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T Fukai

Publications and source records attributed to T Fukai.

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

Modulation of extracellular superoxide dismutase expression by angiotensin II and hypertension.

Angiotensin II and hypertension increase vascular oxidant stress. We examined how these might affect expression of the extracellular superoxide dismutase (ecSOD), a major form of vascular SOD. In mice, angiotensin II infusion (1.1 mg/kg for 7 days) increased systolic blood pressure from 107+/-3 to 152+/-9 mm Hg and caused a 3-fold increase in ecSOD, but there was no change in the cytosolic Cu/Zn SOD protein, as determined by Western blot analysis. This was associated with a similar increase in ecSOD mRNA as assessed by RNase protection assay and was prevented by losartan. Induction of ecSOD by angiotensin II was not due to hypertension alone, because hypertension caused by norepinephrine (5.6 mg. kg-1. d-1) had no effect on ecSOD. Similarly, exposure of mouse aortas to angiotensin II (100 nmol/L) in organoid culture increased ecSOD by approximately 2-fold. In the organoid culture, angiotensin II-induced upregulation of ecSOD was prevented by losartan (10 micromol/L) and PD985059 (30 micromol/L), a specific inhibitor of p42/44 MAP kinase kinase. Angiotensin II activates the NADH/NADPH oxidase; however, diphenyleneiodonium chloride (10 micromol/L), an inhibitor of this oxidase, did not prevent p42/44 MAP kinase phosphorylation or ecSOD induction by angiotensin II. Finally, in human aortic smooth muscle cells, angiotensin II moderately increased transcriptional rate (as assessed by nuclear run-on analysis) but markedly increased ecSOD mRNA stability. Thus, angiotensin II increases ecSOD expression independent of hypertension, and this increase involves both an increase in ecSOD transcription and stabilization of ecSOD mRNA. This effect of angiotensin II on ecSOD expression may modulate the oxidative state of the vessel wall in pathological processes in which the renin-angiotensin system is activated.

Angiotensin II↗
PubMed1999

The role of costimulatory molecules B7-1 and B7-2 in mice with experimental autoimmune uveoretinitis.

BACKGROUND: Onset of experimental autoimmune uveoretinitis (EAU) is believed to involve a CD4-positive type 1 T helper cell (Th1) immune response, with inhibition involving a Th2 immune response. Development of Th1 and Th2 responses involves the participation of the costimulatory molecules B7-1 and B7-2, respectively. The purpose of this study was to investigate the role of B7-1 and B7-2 in the EAU model in mice. METHODS: B10.A mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) and given daily intraperitoneal injections of either phosphate-buffered saline (control), mouse monoclonal antibody (mAb) to B7-1, mAb to B7-2, or mAb to both B7-1 and B7-2. Eyes were evaluated by histopathological criteria and cytokines were assayed in culture medium of IRBP-stimulated lymphocytes. Cellular immune responses were measured by cell proliferation assay under IRBP stimulation. RESULTS: Rates of EAU onset were 5/10 (50%) for control mice, 1/9 (11%) for mice treated with anti-B7-1 mAb, 5/6 (83%) for mice treated with anti-B7-2 mAb, and 2/6 (33%) for mice treated with both anti-B7-1 and anti-B7-2 mAb. Mean histopathological severity scores were 2. 4+/-0.8, 1.0+/-0, 2.6+/-1.0, and 1.0+/-0, respectively. Production of IL-5 was significantly increased in mice treated with anti-B7-1 mAb, while IFN-gamma was increased in mice treated with anti-B7-2 mAb. Spleen cell proliferation was significantly reduced in mice treated with anti-B7-1 mAb. CONCLUSIONS: These results suggest that the costimulatory molecules B7-1 and B7-2, via their influence on generating Th1 and Th2 immune responses, play an important role in the clinical outcome of EAU in mice immunized with IRBP.

Animals↗
PubMed1999

A subthreshold MOS circuit for the Lotka-Volterra neural network producing the winners-share-all solution.

