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Biomedical subjects

M Shimojo

Publications and source records attributed to M Shimojo.

At least 37 records · Page 2Linked to original sources
PubMed1999

Induction of food intake by a noradrenergic system using clonidine and fusaric acid in the neonatal chick.

To clarify noradrenergic systems on food intake of the neonatal chicks, we examined the effects of i.c.v injection of clonidine (CLON), an alpha2-receptor agonist, and fusaric (5-butylpicolinic) acid (FA), a dopamine (DA)-beta-hydroxylase (DBH) inhibitor. Although a high dose (250 ng) of CLON induced a narcoleptic response and reduced food intake, food intake at 30 min post-injection was enhanced by lower doses (25 and 50 ng) of CLON. Central administration of FA (25, 50 and 100 microg) increased food intake in a dose-dependent fashion. It is suggested that feeding behavior is stimulated by low levels of CLON and decreased by further production of norepinephrine (NE), and FA may play the disturbance of sleeping and then enhance food intake.

Adrenergic alpha-Agonists↗
PubMed1999

Intracerebroventricular administration of mouse leptin does not reduce food intake in the chicken.

Recently, it has been suggested that leptin plays an important role in regulation of food intake and metabolism in rats and mice, however, the effect of central administration of leptin on food intake in chicks has not been reported. We have investigated the anorexigenic effect of leptin administered by intracerebroventricular (i.c.v.) injection in chicks using mouse leptin, which shows 97% homology to chicken leptin. Three experiments were conducted. After being deprived of food for 3 h, male broiler chicks were administered leptin by i.c.v. injection at dose levels of 0, 0.2, 1.0 and 5.0 microg (Experiment 1) or 0, 2.5 and 5.0 microg (Experiment 2). The birds were allowed free access to the diet for 2 h (Experiment 1) and 24 h (Experiment 2) after treatment. Male Single Comb White Leghorn chicks were used in Experiment 3 and were treated in the same manner as in Experiment 1. In all experiments, central administration of mouse leptin did not influence food intake in the time periods examined. It appears that either mouse leptin does not bind to the chicken leptin receptor or in the chicken brain the leptin receptor may be absent.

Analysis of Variance↗
PubMed1999

Neuroprotective action of a novel compound--M50463--in primary cultured neurons.

The neuroprotective effects of a novel synthetic compound, M50463, have been determined by using embryonic rat neocortical neurons in various culture conditions. M50463 was initially characterized as a potent specific ligand for a voltage-dependent sodium channel by radioligand binding studies. In fact, M50463 inhibited neuronal cell death induced by veratrine and inhibited an increase of the intracellular calcium level in neurons evoked by veratrine. In addition to such expected effects, M50463 had the ability to prevent glutamate neurotoxicity, to promote the neuronal survival in serum-deprived medium and to prevent nitric oxide-induced neurotoxicity. These results suggested that M50463 is not a simple sodium channel blocker, but a neuroprotective agent which has some crucial mechanism of action on neuronal death occurring in various situations, and it is a novel, innovative candidate for neuroprotective therapy for various neurodegenerative disorders.

Acetylcysteine↗
PubMed1999

Central gastrin inhibits feeding behavior and food passage in neonatal chicks.

The gastrin/cholecystokinin (CCK) family is recognized as the principal family of hormones involved in regulation of the gastrointestinal tract CCK is recognized as a satiety hormone in mammalian species, but it has been suggested that gastrin rather CCK may have an important role in controlling feeding behavior in the neonatal chick through a poorly developed blood brain barrier. So far, however, there is no direct evidence that central gastrin inhibits food intake in neonatal chicks. The aim of this study was to elucidate whether central administration of gastrin 1) inhibits feeding behavior and 2) alters food passage from the crop. The effects of central administration of gastrin on food intake were investigated in experiment 1. Birds (2-day-old) were food-deprived for 3 h and then gastrin or saline was injected intracerebroventricularly. Gastrin strongly inhibited food intake in a dose-dependent fashion for 2 h. Thereafter, the effects of central gastrin on feeding behavior and serum corticosterone concentration were examined in experiment 2. Following central administration of gastrin, food intake was depressed and pecking behavior was inhibited. Serum corticosterone concentration was not altered by central administration of gastrin. The influence of central gastrin on food passage from the crop was investigated in experiment 3. Central administration of gastrin clearly delayed food passage. In conclusion, central gastrin appears to have a strong effect for the satiety and gastrointestinal motility in the neonatal chick.

