Biomedical subjects

Hajime Ishihara

Publications and source records attributed to Hajime Ishihara.

12 recordsLinked to original sources

PubMed2006

Force control between quantum dots by light in polaritonic molecule states.

Photomediated force between quantum dots (QDs) is theoretically studied. An attractive (repulsive) interparticle radiation force (IRF) arises by selectively exciting the lower (higher) split state of coupled polaritons in QDs. Since these states are analogous to bonding and antibonding states of a diatomic molecule, we term this system the "polaritonic molecule (PM)". IRF in PM states is controlled by the photon energy, polarization, and phase at each QD. This mechanism can be used to probe internal quantum properties of nano-objects and to manipulate collective dynamics of QDs.

Journal Article↗

PubMed2005

Impact of SRC homology 2-containing inositol 5'-phosphatase 2 gene polymorphisms detected in a Japanese population on insulin signaling.

Src homology 2-containing 5'-inositol phosphatase 2 (SHIP2) is known to be one of lipid phosphatases converting PI(3,4,5)P3 to PI(3,4)P2 in the negative regulation of insulin signaling with the fundamental impact on the state of insulin resistance. To clarify the possible involvement of SHIP2 in the pathogenesis of human type 2 diabetes, we examined the relation of human SHIP2 gene polymorphisms to type 2 diabetes in a Japanese population. We identified 10 polymorphisms including four missense mutations. Among them, single nucleotide polymorphism (SNP)3 (L632I) was located in the 5'-phosphatase catalytic region, and SNP5 (N982S) was adjacent to the phosphotyrosine binding domain binding consensus motif in the C terminus. SNP3 was found more frequently in control subjects than in type 2 diabetic patients, suggesting that this mutation might protect from insulin resistance. Transfection study showed that expression of SNP3-SHIP2 inhibited insulin-induced PI(3,4,5)P3 production and Akt2 phosphorylation less potently than expression of wild-type SHIP2 in CHO-IR cells. Insulin-induced tyrosine phosphorylation of SNP5-SHIP2 was decreased compared with that of wild-type SHIP2, resulting in increased Shc/Grb2 association and MAPK activation. These results indicate that the polymorphisms of SHIP2 are implicated, at least in part, in type 2 diabetes, possibly by affecting the metabolic and/or mitogenic insulin signaling in the Japanese population.

Aged↗

PubMed2005

Impact of the liver-specific expression of SHIP2 (SH2-containing inositol 5'-phosphatase 2) on insulin signaling and glucose metabolism in mice.

We investigated the role of hepatic SH2-containing inositol 5'-phosphatase 2 (SHIP2) in glucose metabolism in mice. Adenoviral vectors encoding wild-type SHIP2 (WT-SHIP2) and a dominant-negative SHIP2 (DeltaIP-SHIP2) were injected via the tail vein into db/+m and db/db mice, respectively. Four days later, amounts of hepatic SHIP2 protein were increased by fivefold. Insulin-induced phosphorylation of Akt in liver was impaired in WT-SHIP2-expressing db/+m mice, whereas the reduced phosphorylation was restored in DeltaIP-SHIP2-expressing db/db mice. The abundance of mRNA for glucose-6-phosphatase (G6Pase) and PEPCK was increased, that for glucokinase (GK) was unchanged, and that for sterol regulatory element-binding protein 1 (SREBP)-1 was decreased in hepatic WT-SHIP2-overexpressing db/+m mice. The increased expression of mRNA for G6Pase and PEPCK was partly suppressed, that for GK was further enhanced, and that for SREBP1 was unaltered by the expression of DeltaIP-SHIP2 in db/db mice. The hepatic expression did not affect insulin signaling in skeletal muscle and fat tissue in both mice. After oral glucose intake, blood glucose levels and plasma insulin concentrations were elevated in WT-SHIP2-expressing db/+m mice, while elevated values were decreased by the expression of DeltaIP-SHIP2 in db/db mice. These results indicate that hepatic SHIP2 has an impact in vivo on the glucose metabolism in both physiological and diabetic states possibly by regulating hepatic gene expression.

Animals↗

PubMed2004

Evaluation of two-photon nonlinearity by a semiclassical method.

In order to discuss the two-photon nonlinearity theoretically, both photons and nonlinear materials should be treated quantum mechanically, which usually is a heavy theoretical task. Contrarily, nonlinear optics for classical light has been developed well and a detailed analysis is possible for realistic complex nonlinear systems. Here we show that the two-photon nonlinearity can be evaluated from the linear and third-order nonlinear output fields against a classical input pulse, which contains 2(-1/2) photons on average.

