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Biomedical subjects

Y Tokumitsu

Publications and source records attributed to Y Tokumitsu.

At least 19 recordsLinked to original sources
PubMed1997

Suppression of insulin-stimulated phosphatidylinositol 3-kinase activity by the beta3-adrenoceptor agonist CL316243 in rat adipocytes.

Insulin increased 2-deoxyglucose (2-DG) uptake via the translocation of glucose transporter (GLUT) 4 to the plasma membrane fraction in rat adipocytes. The stimulatory actions of insulin were accompanied by both an increase in the immunoreactive p85 subunit of phosphatidylinositol (PI) 3-kinase in the plasma membrane fractions and PI 3-kinase activation by tyrosine phosphorylation of the p85 subunit. The beta3-adrenoceptor agonist CL316243 (CL) suppressed all the insulin actions in adenosine deaminase (ADA)-treated cells, but was without effect in non-ADA-treated cells. The inhibitory effects of CL on GLUT 4 translocation and PI 3-kinase activation were abolished by the addition of N6-phenylisopropyl adenosine. Cholera toxin treatment, which markedly increased intracellular cAMP levels, suppressed increases in the levels of GLUT 4 and PI 3-kinase in the plasma membrane fractions in response to insulin. In addition, dibutyryl (Bt2) cAMP also impaired the activation of PI 3-kinase by insulin. These results indicated that CL suppressed insulin-stimulated glucose transport under conditions where cAMP levels were markedly increased (approximately 12-fold). The inhibitory actions of PI 3-kinase activation by insulin were exerted even when cAMP, 8-bromo-cAMP, or Bt2 cAMP was added to immunoprecipitates of the p85 subunit of PI 3-kinase, after treating the cells with insulin. These results suggest that CL suppressed insulin-stimulated PI 3-kinase activity via a cAMP-dependent mechanism, at least in part, direct cAMP action in ADA-treated adipocytes, by which PI 3-kinase activation was inhibited, resulting in the decrease in GLUT 4 translocation and subsequent 2-DG uptake in response to insulin.

Adenosine Deaminase↗
PubMed1997

Protein kinase A-dependent IL-6 production induced by calcitonin in human glioblastoma A172 cells.

In human glioblastoma A172 cells, interleukin-6 (IL-6) production was induced by interleukin-1 beta (IL-1 beta) and dibutyryl cyclic AMP. These cells have been shown to induce IL-6 production via a cAMP-protein kinase A system. Since calcitonin (CT) and calcitonin gene-related peptide (CGRP) are known to increase cAMP accumulation in murine and rat astrocytes, we examined whether these neuropeptides induced IL-6 production in A172 cells. Human CT and human CGRP increased IL-6 production and cAMP accumulation in a dose-dependent manner. A specific protein kinase A inhibitor, H-89, inhibited both CT- and CGRP-induced IL-6 production. CT and CGRP have been shown to cross-react with each other. To exclude the possibility of this cross-reactivity, we studied the additive effects of CT and CGRP and the inhibitory effects of specific inhibitors. When 100 nM CT was added, cAMP accumulation stimulated by 10 nM CGRP (the maximal dose) was increased. CGRP (8-37), a specific CGRP receptor inhibitor, inhibited cAMP accumulation and IL-6 production induced by CGRP, but did not inhibit these effects when they were induced by CT. Salmon CT (8-32), a specific inhibitor of the CT receptor, inhibited cAMP accumulation induced by CT, but did not inhibit the effect induced by CGRP. These results demonstrated that CT can induce IL-6 production via cAMP accumulation and the effects of CT are mediated via its own receptors.

Calcitonin↗
PubMed1997

Ki-67, p53, and Bcl-2 expression of serrated adenomas of the colon.