Animals↗
PubMed1999

Effects of substitution of N-terminal amino acid of glucagon-like peptide-1 (7-36) amide on food intake of the neonatal chick.

Glucagon-like peptide-1 (GLP-1), a member of glucagon superfamily, is synthesized from a large precursor, preproglucagon, and has been postulated to be a novel incretin. Recently, it was reported that central administration of GLP-1 (7-36) amide decreased food intake in rats and chickens. Generally, the amino acid sequences of the glucagon superfamily members except for gastric inhibitory peptide and growth hormone-releasing factor are identical at N-terminal histidine. It is well known that the GLP-1 receptor is highly specific for GLP-1 and does not bind other peptides of the glucagon superfamily. The aim of this study was to elucidate whether central injection of substituted GLP-1 in which N-terminal histidine of mammalian GLP-1 (7-36) amide was replaced with tyrosine, inhibits food intake in the chick. Intracerebroventricular administration of substituted GLP-1 inhibits food intake in the chick, although the effect of substituted GLP-1 was 11 to 13 fold less than that of mammalian GLP-1 (7-36) amide. These results indicate that N-terminal histidine of GLP-1 (7-36) amide is important for efficacy, but not essential for its bioactivity.

Amino Acid Sequence↗
PubMed1999

Intracerebroventricular injection of orexins does not stimulate food intake in neonatal chicks.

1. Recently, 2 novel neuropeptides were discovered, both derived from the same precursor by proteolytic processing, which bind and activate 2 closely related orphan G protein-coupled receptors, Named orexin-A and -B (Sakurai et al., 1998). Both stimulate food intake when administered centrally to rats. 2. Our aim was to elucidate whether central injection of mammalian orexin-A or -B stimulates food intake in the chick. 3. Under conditions of free access to food, orexin-A did not alter the food intake of chicks, but cumulative food intake was significantly suppressed by orexin-B. 4. The orexin-B was then administered to chicks deprived of food for 3 h to confirm its suppressive effect. No significant effect of orexin-B on food intake was detected. 5. Central injection of orexin-B did not modify food intake when appetite was stimulated by fasting. 6. Neither of these orexins appears to stimulate feeding in chicks.

Animals↗
PubMed1999

Protein kinase A regulates cholinergic gene expression in PC12 cells: REST4 silences the silencing activity of neuron-restrictive silencer factor/REST.

The role of protein kinase A in regulating transcription of the cholinergic gene locus, which contains both the vesicular acetylcholine transporter gene and the choline acetyltransferase gene, was investigated in PC12 cells and a protein kinase A-deficient PC12 mutant, A126.1B2, in which transcription of the gene is reduced. The site of action of protein kinase A was localized to a neuron-restrictive silencer element/repressor element 1 (NRSE/RE-1) sequence within the cholinergic gene. Neuron-restrictive silencer factor (NRSF)/RE-1-silencing transcription factor (REST), the transcription factor which binds to NRSE/RE-1, was expressed at similar levels in both PC12 and A126.1B2 cells. Although nuclear extracts containing NRSF/REST from A126.1B2 exhibited binding to NRSE/RE-1, nuclear extracts from PC12 cells did not. The NRSF/REST isoform REST4 was expressed in PC12 cells but not in A126.1B2. REST4 inhibited binding of NRSF/REST to NRSE/RE-1 as determined by gel mobility shift assays. Coimmunoprecipitation was used to demonstrate interaction between NRSF/REST and REST4. Expression of recombinant REST4 in A126.1B2 was sufficient to transcriptionally activate the cholinergic gene locus. Thus, in PC12 cells, protein kinase A promotes the production of REST4, which inhibits repression of the cholinergic gene locus by NRSF/REST.

Acetylcholinesterase↗
PubMed1998

Effects of various N-terminal fragments of glucagon-like peptide-1(7-36) on food intake in the neonatal chick.

Recently, the suppressive effect on food intake by the central administration of glucagon-like peptide-1 (GLP-1) has been confirmed in both rats and chicks. The importance of the N-terminal amino acid, histidine, for the bioactivity of GLP-1(7-36) in the central nervous system was suggested, though the role for C-terminal amino acids in the central nervous system has not been reported. The present study was done to elucidate the central effect of N-terminal fragments of GLP-1(7-36) on food intake of the neonatal chick. Intracerebroventricular (i.c.v.) administration of mammalian GLP-1(7-36) inhibited food intake of chicks, but the fragments of GLP-1(7-16) and GLP-1(7-26) did not show the suppressive effect on food intake. Furthermore, the extended fragments, GLP-1(7-30) and GLP-1(7-33), also had no effects on food intake. It is concluded that C-terminal amino acids of GLP-1(7-36) have an important role for the bioactivity in the central nervous system with special reference to feeding behavior.

