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Biomedical subjects

Satoshi Ueno

Publications and source records attributed to Satoshi Ueno.

At least 37 records · Page 2Linked to original sources
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

Effects of maturation conditions on spindle morphology in porcine MII oocytes.

Incomplete cytoplasmic maturation of in vitro matured (IVM) oocytes has been known to cause microtubule and microfilament alterations, which may result in abnormal pronuclear formation and failed embryonic development. We examined the influences of maturation conditions on meiotic spindle morphology at metaphase of meiosis II (MII) in porcine oocytes. Porcine oocytes were matured under various conditions, i.e., in vitro or in vivo, with different amounts of cumulus cells, with or without hormonal supplements, and with various exposure durations to the hormones, to examine the effects on spindle morphology in MII oocytes by immunofluorescence under confocal laser microscopy. Interpolar spindle length (microm) and spindle area (microm2) were compared among these maturation conditions. The spindle length was significantly shorter in IVM oocytes compared to those matured in vivo. Oocytes collected from cumulus oocyte complexes (COCs), which were poor in cumulus cells, showed smaller spindle areas than those from cumulus-rich COCs. The spindle length and area were both significantly reduced in oocytes grown without hormonal supplements. When oocytes were grown with hormonal supplements for either 6 or 22 hours for the first half of culture, there was no difference in the spindle morphology between these oocytes. These results suggested that maturation conditions significantly influence morphogenesis of MII spindles in porcine oocytes. Oocytes matured in poor conditions were more likely to have a shorter spindle length (long axis) and smaller spindle areas.

Animals↗
PubMed2005

Humanin detected in skeletal muscles of MELAS patients: a possible new therapeutic agent.

Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis induced by various types of Alzheimer's disease-related insults. We have previously indicated that HN increases cellular ATP levels and speculated that this peptide may rescue energy-deficient cells in mitochondrial disorders. Here, we report, for the first time, increased HN expression in skeletal muscles from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). HN was strongly positive in all ragged-red fibers (RRFs) and some non-RRFs, and most of them were type 1 fibers generally requiring higher energy than type 2 fibers. HN in these fibers was localized in mitochondria. HN expression was also increased in small arteries that strongly reacted for succinate dehydrogenase. Our experiments on muscular TE671 cells indicated the possibility that synthesized HN increases cellular ATP levels by directly acting on mitochondria. From these in vivo and in vitro findings, we propose that HN expression might be induced in response to the energy crisis within affected fibers and vessels in MELAS muscles and further be a possible therapeutic candidate for MELAS.

Adenosine Triphosphatases↗
PubMed2005

Calpain-dependent alpha-fodrin cleavage at the sarcolemma in muscle diseases.

To clarify the involvement of calpains in sarcolemmal remodeling, we examined the expression of calpains and their substrate, alpha-fodrin, in various disorders of muscle. Although immunohistological reactions for alpha-fodrin and calpains were weak in normal control muscles, intense immunoreactivity for alpha-fodrin at the sarcolemma and for calpains throughout the cytoplasm were detected in small muscle fibers from patients with inflammatory myositis (IM), rhabdomyolysis (Rhab), and Duchenne muscular dystrophy (DMD). Most of the calpain-alpha-fodrin double-positive muscle fibers in IM and Rhab also expressed the developmental form of myosin heavy chain. The sarcolemma of these small muscle fibers reacted with an antibody that specifically recognizes the 150-kDa fragments of alpha-fodrin (SBDP 150s) cleaved by calpain, but not caspase 3. Western blot analysis confirmed these results. These observations indicate that calpain is activated and reacts with alpha-fodrin as a substrate at the sarcolemma, and plays a key role in modulating sarcolemmal proteins to adapt to the specific conditions in each myopathy.

Adult↗
PubMed2005

Effect of humanin on decreased ATP levels of human lymphocytes harboring A3243G mutant mitochondrial DNA.

Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis by mutant Alzheimer's disease genes. This 24-residue peptide has been recently shown to suppress apoptosis by interfering with activation of Bcl-2-associated X protein (Bax) in cytosol. In the present study, we showed that HN increases ATP levels in human lymphocytes, muscular TE671 cells, and neural SKN-MC cells, and protects these cells from serum deprivation-induced apoptosis. The suppressed apoptotic death of serum-deprived cells would be explained by the anti-Bax effect of HN; however, HN also increased ATP levels of serum-supplemented cells (non-apoptotic cells), in which Bax is likely to be inactive. This result suggests the presence of a certain mechanism independent of Bax inactivation to increase ATP levels of cells under non-apoptotic condition. By treatment with HN, the ATP levels of lymphocytes from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) associated with A3243G mutant mtDNA were increased as well, suggesting that HN is able to prevent cells in MELAS from falling into ATP deficiency. Our quantitative PCR findings indicated that the HN-induced increase in ATP may not be a consequence of mitochondrial proliferation, because HN rather suppressed mtDNA replication. This suppression may be important in the treatment of affected cells in MELAS, since the mutant mtDNAs that increase during compensatory mtDNA replication for ATP deficiency cause excessive formation of reactive oxygen species, leading to further energy crisis. We thus propose that HN, which increases cellular ATP levels without inducing mtDNA replication, may be suited for the treatment of MELAS.

Adenosine Triphosphate↗
PubMed2005

Autophagic vacuoles with sarcolemmal features delineate Danon disease and related myopathies.

Among the autophagic vacuolar myopathies (AVMs), a subgroup is characterized pathologically by unusual autophagic vacuoles with sarcolemmal features (AVSF) and includes Danon disease and X-linked myopathy with excessive autophagy. The diagnostic importance and detailed morphologic features of AVSF in different AVMs have not been well established, and the mechanism of AVSF formation is not known. To address these issues, we have performed detailed histologic studies of myopathies with AVSF and other AVMs. In Danon disease and related AVMs, at the light microscopic level, autophagic vacuoles appeared to be accumulations of lysosomes, which, by electron microscopy consisted of clusters of autophagic vacuoles, indicative of autolysosomes. Some autolysosomes were surrounded by membranes with sarcolemmal proteins, acetylcholinesterase activity, and basal lamina. In Danon disease, the number of fibers with AVSF increased linearly with age while the number with autolysosomal accumulations decreased slightly, suggesting that AVSF are produced secondarily in response to autolysosomes. Most of the AVSF form enclosed spaces, indicating that the vacuolar membranes may be formed in situ rather than through sarcolemmal indentation. This unique intracytoplasmic membrane structure was not found in other AVMs. In conclusion, AVSF with acetylcholinesterase activity are autolysosomes surrounded by secondarily generated intracytoplasmic sarcolemma-like structure and delineates a subgroup of AVMs.

Acetylcholinesterase↗
PubMed2005

Biological evaluation of 2-aryl-2-fluoropropionic acids as possible platforms for new medicinal agents.

We investigated the cyclooxygenase (COX) inhibitory and anticancer activities of 2-aryl-2-fluoropropionic acids 1a-e. These fluorinated compounds showed lower inhibitory activity toward COX-1 than the corresponding non-fluorinated compounds 2a-e with retained inhibitory activity against COX-2 resulting in modification of the balance of COX-1/COX-2 inhibitions, and they showed little anticancer activity. Interesting differences of the activities between (S)- and (R)-enantiomers were observed in some cases.

Antineoplastic Agents↗
PubMed2005

Evaluation of the quality of porcine somatic cell nuclear transfer embryo by gene transcription profiles.

