functions of NG2, BINCs may be involved in not only phagocytosis of degenerated cells but also the healing and regeneration of lesion cores.


The Journal of Comparative Neurology | 2000

Hearing loss and glutamate efflux in the perilymph following transient hindbrain ischemia in gerbils

Nobuhiro Hakuba; Kenichiro Koga; Masachika Shudou; Futoshi Watanabe; Akira Mitani; Kiyofumi Gyo

The mechanism underlying ischemia‐induced hearing loss was studied in gerbils with transient hindbrain ischemia. Occlusion of the vertebral arteries caused an increase in the concentration of glutamate in the perilymph and elevated the compound action potential (CAP) threshold to 24.6 dB at 5 minutes. the CAP threshold subsequently recovered on reperfusion, gradually reaching 8.3 dB 120 minutes after reperfusion. Under electron microscopy, afferent dendrites of the cochlear nerve in contact with inner hair cells exhibited abnormal swelling 5 minutes after ischemia/reperfusion. These morphological changes were not observed in cochleas treated with an alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA)/kainate‐type glutamate receptor antagonist, 6‐7‐dinitroquinoxaline‐2,3‐dione (DNQX), before hindbrain ischemia; an N‐methyl‐D‐aspartate (NMDA)‐type receptor antagonist, D‐2‐amino‐5‐phosphonopentanoate (D‐AP5), was ineffective. Moreover, the histopathological alterations noted 5 minutes after reperfusion were spontaneously ameliorated 120 minutes after ischemia/reperfusion. These findings suggest that the ischemia‐induced increase in extracellular glutamate concentration with subsequent activation of AMPA/kainate receptors is responsible for neurite degeneration and hearing loss in the early stages following transient hindbrain ischemia. J. Comp. Neurol. 418:217–226, 2000.


The Journal of Comparative Neurology | 2003

Transient cochlear ischemia causes delayed cell death in the organ of Corti: An experimental study in gerbils

Kenichiro Koga; Nobuhiro Hakuba; Futoshi Watanabe; Masachika Shudou; Takayuki Nakagawa; Kiyofumi Gyo

To elucidate whether ischemia–reperfusion can cause delayed cell death in the cochlea, the effects of transient cochlear ischemia on hearing and on neuronal structures in the cochlea were studied in Mongolian gerbils. Ischemia was induced by bilaterally occluding the vertebral arteries for 5 minutes in gerbils, which lack posterior cerebral communicating arteries. In gerbils, the labyrinthine arteries are fed solely by the vertebral arteries. Occlusion of the vertebral arteries caused a remarkable increase in the threshold of compound action potentials (CAPs), which recovered over the following day. However, 7 days after the onset of reperfusion, the threshold began to increase again. Morphologic changes in the hair cell stereocilia were revealed by electron microscopy. The number of nuclear collapses was counted in cells stained for DNA and F‐actin to evaluate the degree of cell death in the organ of Corti. Changes in spiral ganglion cell (SGC) neuron number were detected, whether or not progressive neuronal death occurred in the SGC. These studies showed that sporadic fusion of hair cells and the disappearance of hair cell stereocilia did not begin until 4 days after ischemia. On subsequent days, the loss of hair cells, especially inner hair cells (IHCs), and the degeneration of SGC neurons became apparent. Ten days after ischemia, the mean percentage cell loss of IHCs was 6.4% in the basal turn, 6.4% in the second turn, and 0.8% in the apical turn, respectively, and the number of SGC neurons had decreased to 89% of preischemic status. These results indicate that transient ischemia causes delayed hearing loss and cell death in the cochlea by day 7 after ischemia. J. Comp. Neurol. 456:105–111, 2003.


Neuroscience Letters | 2007

Ginsenoside Rb1 protects against damage to the spiral ganglion cells after cochlear ischemia.

Kensuke Fujita; Nobuhiro Hakuba; Ryuji Hata; Isao Morizane; Tadashi Yoshida; Masachika Shudou; Masahiro Sakanaka; Kiyofumi Gyo

The effects of transient cochlear ischemia on spiral ganglion cells (SGCs) were studied in Mongolian gerbils. Ischemic insult was induced by occluding the bilateral vertebral arteries of gerbils for 15min. Seven days after ischemia, the percentage of SGCs decreased to 67.5% from the preischemic baseline in the basal turn. Evaluation with immunohistochemical staining showed TUNEL-positive reactions in the SGCs with fragmented nuclei. In addition, we investigated the protective effects of ginsenoside Rb1 (gRb1) against ischemic injury to SGCs. Seven days after ischemia, the auditory brainstem response threshold shift was significantly reduced and the percentage of SGCs decreased to 90.2% from the preischemic baseline in the basal turn in the gRb1-treated group. These findings suggest that gRb1 prevented hearing loss caused by ischemic injury to SGCs in Mongolian gerbils.


Journal of Neuroimmunology | 2012

Divalent and monovalent autoantibodies cause dysfunction of MuSK by distinct mechanisms in a rabbit model of myasthenia gravis.

