Biomedical subjects

Hiroyuki Sugiyama

Publications and source records attributed to Hiroyuki Sugiyama.

11 recordsLinked to original sources

PubMed2005

A novel protein specifically interacting with Homer2 regulates ubiquitin-proteasome systems.

Homer family proteins are encoded by three genes, homer1, 2 and 3. Most of these proteins are expressed constitutively in nervous systems and accumulated in postsynaptic regions. However, the functional significance of these proteins, especially the significance of the distinction among the proteins encoded by homer1, 2 and 3, is still obscure. In the present study, we isolated a cDNA clone encoding a novel protein by two-hybrid system screening using the C-terminal half of Homer2b as the bait. This protein, termed 2B28, has 297 amino acid residues and contains three major domains: a UBA domain, a coiled-coil region, and a UBX domain. When expressed in HEK293T cells, 2B28 showed colocalization with uniquitin and enhanced the expression levels of IkappaB or Homer1a proteins, which are known to be degraded by proteasomes, indicating that 2B28 is involved in ubiquitin-proteasome functions. 2B28 specifically interacted and colocalized with Homer2 proteins, but not with Homer1 proteins. So far, we have identified no counterpart of 2B28 for Homer1 experimentally or in the protein databases. These results suggest that the specific interaction of 2B28 with Homer2 may play a role in regulation of protein degradation by ubiquitin-proteasome systems and that this function may be specific to Homer2 proteins among Homer family proteins.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Regeneration of bacteriorhodopsin from thermally unfolded bacterio-opsin and all-trans retinal at high temperatures.

The temperature dependence of regeneration of bacteriorhodopsin (bR) from its apoprotein, bacterio-opsin (bO), and all-trans retinal was investigated using two different procedures to probe the structural properties of bO at high temperatures. Regeneration experiments performed at 25 degrees C after incubation of bO within the temperature range of 35-75 degrees C indicate that irreversible thermal unfolding begins at 50 degrees C. When bO is incubated for one hour and mixed with retinal at the same elevated temperatures, however, a greater extent of regeneration to bR occurs, even at temperatures ranging from 50 to 65 degrees C. These experimental results indicate that regeneration of bR occurs from thermally unfolded bO and suggest dynamic structural fluctuation of bO in the unfolded state.

Bacteriorhodopsins↗

PubMed2004

Activity-inducible protein Homer1a/Vesl-1S promotes redistribution of postsynaptic protein Homer1c/Vesl-1L in cultured rat hippocampal neurons.

In cultured rat hippocampal neurons, overexpression of Homer1a/Vesl-1S, an inducible protein upregulated by seizure or long-term potentiation, caused a reduction of punctate distribution of a postsynaptic protein Homer1c/Vesl-1L, without significant decrease in its total amount. Clusters of F-actin were also decreased. Treatments of cells with BDNF or a proteasome inhibitor, which cause increase in the expression level of endogenous Homer1a, also resulted in the reduction of Homer1c puncta. These results indicate that the accumulation of Homer1a, either exogenously expressed or endogenously induced, caused redistribution and dispersion of postsynaptic clusters of Homer1c and F-actin, suggesting an important role of Homer1a in synaptic remodeling.

Actins↗

PubMed2004

[Molecular mechanisms of excitatory synaptic transmission: dynamic regulation of AMPA receptors].

AMPA receptors play central roles for synaptic transmission in the central nervous system in mammals. Here we review the molecular mechanisms for how AMPA receptor subunits are correctly assembled, how AMPA receptors are conveyed to dendrites, and how AMPA receptors are exposed in postsynaptic sites. We also discuss the molecular mechanisms of synaptic plasticity that is the cellular basis of learning and memory.

Animals↗

PubMed2003

Activation of ERK cascade promotes accumulation of Vesl-1S/Homer-1a immunoreactivity at synapses.