This study aimed to evaluate the quality of porcine somatic cell nuclear transfer (SCNT) embryos by examining its gene transcription patterns. Embryos were produced by SCNT, intracytoplasmic sperm injection (ICSI) or under different conditions, and transcripts of genes for fibroblast growth factor receptor (FGFr) 2IIIc, FGFr72IIIb, X inactive-specific transcript (Xist), interleukin 6 (IL6), IL6 receptor (IL6r) alpha and c-kit ligand, were detected by real-time RT-PCR. The percentages of embryos in which these transcripts were detected were similar in SCNT and ICSI embryos. On the other hand, the transcriptional levels of the FGFr72IIIb and IL6ralpha genes were 0.5 times less and 2 times more, respectively, in SCNT blastocysts than those of ICSI blastocysts (p<0.05). When nuclear transfer was performed before or after activation of oocytes, embryos in the latter case showed significantly lower frequencies of having FGFr72IIIb (74% vs. 90%) and Xist (3% vs. 33%) transcripts compared to the former case embryos (p<0.05). When two lines of nuclear donor cells with different developmental potencies were used, the transcriptional profiles in the reconstructed embryos did not show any significant differences. Our study suggests that expression profiles of FGFr72IIIb, IL6ralpha, and Xist can be used as markers for the diagnosis of the developmental potency of porcine nuclear transfer embryos.

Animals↗
PubMed2005

Humanin attenuates apoptosis induced by DRPLA proteins with expanded polyglutamine stretches.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal-dominant neurodegenerative disorder caused by expansion of CAG repeats in the DRPLA gene, which codes for a polyglutamine (polyQ) stretch. The expanded polyQs are known to form intracellular aggregates and to confer neurotoxic activity. Recent studies have indicated that activation of apoptosis signal-regulating kinase 1 (ASK1) is involved in polyQ-induced apoptosis. Humanin (HN) is an endogenous peptide that inhibits neuronal cell death caused by mutant Alzheimer's disease genes, and this neuroprotective factor has recently been reported to suppress apoptosis by inhibiting activation of ASK1. To test the anti-ASK1 effect of HN on polyQ neurotoxicity, we constructed neuronal PC12 cells expressing expanded polyQs under the control of the Tet-Off system. Using this cell line, we showed that HN suppresses apoptotic cell death induced by expanded polyQs. However, the suppression was incomplete, suggesting that polyQs also stimulate other pathogenic cascades unrelated to ASK1. We further showed that HN suppresses polyQ aggregate formation. This result implied the possibility that aggregation is also related to the polyQ-mediated cascade involving ASK1 activation. Although the details remain uncertain, our results suggest that ASK1 is potentially involved in pathogenesis of DRPLA and that HN might contribute partially to the suppression of neurodegeneration in polyQ diseases.

Amino Acid Sequence↗
PubMed2005

Increased vulnerability to L-DOPA toxicity in dopaminergic neurons From VMAT2 heterozygote knockout mice.

Parkinson's disease (PD) is characterized by a preferential loss of dopaminergic neurons in the substantia nigra pars compacta. The etiology of PD remains unclear; however, generation of reactive oxygen species during oxidation of free dopamine (DA) in the cytoplasm might be one of the causes of selective dopaminergic neuron loss in PD. Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals take up and partition DA from neuronal cytoplasm into synaptic vesicles. Alterations of VMAT2 function might therefore cause cytoplasmic accumulation of free DA, which is toxic for dopaminergic neurons. We showed that dopaminergic neurons from VMAT2 heterozygous knockout mice were more vulnerable to the toxic effect of L-3, 4-dihydroxyphenylalanine (L-DOPA, a DA precursor) than those from wild-type mice. Our results suggest that reduction of VMAT2 activity might attenuate the efficacy of L-DOPA therapy for patients with PD.

Animals↗
PubMed2005

Proton MR spectroscopy of adult-onset dentatorubral-pallidoluysian atrophy.