Shuuichi Mori; Shigeru Yamada; Sachiho Kubo; Jie Chen; Seiji Matsuda; Masachika Shudou; Naoki Maruyama; Kazuhiro Shigemoto

Muscle-specific kinase (MuSK), a receptor tyrosine kinase, is required for the formation and maintenance of neuromuscular junctions (NMJs). Although autoantibodies against MuSK have been demonstrated to cause myasthenia gravis (MG), the underlying pathogenic mechanism remains unclear because a major subclass of these antibodies is functionally monovalent. We investigated the pathogenic role of MuSK antibodies in the onset of MG in vivo and in vitro. Ultrastructural visualization of NMJs in paretic rabbits with MuSK antibodies indicated that postsynaptic membranes were preserved, despite a significant loss of complexity in the convoluted synaptic folds. In addition, an in vitro assay indicated that both divalent and monovalent antibodies from paretic rabbits could interfere with agrin-induced acetylcholine receptor (AChR) clustering in cultured myotubes. Furthermore, in the absence of agrin, divalent antibodies induced MuSK phosphorylation and accelerated downregulation of Dok-7, an essential intracellular MuSK binding protein, while monovalent antibodies inhibited agrin-induced phosphorylation of MuSK, thus demonstrating distinct molecular mechanisms underlying the MuSK dysfunction induced by these two types of antibodies. Taken together, these findings suggest that complement activation is not necessary for the MG onset and that both divalent and monovalent antibodies may cause MG in vivo by inducing MuSK dysfunction.


Journal of Cell Science | 2008

Plasma-membrane-anchored growth factor pro-amphiregulin binds A-type lamin and regulates global transcription.

Mayumi Isokane; Miki Hieda; Satoshi Hirakawa; Masachika Shudou; Koichi Nakashiro; Koji Hashimoto; Hiroyuki Hamakawa; Shigeki Higashiyama

Amphiregulin (AR), a member of the EGF family, is synthesized as a type I transmembrane protein precursor (proAR) and expressed on the cell surface. Shedding of proAR yields a transmembrane-cytoplasmic fragment (AR-CTF), as well as a soluble AR. Here we demonstrate that the proAR-shedding stimuli trigger endocytosis of both AR-CTF and un-shed proAR. ProAR translocates from the plasma membrane to the inner nuclear membrane, whereas AR-CTF is translocated to the lysosome via retrograde membrane trafficking. Nuclear envelope localization of proAR involves truncation of the C-terminus, which subsequently activates the ER-retrieval signal. The truncated form of proAR interacts with A-type lamin and is retained at the inner nuclear membrane. Heterochromatin formation is then induced and global transcription is transiently suppressed. This study gives new insight into epigenetic chromatin organization in mammalian cells: a plasma-membrane-anchored growth factor is targeted to the inner nuclear membrane where it participates in dynamic chromatin organization and control of transcription.


Brain Research | 2003

AMPA/kainate-type glutamate receptor antagonist reduces progressive inner hair cell loss after transient cochlear ischemia.

Nobuhiro Hakuba; Atsushi Matsubara; Jun Hyodo; Masafumi Taniguchi; Toshiki Maetani; Yoshitaka Shimizu; Yuko Tsujiuchi; Masachika Shudou; Kiyofumi Gyo

We investigated the effect of glutamate receptor antagonists on progressive inner hair cell (IHC) loss following transient cochlear ischemia in gerbils. Transient cochlear ischemia was induced by 15-min bilateral vertebral artery occlusion. An alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate-type glutamate receptor antagonist, 6-7-dinitroquinoxaline-2,3-dione (DNQX), or an N-methyl-D-aspartate (NMDA)-type receptor antagonist, MK-801, was administered 10 min before the ischemic insult. Hearing was assessed by sequentially recording compound action potentials (CAPs) before, during, and after the ischemia. The degree of hair cell loss in the organ of Corti was evaluated in specimens stained with rhodamine-phalloidin and Hoechst 33342. On the seventh day after ischemia, the increases in the CAP threshold and the progressive IHC loss were significantly reduced in cochleae treated with DNQX, while MK-801 was ineffective. These results suggest that the AMPA receptor plays a critical role in the development of the progressive IHC loss induced by ischemia/reperfusion injury in the cochlea.


Neuroreport | 2001

Hypothermia reduces glutamate efflux in perilymph following transient cochlear ischemia.

Jun Hyodo; Nobuhiro Hakuba; Kenichiro Koga; Futoshi Watanabe; Masachika Shudou; Masafumi Taniguchi; Kiyofumi Gyo

The effect of hypothermia on ischemic injury of the cochlea in gerbils was studied with particular regard to glutamate efflux in the perilymph. Under normothermic conditions interruption of the blood supply to the cochlea for 15 min caused a remarkable elevation of the compound action potential (CAP) threshold, and an increase in perilymphatic glutamate. The CAP threshold recovered to some extent with reperfusion, but not to preischemic levels. CAP thresholds, under hypothermic condi- tions and with reperfusion, recovered promptly to near pre-ischemic levels, while glutamate concentration did not change. These results, together with electron microscopy studies, suggest that hypothermia prevents hearing loss primarily through reduction of glutamate efflux at the synopses between inner hair cells and primary afferent auditory neurons.

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