Amino Acid Sequence↗
PubMed1998

Regulation of the cholinergic gene locus.

DNase I hypersensitive site mapping of the human cholinergic gene locus has been used to detect cholinergic specific potential regulatory sites. Analysis of mutant PC12 cell lines provides evidence that protein kinase A II is required and coordinately regulates basal expression of both the ChAT and VAChT genes.

Adenocarcinoma↗
PubMed1998

Human ACTH hypersensitivity syndrome associated with abnormalities of the ACTH receptor gene.

OBJECTIVE: Activating mutations of the ACTH receptor have not been previously described. We investigated a 69-year-old woman with normal blood cortisol but undetectable blood ACTH concentrations. The aim of this study was to evaluate her hypothalamo-pituitary-adrenal axis by measuring circadian variation in blood ACTH and cortisol, and by performing CRH and ACTH stimulation and dexamethasone suppression tests. We also examined biological activity of her circulating blood ACTH using bovine adrenocortical cell suspensions and ACTH receptor gene structure by Northern blotting analysis. RESULTS: Random plasma cortisol concentrations ranged from 182 to 328 nmol/l, while ACTH concentrations were always undetectable. After an intravenous bolus injection of human CRH 100 micrograms, plasma ACTH rose slightly, while plasma cortisol increased appropriately. ACTH stimulation tests revealed that a small amount of ACTH (5 ng/kg b.w.) had the maximal cortisol stimulatory activity, and even smaller amounts of ACTH (0.5 and 0.05 ng/kg b.w.) produced significant increases in cortisol levels. ACTH bioassay of the patient's plasma demonstrated weak biological activity in the HPLC fractions which corresponded to the band of synthetic human ACTH 1-39. The ACTH receptor coding region was amplified by polymerase chain reaction using the leucocyte genomic DNA. There were two base mutations; cysteine 21-->arginine and serine 247-->glycine in the sequences coding for the first extramembranous N-terminal domain and the third extramembranous loop of the ACTH receptor. CONCLUSIONS: This patient with normal blood cortisol but undetectable ACTH levels showed increased adrenocortical sensitivity to ACTH and two point mutations in the ACTH receptor gene. This study, therefore, reports a previously undescribed syndrome--ACTH hypersensitivity syndrome--and provides insights into the molecular mechanism of ACTH receptor action.

Adrenal Cortex Function Tests↗
PubMed1998

The cholinergic gene locus is coordinately regulated by protein kinase A II in PC12 cells.

The vesicular acetylcholine transporter (VAChT) gene and the choline acetyltransferase (ChAT) gene comprise the cholinergic gene locus. We have studied the coordinate regulation of these genes by cyclic AMP-dependent protein kinase (PKA) in the rat pheochromocytoma cell line PC12 and PC12 PKA-deficient mutants. Both ChAT and VAChT mRNA increased approximately fourfold after treatment of PC12 cells with dibutyryl cyclic AMP (dbcAMP). ChAT and PKA activity were also increased by dbcAMP. The basal levels of ChAT and VAChT mRNAs in the PKA-deficient cell lines were both about six times lower than in wild-type PC12 cells, and were induced less than twofold by addition of dbcAMP. H-89 and H-9, specific inhibitors for PKA, reduced ChAT and VAChT mRNA levels to approximately one-third that of untreated cells and ChAT activity to approximately one-fourth that of untreated PC12 cells. Activation of PKA type II, but not PKA type I, increased ChAT activity approximately threefold. Analysis of reporter gene constructs indicates that PKA affects gene transcription at an upstream site in the cholinergic gene locus. These results demonstrate that the expression of the ChAT and VAChT genes is regulated coordinately at the transcriptional level, and a signaling pathway specifically involving PKA II plays an important role in this process.

Animals↗
PubMed1997

A novel control system for polymerase chain reaction using a RIKEN GS384 thermalcycler.