An analog MOS circuit is proposed for implementing a Lotka-Volterra (LV) competitive neural network which produces winners-share-all solutions. The solutions give multiple winners receiving large inputs and are particularly useful for selecting a set of inputs through "decision by majority". We show that the LV network can easily be implemented using subthreshold MOS transistors. Results of extensive circuit simulations prove that the proposed circuit does exhibit a reliable selection compared with winner-take-all circuits, in the possible presence of device mismatches. These results pave a way to future implementation on a real device.

Journal Article↗
PubMed1999

Sequence generation in arbitrary temporal patterns from theta-nested gamma oscillations: a model of the basal ganglia-thalamo-cortical loops.

A computational model that is able to generate sequences at arbitrary rates in a given serial order is presented for the cortico-basal ganglia (BG)-thalamic neural circuitry. Upon generating a sequence, this model stores information on the serial order of components in a cortical buffer by means of theta-nested gamma frequency oscillations observed experimentally in cortico-striatal neurons. This model assumes the existence of at least two functionally different classes of striatal spiny neurons. One class of striatal projection neurons (S-cells) select the first component in the cortical buffer through a temporal winner-take-all mechanism implemented by lateral inhibition. The inhibition should last for at least a few hundred milliseconds. In reality, it may be mediated by GABA(B) receptors at the presynaptic terminals of the cortico-striatal projection. The other class of striatal projection neurons (M-cells) retain the currently executed component in a cortico-BG-thalamic loop, for which the strong nonlinearity in transitions between up and down states of striatal neurons is crucial. For sequence generation at the level of striatum, the cortical neurons encoding the component selected for execution are inactivated by the feedback from the activated cortico-BG-thalamic loop. This model predicts that the transition to next component is triggered by a single external signal, i.e. the subthalamic input to the globus pallidum. This input gives a neural substrate for adjusting the rate of sequence generation.

Journal Article↗
PubMed1998

Vascular expression of extracellular superoxide dismutase in atherosclerosis.

We characterized a novel form of extracellular superoxide dismutase (ecSOD) in atherosclerotic vessels. Specific activity and protein expression of ecSOD was increased two- to threefold in apo E-deficient compared with control aortas. RNase protection assays demonstrated that the expected ecSOD transcript was not increased in either apo E-deficient mice or cholesterol-fed LDL receptor-deficient mice, but that a second, lower molecular weight transcript was present and became predominant as atherosclerosis progressed. Sequence analysis revealed that this novel ecSOD has a 10-bp deletion in the 3' untranslated region and an asparagine to aspartic acid mutation at amino acid 21. Studies of isolated macrophages and immunohistochemistry suggested that the truncated ecSOD transcript was expressed by lipid-laden but not control macrophages. Recombinant wild-type and novel ecSODs expressed in Sf9 cells exhibited similar SOD activities. These experiments show that ecSOD expression is increased in atherosclerotic vessels and that this is characterized by an alteration in mRNA and protein structure. Further, the source of this altered ecSOD is likely the lipid-laden macrophage. The enzymatic properties of this novel ecSOD may have important implications for the function of the lipid-laden macrophage and the atherosclerotic process.

Animals↗
PubMed1998

Effect of type I interferon on experimental autoimmune uveoretinitis in rats.

In order to establish a scientific basis for the potential use of type I interferons (IFNs) in clinical uveitis, we examined the effect of a preparation of IFN-alpha/beta on experimental autoimmune uveoretinitis (EAU). Lewis rats were immunized with bovine interphotoreceptor retinoid-binding protein (IRBP) and given daily intramuscular injections of 10(5) IU mouse natural IFN-alpha/beta. Intraocular inflammation was assessed by slit-lamp biomicroscopy and histopathological examination. Rats treated daily with IFN-alpha/beta starting on the day of IRBP immunization showed decreased intraocular inflammation as well as a slight delay in onset of inflammation when compared to control rats. This effect was also observed to a lesser extent in rats treated during either the induction phase of EAU only, or starting immediately after the onset of inflammation in the effector phase of EAU. Measurement of IRBP-stimulated splenocyte proliferation and serum anti-IRBP antibody subtypes did not reveal a significant difference between IFN-alpha/beta-treated rats and control rats. Measurement of cytokine production by IRBP-stimulated splenocytes in vitro showed significantly decreased TNF-alpha for IFN-alpha/beta-treated rats compared to control, but no difference for IFN-gamma, IL-2, IL-4, and IL-10. These results indicate that systemic administration of IFN-alpha/beta suppresses IRBP-induced EAU in rats, and suggest that such suppression may be mediated in part by a reduction in TNF-alpha production.

