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Biomedical subjects

Y Toyoshima

Publications and source records attributed to Y Toyoshima.

At least 19 recordsLinked to original sources
PubMed2005

Studies involving the GH-IGF axis: Lessons from IGF-I and IGF-I receptor gene targeting mouse models.

The IGFs are ubiquitous and have pleoitropic effects. They are critical for normal growth and development, and for normal functioning of adult tissues. A liver-specific gene-deletion knockout of the IGF-I gene resulted in a mouse model with reduced circulating IGF-I levels, that led to insulin resistance due to the secondary elevation of circulating GH levels. The reduction in circulating IGF-I levels was also associated with a reduction in cancer growth and metastases in three cancer models, one for colon cancer and two for breast cancer. A second mouse model, using the transgenic approach, inhibited the IGF-I and insulin receptor function in skeletal muscle, and resulted in severe insulin resistance in muscle followed by insulin resistance in fat and liver and, eventually, beta-cell dysfunction and development of Type 2 diabetes. This progression from insulin resistance to Type 2 diabetes was most likely due to lipotoxicity with elevated serum and tissue triglyceride levels. Evidence supporting the hypothesis came from the use of fibrates and leptin injections, each of which enhanced fatty acid (FA) oxidation in liver and muscle and was associated with a reversal of the insulin resistance and diabetes.

Animals↗
PubMed2004

Dietary protein deprivation decreases the serine phosphorylation of insulin receptor substrate-1 in rat skeletal muscle.

Evidence has shown that protein malnutrition tends to increase peripheral insulin sensitivity, but the molecular mechanism underlying this increase is not yet clear. Here we show that, in rat muscle, the state of insulin receptor (IR) substrate-1 (IRS-1), a pivotal component of the signaling pathway of the IR, changes drastically according to protein supply. After rats were fed a protein-free diet (PF) or a 12% casein diet for 1 week, their IR and IRS-1 states were analyzed by immunoblotting using various antibodies. PF slightly increased the amount of IR without affecting the state of IR tyrosine phosphorylation. In contrast, PF decreased the amount of IRS-1 and markedly increased phosphorylation of IRS-1 tyrosine residues after insulin injection. Moreover, IRS-1 in PF rats exhibited faster mobility in SDS-PAGE as well as far less phosphorylation of Ser612 and Ser307, indicating hypophosphorylation on its serine residues. Results of additional experiments using energy-restricted (pair-fed) rats and streptozotocin-induced diabetic rats suggest that dietary protein deficiency by itself alters serine phosphorylation of IRS-1, while the up-regulation of tyrosine phosphorylation requires other factors, such as a reduction in basal plasma insulin. The serine dephosphorylation followed by up-regulation of insulin-dependent IRS-1 tyrosine phosphorylation in skeletal muscle of PF rats in vivo is similar to a phenomenon observed in cultured cells under restriction of amino acids in the medium. With these findings, it could be inferred that the reduction of serine phosphorylation contributes to the sensitization of IRS-1 to IR tyrosine kinase under protein malnutrition.

Animals↗
PubMed2001

PAL31, a nuclear protein required for progression to the S phase.

PAL31 is a nuclear protein expressed by various cell types. In the present study, the expression and function of PAL31 were examined in the cytokine-regulated growth of T and B cell lines. Treatment of the cells with mitogens [ovine PRL, recombinant rat placental lactogen-I (PL-I) and human IL-3] caused a dose-dependent increase in the expression of PAL31 mRNA in the PRL-dependent cell line Nb2, and IL-3 dependent cell line BaF3. A time-course study on synchronized Nb2 cells revealed that the expression of PAL31 is specific to the late G1 and S phases. Immunocytological studies revealed that PAL31 accumulates in the nuclei at the S phase. Furthermore, the antisense oligonucleotide for PAL31 severely inhibited the proliferation of Nb2 cells by inhibiting cells progressing to the S phase. Thus, PAL31 is a nuclear protein associated with cell cycle progression.

Animals↗
PubMed2001

Placentomegaly in cloned mouse concepti caused by expansion of the spongiotrophoblast layer.