Journal Article↗

PubMed2004

Impact of Src homology 2-containing inositol 5'-phosphatase 2 on the regulation of insulin signaling leading to protein synthesis in 3T3-L1 adipocytes cultured with excess amino acids.

Src homology 2-containing inositol 5'-phosphatase 2 (SHIP2) possesses 5'-phosphatase activity to specifically hydrolyze the phosphatidylinositol 3-kinase product PI(3,4,5)P3 in the regulation of insulin signaling. In the present study, we examined the impact of SHIP2 on the regulation of insulin signaling leading to protein synthesis in 3T3-L1 adipocytes cultured with standard and excess concentrations of amino acids. Insulin-induced translocation of PDK1 to the plasma membrane, phosphorylation of Akt and p70S6-kinase and ribosomal protein S6, increase in the amount of 4E-BP1 gamma-form, association of eIF4E with eIF4G, and protein synthesis were decreased by overexpression of wild-type SHIP2 by adenovirus-mediated gene transfer. The effect of SHIP2 overexpression on the regulation of insulin-induced phosphorylation of Akt and p70S6-kinase was somewhat augmented by the incubation with 5-fold excess concentrations of amino acids for 30 min. In contrast, the impact of SHIP2 expression was diminished in insulin-induced phosphorylation of p70S6-kinase and S6, but not of Akt, after the incubation for 16 h. Interestingly, incubation with the excess concentrations of amino acids for 30 min induced activation of phosphatidylinositol 3-kinase and phosphorylation of Akt, whereas phosphorylation of p70S6-kinase and S6 was decreased. Furthermore, although the exposure for longer time periods up to 24 h did not elicit phosphorylation of Akt, it markedly induced phosphorylation of p70S6-kinase and S6. These results indicate that SHIP2 plays an important role in the negative regulation of insulin signaling for the protein synthesis and that the impact of SHIP2 is altered, dependent on the acute or chronic exposure of excess concentrations of amino acids in culture.

3T3-L1 Cells↗

PubMed2004

SH2-containing inositol phosphatase 2 predominantly regulates Akt2, and not Akt1, phosphorylation at the plasma membrane in response to insulin in 3T3-L1 adipocytes.

SH2-containing inositol phosphatase 2 (SHIP2) is a physiologically important negative regulator of insulin signaling by hydrolyzing the phosphatidylinositol (PI) 3-kinase product PI 3,4,5-trisphosphate in the target tissues of insulin. Targeted disruption of the SHIP2 gene in mice resulted in increased insulin sensitivity without affecting biological systems other than insulin signaling. Therefore, we investigated the molecular mechanisms by which SHIP2 specifically regulates insulin-induced metabolic signaling in 3T3-L1 adipocytes. Insulin-induced phosphorylation of Akt, one of the molecules downstream of PI3-kinase, was inhibited by expression of wild-type SHIP2, whereas it was increased by expression of 5'-phosphatase-defective (DeltaIP) SHIP2 in whole cell lysates. The regulatory effect of SHIP2 was mainly seen in the plasma membrane (PM) and low density microsomes but not in the cytosol. In this regard, following insulin stimulation, a proportion of Akt2, and not Akt1, appeared to redistribute from the cytosol to the PM. Thus, insulin-induced phosphorylation of Akt2 at the PM was predominantly regulated by SHIP2, whereas the phosphorylation of Akt1 was only minimally affected. Interestingly, insulin also elicited a subcellular redistribution of both wild-type and DeltaIP-SHIP2 from the cytosol to the PM. The degree of this redistribution was inhibited in part by pretreatment with PI3-kinase inhibitor. Although the expression of a constitutively active form of PI3-kinase myr-p110 also elicited a subcellular redistribution of SHIP2 to the PM, expression of SHIP2 appeared to affect the myr-p110-induced phosphorylation, and not the translocation, of Akt2. Furthermore, insulin-induced phosphorylation of Akt was effectively regulated by SHIP2 in embryonic fibroblasts derived from knockout mice lacking either insulin receptor substrate-1 or insulin receptor substrate-2. These results indicate that insulin specifically stimulates the redistribution of SHIP2 from the cytosol to the PM independent of 5'-phosphatase activity, thereby regulating the insulin-induced translocation and phosphorylation of Akt2 at the PM.