We have developed a novel high-throughput thermalcycler, the RIKEN GS384, which has a maximum of 1536 wells and whose temperature can be controlled accurately and simultaneously for a very small volume of a reaction mixture. In practice, the reaction is carried out using four 384-well (3.5 mm in diameter) plate formats which can be automatically moved using a robotic arm. To achieve accurate temperature control with high thermo-conductivity, we adopted Teflon-coated aluminum well plates closely sandwiched between silicon sheet-covered lids on top and a graphite sheet below. The lids were kept at a higher temperature (2 to 5 degrees C) than the reaction wells. The temperature of the 1536 sample wells was controlled accurately without temperature variability among the wells or evaporation, even for samples of very small volume (minimum 2 microliters). We also developed a new type of plate format which is similar to the 384-well place in terms of plate size, shape, and material, but which differs in the number (1536) and size (1.6 mm in diameter) of the wells. Since the amplification reactions could be done precisely as well, a total of 6144 reactions can potentially be carried out simultaneously using the GS384 thermalcycler. This is very promising for DNA microfabrication technology. This thermalcycler offers the advantage of high-throughput DNA analysis which should be useful for DNA diagnoses or for the human genome project.

Humans↗
PubMed1997

Pain-related somatosensory evoked magnetic fields following lower limb stimulation.

Somatosensory evoked magnetic fields (SEFs) following painful electrical stimulation of the sural nerve were examined in 6 normal subjects. Equivalent current dipoles (ECDs) of the deflections shorter than 100 ms in latency were located in the foot area of the primary sensory cortex (SI) in the contralateral hemisphere following both weak and painful stimulations. Two main deflections, N150m-P150m and N250m-P250m, were independently identified only following painful stimulation. ECDs of the N150m-P150m were considered to be located in bilateral second sensory cortices (SII). ECDs of the N250m-P250m were identified in multiple areas including bilateral cingulate cortices and SII. These findings were consistent with the pain-related SEFs following upper limb stimulation. Therefore, we considered that bilateral SII and the cingulate cortices were activated by the painful stimulation and that pain-specific brain activities in those areas did not depend on the stimulation site.

Adult↗
PubMed1997

Identification of motor and sensory brain activities during unilateral finger movement: spatiotemporal source analysis of movement-associated magnetic fields.

We investigated the movement-related cortical fields (MRCFs) recorded by magnetoencephalography (MEG) to identify the motor and sensory brain activities at the instant of the unilateral finger movement using six normal subjects. We focused our investigation on the source analysis of the events tightly linked to movement onset, and we used brain electric source analysis (BESA) to model the sources generating MRCFs during the interval from 200 ms before to 150 ms after the movement onset. Four sources provided satisfactory solutions for MRCF activities in this interval. Sources 1 and 2, which were located in the pre-central regions in the hemisphere contralateral and ipsilateral to the moved finger, respectively, generated the readiness fields (RF), but source 1 was predominant just before movement onset. The motor field (MF), the peak of which was just after movement onset, was mainly generated by source 1. Sources 3 and 4 were located in the post-central regions in the hemisphere contralateral and ipsilateral to the moved finger, respectively. The first motor evoked field (MEF-I), the peak of which was about 80 ms after the movement, was mainly generated by source 3, but with the participation of sources 1, 2 and 4. The results indicated that the activities of both pre -and post-central regions in bilateral hemispheres were related to voluntary movements, although the predominant areas varied over time. This is the first noninvasive study to clarify the complex spatiotemporal activities relating movements in humans using a multi-channel MEG system.

Adult↗
PubMed1997

Human 11 beta-hydroxysteroid dehydrogenase: studies on the stably transfected isoforms and localization of the type 2 isozyme within renal tissue.