Hypertrophic placenta, or placentomegaly, has been reported in cloned cattle and mouse concepti, although their placentation processes are quite different from each other. It is therefore tempting to assume that common mechanisms underlie the impact of somatic cell cloning on development of the trophoblast cell lineage that gives rise to the greater part of fetal placenta. To characterize the nature of placentomegaly in cloned mouse concepti, we histologically examined term cloned mouse placentas and assessed expression of a number of genes. A prominent morphological abnormality commonly found among all cloned mouse placentas examined was expansion of the spongiotrophoblast layer, with an increased number of glycogen cells and enlarged spongiotrophoblast cells. Enlargement of trophoblast giant cells and disorganization of the labyrinth layer were also seen. Despite the morphological abnormalities, in situ hybridization analysis of spatiotemporally regulated placenta-specific genes did not reveal any drastic disturbances. Although repression of some imprinted genes was found in Northern hybridization analysis, it was concluded that this was mostly due to the reduced proportion of the labyrinth layer in the entire placenta, not to impaired transcriptional activity. Interestingly, however, cloned mouse fetuses appeared to be smaller than those of litter size-matched controls, suggesting that cloned mouse fetuses were under a latent negative effect on their growth, probably because the placentas are not fully functional. Thus, a major cause of placentomegaly is expansion of the spongiotrophoblast layer, which consequently disturbs the architecture of the layers in the placenta and partially damages its function.

Animals↗
PubMed2001

Identification of 3,4-dihydroxy-2-oxo-butanal (L-threosone) as an intermediate compound in oxidative degradation of dehydro-L-ascorbic acid and 2,3-diketo-L-gulonic acid in a deuterium oxide phosphate buffer.

Dehydro-L-ascorbic acid (DAA), an oxidation product of L-ascorbic acid (vitamin C), is unstable in the neutral and basic pH regions. When DAA was incubated in a phosphate buffer with deuterium oxide (pH 7.4), it was degraded to form the main degradation compound, which was identified as 3,4-dihydroxy-2-oxobutanal (L-threosone). This compound was also formed from diketo-L-gulonic acid (DKG) in a phosphate buffer with deuterium oxide. L-threosone had reducing activity, probably due to its enolization, and is likely to have been involved in the formation of the reducing activity that was observed in aqueous DAA and DKG solutions. As a reactive dicarbonyl compound, L-threosone might also take some role in the cross-linking of tissue proteins that are formed in vivo in the Maillard reaction.

2,3-Diketogulonic Acid↗
PubMed2000

PAL31, a novel nuclear protein, expressed in the developing brain.

We cloned a cDNA encoding a novel protein (PAL31) predominantly expressed in the fetal rat brain by differential display. PAL31 contains leucine-rich repeat domains, a highly acidic region and a putative nuclear localization signal. PAL31 has 50-70% similarity to SSP29, APRIL, LANP, PHAP I, and PP32. Expression of PAL31 mRNA in the brain was high during the fetal period and decreased after birth. Immunohistochemical studies showed that PAL31 is expressed in the entire embryonic brain, whereas in the adult brain its expression is restricted to the subventricular zone where there are neural progenitor cells. It was also revealed that PAL31 is colocalized with PCNA in the nucleus, indicating that the PAL31 expression is developmentally regulated. Considering the primary structure of PAL31 and its spatiotemporal expression pattern, PAL31 is a novel nuclear protein related to the development of the brain through the proliferation of neuronal cells.

Amino Acid Motifs↗
PubMed2000

Ubiquitinated filamentous inclusions in cerebellar dentate nucleus neurons in dentatorubral-pallidoluysian atrophy contain expanded polyglutamine stretches.

We have recently reported that, in addition to the widespread occurrence of ubiquitinated neuronal intranuclear inclusions (NIIs), the restricted occurrence of ubiquitinated intracytoplasmic filamentous inclusions in the neurons of the cerebellar dentate nucleus (CDN) is a characteristic feature of dentatorubral-pallidoluysian atrophy (DRPLA). Interestingly, these neuronal intracytoplasmic filamentous inclusions (NIFIs) were morphologically indistinguishable from the skein-like inclusions (SLIs) described previously in the spinal anterior horn cells in amyotrophic lateral sclerosis (ALS). In the present study, we examined immunohistochemically the CDN in ten patients with clinicopathologically and genetically confirmed DRPLA and the spinal anterior horns in five patients with sporadic ALS, using a monoclonal antibody (1C2) directed against long polyglutamine stretches. In all of the patients with DRPLA, both the NIFIs and the NIIs were visualized clearly with 1C2. Conversely, in the patients with ALS all structures, including the SLIs, were completely negative. These findings indicate that in DRPLA, the NIFIs in the CDN are an alteration that is directly related to the causative gene abnormality (an expanded CAG repeat encoding polyglutamine) and that, from the molecular point of view, they are distinct from the SLIs in ALS.