PURPOSE: To quantify impairment of the basal ganglia (globus pallidus and thalamus) in adult-onset dentatorubral-pallidoluysian atrophy (DRPLA). METHODS: Five patients with genetically definite adult-onset DRPLA (aged 51 to 65 years, mean 55.6 years) and 5 age- and sex-matched healthy controls underwent conventional magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) of the brain in the voxels predominantly containing the globus pallidus or the thalamus. RESULTS: Conventional MRI studies showed apparently normal intensities in the globus pallidus and thalamus. MRS showed that the choline (Cho)/creatine (Cr) ratio for the patients' globus pallidus, the region preferentially affected in DRPLA, was significantly higher than that in the controls (p<0.05). The N-acetylaspartate (NAA)/Cr ratio for the globus pallidus and the Cho/Cr and NAA/Cr ratios for the thalamus, the region relatively spared in this disease, did not differ significantly between the patients and controls. CONCLUSIONS: MRS may sensitively and specifically detect biochemical alterations in susceptible regions of patients with adult-onset DRPLA.

Aged↗
PubMed2005

Mechanisms of bihemispheric brain infarctions in the anterior circulation on diffusion-weighted images.

BACKGROUND AND PURPOSE: Multiple acute brain infarctions in both cerebral hemispheres usually suggest an embolic mechanism, particularly one of aortic or cardiac origin. The purpose of this study was to clarify the etiologic mechanisms and topographic features of bihemispheric infarctions depicted on diffusion-weighted imaging (DWI). METHODS: Among 411 consecutive patients with ischemic stroke who underwent MR imaging in the acute phase, DWI showed bilateral infarctions in 19 (4.6%). In these patients, we analyzed the presence of carotid, aortic or cardiac embolic sources by using ultrasonography, cerebral angiography, and/or transesophageal echocardiography and evaluated the size and topographic distribution of the lesions. We assessed intracranial cross-flow through the anterior communicating artery, mainly on the basis of the anatomic information obtained from angiography or MR angiography. RESULTS: Bilateral lesions were derived from cardiac and/or aortic embolic sources in 16 (84%) of 19 patients and appeared to originate from unilateral carotid diseases in three (16%). In nine (82%) of 11 patients with cardiac embolic sources, at least one large territorial or subcortical lesion was found in either hemisphere, whereas in all eight patients without a cardiac embolic source, the lesions were small and disseminated bilaterally. CONCLUSION: Unilateral carotid lesions can cause bihemispheric infarctions through cross-flow in the anterior communicating artery. On DWI, small bihemispheric, disseminated lesions strongly suggest an artery-to-artery embolism. In such cases, aortic and carotid lesions should be assessed as potential embolic sources.

Aged↗
PubMed2005

Expression of CD29 on lymphoma cells and/or CD36 on microvascular endothels correlates with high serum LDH level in diffuse large B-cell lymphomas (DLBCLs) and is frequent in de novo CD5-positive DLBCLs.

Our previous study demonstrated that CD29 and CD36 mRNAs were overexpressed in de novo CD5-positive diffuse large B-cell lymphomas (CD5+ DLBCLs) compared with CD5-negative (CD5-) DLBCLs. CD29 was expressed on lymphoma cells, and CD36 on microvascular endothels. In the present study, we analyzed the clinicopathological significance of CD29 and microvascular CD36 (mvCD36) expression in many cases of DLBCLs. CD29 and CD36 expression was examined by immunohistochemistry on frozen sections of 159 specimens, consisting of 120 cases of CD5-DLBCL, 14 cases of de novo CD5+ DLBCL, 11 cases of follicular lymphoma, 8 cases of mantle cell lymphoma, and 6 cases of reactive lymphoid hyperplasia. Three cases of CD5- intravascular large B-cell lymphomas (IVLs) with hepatic intrasinusoidal infiltration were also examined. CD29+ and/or mvCD36+ DLBCL cases had significantly higher serum LDH levels compared with CD29- mvCD36- DLBCL cases. The number of CD29+ and mvCD36+ cases, and the number of CD29+ or mvCD36+ cases, were significantly higher in de novo CD5+ DLBCLs than in CD5- DLBCLs. The frequencies of CD29 and mvCD36 expression were low in follicular lymphomas, and mvCD36 was negative in reactive lymphoid hyperplasias. Liver biopsies of three IVL cases showed that CD29 was positive on lymphoma cells, and, that CD36 was expressed on hepatic sinusoids. The present study supports the notion that CD29 and/or mvCD36 expression manifests the aggressive feature of a subset of DLBCLs because of its correlation with high serum LDH levels. Furthermore, CD29 and mvCD36 expression should be evaluated in relation to the intravascular growth pattern of lymphoma cells.