3T3-L1 Cells↗

PubMed2003

Association of the polymorphisms in the 5'-untranslated region of PTEN gene with type 2 diabetes in a Japanese population.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is known to act as a lipid phosphatase hydrolyzing phosphatidylinositol (PI)(3,4,5)P(3) to PI(4,5)P(2). Since the PI3-kinase product, PI(3,4,5)P(3), is an important second messenger leading to the metabolic action of insulin, PTEN functions as a potent negative regulator of insulin signaling and its gene is one of the possible candidates involved in susceptibility to the development of type 2 (non-insulin-dependent) diabetes. In the present study, we investigated the polymorphisms of the PTEN gene in Japanese patients with type 2 diabetes and non-diabetic control subjects. We identified three mutations of the gene in the type 2 diabetes patients. Among these mutations, the frequency of the substitution of C with G at position -9 (-9C-->G) (SNP1), located in the untranslated region of exon 1, was significantly higher in type 2 diabetic patients than in control subjects. In addition, transfection of the PTEN gene with SNP1 resulted in a significantly higher expression level of PTEN protein compared with that of the wild-type PTEN gene in Cos1 and Rat1 cells. Furthermore, insulin-induced phosphorylation of Akt in HIRc cells was decreased more greatly by transfection of SNP1 PTEN gene than that of wild-type PTEN gene. These findings suggest that the change of C to G at position -9 of the PTEN gene is associated with the insulin resistance of type 2 diabetes due possibly to a potentiated hydrolysis of the PI3-kinase product.

5' Untranslated Regions↗

PubMed2003

Theoretical study of the optical manipulation of semiconductor nanoparticles under an excitonic resonance condition.

We theoretically study the mechanical interaction between radiation and a semiconductor nanoparticle, based on a microscopic model of confined excitons. The exerted force is calculated by using the Maxwell stress tensor expressed in terms of the microscopic response field. The numerical demonstrations clarify the following: (1) The enhancement of the force by using electronic resonance is remarkable for a particle with a radius of less than 100 nm for semiconductor materials. (2) The spectral peak position of the exerted force is considerably sensitive to nanoscale-size changes which would be useful for highly accurate size-selective manipulation.

Journal Article↗

PubMed2003

Dual role of SRC homology domain 2-containing inositol phosphatase 2 in the regulation of platelet-derived growth factor and insulin-like growth factor I signaling in rat vascular smooth muscle cells.

Src homology domain 2 (SH2)-containing inositol phosphatase 2 (SHIP2) possesses 5-phosphatase activity and an SH2 domain. The role of SHIP2 in platelet-derived growth factor (PDGF) and IGF-I signaling was studied by expressing wild-type (WT-) and a catalytically defective (Delta IP-) SHIP2 into rat aortic smooth muscle cells by adenovirus-mediated gene transfer. PDGF- and IGF-I-induced tyrosine phosphorylation of their respective receptors and phosphatidylinositol 3-kinase (PI3-kinase) activity were not affected by the expression of either WT- or Delta IP-SHIP2. SHIP2 possessed 5'-phosphatase activity to hydrolyze the PI3-kinase product phosphatidylinositol 3,4,5-trisphosphate in vivo. Akt and glycogen synthase kinase 3beta are known to be downstream molecules of PI3-kinase, leading to the antiapoptotic effect. Overexpression of WT-SHIP2 inhibited PDGF- and IGF-I-induced phosphorylation of these molecules and the protective effect of poly(ADP-ribose) polymerase degradation, whereas these phosphorylations and the protective effect were enhanced by the expression of Delta IP-SHIP2, which functions in a dominant negative fashion. Regarding the Ras-MAPK pathway, PDGF- and IGF-I-induced tyrosine phosphorylation of Shc was not affected by the expression of either WT- or Delta IP-SHIP2, whereas both expressed SHIP2 associated with Shc. Importantly, PDGF and IGF-I stimulation of Shc/Grb2 binding, MAPK activation, and 5-bromo-2'-deoxyuridine incorporation were all decreased in both WT- and Delta IP-SHIP2 expression. These results indicate that SHIP2 plays a negative regulatory role in PDGF and IGF-I signaling in vascular smooth muscle cells. As the bifunctional role, our results suggest that SHIP2 regulates PDGF- and IGF-I-mediated signaling downstream of PI3-kinase, leading to the antiapoptotic effect via 5-phosphatase activity, and that SHIP2 regulates the growth factor-induced Ras-MAPK pathway mainly via the SH2 domain.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Large four-wave mixing of spatially extended excitonic states in thin GaAs layers.

