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Biomedical subjects

Mikio Shoji

Publications and source records attributed to Mikio Shoji.

At least 37 records · Page 2Linked to original sources
PubMed2005

Neural precursor cells division and migration in neonatal rat brain after ischemic/hypoxic injury.

Ischemia/hypoxia (I/H) causes severe perinatal brain disorders such as cerebral palsy. The neonatal brain possesses much plasticity, and to enhance new cell production would be an innovative means of therapy for such disorders. In order to elucidate the dynamic changes of neural progenitor cells in the neonatal brain after ischemia, we investigated new cells production in the subventricular zone and subsequent migration of these cells to the injured area. Newly produced cells were confirmed by incorporation of bromodeoxyuridine (BrdU), and attempt for differentiation was investigated by immunohistochemistry for molecular markers of each cellular lineage. In the sham-control brain, there were many BrdU-labeled cells which gradually decreased as the animal becomes older. Many of these cells were oligodendroglial progenitor or microglial cells. Although there were only few neuronal cells labeled for BrdU in the sham-control, they dramatically increased after I/H. They were located at just beneath the subventricular zone where the progenitor cells reside and to the injured area, indicating that newly produced cells migrated to the infarct region and differentiated into neuronal precursor cells in order to compensate the lost neural cells. We found that BrdU-labeled astroglial, oligodendroglial progenitor, and microglial cells were also increased after I/H, suggesting that they also play active roles in recovery. Progenitor cells may have potential for treating perinatal brain disorders.

Animals↗
PubMed2005

Expression of neurocan after transient middle cerebral artery occlusion in adult rat brain.

Neurocan is one of the major chondroitin sulfate proteoglycans in the nervous tissues. The expression and proteolytic cleavage of neurocan are developmentally regulated in the normal rat brain, and the full-length neurocan is detected in juvenile brains but not in normal adult brains. Recently, some studies showed that the full-length neurocan was detectable even in the adult brain when it was exposed to mechanical incision or epileptic stimulation. In the present study, we demonstrated by Western blot analysis that the full-length neurocan transiently appeared in the peri-ischemic region of transient middle cerebral artery occlusion (tMCAO) in adult rat with a peak level at 4 days after tMCAO. Immunohistochemical analysis showed that a clear positive signal of neurocan was observed 4 days after tMCAO in the peri-ischemic region of cerebral cortex and caudate, where cells strongly positive in GFAP expression were also distributed. These results indicate that accumulation of the full-length neurocan produced by reactive astrocytes may be one of the processes for tissue repair and reconstruction of neural networks after focal brain ischemia as well.

Animals↗
PubMed2005

HMG CoA reductase inhibitors reduce ischemic brain injury of Wistar rats through decreasing oxidative stress on neurons.

Statins possess neuroprotective effect against ischemic damage, but how they protect neurons is not exactly made clear. We speculated that anti-oxidative property of statins is implicated, and investigated statins' influences on the oxidative neuronal damage in the brain after ischemia. After 14 days of atorvastatin, pitavastatin, simvastatin, or vehicle administration, 90 min of middle cerebral artery occlusion was imposed on Wistar rats. The production of 4-hydroxynonenal (HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), both of which are oxidative stress markers, as well as infarction formation were investigated at 1 day after the reperfusion. In the vehicle group, massive infarction was confirmed and HNE and 8-OHdG are robustly produced. In the statins-treated group, the infarction was smaller and the HNE and 8-OHdG production was less prominent than the vehicle group. Among the statins investigated, simvastatin was most effective for reducing oxidative stress and infarction volume, which may be brought by its highly lipophilic property. Reduction of oxidative stress by statins may be one main reason in ameliorating ischemic brain damage in rats.

Aldehydes↗
PubMed2005

Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid beta-peptides.

Familial Alzheimer disease-causing mutations in the presenilins increase production of longer pathogenic amyloid beta-peptides (A beta(42/43)) by altering gamma-secretase activity. The mechanism underlying this effect remains unknown, although it has been proposed that heteromeric macromolecular complexes containing presenilins mediate gamma-secretase cleavage of the amyloid beta-precursor protein. Using a random mutagenesis screen of presenilin-1 (PS1) for PS1 endoproteolysis-impairing mutations, we identified five unique mutants, including R278I-PS1 and L435H-PS1, that exclusively generated a high level of A beta43, but did not support physiological PS1 endoproteolysis or A beta40 generation. These mutants did not measurably alter the molecular size or subcellular localization of PS1 complexes. Pharmacological studies indicated that the up-regulation of activity for A beta43 generation by these mutations was not further enhanced by the difluoroketone inhibitor DFK167 and was refractory to inhibition by sulindac sulfide. These results suggest that PS1 mutations can lead to a wide spectrum of changes in the activity and specificity of gamma-secretase and that the effects of PS1 mutations and gamma-secretase inhibitors on the specificity are mediated through a common mechanism.

