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Biomedical subjects

Nozomu Mori

Publications and source records attributed to Nozomu Mori.

At least 19 recordsLinked to original sources
PubMed2006

Large Na(+) influx and high Na(+), K (+)-ATPase activity in mitochondria-rich epithelial cells of the inner ear endolymphatic sac.

Fluid in the mammalian endolymphatic sac (ES) is connected to the endolymph in the cochlea and the vestibule. Since the dominant ion in the ES is Na(+), it has been postulated that Na(+) transport is essential for regulating the endolymph pressure. This study focused on the cellular mechanism of Na(+) transport in ES epithelial cells. To evaluate the Na(+) transport capability of the ES epithelial cells, changes in intracellular Na(+) concentration ([Na(+)](i)) of individual ES cells were measured with sodium-binding benzofurzan isophthalate in a freshly dissected ES sheet and in dissociated ES cells in response to either the K(+)-free or ouabain-containing solution. Analysis of the [Na(+)](i) changes by the Na(+) load and mitochondrial staining with rhodamine 123 showed that the ES cells were classified into two groups; one exhibited an intensive [Na(+)](i) increase, higher Na(+), K(+)-ATPase activity, and intensive mitochondrial staining (mitochondria-rich cells), and the other exhibited a moderate [Na(+)](i) increase, lower Na(+), K(+)-ATPase activity, and moderate mitochondrial staining (filament-rich cells). These results suggest that mitochondria-rich ES epithelial cells (ca. 30% of ES cells) endowed with high Na(+) permeability and Na(+), K(+)-ATPase activity potentially contribute to the transport of Na(+) outside of the endolymphatic sac.

Animals↗
PubMed2006

SCG10, a microtubule destabilizing factor, stimulates the neurite outgrowth by modulating microtubule dynamics in rat hippocampal primary cultured neurons.

Microtubule dynamics, one of the key elements in neurite outgrowth, is regulated by various regulatory factors to determine the behavior of the neuronal growth cone and to form the specialized neuronal shape. SCG10 is a neuron-specific stathmin protein with a potent microtubule destabilizing factor and is enriched in the growth cones of the developing neurons. We investigated the functional role of SCG10 in neurite outgrowth using rat hippocampal primary cultured neurons. Genetic manipulation of SCG10 using a short-interfering RNA duplex markedly decreased the SCG10 expression level and significantly suppressed neurite outgrowth. This result was confirmed by immunodepletion experiments. On the other hand, the protein transduction of SCG10 using a polyarginine tag stimulated neurite outgrowth. Such manipulation of the SCG10 expression level affected microtubule morphology within the growth cones. A decrease in the SCG10 level converted the morphology to a more stable state, while an increase converted the morphology to a more dynamic state. However, an excess of SCG10 induced neurite retraction due to an excess of microtubule disassembly. These results suggest that SCG10 serves as an important regulatory factor of growth cone motility by enhancing microtubule dynamics, possibly through increasing the catastrophe frequency.

Animals↗
PubMed2006

Chronic DHEAS administration facilitates hippocampal long-term potentiation via an amplification of Src-dependent NMDA receptor signaling.

Dehydroepiandrosterone sulfate (DHEAS) has well characterized effects on memory and cognitive performances. Recently we have reported that repetitive administration of DHEAS lowers the threshold pulse number in inducing activity-dependent long-term potentiation (LTP) in rat hippocampal Schaffer collateral-CA1 synapses, in which a sub-threshold high frequency stimulation (HFS, 30 pulses at 100 Hz) for normal rats could induce robust LTP in DHEAS-treated rats (Chen et al., 2006). Here we report that the sub-threshold HFS could trigger the phosphorylation of Src and ERK2 in the DHEAS-treated rats, but not in control rats. We found in slices obtained from the DHEAS-treated rats that NMDA-induced intracellular Ca2+([Ca2+]i) transients in CA1 pyramidal neurons were significantly potentiated, which was essential for the Src and ERK2 phosphorylations. The activation of ERK2, a downstream factor of Src family kinase, was required for the DHEAS-facilitated LTP. The Src family kinase inhibitor PP2, but not its inactive homologue PP3, attenuated the NMDA-induced [Ca2+]i increase and abolished the DHEAS-facilitated LTP. These findings suggest that the chronic administration of DHEAS brings the NMDA receptor (NMDAr) to a potentiated state that causes an enough level of [Ca2+]i increase for LTP induction even by the sub-threshold HFS. The potentiated [Ca2+]i transient by the sub-threshold HFS may trigger the Src phosphorylation that will further potentiate NMDAr followed by an activation of ERK2 and LTP induction. This novel postsynaptic NMDAr/Src-mediated signal amplification through "NMDAr-Ca2+-->Src-->NMDAr-Ca2+" cycle may play a pivotal role in the DHEAS-facilitated LTP induction.