The type 1 and type 2 isoforms of human 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) play a crucial role, respectively, in modulating glucocorticoid and mineralocorticoid hormone action. Deficiency of the 11 beta-HSD2 isoform, as described in the syndrome of apparent mineralocorticoid excess and following liquorice (glycyrrhetinic acid) or carbenoxolone ingestion, results in hypertension in which cortisol acts as a potent mineralocorticoid. Several studies have addressed the effects of progesterone, glycyrrhetinic acid, and their derivatives on 11 beta-HSD activity, but these were largely undertaken before the characterization of the 11 beta-HSD isoforms. The aim of this study was to evaluate the localization of 11 beta-HSD2 in human kidney and to study the effects of progesterone, glycyrrhetinic acid, and their related compounds on stable transfectants of the human 11 beta-HSD isoforms. Using an in-house sheep antibody against human 11 beta-HSD2, immunoperoxidase studies localized 11 beta-HSD2 to renal cortical and medullary collecting ducts. Glomeruli, vascular structures, loops of Henle, and proximal tubules were all negative. Confocal laser microscopy studies indicated both a cytoplasmic and nuclear localization for the enzyme within renal collecting ducts. The nuclear staining, which was intranuclear and was not associated with the nuclear membrane, accounted for 40% of the total cellular 11 beta-HSD2 immunoreactivity. Kinetic analysis of 11 beta-HSD activity in fetal kidney 293 cells stably transfected with h11 beta-HSD1/pcDNA3 or 11 beta-HSD2/pCR3, indicated, respectively, low-affinity dehydrogenase/oxoreductase activity (Km for F, 1.8 microM; Km for E, 270 nM) and high-affinity dehydrogenase activity (Km for F, 190 nM). The reductase activity of 11 beta-HSD1 was inhibited by 11 alpha-hydroxyprogesterone > carbenoxolone = glycyrrhetinic acid = progesterone > 11 beta-hydroxyprogesterone. The dehydrogenase activity of 11 beta-HSD2 was inhibited 11 alpha-hydroxyprogesterone = 11 beta-hydroxyprogesterone > glycyrrhetinic acid > carbenoxolone = progesterone. 11 beta-HSD2, expressed in the renal collecting duct, serves to protect the mineralocorticoid receptor (MR) in an autocrine fashion. The demonstration of a nuclear localization for what was thought to be principally a microsomal enzyme suggests that interaction between the MR and its ligand (either aldosterone or cortisol) may be a nuclear rather than a cytoplasmic event. The inhibitory effects of progesterone, glycyrrhetinic acid, and related compounds on 11 beta-HSD1 and 2 were similar, and it remains to be seen what implication these findings have for 11 beta-HSD1 action in tissues such as the liver and gonad and renal 11 beta-HSD2 activity in relation to sodium homeostasis and blood pressure control.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

Magnetoencephalographic study of intracerebral interactions caused by bilateral posterior tibial nerve stimulation in man.

We studied somatosensory evoked magnetic fields (SEFs) following stimulation of bilateral posterior tibial nerves ('bilateral' waveform) in normal subjects to determine the inter- and intra-hemispheric interference effects caused by activation of sensory areas in bilateral hemispheres. Activated areas in the primary and second sensory cortices (SI and SII) in each hemisphere following bilateral stimulation were clearly identified by estimation of the double best-fitted equivalent current dipoles (ECD) using the spherical head model, and the large inter-individual differences were identified. SEFs following the right posterior tibial nerve stimulation and those following the left stimulation were summated ('summated' waveform). The 'difference' waveform was induced by a subtraction of 'bilateral' waveforms from the 'summated' waveform. Short-latency deflections showed no consistent changes between the 'summated' and 'bilateral' waveforms, but the long-latency deflection, the N100m-P100m, in the 'bilateral' waveform was significantly (P < 0.02) reduced in amplitude as compared with the 'summated' waveform. The differences were clearly identified in the 'difference' waveform, in which the main deflections, U100m-D100m, were found. The ECDs of the short-latency deflections were located in SI contralateral to the stimulated nerve, but the ECDs of the N100m-P100m were located in bilateral SII which are considered to receive ascending signals from the body bilaterally. Therefore, some inhibitory interactions might take place in SII by receiving inputs from the body bilaterally.

Adult↗
PubMed1997

Temporal changes of pyramidal tract activities after decision of movement: a study using transcranial magnetic stimulation of the motor cortex in humans.

To elucidate the effects of the decision to move on the pyramidal tract in humans, we examined the changes in the motor evoked potentials (MEP) of the forearm muscles following transcranial magnetic cortical stimulation (TMS) of the hand area during a go/no-go hand-movement task in 10 normal subjects. The subjects performed an extension of the right wrist according to the go, no-go and control signals, one of which was randomly presented on a TV. A single TMS was applied to the primary hand motor area in the left hemisphere 0-300 ms after each signal. The MEPs recorded from the wrist extensor and flexor muscles changed in amplitude after both go and no-go signals. In comparison with the control, the MEPs were significantly facilitated in the agonistic muscles (wrist extensor muscles) and attenuated in the antagonistic muscles (wrist flexor muscles), at the latencies of 100-200 ms after the go signal (P < 0.02). In contrast, the MEPs of both the extensor and flexor muscles were significantly attenuated during the period of 100-200 ms after the no-go signal (P < 0.001). We speculate that there is strong inhibition on the pyramidal tract after the no-go signal and that the inhibitory effect is non-specific to the target muscles. This inhibition differs from the reciprocal inhibition of the MEP observed in antagonistic muscles after the go signal, and it is probably related to the movement decision originating in the prefrontal cortex.

Adult↗