Biomarkers, Tumor↗
PubMed2004

Loss of function mechanism in aprataxin-related early-onset ataxia.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is an autosomal recessive form of cerebellar ataxia that occurs most commonly in Japan but is also frequently seen in Europe. This disease is caused by mutations in the aprataxin gene, but the functions of the gene product and the pathogenic mechanism remain unclear. The present study provides experimental evidence that the histidine triad (HIT) domain in aprataxin has enzymatic activity that is negatively regulated by the intramolecular interaction of the N-terminal domain. Furthermore, the reduction in HIT activity seen in all the disease-causing mutants tested, and the correlation between the reduced activity and the severe phenotype, support that aprataxin's physiological function is associated with its catalytic activity. Our findings suggest that the clinical phenotypes are caused by a loss of aprataxin function, attributable largely to diminished HIT activity but partially to a reduction in the levels of gene products.

Acid Anhydride Hydrolases↗
PubMed2004

Novel splice variants increase molecular diversity of aprataxin, the gene responsible for early-onset ataxia with ocular motor apraxia and hypoalbuminemia.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is one of the most common forms of autosomal recessive cerebellar ataxia. We identified six new alternative transcripts produced by the aprataxin gene responsible for EAOH. Total eight transcripts encoded truncated proteins that were located within the nucleus or cytoplasm and showed different binding abilities to wild-type (WT) aprataxin. Thus, the alternative splicing increases the molecular diversity of aprataxin and the expression profiles of these transcripts in various tissues may be related to the tissue-specific phenotypes.

Adult↗
PubMed2004

Vertebral artery occlusion in duplex color-coded ultrasonography.

BACKGROUND AND PURPOSE: To establish the diagnostic criteria for the site of occlusion in the vertebral arteries (VAs) using duplex color-coded ultrasonography. METHODS: In 128 consecutive patients who underwent conventional cerebral angiography, we prospectively measured the diameter, mean flow velocity (MV), peak systolic flow velocity, and end-diastolic flow velocity of both VAs. The diameter-ratio (diameter of contralateral VA divided by that of target VA) and MV-ratio (MV of contralateral VA divided by that of target VA) were determined. Based on the angiographic findings, we classified the VAs into 4 types (5 groups) as follows: (1) the origin of VA occlusion (Origin group: n=9); (2) VA occlusion before branching into the posterior inferior cerebellar artery (PICA) (Before group: n=10); (3A) symptomatic VA occlusion after branching into the PICA (After group: n=12); (3B) asymptomatic or hypoplastic occlusive VA after branching into the PICA (PICA end group: n=15); and (4) no significant occlusive lesions in the VA (Control group: n=194). RESULTS: No flow signals in the VAs apparently indicated the Origin group. Preserved peak systolic flow velocity but end-diastolic flow velocity of zero cm/s indicated the Before group. MV <18 cm/s and MV-ratio > or =1.4 indicated the PICA end group or After group. Furthermore, these groups could be distinguished as follows: a diameter-ratio <1.4 indicated the After group. A diameter-ratio > or =1.4 indicated the PICA end group. Either MV > or =18 cm/s or MV <18 cm/s in combination with MV-ratio <1.4 indicated the Control group. CONCLUSIONS: Duplex color-coded ultrasonography can accurately diagnose the site of VA occlusion.

Angiography, Digital Subtraction↗