Analysis of Variance↗
PubMed2006

Molecular characterization of a transport vesicle protein Neurensin-2, a homologue of Neurensin-1, expressed in neural cells.

We have isolated and characterized a novel cDNA encoding a small neuronal membrane protein showing high sequence homology to Neuro-p24/Neurensin-1, a protein containing a microtubule-associated domain at the carboxyl-terminus and exclusively localized to small vesicles of neurons. The newly identified Neurensin-2 constitutes two-membrane spanning domains but not the microtubule-binding domain, with a molecular mass of 28 kDa. Neurensin-2 mRNA is expressed only in brain, whereas the protein expressed in various neurons including those of the thalamus/hypothalamus and hippocampus, of postnatally developing mice. While the levels of Neurensin-1 mRNA and protein in retinoic acid-exposed mouse neuroblastoma Neuro2a cells increased, those of Neurensin-2 mRNA and protein remained unchanged. When the Neurensin-2 cDNA was transfected into Neuro2a cells, Neurensin-2 was expressed in small vesicles including lysosomes in the perinuclear region. On the cotransfection of Neurensin-1 and -2 cDNA into Neuro2a cells, Neurensin-2 was mainly found in small vesicles of the cell body and Neurensin-1 in those of growth cones. In nerve growth factor-stimulated PC12 cells, the intracellular localization of these proteins also differed. Furthermore, immunochemical staining of mouse brain revealed that Neurensin-1 and -2 had a similar distribution in many regions such as the Diagonal band, hippocampus, amygdaloid nucleus, and habenula nucleus, but differed in the intracellular localization as follows: Neurensin-1 was found mainly in neuritic processes, while Neurensin-2 was found in cell bodies. Thus, both Neurensin-1, and -2 are localized in small vesicles in neural cells, but their localizations of the vesicles are not always the same by each other, suggesting that they are under separate regulation.

Animals↗
PubMed2006

Potential contribution of vasoconstriction to suppression of heat loss and homeothermic regulation in UCP1-deficient mice.

To investigate the thermoregulatory mechanism in mice lacking uncoupling protein 1 (UCP1) from the viewpoint of heat loss, we measured oxygen consumptions (VO2), skin-surface temperatures (Tskin, an index of heat release), blood flows in the tails, and rectal temperatures (Trectal) of mice housed in an animal room under the standard thermal condition of approximately 23 degrees C. Compared with wild-type (Ucp1+/+) mice, adult UCP1-deficient (Ucp1-/-) mice tended to show a reduced VO2. Thermograhic analysis of the acute response of Ucp1-/- mice to a small change (a drop of 1-2 degrees C) in the ambient temperature revealed a sustained fall in the Tskin of Ucp1-/- mice; but this fall was only transient in Ucp1+/+ mice. Analysis of tail blood flow under anesthesia clearly showed a stronger vasoconstrictor response in Ucp1-/- mice than in Ucp1+/+ mice. Administration of a vasodilator, evodiamine, transiently increased Tskin in Ucp1+/+ and Ucp1-/- mice similarly; whereas the induction of vasodilation caused a greater and more prolonged reduction in Trectal in Ucp1-/- mice than in Ucp1+/+ mice. These results indicate that Ucp1-/- mice highly, or at least partly, rely on vasoconstriction for heat conservation to compensate for their UCP1 deficiency and to maintain homeothermy under the condition of normal housing temperature.

Animals↗
PubMed2006

Cyclooxygenase isozymes are expressed in human myeloma cells but not involved in anti-proliferative effect of cyclooxygenase inhibitors.