We study the size dependence of the nonlinear response of weakly confined excitons for the size region beyond the long wavelength approximation regime. The observed degenerate-four-wave mixing signal of GaAs thin layers exhibits an anomalous size dependence, where the signal is resonantly enhanced at a particular thickness region. The theoretical analysis elucidates that this enhancement is due to the size-resonant enhancement of the internal field with a spatial structure relevant to the nondipole-type excitonic state. These results establish the formerly proposed new type of size dependence of nonlinear response due to the nonlocality induced double resonance.

Journal Article↗

PubMed2002

Membrane localization of Src homology 2-containing inositol 5'-phosphatase 2 via Shc association is required for the negative regulation of insulin signaling in Rat1 fibroblasts overexpressing insulin receptors.

Lipid phosphatase SHIP2 [Src homology 2 (SH2)-containing inositol 5'-phosphatase 2] has been shown to be a physiologically critical negative regulator of insulin signaling. We investigated the molecular mechanism by which SHIP2 negatively regulates insulin-induced phosphorylation of Akt, a key downstream molecule of phosphatidylinositol 3-kinase important for the biological action of insulin. Overexpression of wild-type SHIP2 (WT-SHIP2) inhibited insulin-induced phosphorylation of Akt at both Thr(308) and Ser(473) in Rat1 fibroblasts expressing insulin receptors. The degree of inhibition was less in the cells expressing either a mutant SHIP2 with R47Q change (R/Q-SHIP2) in the SH2 domain, or a mutant SHIP2 with Y987F change (Y/F-SHIP2) in the C-terminal tyrosine phosphorylation site. However, on addition of a myristoylation signal, WT-SHIP2, R/Q-SHIP2, and Y/F-SHIP2 all efficiently inhibited insulin-induced Akt phosphorylation at both residues, whereas a 5'-phosphatase-defective mutant SHIP2 (deltaIP-SHIP2) with the myristoylation signal did not. Interestingly, the degree of inhibition of Akt phosphorylation by R/Q-SHIP2 and Y/F-SHIP2 is well correlated with the extent of their association with Shc. In addition, overexpression of WT-Shc increased the insulin-induced association of SHIP2 with Shc, whereas a decrease in the amount of Shc on expression of antisense Shc mRNA led to a reduction in the SHIP2-Shc association. Furthermore, the inhibitory effect on insulin-induced Akt phosphorylation by WT-SHIP2 was decreased in antisense-Shc cells. These results indicate that the membrane localization of SHIP2 with its 5'-phosphatase activity is required for negative regulation of insulin-induced Akt phosphorylation and that the localization is regulated, at least in part, by the association of SHIP2 with Shc in Rat1 fibroblasts.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Association of SH2-containing inositol phosphatase 2 with the insulin resistance of diabetic db/db mice.

SH-2-containing inositol 5'-phosphatase 2 (SHIP-2) is a physiologically important lipid phosphatase that functions to hydrolyze phosphatidylinositol (PI) 3-kinase product PI(3,4,5)P3 to PI(3,4)P2 in the negative regulation of insulin signaling. We investigated whether SHIP-2 is associated with the insulin resistance of diabetic db/db mice. The amount of SHIP-2 protein was elevated in quadriceps muscle and epididymal fat tissue, but not in the liver, of db/db mice relative to that in control db/+m mice. In accordance with the enhanced expression of SHIP-2, its localization at the membrane preparation was increased in the skeletal muscle and fat tissue of db/db mice. Insulin stimulation of PI 3-kinase activity was modestly decreased in skeletal muscle, fat tissue, and liver of db/db mice compared with that of db/+m mice. In addition to the modest decrease at the level of PI 3-kinase, the activity of Akt and protein kinase C (PKC)-zeta/lambda, which are downstream molecules of PI 3-kinase, was more severely reduced in the skeletal muscle and fat tissue, but not in liver of db/db mice. Treatment with the insulin-sensitizing agent rosiglitazone decreased the elevated expression of SHIP-2 in the skeletal muscle and fat tissue of db/db mice. Insulin-induced Akt activation and PKC-zeta/lambda phosphorylation were restored to the control level, although insulin-stimulated PI 3-kinase activation was minimally affected in the skeletal muscle and fat tissue of db/db mice. These results indicate that SHIP-2 is a novel molecule associated with insulin resistance in the skeletal muscle and fat tissue, and that insulin-induced activity of the downstream molecules of PI 3-kinase is decreased, at least in part, by the elevated expression of SHIP-2 in diabetic db/db mice.

Adipose Tissue↗