Adolescent↗
PubMed2000

Chloroplast tubules visualized in transplastomic plants expressing green fluorescent protein.

A fusion between the plastid psbA promoter and the green fluorescent protein gene (gfp) was introduced into the tobacco chloroplast genome by stable plastid transformation. GFP was synthesized actively and exclusively in the chloroplasts. Tubular projections filled with GFP but containing no chlorophyll were visualized for the first time in chloroplasts of these transplastomic plants. Occasionally, the tubules connect chloroplasts with each other, suggesting the possibility of the exchange of endogenous proteins. However, the fusion of protoplasts between the transplastomic and wild-type plants showed that such chloroplast connections might be rare in mesophyll protoplasts.

Chloroplasts↗
PubMed2000

2-Bromoethylamine, a suicide inhibitor of tissue-bound semicarbazide-sensitive amine oxidase.

Various mammalian tissues contain plasma membrane-bound amine oxidase, termed semicarbazide-sensitive amine oxidase (SSAO). In the present study, 2-bromoethylamine has been studied with regard to inhibitory properties towards tissue-bound SSAO in rat lung. Without preincubation, 2-bromoethylamine was a competitive and reversible SSAO inhibitor with a Ki value of 2.5 microM. After preincubation, it time-dependently and non-competitively inhibited SSAO activity, probably by forming the covalently-bound enzyme-inhibitor adduct. The data presented suggest that 2-bromoethylamine may act as a suicide inhibitor of SSAO.

Amine Oxidase (Copper-Containing)↗
PubMed2000

[Monitoring of the cryptococcus count in the cerebrospinal fluid with negative cultures in two cases of serious cryptococcal meningitis].

We monitored the cryptococcus count in the cerebrospinal fluid(CSF) using the filter technique in two cases of serious cryptococcal meningitis during the course of treatment with antifungal agents. Lumbar puncture was performed once a week, and 1 ml of CSF was filtered through a Millipore filter(5.0-micron pore for cells), followed by staining of the filters with Alcian blue. All of the cryptococci on the filter were counted under a light microscope at a magnification of x 100. More than 500/ml and 2,000/ml of cryptococci were still observed in the CFS in Cases 1 and 2, respectively, in whom CFS cultures for Cryptococcus neoformans became negative after 4 weeks of treatment. Even though the treatment with antifungal agents were continued in these cases, cryptococci could still be observed for 5 weeks and 60 weeks on the filter preparations of Cases 1 and 2, respectively, after the CSF cultures became negative. The cryptococcal antigen could also be detected in the CSF during the positive filter preparations in these cases. At autopsy in Case 2, patchy lepromeningeal inflammatory lesions with the characteristic capsules of cryptococci were observed in the subarachnoid space. These observations suggest that cryptococci, which persisted in the CSF despite the negative cultures, were responsible for the lesions in the subarachnoid space and protracted clinical course in the two cases of cryptococcal meningitis.

Aged↗
PubMed1999

Restricted occurrence of Lewy bodies in the dorsal vagal nucleus in a patient with late-onset parkinsonism.

Lewy body (LB) is consistently found in the substantia nigra in Parkinson's disease. We report a 68-year-old woman with late-onset, dopa-responsive parkinsonism. Her parents were first cousins, but no other affected individuals were present in the family. Autopsy revealed moderate loss of pigmented neurons with gliosis, but neither LBs nor neurofibrillary tangles in the substantia nigra. The locus ceruleus showed neuronal loss with scarce LBs. The most striking change was found in the dorsal vagal nucleus, where marked neuronal loss and fibrillary gliosis with many LBs were evident. Despite the use of ubiquitin and alpha-synuclein immunohistochemistry, no further LBs were identified in other brain regions. These findings suggest that this case was an unusual, anatomically restricted manifestation of LB disease.

Antiparkinson Agents↗
PubMed1999

Circadian-regulated expression of a nuclear-encoded plastid sigma factor gene (sigA) in wheat seedlings.

The activity of a light-responsive psbD promoter in plastids is known to be regulated by a circadian clock. However, the mechanism of the circadian regulation of the psbD light-responsive promotor, which is recognized by an Escherichia coli-type RNA polymerase, is not yet known. We examined the time course of mRNA accumulation of two E. coli-type RNA polymerase subunit genes, sigA and rpoA, under a continuous light condition after 12 h light/12 h dark entrainment. Accumulation of the sigA mRNA was found to be regulated by a circadian clock, while rpoA mRNA did not show any significant oscillation throughout the experiment.