Considering possible tumorigenic activity of cyclooxygenase (COX) isozymes in myeloma, we examined expression levels of COX-1 and -2 in seven human myeloma cell lines (ARH-77, IM-9, RPMI-8226, HPC, HS-Sultan, TSPC-1, and U-266). As analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR), all the cell lines constitutively expressed COX-1, while COX-2 levels markedly varied among different cell lines. Induction of COX-2 by phorbol ester was observed in RPMI-8226 and HPC cells. In contrast, COX-2 was constitutively expressed in ARH-77 and IM-9 cells. Moreover, the high expression level of COX-2 protein in ARH-77 cells was verified by Western blotting. Intact cells of ARH-77 converted 14C-labeled arachidonic acid to prostaglandin E2, F2alpha, and D2, and this activity was dose-dependently inhibited by selective COX-2 inhibitors (SC-58125 and NS-398), a non-selective COX inhibitor (indomethacin), and relatively high concentrations of a selective COX-1 inhibitor (SC-560). These COX inhibitors also suppressed the proliferation of ARH-77 cells, but significant suppression was seen only at 100 microM, a much higher concentration than those sufficient for the COX inhibition. Moreover, proliferation of the myeloma cells lacking COX-2 was also suppressed by 100 microM of SC-58125. These results suggested that the anti-proliferative effect of the COX inhibitors is independent of the inhibition of COX-2.

Arachidonic Acid↗
PubMed2006

Postoperative complications and long-term prognosis of microsurgical reconstruction after total maxillectomy.

Between 1986-2004, 13 patients (11 males and 2 females; mean age, 63.9 years) underwent microsurgical reconstruction after total maxillectomy in our hospital. Reconstructions using a rectus abdominis musculocutaneous flap were primarily carried out in our hospital by emphasizing soft-tissue filling. No postoperative complication related to a vascular anastomosis (such as thrombosis) was noted (success rate, 100%). In 3 cases, fistula formation was observed postoperatively (23.0%). In one case reconstructed with a scapular flap with a vascularized scapula, atelectasis followed by serious pneumonia was observed, and the patient temporarily fell into a life-threatening condition. Five patients died after 1-2 years due to recurrence of maxillary sinus carcinoma, and 2 died after 3-4 years due to another tumor (lung and esophageal). The disease-specific 5-year survival rate of all 40 patients with maxillary sinus carcinoma treated in our hospital by the Kaplan-Meier method was 54.6%, and the overall survival rate was 45.8%. As the prognosis of maxillary sinus carcinoma is poor, we consider that priority should be given to filling of defects with soft tissues, and we also consider that this study is significant to reevaluate strategies for maxillary reconstruction.

Aged↗
PubMed2006

Brain-derived neurotrophic factor enhances expression of superior cervical ganglia clone 10 in lateral geniculate nucleus and visual cortex of developing kittens.

Neuronal growth-associated proteins, including superior cervical ganglia clone 10 (SCG10) family molecules, play roles in neurite outgrowth and network formation as well as structural and functional plasticity. The present ontogenetic study revealed that the expression of neuronal growth-associated proteins in the visual cortex (VC) exhibited a sharp peak in the early postnatal period when growing lateral geniculate nucleus (LGN) axon terminals segregate into the ocular dominance columns depending on retinal activity. We then hypothesized that SCG10 family molecules, known for catastrophic factors of microtubules, play important roles in the formation of ocular dominance columns. To test this hypothesis, we studied whether: (i) monocular blockade of retinal activity changed the SCG10 expression in LGN and VC and (ii) brain-derived neurotrophic factor (BDNF) cortical infusion modified the expression of SCG10 family molecules and the number of excitatory/inhibitory cortical synapses. Using northern blot and in situ hybridization, we revealed that: (i) silencing retinal activity with tetrodotoxin eye injections dynamically reduced the expression of SCG10 mRNA and (ii) it was enhanced by BDNF in VC and LGN of kittens but not adult cats. These findings suggest that cortical infusion of BDNF and retinal activity up-regulate the expression of SCG10 in the LGN and VC and that up-regulated SCG10 in turn initiates marked reorganization of the microtuble network, eventually resulting in increase in synapse formation in the VC.