The Vesl-1S/Homer-1a protein is induced during long-term potentiation (LTP), and contains a motif that binds postsynaptic proteins. We have previously reported that synaptic accumulation of Vesl-1S/Homer-1a immunoreactivity (IR) at synapses on the contour of neuronal somata is promoted by stimulation of cells with phorbol esters, 90 mM KCl or proteasome inhibitors. In the present study, we investigated the intracellular mechanism that results in the synaptic accumulation of this protein at synapses. MEK inhibitors completely blocked the effects of phorbol esters and KCl on the accumulation of Vesl-1S/Homer-1a and partially blocked the effect of proteasome inhibitors. Conversely, brain-derived neurotrophic factor (BDNF) and NT3 promoted the accumulation of Vesl-1S/Homer-1a IR at synapses. The extent of this accumulation is correlated with the level of activation of extracellular signal-regulated kinases, ERK following treatment with BDNF. BDNF also caused an increase in the amount of Vesl-1S/Homer-1a protein, but this occurred after Vesl-1S/Homer-1a had accumulated at the synapses. In addition, inhibition of de novo protein synthesis did not affect the phorbol ester-mediated accumulation of Vesl-1S/Homer-1a IR at synapses. These results indicate that activation of the ERK cascade plays a crucial role in the synaptic accumulation of Vesl-1S/Homer-1a IR, and suggest that this accumulation occurs mainly by re-localization of Vesl-1S/Homer-1a protein, and not through an increase in the level of Vesl-1S/Homer-1a. Activity-dependent release of neurotrophins or depolarization may cause local activation of the ERK cascade to produce the synapse-specific localization of Vesl-1S/Homer-1a.

Action Potentials↗

PubMed2003

Synthesis and antibacterial activity of a novel series of acylides: 3-O-(3-pyridyl)acetylerythromycin A derivatives.

A novel series of acylides, 3-O-(aryl)acetylerythromycin A derivatives, were synthesized and evaluated. These compounds have significant potent antibacterial activity against not only Gram-positive pathogens, including inducibly macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens, such as H. influenzae. 6,9:11,12-dicarbonate acylide 47 (FMA0122) was twice as active against H. influenzae than azithromycin, whereas it showed only moderate in vivo efficacy in mouse protection tests. However, the 11,12-carbamate acylide 19 (TEA0929), which showed potent antibacterial activity against almost all of the main causative pathogens of community-acquired pneumonia tested, exhibited excellent in vivo efficacy comparable to those of second-generation macrolides.

Administration, Oral↗

PubMed2003

Asymmetrical allocation of NMDA receptor epsilon2 subunits in hippocampal circuitry.

Despite its implications for higher order functions of the brain, little is currently known about the molecular basis of left-right asymmetry of the brain. Here we report that synaptic distribution of N-methyl-D-aspartate (NMDA) receptor GluRepsilon2 (NR2B) subunits in the adult mouse hippocampus is asymmetrical between the left and right and between the apical and basal dendrites of single neurons. These asymmetrical allocations of epsilon2 subunits differentiate the properties of NMDA receptors and synaptic plasticity between the left and right hippocampus. These results provide a molecular basis for the structural and functional asymmetry of the mature brain.

Animals↗

PubMed2003

Recent developments in macrolide antimicrobial research.

Clarithromycin and azithromycin, which are more acid-stable than erythromycin A (EM), have been widely prescribed for the treatment of respiratory tract infections because of their high efficacy and safety. However, these macrolide antibiotics are only weakly active against pathogens with an efflux gene (mef) and are inactive against pathogens with a methyltransferase-inducible gene (erm) and constitutively resistant organisms. To address the drug resistance issue, tremendous efforts have been devoted to the modification of the macrolide structure. As a consequence, several types of decladinosyl derivatives, such as ketolide and acylides, have been recognized to be effective against mef-type resistant streptococci and methylase-inducible staphylococci. It has also been recognized that derivatives containing certain 11-, 6- or 4 -tethered aryl substituents, such as telithromycin (HMR 3647), cethromycin (ABT-773) and CP-544372, are effective against erm(B)-type resistant streptococci. Telithromycin was recently approved in several European countries for the treatment of respiratory tract infections and cethromycin is now in the final stage of clinical study. Macrolide antibiotics have been modified to address the issues of acid-instability and inactivity against resistant strains. In this review, we will summarize the progress in the macrolide research area and discuss the desirable features of the next generation macrolide antibiotics.

Anti-Bacterial Agents↗

PubMed2003

Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect.