Allosteric Site↗
PubMed2005

Reduction of cerebral infarction in stroke-prone spontaneously hypertensive rats by statins associated with amelioration of oxidative stress.

BACKGROUND AND PURPOSE: This study aimed to clarify the effect of statins on spontaneous stroke and to examine the antioxidative effect in artificial transient middle cerebral artery occlusion (tMCAO). METHODS: Stroke-prone spontaneous hypertensive rats (SHR-SP) were treated with pitavastatin, atorvastatin, simvastatin, or vehicle for 4 weeks. Physiological parameters, serum lipids, and infarct volumes were examined. The markers for oxidative stresses on lipids and DNA were immunohistochemically detected in vehicle-treated or simvastatin-treated SHR-SP with tMCAO. RESULTS: Atorvastatin and simvastatin decreased infarct volumes, with simvastatin most effective. Simvastatin significantly reduced immunoreactivities for oxidative stress markers for lipids and DNA in neurons after tMCAO. CONCLUSIONS: The results suggest that the antioxidative properties of statins may be implicated in their beneficial effects against neuronal damage in cerebral ischemia.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Identification of a new membrane-associated protein that influences transport/maturation of gingipains and adhesins of Porphyromonas gingivalis.

The dual membrane envelopes of Gram-negative bacteria provide two barriers of unlike nature that regulate the transport of molecules into and out of organisms. Organisms have developed several systems for transport across the inner and outer membranes. The Gram-negative periodontopathogenic bacterium Porphyromonas gingivalis produces proteinase and adhesin complexes, gingipains/adhesins, on the cell surface and in the extracellular milieu as one of the major virulence factors. Gingipains and/or adhesins are encoded by kgp, rgpA, rgpB, and hagA on the chromosome. In this study, we isolated a P. gingivalis mutant (porT), which showed very weak activities of gingipains in the cell lysates and culture supernatants. Subcellular fractionation and immunoblot analysis demonstrated that precursor forms of gingipains and adhesins were accumulated in the periplasmic space of the porT mutant cells. Peptide mass fingerprinting and N-terminal amino acid sequencing of the precursor proteins and the kgp'-'rgpB chimera gene product in the porT mutant indicated that these proteins lacked the signal peptide regions, consistent with their accumulation in the periplasm. The PorT protein seemed to be membrane-associated and exposed to the periplasmic space, as revealed by subcellular fractionation and immunoblot analysis using anti-PorT antiserum. These results suggest that the membrane-associated protein PorT is essential for transport of the kgp, rgpA, rgpB, and hagA gene products across the outer membrane from the periplasm to the cell surface, where they are processed and matured.

Adhesins, Bacterial↗
PubMed2005

Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice.

Missense mutations of the tau gene cause autosomal dominant frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory loss between 10 to 12 months of age. These findings suggested that TgTauR406W mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).

Amygdala↗
PubMed2005

Novel stationary-phase-upregulated protein of Porphyromonas gingivalis influences production of superoxide dismutase, thiol peroxidase and thioredoxin.

Porphyromonas gingivalis, an obligately anaerobic bacterium, is implicated as a major pathogen in the development and progression of chronic periodontitis. Although expression of several virulence factors of the bacterium has been found to be affected by environmental stress such as entrance into the stationary growth phase and heat, there is relatively little information on the mechanisms that may operate in the bacterium in response to environmental stress. In this study, a novel protein (UstA) was investigated that was initially identified following two-dimensional gel analysis. Expression of UstA was upregulated in stationary phase or by exposure to atmospheric oxygen. N-terminal sequencing and database analysis with the P. gingivalis genome sequence revealed that the UstA-encoding gene (ustA) was located upstream of a homologue of the usp gene encoding the universal stress protein on the chromosome. The ustA gene appeared to be transcribed in a monocistronic fashion, as revealed by primer extension and Northern blot analysis. To elucidate the role of UstA in the bacterium, chromosomal mutants carrying a disruption of the ustA gene were constructed. The ustA mutant grew slower than the wild-type parent strain in rich medium, resulting in a lower yield in stationary phase. Furthermore, in this mutant, expression levels of the P. gingivalis homologues of superoxide dismutase, thiol peroxidase and thioredoxin were markedly higher than those in the wild-type, especially in stationary phase. The ustA mutant was more resistant to diamide, a thiol-specific oxidant, than the wild-type. In addition, the ustA mutation suppressed hypersensitivities of the oxyR mutant to diamide, metronidazole and mitomycin C. These results suggest that UstA may play a significant role in oxidative stress responses in the bacterium.