To investigate epithelial cell proliferation and oncoprotein expression of the serrated adenoma, a term that has been used synonymously with mixed hyperplastic and adenomatous polyp, immunohistochemical staining using polyclonal antibodies against Ki-67 and p53, and a Bcl-2 monoclonal antibody, was performed and the results compared with those in hyperplastic polyps and tubular adenomas. A total of 20 serrated adenomas all characterized by a serrated glandular pattern, contained immature goblet cells, upper crypt zone mitotic figures, and a few nucleoli within the epithelial cells. Twenty hyperplastic polyps and 20 tubular adenomas (all with low-grade dysplasia) were examined, and lesions that contained separate areas of hyperplastic and adenomatous glands were excluded. The Ki-67-positive rate in the middle zone of the crypts in serrated adenomas was significantly higher than in hyperplastic polyps but lower than in tubular adenomas; a similar tendency was also noted for the upper zone. Both serrated adenomas and hyperplastic polyps demonstrated Bcl-2-positive reactivity that was essentially limited to the lower crypt zone, while in contrast, involvement in tubular adenomas often extended to the middle zone. No p53 overexpression was found in any category. These results suggest that serrated adenomas may be committed to independent growth.

Adenoma↗
PubMed1996

Adenylyl cyclase activity in turtle vomeronasal and olfactory epithelium.

Many vertebrates have two olfactory systems such as the main olfactory organ and the vomeronasal organ. To compare the transduction mechanism in both systems, we measured adenylyl cyclase activity in turtle vomeronasal and olfactory epithelium preparations. Whereas forskolin and GTP induced cAMP accumulation in vomeronasal preparations, common odorants, which induced cAMP accumulation in olfactory preparations and electrophysiological responses in vomeronasal organs, did not induce cAMP accumulation in vomeronasal preparations. The present results suggest that the cAMP-mediated transduction pathway in the vomeronasal organ is not involved in transduction for common odorants and probably plays a role in perception of specific chemosignals.

Adenylyl Cyclases↗
PubMed1996

Dominance of the 'nondominant' hemisphere in depression.

We examined 36 patients with major depression diagnosed by DSM-III-R to find and qualify disturbances in brain oxygenation and hemodynamics during a psychological task. A group of 36 age- and sex-matched healthy volunteers were monitored as controls. Multichannel near-IR spectrophotometry (NIRS) was used to observe real-time alterations in the oxygenation in corresponding areas of the hemispheres at the forehead during the mirror drawing task (MDT). Nearly half of the patients (12 of 24 males and 4 of 12 females) showed a 'nondominant hemisphere response pattern', which was never observed in normal volunteers during the MDT. The other half of the patients showed a 'bilateral response pattern'. There was no 'dominant hemisphere response pattern', the pattern observed in most normal males. When re-examined after recovery from depression, the response pattern of the two patients who had shown the 'nondominant hemisphere response pattern' during the course of the illness had changed to the 'bilateral response pattern'. The response pattern of the three patients with refractory depression who first showed the 'bilateral response pattern' changed to the 'nondominant response pattern' after several months. The nominally 'nondominant' hemisphere may become dominant during the course of depression.

Adult↗
PubMed1996

Long-term neuroleptic treatments counteract dopamine D2 agonist inhibition of adenylate cyclase but do not affect pertussis toxin ADP-ribosylation in the rat brain.

We have investigated the response of adenylate cyclase to GTP and to dopamine (DA) in striatal membranes of rats treated for 3 weeks with chlorpromazine or haloperidol, and further measured the level of Gi (an inhibitory GTP-binding protein) or Go (a similar GTP-binding protein of unknown function) in 3 areas (cerebral cortex, striatum and hippocampus) utilizing pertussis toxin-catalyzed ADP ribosylation. In saline-treated control membranes, GTP exerted a biphasic effect on basal and DA-stimulated enzyme activity--peak levels of stimulation by DA plus GTP were observed at 1 microM GTP. Conversely, dopaminergic inhibitory effects at 10-100 microM GTP were completely attenuated in chlorpromazine or haloperidol-treated membranes. D2 inhibition of adenylate cyclase by the selective D2 agonist PPHT was also attenuated due to these neuroleptic treatments, while an increase in D2 receptor binding was observed. The pertussis toxin ADP-ribosylation of G-proteins (Gi/Go) did not differ significantly in any area. This indicates that long-term neuroleptic treatments increased D2 receptor binding, but attenuated D2 inhibition of adenylate cyclase, and exercised no influence on pertussis toxin ADP-ribosylation.

Adenosine Diphosphate Ribose↗
PubMed1995

Wortmannin inhibits insulin-induced Ras and mitogen-activated protein kinase activation related to adipocyte differentiation in 3T3-L1 fibroblasts.

Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI 3-kinase), inhibited adipocyte differentiation of 3T3-L1 fibroblasts induced by insulin/dexamethasone/IBMX (hormones/IBMX). Insulin as a key factor in the process of the adipocyte differentiation activated PI 3-kinase, Ras protein, and mitogen-activated protein kinase (MAP kinase, ERK) in 3T3-L1 fibroblasts. Pretreatment with wortmannin almost completely suppressed all these activations. These findings suggest that the sequential activation of PI 3-kinase, Ras protein, and MAP kinase is involved in the insulin signaling pathway(s) during differentiation by hormones/IBMX and in consequence of the inhibition of PI 3-kinase by wortmannin, the activation of Ras protein and MAP kinase which acts downstream of PI 3-kinase is suppressed and results in the inhibition of adipocyte differentiation.

3T3 Cells↗
PubMed1995

Region-dependent asymmetrical or symmetrical variations in the oxygenation and hemodynamics of the brain due to different mental stimuli.

The present paper demonstrates region-dependent variations in the oxygenation and hemodynamics of the brain hemispheres due to three different types of mental stimulation. The variations were observed with a four-channel optical imaging system using tissue-transparent near-infrared light and described changes from baseline of both the hemoglobin oxygenation state and blood volume during three kinds of psychological or mental tasks. During the mirror drawing task, a lateralized hemisphere response (the dominant hemisphere response pattern) was observed in 57% of 14 right handed volunteers in the frontal region (Brodmann's area 10), while in the temporal region (area 38), 80% showed the bilateral response pattern. A large majority of the subjects showed the bilateral response pattern in the frontal and temporal regions while calculating. A smaller majority showed this while looking at anatomical charts, though 30% did not show any response at all in the temporal region. This showed that there were region-dependent asymmetrical or symmetrical variations of the oxygen delivery-oxygen utilization relationship due to different types of mental stimuli.

Adult↗
PubMed1994

Possible involvement of phosphatidylinositol-specific phospholipase C related to pertussis toxin-sensitive GTP-binding proteins during adipocyte differentiation of 3T3-L1 fibroblasts: negative regulation of protein kinase C.

Insulin/dexamethasone/methylisobutylxanthine (hormones/IBMX) induce 3T3-L1 fibroblasts to differentiate into adipocytes. Our previous study suggested that pertussis toxin (IAP)-sensitive GTP-binding protein(s) (G-protein) is involved in the process of differentiation by hormones/IBMX, accompanied by c-fos induction. Northern blotting indicated that among the IAP-sensitive G-proteins, the levels of Gi2 alpha, Go alpha, and Gi3 alpha mRNA were decreased, increased and unchanged, respectively. Gi1 alpha was undetectable and IAP attenuated the decrease in Gi2 alpha mRNA level but did not affect the change in Go alpha mRNA level during the adipocyte differentiation. These results indicate that IAP-sensitive Gi2 alpha mRNA level is decreased during adipocyte differentiation. A combination of phosphatidylinositol-specific phospholipase C (PI-PLC) and IBMX induced c-fos expression in 3T3-L1 fibroblasts similar to that induced with hormones/IBMX. c-fos induced by both stimulators was also diminished by anti-inositolglycan antibody or anti-PI-PLC antiserum. Insulin stimulated the release of inositolproteoglycan and diacylglycerol from 3T3-L1 fibroblasts, which was suppressed by IAP treatment. These findings suggested that one of the pathways of adipocyte differentiation induced by hormones/IBMX occurs via the inositolglycan-specific PI-PLC cascade coupled to IAP-sensitive G-protein(s). Both activation of glycerophosphate dehydrogenase and stimulation of insulin-dependent 2-deoxyglucose uptake induced by hormones/IBMX were enhanced in protein kinase C-depleted cells exposed to phorbol 12-myristate 13-acetate (PMA), and attenuated in IAP-treated cells. The level of a 32P-labeled 52 kDa protein in plasma membrane fractions immunoprecipitated by anti-PI-PLC antiserum was increased by PMA stimulation, abolished in PMA-treated cells, and increased in IAP-treated cells. These findings suggest that protein kinase C phosphorylates PI-PLC, resulting in a decrease in PI-PLC activity related to the signal transduction pathway of adipocyte differentiation of 3T3-L1 fibroblasts.