Age Factors↗
PubMed2006

Removal of an orbital apex hemangioma using an endoscopic transethmoidal approach: technical note.

OBJECTIVE: The posterior orbit contains a number of important and vulnerable structures, including the optic nerve, the ophthalmic artery and vein, and the ocular muscles and their motor nerves, which makes surgical access to the lesion in this region quite difficult. Transfrontal, transfrontal-ethmoidal, and transmaxillary procedures have the disadvantage of possible injuries to a number of nontumor structures, whereas an endoscopic transethmoidal approach is a minimally invasive surgery for the retrobulbar lesions. Retrobulbar cavernous hemangioma was successfully removed by a transethmoidal approach. METHODS: Tumor removal was performed in a patient with an intraconal cavernous hemangioma of approximately 15 mm in diameter. By a transethmoidal approach, the medial-inferior part of the orbit, as well as the apex of the orbit, were clearly visualized after endonasal ethmoidectomy. After the removal of the medial orbital bone, the orbital periosteum was incised and elevated. By elevating the orbital fat, the tumor could be identified separately from the orbital contents. RESULTS: Cavernous hemangioma at the orbital apex was removed without complications. CONCLUSION: An endoscopic transethmoidal approach, which requires no skin incision, is a minimally invasive surgery for retrobulbar orbital tumor, leading to excellent cosmetic results with less bleeding.

Adipose Tissue↗
PubMed2005

N-Methyl-D-Aspartic acid suppresses Akt activity through protein phosphatase in retinal ganglion cells.

PURPOSE: To investigate the relationship between Akt activity and retinal ganglion cell (RGC) death induced by N-Methyl-D-Aspartic acid (NMDA) in the rat retina. METHODS: Two microlitres of 1, 10, 50, 100, or 200 mM NMDA, or vehicle was injected into the vitreous cavity of Sprague-Dawley (SD) rats (n=125). Retinal damage was estimated by counting ganglion cells labeled with fluorochrome and retinal apoptosis was detected by TUNEL. Akt activity was determined by immunohistochemical analysis with a specific antibody to the activated (phosphorylated) form of Akt. To investigate the mechanism of dephosphorylation of Akt, Okadaic acid, a potent protein phosphatase inhibitor, was injected 1 h before NMDA injury and accessed the number of phosphorylated Akt positive cells 1 h after NMDA injection. To stimulate Akt activity in the retina, brain derived neurotrophic factor (BDNF) was injected into the vitreous 15 min before NMDA injection. RESULTS: Immunohistochemical analysis revealed a reduction in phosphorylated Akt in RGCs and amacrine cells one hour after NMDA injury. The RGCs and amacrine cells showed TUNEL positivity at 6 h and a decrease in cell number at 7 days after NMDA injury. No other cells in the retina stained positive with phosphorylated Akt antibody and TUNEL. Okadaic acid prevented the dephosphorylation of Akt by NMDA. The exogenous administration of BDNF prevented the dephosphorylation of Akt in N-Shc/ShcC-positive RGCs and significantly suppressed the NMDA-induced RGC death. CONCLUSIONS: These observations suggest that Akt is one of the key signaling proteins in RGC death induced by NMDA, and that the presence of N-Shc/ShcC enhances BDNF-mediated neuroprotection via phosphorylated Akt. The regulation of phosphorylated Akt by growth factors and protein phosphatase activity may play an important role in cell fate following NMDA injury. Thus, an increase in phosphorylated Akt may have potential therapeutic implications in the treatment of glutamate-related disease.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Site-specific phosphorylation of SCG10 in neuronal plasticity: role of Ser73 phosphorylation by N-methyl D-aspartic acid receptor activation in rat hippocampus.