Amino Acid Sequence↗
PubMed1999

PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance.

Agonist-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to cause adipocyte differentiation and insulin sensitivity. The biological role of PPAR gamma was investigated by gene targeting. Homozygous PPAR gamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Quite unexpectedly, heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma.

Adipocytes↗
PubMed1999

Developmental stage-specific multi-subunit plastid RNA polymerases (PEP) in wheat.

Most photosystem I and II plastid genes are transcribed by a plastid encoded Escherichia coli-like RNA polymerase (PEP). In this study, we show that both promoter selectivity and light-dependency of PEP change dramatically during development in wheat leaves. In the leaf tip, psbA and psbD promoter activities are light induced, whilst psbC, psbE and 16S rRNA promoters do not function efficiently irrespective of light conditions. In contrast to the leaf tip, in the basal portion all PEP promoters studied function in the dark as well as the light, except for psbD. Using in vitro transcription, we found that PEP in the illuminated leaf tip can initiate transcription from the -35 destructed psbA promoter, but the -35 element is essential for transcription in the basal portion. There is an extended -10 element in the psbA promoter, recognized by the PEP in the illuminated leaf tip or purified sigma 70-type Escherichia coli RNA polymerase but not by the PEP in the leaf base. These results suggest that during wheat leaf development, PEP in the leaf base that is functional for most PEP promoters even in the dark is replaced by the light-dependent PEP selectively transcribing the psbA and psbD promoters.

Base Sequence↗
PubMed1999

[Frontoparietal dementia and parkinsonism: autopsy report of a sporadic case].

We report a 75-year-old man who presented with parkinsonism, dementia and vertical gaze palsy. Postmortem examination revealed frontoparietal atrophy and nigral depigmentation. The temporal lobe was well preserved. Histologically, the affected cerebral cortex showed vacuolation and neuronal loss in layers 2 and 3. The substantia nigra and globus pallidus were also affected. There was gliosis in the thalamic medial nuclei and midbrain tegmentum. Neither ballooned neurons nor taupositive, argyrophilic inclusions could be found. Moreover, there was no Alzheimer pathology manifested by senile plaques and neurofibrillary tangles. In fact, the clinical and pathological features of the present case were consistent with those observed previously in two other cases reported elsewhere (Kawasaki et al. Acta Neuropathol 91: 140, 1996). In these cases, corticobasal degeneration (CBD) and frontotemporal dementia (FTD) were considered to be the principal entities in the differential diagnosis. However, we believe that these three cases, including the present one, were not examples of CBD or FTD, since neither ballooned neurons nor tau abnormalities were present, and the precentral gyrus was the area most severely involved, the temporal lobes being obviously spared. Therefore we considered that they might represent a hitherto unrecognized new disease entity.

Aged↗
PubMed1999

[Development of ADL index for partially dependent older adults].

The purpose of this study was to develop an index of activities of daily living (ADL) for partially dependent older adults (PD). The index is intended to assess the capability of PD in performing basic daily tasks. A questionnaire of 22 items representing 7 ADL domains was administered by institutional therapists (nurse, OT, PT, social worker) on 466 PD 60 years or more of age, excepting completely dependent people. As a result of examining achievement rates and sex/age differences, inter- and intra-rater reliability (perfect agreement rates), and scalability, 17 reliable items were selected. The validity, reliability and unidimensionality of the ADL index using the 17 items were verified. Age and ADL score calculated based on Hosokawa's extended ADL scale were used as the external standard of validity. Furthermore, the relationships between ADL score and self-assessment of health status and physical fitness level were examined. The main findings of this study can be summarized as follows: 1) The reliability of the ADL index using 17 items was high (r = 0.996 in inter-reliability, and r = 0.940 in intra-reliability). Cronbachs' alpha coefficient of the ADL index was also high (0.926). 2) Based on scalogram analysis, the Guttman's CR, an index of unidimensionality, was very high (CR = 0.939, CS = 0.691). 3) The validity examination showed that ADL score tended to decrease significantly with age, and had a high correlation with Hosokawa's extended ADL scale (r = 0.939). 4) The ADL score tended to be higher in people with a higher self-assessment of health status and physical fitness level.

Activities of Daily Living↗