3T3 Cells↗
PubMed1994

Reduced concentrations of the alpha-subunit of GTP-binding protein Go in schizophrenic brain.

Concentrations of the alpha-subunits of GTP-binding protein, Go (Go alpha) and of Gi2 (Gi2 alpha) in 6 areas (the hippocampus, parahippocampus, putamen, caudate head, orbital frontal cortex, and lateral temporal cortex) of control and schizophrenic postmortem brains were investigated using the highly sensitive enzyme immunoassay method. There was a significant decrease in Go alpha in the hippocampus and caudate head of the right hemisphere in schizophrenic patients compared to controls; the ANOVA (a general linear model; SAS Type II) demonstrated a significant diagnosis x side interaction only in the hippocampus. In other areas of the brain, analysis by grouping under diagnosis, side, age, gender, and postmortem delay showed no significant deviations in Go alpha between controls and schizophrenics. The concentrations of Gi2 alpha did not differ significantly in any area. These findings contrasted with the results yielded by ADP-ribosylation, which showed decreased pertussis toxin ADP-ribosylated amounts in the hippocampus and putamen of the contralateral (left) hemisphere. Some abnormal receptor-Go or Gi 1 signalling in hippocampus, putamen or caudate head may be involved in the pathogenesis of schizophrenia.

Aged↗
PubMed1994

Acceleration of desipramine-induced changes on the dopamine receptor-coupled adenylate cyclase system by pertussis toxin.

The response of adenylate cyclase to GTP and to dopamine (DA) was investigated in striatal membranes from desipramine (DMI)-treated rats (10 mg/kg, b.i.d., for 5 days). GPT exerted the same biphasic effect on basal and DA-stimulated enzyme activity in membranes from DMI-treated rats as on saline-treated rats. Rats were injected intraventricularly once with islet activating protein (IAP), pertussis toxin, and given extended treatment with DMI in order to study the effects on the inhibitory GTP-binding protein (Gi). Gi loses its function as a signal transducer on being ADP-ribosylated selectively by the IAP. D2 inhibition of adenylate cyclase by DA was attenuated by the IAP treatment in both DMI-and saline-treated rats; peak levels of DA plus GTP stimulation shifted from 1 microM to 100 microM GTP. D1 stimulation of adenylate cyclase by DA was also attenuated by the IAP in the DMI-treated rats. Since long-term treatment with DMI (15 mg/kg, once a day, for 3 weeks) resulted in suppression of D1 stimulation similar to that seen in the present findings, uncoupling between D2 receptors and Gi due to IAP treatment might accelerate DMI-induced adaptive changes of dual control of adenylate cyclase system by DA.

Adenosine Diphosphate Ribose↗
PubMed1994

Impaired interhemispheric integration in brain oxygenation and hemodynamics in schizophrenia.

We examined 38 patients with chronic schizophrenia to find and qualify disturbances in interhemispheric integration in brain oxygen metabolism and hemodynamics during a psychological task. A group of thirty-eight age- and sex-matched healthy volunteers were monitored as controls. Multi channel near-infrared (NIR) spectrophotometry was used to observed real-time alterations in cerebral oxygenation in areas of both hemispheres of the forebrain adjacent to the forehead during the mirror drawing task (MDT). In response to MDT normal volunteers showed distinct and well-integrated patterns of changes in oxygenated hemoglobin Hb, deoxygenated Hb, and blood volume total Hb. On the other hand, half the schizophrenics showed dysregulated patterns between hemispheres which never appeared in normal volunteers. Certain schizophrenic symptoms may be related to defective interhemispheric integration.

Adult↗
PubMed1994

Chronic desipramine treatment influences D1 stimulation and D2 inhibition (dual control) of adenylate cyclase by dopamine in rat striatum.