Accumulated evidence suggests that actin and microtubule regulating proteins contribute to neuronal structural dynamics, which subsequently affect neuronal plasticity. SCG10 is a neuronal-specific stathmin protein with microtubule destabilizing activity that is affected by multiple phosphorylation, at least in vitro. SCG10 has four major phosphorylation sites: Ser50 and Ser97 targeted by protein kinase A (PKA), and Ser62 and Ser73 targeted by mitogen-activated protein kinase (MAPK). To explore the potential roles of site-specific phosphorylation in physiological models, we developed phosphorylation site-specific antibodies and examined the SCG10 status in primary cultured hippocampal neurons and tissues. Although SCG10 is concentrated in growth cones and the Golgi apparatus in primary cultured neurons, the phosphorylated form was also detected in both regions, suggesting that MT dynamics within the growth cone may be regulated by protein phosphorylation. In the adult hippocampus, an intense stimulus such as kainate treatment induced a rapid phosphorylation of Ser73 within 15 min that was sustained for at least 60 min. This response was mediated through the N-methyl D-aspartic acid (NMDA) receptor and was ablated by the antagonist MK-801. The MAPK enzyme Erk2 was simultaneously activated along a similar time course to SCG10, suggesting that Erk2 may directly phosphorylate Ser73. These results demonstrate that changes in the phosphorylation status of SCG10 in vivo, dependent upon neural activity and/or plasticity, could affect the microtubule dynamics in neuronal dendrites.

Amino Acid Sequence↗
PubMed2005

The neural repressor NRSF/REST binds the PAH1 domain of the Sin3 corepressor by using its distinct short hydrophobic helix.

In non-neuronal cells and neuronal progenitors, many neuron-specific genes are repressed by a neural restrictive silencer factor (NRSF)/repressor element 1 silencing transcription factor (REST), which is an essential transcriptional repressor recruiting the Sin3-HDAC complex. Sin3 contains four paired amphipathic helix (PAH) domains, PAH1, PAH2, PAH3 and PAH4. A specific target repressor for Sin3 is likely to bind to one of them independently. So far, only the tertiary structures of PAH2 domain complexes, when bound to the Sin3-interacting domains of Mad1 and HBP1, have been determined. Here, we reveal that the N-terminal repressor domain of NRSF/REST binds to the PAH1 domain of mSin3B, and determine the structure of the PAH1 domain associated with the NRSF/REST minimal repressor domain. Compared to the PAH2 structure, PAH1 holds a rather globular four-helix bundle structure with a semi-ordered C-terminal tail. In contrast to the amphipathic alpha-helix of Mad1 or HBP1 bound to PAH2, the short hydrophobic alpha-helix of NRSF/REST is captured in the cleft of PAH1. A nuclear hormone receptor corepressor, N-CoR has been found to bind to the PAH1 domain with a lower affinity than NRSF/REST by using its C-terminal region, which contains fewer hydrophobic amino acid residues than the NRSF/REST helix. For strong binding to a repressor, PAH1 seems to require a short alpha-helix consisting of mostly hydrophobic amino acid residues within the repressor. Each of the four PAH domains of Sin3 seems to interact with a characteristic helix of a specific repressor; PAH1 needs a mostly hydrophobic helix and PAH2 needs an amphipathic helix in each target repressor.

Animals↗
PubMed2005

Selective upregulation of RB3/stathmin4 by ciliary neurotrophic factor following optic nerve axotomy.

In this study, we examined the cellular responses of stathmin-related proteins in the rat retina following optic nerve (ON) axotomy. To examine the distribution of stathmin-related gene products, we performed semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemical analyses. Retrograde labeling using a fluorescein tracer, fluorogold (FG), was used for the identification of retinal ganglion cells (RGCs). RT-PCR and ISH analyses indicated that the expression of RB3 was specifically increased in the ganglion cell layer (GCL) comparing to other members of stathmin-related gene family examined 3 days following the ON axotomy. When brain-derived neurotrophic factor was administrated intravitreously, the induction of RB3 mRNA sustained up to 7 days after axotomy, although the peak induction level was unchanged. In contrast, ciliary neurotrophic factor (CNTF) administration increased the peak level of RB3 mRNA induction significantly at 3 days after axotomy. Immunohistochemistry in combination with the retrograde labeling of axotomized cells by FG revealed that RB3 was increased following axotomy in FG-labeled RGCs. These data suggest that RB3 is the unique response protein in the stathmin-related proteins following ON axotomy and the induced RB3 may play a critical role in the CNTF-induced response on the axotomized RGCs, e.g. axonal regeneration and/or neuroprotection.