Amino Acid Sequence↗
PubMed2005

Passive immunization of the Abeta42(43) C-terminal-specific antibody BC05 in a mouse model of Alzheimer's disease.

BACKGROUND: Over the past few years, amyloid beta protein (Abeta) vaccination has become one of the most effective treatments for Alzheimer's disease. However, the appearance of severe side effects during clinical trials has highlighted the need for improved safety and efficacy. Although antibodies directed against the amino (N)-termini of Abeta are highly effective for passive immunization, a substantial risk of inducing cerebral hemorrhage has been documented. OBJECTIVE: We investigated the effect of the administration of BC05, which was the first antibody developed against the carboxyl (C)-termini of Abeta42(43), on the clearance of brain Abeta42(43). METHOD: The BC05 antibody was injected into the peritoneal cavity of Tg2576 transgenic mice expressing betaAPP(KM670/671NL) once a week from 3 to 12 months of age. RESULTS: BC05 caused a selective 44-fold increase in plasma Abeta42(43) and a significant increase in brain soluble Abeta42(43), showing a 156% difference. Brain insoluble Abeta40 and Abeta42(43) levels were decreased by 27.3 and 31.5%, respectively. A reduction in the number of BAN50-labeled plaques was observed. CONCLUSIONS: BC05 might render Abeta42(43) soluble within the brain and inhibit the insoluble deposition of Abeta40 and Abeta42(43). By analyzing the mechanism of the elevation of soluble Abeta42(43) after passive immunization of BC05, safer and more effective methods of immunotherapy for Alzheimer's disease might be developed.

Alzheimer Disease↗
PubMed2005

Beneficial effects of intrathecal IGF-1 administration in patients with amyotrophic lateral sclerosis.

OBJECTIVES: There is currently no effective pharmacological treatment for amyotrophic lateral sclerosis (ALS). In a transgenic mouse model of ALS, intrathecal infusion of insulin-like growth factor (IGF)-1 showed a promising increase in survival. We performed a double-blind clinical trial to assess the effect of intrathecal administration of IGF-1 on disease progression in patients with ALS. METHODS: Nine patients with ALS were randomly assigned to receive either a high dose (3 microg/kg of body weight) or low dose (0.5 microg/kg of body weight) of IGF-1 every 2 weeks for 40 weeks. The outcome measurements were the rate of decline of bulbar and limb functions (Norris scales) and forced vital capacity. RESULTS: The high-dose treatment slowed a decline of motor functions of the ALS patients in total Norris and limb Norris scales, but not in bulbar Norris or vital capacity. The intrathecal administration of IGF-1 had a modest but significant beneficial effect in ALS patients without any serious adverse effects. DISCUSSION: Intrathecal IGF-1 treatment could provide an effective choice for ALS although further studies in more patients are needed to confirm its efficacy and optimize dosages of IGF-1.

Dose-Response Relationship, Drug↗
PubMed2005

Unique cerebellar-cerebral form of autosomal recessive ataxia.

We describe a unique condition affecting two siblings with a form of progressive spinocerebellar ataxia. After a period of very slowly progressive ataxia, the patients developed an extremely accelerated progression of the condition which consisted of cerebellar ataxia, seizure, progressive dementia and spastic tetraparesis. Age of onset was variable at 7 to 18 years. Brain magnetic resonance image (MRI) showed marked atrophy of the cerebellum and cerebrum with strikingly preserved brainstem dimensions. Biochemical or molecular genetic analysis was performed in an elder sister and her parents to exclude known forms of familial spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), progressive myoclonic epilepsy, and some metabolic disorders which could have a similar phenotype. The mode of inheritance appears to be autosomal recessive. We think that the affected siblings may have a new type of autosomal recessive cerebellar ataxia.

Adolescent↗
PubMed2005

[A case of corticobasal degeneration that progressed from primary progressive aphasia].

A 65-year-old woman began to experience slowly progressive speech disturbance from 2001. She was admitted to our hospital for examination on May 2003. She had dysprosody, paragraphia, and mild disturbance in comprehension of spoken language. Repetition was preserved. No clear paraphasia was found. Calculation was disturbed, but there were no other neurological abnormalities including apraxia and agnosia. Brain MRI showed atrophy of the left frontal and parietal lobes. 99mTc-ECD SPECT showed decreased blood flow in the left frontal lobe and parietal lobe, especially in the Broca area and supplemental motor cortex. Primary progressive aphasia was diagnosed, because aphasia lasted for 2 years without other neurological deficits, and her daily activity was well preserved. During follow up, facial apraxia appeared from December 2003, and limb apraxia appeared from May 2004, followed by rigidity predominantly in the right upper limb and dementia. She was diagnosed as having corticobasal degeneration (CBD). The second SPECT on December 2004 showed progression of the decrease in cerebral flow at the same area showed by the first SPECT. SPECT is useful examination to predict the progress of the disease because the decrease of blood flow was recognized before the progression to CBD.