The response of adenylate cyclase to GTP and to dopamine (DA) was investigated in striatal membranes from desipramine (DMI)- or saline-treated rats. DMI (15 mg/kg) or saline was injected i.p. once a day for 3 weeks. In saline-treated control membranes, GTP exerted a biphasic effect on basal and DA-stimulated enzyme activity; peak levels of stimulation by DA plus GTP were observed at 1 microM GTP. On the other hand, peak levels moved to the right in the GTP dose response curve in DMI-treated membranes. Therefore, D2 inhibition might be attenuated, while the D2 specific agonist, PPHT, was not observed to cause inhibition of adenylate cyclase. Furthermore, D1 stimulation of adenylate cyclase via D1 specific agonist SKF was attenuated in DMI-treated membranes. It seems, therefore, that chronic treatment of rat striatum with DMI exerts a dual influence, that is, a lessening of both D1 stimulation and D2 inhibition of adenylate cyclase, and alters specifically the overall process of the adenylate cyclase system.

Adenylyl Cyclase Inhibitors↗
PubMed1994

Developmental changes in ANP-stimulated guanylyl cyclase activity enhanced by ATP in rat lung membrane fractions.

1. ANP (atrial natriuretic peptides)- or ANP/ATP-stimulated guanylyl cyclase activities were compared in adult (2 month old) and neonatal (5-7 day old) rat lung membrane fractions. 2. The enzyme activities of both membranes depended on the incubation time and ATP concentration: although the activities of both membranes were similar after a short incubation time (4 min), those in adult membranes were lower than those of neonatal membranes after longer incubation times (10 and 30 min) or at lower concentrations of ATP. 3. ANP/ATP gamma S-stimulated guanylyl cyclase activities, which were much higher than ANP/ATP-stimulated activities, were similar in both membranes. 4. ATPase activity of adult membranes was higher than that of neonatal membranes, suggesting that hydrolysis of ATP leads to a decrease of ANP/ATP-guanylyl cyclase activity in adult membranes. Triton X-100 enhanced and diminished ANP/ATP-stimulated guanylyl cyclase activities of adult and neonatal membranes, respectively, and thereby abolished the adult/neonatal difference in the membrane response to ATP. 5. ANP-stimulated activities of both membranes were much more activated by pre-incubation with ATP gamma S than those induced by simultaneous addition of ATP gamma S. The former activities were decreased to levels of the latter by Triton X-100. The latter activities were not affected by Triton X-100. 6. The present results suggested that conformation of lung plasma membranes is related to activation of the ANP receptor/guanylyl cyclase system.

Adenosine Triphosphatases↗
PubMed1994

Urinary levels of gamma-carboxyglutamic acid and its clinical significance.

Urinary gamma-carboxyglutamic acid (gamma-Gla) levels were determined in healthy subjects of all ages. The urinary gamma-Gla levels were highest in infants (0-1 years), then fell in an age-dependent manner, again in subjects reaching a minimum value in adults, then gradually increased over 60 years of age. Urinary gamma-Gla levels therefore change markedly with aging. The relationships between the urinary gamma-Gla excretion and plasma levels of prothrombin and protein C in patients with various hepatic diseases or diabetes mellitus were examined and compared with those in healthy adults. Both plasma prothrombin and protein C levels were decreased in all patients with liver disease compared with healthy adults. In patients with hepatitis and liver cirrhosis, the decrease did not, however, affect the gamma-Gla excretion. In addition, in patients with hepatoma or carcinoma with liver metastases, the urinary gamma-Gla levels were increased. In patients with diabetes mellitus, the urinary gamma-Gla levels and plasma levels of prothrombin and protein C tended to increase, but this was not significant. The present results indicate that simultaneous measurement of the levels of urinary gamma-Gla and plasma prothrombin and protein C is a useful tool for the diagnosis of liver diseases and diabetes mellitus.

1-Carboxyglutamic Acid↗
PubMed1993

Gender- and handedness-related differences of forebrain oxygenation and hemodynamics.

To elucidate gender- and handedness-related differences between the hemispheres of the brain in their metabolisms and hemodynamics, simultaneous monitoring by near-infrared (NIR) spectrophotometry of hemoglobin (Hb) in both hemispheres of the forebrain during the mirror drawing task (MDT) was performed. Bilaterally simultaneous increases of oxygenated Hb and decreases of deoxygenated Hb in forebrain occurred symmetrically in all cases of volunteer subjects except for two. There were gender- and handedness-related differences of hemodynamics between the hemispheres of the brain; NIR results showed that a large majority of women used both sides of the brain when concentrating on carrying out the MDT, whilst most men, especially left-handers, reacted mainly using the hemisphere which was 'dominant' according to handedness.

Adult↗