Animals↗
PubMed2005

Expression of interleukin-16 in allergic rhinitis.

BACKGROUND: Interleukin-16 (IL-16) has been characterized as a chemoattractant for a variety of CD4+ T cells. Several inflammatory diseases, including allergic disorders, have been reported to correlate with IL-16. We first examined the IL-16 expression of serum and mucosal tissue in patients with allergic rhinitis. METHODS: Forty-eight patients with a clinical history of house dust mite (HDM) or pollen-sensitive allergic rhinitis were included in this study. Serum IL-16 was analyzed by enzyme-linked immunosorbent assay (ELISA). IL-16 expression of nasal mucosa was detected by immunohistochemistry. RESULTS: IL-16 levels were elevated in the serum of patients with allergic rhinitis compared with normal controls. In particular, serum IL-16 levels in HDM-sensitive patients were higher than those in pollen-sensitive patients. IL-16 was significantly correlated with eosinophils in the peripheral blood of allergic rhinitis patients. Histologically, IL-16 was expressed in infiltrated lymphocytes and nasal gland cells. CONCLUSIONS: Our data indicate that one of the sources of elevated serum IL-16 in allergic patients may be gland cells and lymphocytes in allergic nasal mucosa. This IL-16 cytokine may be strongly associated with the developmental mechanism of allergic rhinitis.

Adolescent↗
PubMed2005

Role of NRSF/REST in the molecular mechanisms regulating neural-specific expression of trkC/neurotrophin-3 receptor gene.

The processes of differentiation and development of neurons involve the induction of neuron-specific genes by instructive signals with subsequent neurotrophic factor-driven survival and functional maturation. We have previously shown that bone morphogenetic protein-2 (BMP2) and retinoic acid synergistically induce the responsiveness of developing sympathetic neurons to neurotrophic factors, neurotrophin 3 (NT-3), and GDNF by upregulating corresponding receptors concomitantly with the induction of other neuron-specific genes including BRINP1, a neuron-specific cell-cycle regulatory protein. In the present study, we analyzed transcriptional mechanisms regulating the neuron-specific expression of TrkC/NT-3 receptor gene. TrkC gene contains at least four NRSE/RE-1 (neuron-restrictive silencing element/repressor element 1)-like elements (TrkC-NRSE A-D). Consequently, we found that in non-neuronal cells, neuron-restrictive silencing factor (NRSF) acts on TrkC-NRSE D located at the downstream of exon 3 to suppress the promoter activity of TrkC gene in a manner similar to the mechanism of NRSF suppressing BRINP1 transcription. In contrast, in neuronal cells, the biological activity of NRSF on TrkC was suppressed. From these observations, molecular mechanisms regulating the expression of neuron-specific genes via NRSE during neuronal differentiation are discussed.

Animals↗
PubMed2005

Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor.

N-Shc (neural Shc) (also ShcC), an adapter protein possessing two phosphotyrosine binding motifs [PTB (phosphotyrosine binding) and SH2 (Src homology 2) domains], is predominantly expressed in mature neurons of the CNS and transmits neurotrophin signals from the TrkB receptor to the Ras/mitogen-activated protein kinase (MAPK) pathway, leading to cellular growth, differentiation, or survival. Here, we demonstrate a novel role of ShcC, the modulation of NMDA receptor function in the hippocampus, using ShcC gene-deficient mice. In behavioral analyses such as the Morris water maze, contextual fear conditioning, and novel object recognition tasks, ShcC mutant mice exhibited superior ability in hippocampus-dependent spatial and nonspatial learning and memory. Consistent with this finding, electrophysiological analyses revealed that hippocampal long-term potentiation in ShcC mutant mice was significantly enhanced, with no alteration of presynaptic function, and the effect of an NMDA receptor antagonist on its expression in the mutant mice was notably attenuated. The tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B was also increased, suggesting that ShcC mutant mice have enhanced NMDA receptor function in the hippocampus. These results indicate that ShcC not only mediates TrkB-Ras/MAPK signaling but also is involved in the regulation of NMDA receptor function in the hippocampus via interaction with phosphotyrosine residues on the receptor subunits and serves as a modulator of hippocampal synaptic plasticity underlying learning and memory.

Amino Acid Motifs↗