Aged↗
PubMed2005

[A proposal for diagnostic and clinical assessment criteria for Alzheimer's disease].

To clarify the risk and associated genes of Alzheimer's disease by genome-wide screening, a Japanese study group was organized in 2000 under Yasuo Ihara, Tokyo University, supported by a Grant-in-Aid for Science Research on Priority Areas (C) -Advanced Brain Science Project from Ministry of Education, Culture, Sports, Science and Technology, Japan. This is the first Japanese consortium study under permission of the ethical committees of the enrolled institutes based on the ethics guidelines for human genome/gene analysis research, Ministry of Education, Culture, Sports, Science and Technology Ministry of Health, Labor and Welfare Ministry of Economy, Trade and Industry. In this project, 2,000 genome samples from patients with Alzheimer's disease, 2,000 control subjects, and 200 siblings affected with Alzheimer's disease are collected and analyzed. For this purpose, it is necessary to analyze samples from accurately diagnosed Alzheimer patients and controls using standard criteria for diagnosis and neuropsychological evaluation, which have been confirmed by an evidence-based studying a Japanese population. Here, we propose criteria for the diagnosis and clinical assessment of Alzheimer's disease. This proposal consists of a definition of Alzheimer's disease based on recent advances in research, diagnostic criteria based on DSM-IV, NINCDS-ADRDA and ICD-10, exclusion criteria for other dementia disorders, routine and detailed tests for neuropsychological and laboratory evaluations, criteria for neuroimaging and biomarkers, definitive diagnostic criteria and classification of clinical subtypes.

Alzheimer Disease↗
PubMed2004

Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease.

The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 with p53 mRNA elevation in guinea-pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.

Aged↗
PubMed2004

Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia.

We reported elsewhere that an untranslated CTG expansion causes the dominantly inherited neurodegenerative disorder spinocerebellar ataxia type 8 (SCA8). SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only one or two affected individuals are found in a given family. SCA8 expansions have also been found in control chromosomes, indicating that separate genetic or environmental factors increase disease penetrance among SCA8-expansion-carrying patients with ataxia. We describe the molecular genetic features and disease penetrance of 37 different families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. Haplotype analysis using 17 STR markers spanning an approximately 1-Mb region was performed on the families with ataxia, on a group of expansion carriers in the general population, and on psychiatric patients, to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A') were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia (haplotype C). Our finding that SCA8 expansions on three independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supports the direct role of the CTG expansion in disease pathogenesis.

Case-Control Studies↗
PubMed2004

Nonparaneoplastic limbic encephalitis with relapsing polychondritis.

Relapsing polychondritis (RP), which shows pain, swelling and destruction of the affected parts, is a rare autoimmune disorder affecting cartilage. We report a patient with RP that affected skull cartilage, who subsequently developed multifocal meningoencephalitis. The patient presented with severe recent memory disturbance, anxiety and moderate depression. MRI study showed bilateral median temporal lobe lesions including hippocampi and amygdaloidal bodies, abnormal findings that disappeared after treatment with high-dose steroids. This is thought to be the first case of RP presenting amnesic syndrome and mental disorder associated with nonparaneoplastic limbic encephalitis involving bilateral hippocampi and amygdaloidal bodies detected by MRI.

Anxiety↗
PubMed2004

Protection against ischemic brain damage in rats by immunophilin ligand GPI-1046.

To determine the effect of immunophilin ligand GPI-1046 on ischemic brain injury, 90 min of transient middle cerebral artery occlusion (MCAO) was carried out in rat brains. In contrast to cases treated with vehicle, the infarct volume was reduced greatly and rotamase activity was inhibited significantly at 24 hr of reperfusion by treatment with GPI-1046. Immunoreactivity and the number of cells stained positively for FKBP12, FKBP52, caspase-8, cytochrome c, and caspase-3 were also reduced markedly in the brain after GPI-1046 treatment. The present results suggest that GPI-1046 significantly decreased infarct volume and provided neuroprotective effect on rats after transient focal cerebral ischemia by inhibiting the increase of rotamase activity and of the number of FKBP12-, FKBP52-, caspase-8-, cytochrome c-, and caspase-3-positive cells in the ischemic area.

Analysis of Variance↗