OBJECTIVE: Thiazolidinediones (TZDs), a class of insulin-sensitizing agents used clinically to treat type 2 diabetes, are also antiatherogenic. This study was designed to elucidate the relationship between the antiatherogenic and antidiabetic effects of pioglitazone, a TZD, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 136 Japanese type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (30 mg daily for 3 months) (n = 70) and the untreated control group (n = 66). The changes in glycolipid metabolism as well as plasma high-sensitivity C-reactive protein (CRP), leptin, adiponectin, and pulse wave velocity (PWV) were monitored to analyze the relationship between the antiatherogenic and antidiabetic effects of pioglitazone. RESULTS: The pioglitazone treatment significantly reduced hyperglycemia, hyperinsulinemia, and HbA(1c) levels and increased plasma adiponectin concentrations relative to the control group (P < 0.01). It also significantly decreased CRP and PWV (P < 0.01). The antiatherogenic effect was observed in both the nonresponders showing <1% of reduction in HbA(1c) (n = 30) and responders showing >1% of reduction (n = 40). ANCOVA revealed that treatment with pioglitazone was associated with a low CRP and PWV, independent of the changes in parameters related to glucose metabolism. CONCLUSIONS: This study represents the first demonstration of the antiatherogenic effect of pioglitazone in both nonresponders and responders with respect to its antidiabetic effect and suggests that pioglitazone can exert its antiatherogenic effect independently of its antidiabetic effect.

Adiponectin↗

PubMed2002

Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor alpha 4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes.

To date five mutations in two major constituents of neuronal nicotinic acetylcholine receptor (nAChR) in the brain, i.e. alpha4 and beta2 subunits, have been identified to be associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Among them, only Ser284Leu, a point mutation in alpha4 subunit identified in ADNFLE as well as in a sporadic case with nocturnal frontal lobe epilepsy, remains to be characterized electrophysiologically. We examined the properties of rat nAChR harboring Ser284Leu reconstituted on Xenopus oocytes. Currents elicited in response to application of acetylcholine to oocytes expressing wild type or mutant nAChR were measured by a standard two-microelectrode voltage clamp method. Compared with wild-type nAChR, the mutant nAChR had a comparable EC(50) value for acetylcholine whereas it showed faster desensitization and lower Cs(+)/Na(+) permeability ratio. Ser284Phe, a putative mutation constructed for comparison, exhibited similar properties. These findings indicate that Ser(284) plays an important role in gating of nAChR along with Thr(276) and Ser(280), and suggest that mutation at Ser(284) could reduce nAChR activity similar to other mutations of alpha4 subunit found in ADNFLE.

Acetylcholine↗

PubMedDate not supplied

Brown-Sèquard syndrome produced by cervical disc herniation: report of two cases and review of the literature.

BACKGROUND CONTEXT: Brown-Sèquard syndrome is most commonly seen with spinal trauma and extramedullary spinal neoplasm. A herniated cervical disc has rarely been considered to be a cause of Brown-Sèquard syndrome. PURPOSE: To report and discuss two cases of Brown-Sèquard syndrome produced by herniated cervical disc. STUDY DESIGN/SETTING: Case studies in Japan. PATIENT SAMPLE: The first patient was a 64-year-old man who presented with right leg weakness and diminished sensation to pain and temperature in the left side below the T4 dermatome. The second patient was a 39-year-old man who presented with right-sided weakness and diminished sensation to pain and temperature in the left side below the T6 dermatome. OUTCOME MEASURES: American Spinal Cord Injury Association (ASIA) impairment scale (only our cases). METHODS: These patients were diagnosed to have Brown-Sèquard syndrome produced by herniated cervical disc. Anterior cervical discectomy with fusion was performed for these patients. RESULTS: These cases revealed contralateral deficit in sensation of pain and temperature of more than a few levels below the cord compression, and showed paracentral protruded disc in magnetic resonance images and cervical spinal stenosis in cervical spine X-rays. Postoperatively, motor and sensory function of these patients returned to normal. CONCLUSIONS: Characteristic finding in discogenic Brown-Sèquard syndrome are contralateral deficit in sensation of pain and temperature of more below than a few levels below the cord compression and paracentral protruded disc with cervical spinal stenosis. Outcomes are favorable in rapid diagnosis by magnetic resonance images and performance of anterior approach.

Adult↗