Animals↗
PubMed1998

Probucol improves endothelial-dependent relaxation and decreases vascular superoxide production in cholesterol-fed rabbits.

Recent data indicate that hypercholesterolemia increases endothelial superoxide anion (.O2-) production, and that this diminishes the bioactivity of nitric oxide produced in the endothelium. Probucol, a drug commonly employed for treatment of hypercholesterolemia, has antioxidant properties and inhibits oxidation of low density lipoproteins in vitro. We tested the hypothesis that probucol would decrease vascular .O2- production and improve endothelium-dependent relaxations in cholesterol-fed rabbits. Rabbits were divided into four groups: 1) a control group fed a standard diet; 2) a probucol group fed a standard diet containing 0.3% probucol; 3) a hypercholesterolemic group fed a diet containing 0.5% cholesterol; 4) a hypercholesterolemia-probucol group fed a diet containing 0.5% cholesterol and 0.3% probucol. The cholesterol-rich diet markedly increased plasma total cholesterol level and lipid peroxidation in the plasma, as reflected by thiobarbituric acid-reactive substances (TBARS). This concentration of probucol did not lower plasma cholesterol, but markedly reduced TBARS in the plasma of cholesterol-fed rabbits. Aortic segments from cholesterol-fed rabbits produced 1.8-fold more .O2- (assessed by lucigenin-enhanced chemiluminescence) and decreased endothelium-dependent vascular relaxations to acetylcholine compared to vessels from normal rabbits. In cholesterol-fed rabbits, probucol treatment normalized both .O2- production and endothelium-dependent relaxations to acetylcholine. In control rabbits, probucol had no effect on either of these parameters. We conclude that probucol treatment may prevent .O2(-)-induced inactivation of endothelium-derived nitric oxide and reduce vascular oxidant stress via reducing the level of .O2-.

Animals↗
PubMed1997

Senescence-related change in autologous mixed-lymphocyte reaction in senescence-accelerated mice.

Using the senescence-accelerated mouse (SAM) strains, we examined the senescence-related changes of autologous mixed-lymphocyte reaction (AMLR) as well as the phenotypic alteration of the T cell subsets. Splenic T cells from senescence-prone (SAM-P) and resistant (SAM-R) strains of mice were incubated with autologous non-T cells, and AMLR was measured on day 1-5. The kinetics of AMLR responses revealed a marked alteration in senescent SAM-P but not in non-senescent SAM-R mice, in which the peak response occurred at day 1, the response decreasing thereafter up to day 5. Similar senescence-related change was observed in aged (24-month-old) SAM-R and BALB/c mice. Furthermore, the T cells from the aged SAM-R mice cultured with non-senescent syngeneic non-T cells showed a very similar pattern to that cultured with autologous non-T cells. Flow cytometric analysis of T cell phenotype indicated that the percentage of CD4+ CD45RBhi T cells correlated with the peak AMLR responses in both SAM-P and SAM-R mice, and that the percentage of the T cell subset with extrathymic properties was significantly higher in SAM-P mice. These findings suggest that the alteration in kinetics of AMLR is related to senescence but not to the strain of mice, and may reflect a senescence-related dysfunction of the autoregulatory immune mechanisms of T cells.

Aging↗
PubMed1997

A simple neural network exhibiting selective activation of neuronal ensembles: from winner-take-all to winners-share-all.

