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Biomedical subjects

Y Tokumitsu

Publications and source records attributed to Y Tokumitsu.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1993

Drugs acting on the intracellular signalling system.

Cellular response to extracellular messages is a basic process to maintain and to support cell life. Several signalling molecules important as sites of therapeutic drug action are involved in the response. Recent studies on life sciences have elucidated molecular properties of intracellular signalling factors and mechanisms of cascading. Novel drugs acting on signalling molecules and possessing new sites and mechanisms of action have been found. This article summarizes the properties (subtypes, structures, functions) of signalling factors (receptors, ion channels, GTP binding proteins, second messenger-generating enzymes, second messenger-metabolizing enzymes, second messengers protein kinases, protein phosphatases) and lists in Tables A-H drugs that act on signalling molecules and which should find clinical use.

Animals↗
PubMed1993

Decrease in coupling of Gs in v-src-transformed NIH-3T3 fibroblasts: possible involvement of tyrosine phosphorylation of Gs by pp60v-src.

In Rous sarcoma virus (RSV)-transformed NIH-3T3 fibroblasts expressing pp60v-src as tyrosine protein kinase, isoproterenol-stimulated cAMP accumulation was much lower than in normal cells. The reduction in v-src-transformed cells seemed to be mainly due to a decrease in the number of beta 2-adrenoceptors. When the membranes were phosphorylated with ATP, however, the binding affinity of isoproterenol to beta 2-adrenoceptors was reduced in transformed cell membranes by 34% compared to that in normal cell membranes. The reduction in transformed cell membranes was restored to the level of normal cell membranes by treatment of membranes with anti-pp60v-src antibody. GTP gamma S- and cholera toxin-stimulated adenylyl cyclase activities were reduced with no change in forskolin-stimulated adenylyl cyclase activity in transformed cell membranes. The reduced effect of GTP gamma S was also restored by treatment with anti-pp60v-src antibody or by adding staurosporine, which inhibits a variety of protein kinases, including tyrosine protein kinase. One of the 32P-phosphoproteins phosphorylated with [gamma-32P]ATP in v-src-transformed cell membranes was bound to GTP-agarose, and was a 46-kDa molecule on a sodium dodecyl sulfate-polyacrylamide gel. This 46-kDa 32P-labeled phosphoprotein was immunoprecipitated with anti-phosphotyrosine antibody or anti-stimulatory GTP-binding protein (anti-Gs) antibody. These results suggest that pp60v-src phosphorylates the alpha-subunit of Gs and consequently causes a decrease in the coupling of beta 2-receptors to Gs and in the coupling of Gs to adenylyl cyclase.

3T3 Cells↗
PubMed1991

Stimulation of DNA synthesis in Jurkat cells by synergistic action between adenine and guanine nucleotides.

P2-purinoceptor agonists stimulated the DNA synthesis of Jurkat cells via a pathway independent of cAMP and intracellular free calcium. The response was greatly enhanced by the synergistic action between adenine and guanine nucleotides, suggesting that binding sites of these nucleotides are different from each other, and the proliferation is stimulated by a novel interaction between adenine and guanine nucleotide receptors. The stimulatory effects of P2-agonists on proliferation was completely abolished by cholera toxin and attenuated by pertussis toxin, which suggests that substrates for cholera toxin and pertussis toxin are involved in the proliferative pathways associated with P2-purinoceptors.

Adenine Nucleotides↗
PubMed1991

Possible involvement of pertussis toxin-sensitive GTP-binding protein(s) in c-fos expression during differentiation of 3T3-L1 fibroblasts to adipocytes.

Following the differentiation of 3T3-L1 fibroblasts by insulin/dexamethasone/methylisobutylxanthine, marked increases in cAMP levels by isoproterenol but not forskolin and in 2-deoxyglucose uptake by insulin occurred. Pertussis toxin-pretreatment prior to addition of insulin/dexamethasone/methylisobutylxanthine and exposure of cells to pertussis toxin during differentiation attenuated glycerophosphate dehydrogenase activity as a differentiation marker enzyme and the responses to isoproterenol and insulin by approximately 50% of those in pertussis toxin-untreated cells. On the other hand, insulin/dexamethasone/methylisobutylxanthine caused induction of c-fos proto-oncogene in confluent 3T3-L1 fibroblasts. This induction was also reduced in pertussis toxin-pretreated cells. These results suggested that pertussis toxin-sensitive GTP-binding protein(s) is involved in expression of c-fos mRNA accompanied by differentiation. In addition, accumulation of c-fos mRNA by insulin/dexamethasone/methylisobutylxanthine was enhanced in protein kinase C-depleted cells pretreated with phorbol 12-myristate 13-acetate, indicating that protein kinase C may negatively regulate c-fos expression induced by insulin/dexamethasone/methylisobutylxanthine.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Insulin-stimulated glucose transport regulated by adenylate cyclase system in rat adipocytes.

1. In rat adipocytes, there was an inverse correlation between insulin-stimulated 2-deoxyglucose (2-DG) uptake and cAMP levels, indicating that cAMP suppressed the 2-DG uptake stimulated by insulin. 2. This inhibitory effect of cAMP was due to suppression of translocation of glucose transporters rather than that of insulin-binding to its receptors. 3. Phosphodiesterase inhibitors (IBMX, Ro 20-1724, and cilostamide) inhibited the 2-DG uptake, which was brought about by direct interaction with glucose transporters in the plasma membranes.

Adenosine↗