A neuroecological equation of the Lotka-Volterra type for mean firing rate is derived from the conventional membrane dynamics of a neural network with lateral inhibition and self-inhibition. Neural selection mechanisms employed by the competitive neural network receiving external inputs are studied with analytic and numerical calculations. A remarkable findings is that the strength of lateral inhibition relative to that of self-inhibition is crucial for determining the steady states of the network among three qualitatively different types of behavior. Equal strength of both types of inhibitory connections leads the network to the well-known winner-take-all behavior. If, however, the lateral inhibition is weaker than the self-inhibition, a certain number of neurons are activated in the steady states or the number of winners is in general more than one (the winners-share-all behavior). On the other hand, if the self-inhibition is weaker than the lateral one, only one neuron is activated, but the winner is not necessarily the neuron receiving the largest input. It is suggested that our simple network model provides a mathematical basis for understanding neural selection mechanisms.

Algorithms↗
PubMed1997

[Inhibition of experimental autoimmune uveoretinitis by transforming growth factor-beta 1 in B10. A mice].

Experimental autoimmune uveoretinitis (EAU) in mice, an organ specific autoimmune disease, has been investigated as an animal model for human endogenous uveitis. In this study, we report on the immunosuppressive effect of transforming growth factor-beta 1 (TGF-beta 1) on the development of EAU in mice. Inhibition by TGF-beta 1 of proliferation of interphotoreceptor retinoid-binding protein (IRBP)-specific T cell lines in B10.A mice against IRBP antigen was dose-dependent. However, when spleen cells used as the antigen presenting cell were first cultured with TGF-beta 1, this anti-proliferation effect was abolished. When IRBP-immunized mice were injected intraperitoneally with TGF-beta 1, dose-dependent suppression of EAU was obtained. The proliferation response of lymph node cells from TGF-beta 1 injected mice with IRBP-induced EAU was suppressed compared with phosphate buffered saline (PBS)-injected mice. These findings suggest that TGF-beta 1 may be a cytokine that plays a role in suppressing IRBP induced EAU in mice.

Animals↗
PubMed1996

Bulbocortical interplay in olfactory information processing via synchronous oscillations.

Emergence of synchronous oscillatory activity is an inherent feature of the olfactory systems of insects, mollusks and mammals. A class of simple computational models of the mammalian olfactory system consisting of olfactory bulb and olfactory cortex is constructed to explore possible roles of the related neural circuitry in olfactory information processing via synchronous oscillations. In the models, the bulbar neural circuitry is represented by a chain of oscillators and that of cortex is analogous to an associative memory network with horizontal synaptic connections. The models incorporate the backprojection from cortical units to the bulbar oscillators in particular ways. They exhibit rapid and robust synchronous oscillations in the presence of odorant stimuli, while they show either nonoscillatory states or propagating waves in the absence of stimuli, depending on the values of model parameters. In both models, the backprojection is shown to enhance the establishment of large-scale synchrony. The results suggest that the modulation of neural activity through centrifugal inputs may play an important role at the early stage of cortical information processing.

Animals↗
PubMed1996

Competition in the temporal domain among neural activities phase-locked to subthreshold oscillations.

In the presence of a subthreshold membrane oscillation, analog information may be encoded in the timing of spike generation phase-locked to the oscillation. With this spike timing neural code, a competitive network of inhibitory spiking neurons was shown to achieve a novel timing mechanism of neural activity selection: the neurons had higher probabilities of becoming winners if they were stimulated earlier in each oscillatory cycle. Here the timing mechanism and its robustness are studied both numerically and analytically, and the conditions to yield a given number of winners (the inhibitory neurons that remain active after the competition) are investigated. The analysis revealed that activity selection with a small number of winners is ensured for broad ranges of values of the parameters such as the strength and time constant of inhibition. In particular, the number of winners is almost unchanged for various timing differences between stimuli to different neurons. This implies that the timing mechanism is useful for such biological information processing as required perception of a relatively small number of significant stimulus components.

Action Potentials↗
PubMed1996

Shear stress modulates expression of Cu/Zn superoxide dismutase in human aortic endothelial cells.

A major determinant of the level of cellular superoxide anion (O2-.) is the dismutation of O2-. to hydrogen peroxide by the enzyme superoxide dismutase (SOD). Three forms of SOD exist, but in endothelial cells, the major form outside of the mitochondria is the cytosolic copper/zinc-containing superoxide dismutase (Cu/Zn SOD). Since fluid shear stress is an important determinant of the function and structure of endothelial cells in vivo, we examined the effect of laminar shear stress on the expression of Cu/Zn SOD in cultured human aortic endothelial cells. Laminar shear stress of 0.6 to 15 dyne/cm2 increased Cu/Zn SOD mRNA in a time- and dose-dependent manner in human aortic endothelial cells. Shear stress also increased both Cu/Zn SOD protein content and the enzyme activity. Nuclear runon assays showed that nuclei from human aortic endothelial cells exposed to laminar shear stress had a 1.6-fold greater transcriptional activity of the Cu/Zn SOD gene compared with cells not exposed to shear, indicating that an increase in Cu/Zn SOD mRNA induced by laminar shear stress is at least in part mediated by increased transcription. In contrast, shear stress had no effect on Cu/Zn SOD mRNA levels in human aortic smooth muscle cells. These findings show that physiological levels of shear stress increase expression of Cu/Zn SOD in the endothelium. This adaptation to shear stress might augment the effect of locally produced NO. and thereby promote the antiatherogenic and anti-inflammatory properties of the endothelial cell.

Aorta↗
PubMed1996

Modulation of endothelial cell nitric oxide synthase expression.

The 5' promoter region of endothelial cell nitric oxide synthase (ecNOS) gene has several features which are compatible with a constitutively expressed, so called "housekeeping" gene. These include absence of a TATA box and the presence of Sp1 binding sites situated near the transcription start site. The promoter also contains sequences which suggest that it may be regulated by a variety of transcription factor-mediated signals. Studies of cultured endothelial cells show that ecNOS expression is modulated by shear stress, transforming growth factor beta, inhibition of protein kinase C, and the state of proliferation. These experiments indicate that although the ecNOS is a "constitutively expressed" gene, its content in the endothelium is subject to modest degrees of regulation which may have important physiological and pathophysiological implications.

Animals↗
PubMed1995

Oscillations for rapid selection of neural activities based on spike timing.

In cortical information processing, neuronal inputs are transformed into sequences of action potentials. However, the neural codes used for embedding information in the spike trains remain unclear. Here a neural network consisting of recurrent inhibitory connections is shown to achieve selective activation and inactivation of neurones very efficiently according to spike timing rather than firing rates, when they are stimulated by periodic spike trains. Oscillatory neural activities serve as an accurate clock for the spike-timing code utilized in the rapid selection of neural activities. These results suggest that differences in spike timing of < 1 ms can be of functional significance in certain neural information processing.

Action Potentials↗
PubMed1995

Non-peptide bombesin receptor antagonists, kuwanon G and H, isolated from mulberry.

Kuwanon G and H, isolated from the methanol extract of Morus bombycis, inhibited specific binding of [125I]gastrin-releasing peptide (GRP) to GRP-preferring receptors in murine Swiss 3T3 fibroblasts with Ki values of 470 and 290 nM, respectively. Kuwanon H was one order of magnitude less potent for inhibiting [125I]bombesin binding to neuromedin B (NMB)-preferring receptors in rat esophagus membranes. This compound antagonized bombesin-induced increases in the cytosolic free calcium concentration and GRP-induced DNA synthesis in Swiss 3T3 cells. Thus, kuwanon H, and possibly kuwanon G also, are specific antagonists for the GRP-preferring receptor and can be useful for studying the physiological and pathological role of GRP.

3T3 Cells↗