Biomedical subjects

Hideo Sekino

Publications and source records attributed to Hideo Sekino.

16 recordsLinked to original sources

PubMed2007

Polarizability and second hyperpolarizability evaluation of long molecules by the density functional theory with long-range correction.

Polarizabilities and second hyperpolarizabilities of polyacetylene and a hydrogen chain are evaluated by density functional theory (DFT) using a hybrid generalized gradient approximation functional with correct long-range electron-electron interactions. The well known catastrophic overestimate of the hyperpolarizabilities for molecular systems of enhanced length is corrected by the two-electron repulsion operator decomposition technique, integrating the distance-dependent nonlocal exchange effects for long-range interaction, while neither the asymptotically corrected exchange functional for long-range interaction nor ordinary hybrid methods seem to be capable of overcoming the serious drawback of the DFT in polarizability/hyperpolarizability evaluation.

Journal Article↗

PubMed2006

A crossover from metal to plasma in dense fluid hydrogen.

Thermodynamic properties in dense fluid hydrogen are studied by using a density-functional theory for electron-proton binary mixtures that is called quantal hypernetted-chain (QHNC) integral equation. A nonlocal approximation for the exchange-correlation potential in a finite-temperature Kohn-Sham equation is presented. Results obtained from the QHNC with the nonlocal approximation are compared with those obtained from the QHNC with a local density approximation. Temperature variation of thermodynamic quantities between 10(4) and 10(6) K are investigated along an isochor specified by a dimensionless density parameter of rs=0.5. These quantities obtained from the QHNCs show that a crossover from metal to plasma occurs around a temperature of T=1.78 x 10(5) K. Electrical resistivity Re of the dense fluid hydrogen evaluated from a Ziman formula [The Properties of Liquid Metals, edited by S. Takenohi (Wiley, New York, 1973)] extended to finite temperature is about 0.7 muOmega cm at T=10(4) K. The dense fluid hydrogen at the temperature can be considered as a metallic fluid, because the value is smaller than typical values of Re in alkali metals at room temperature. The Re slightly increases with the temperature increase, and the temperature valuation of Re is monotonic. We clearly show that the contribution from the electronic excited states plays an important role for the sharp crossover from the metal to the plasma, and that the crossover is interpreted as a crossover from degenerate electron gas to nondegenerate electron gas.

Journal Article↗

PubMed2006

An interaction site model integral equation study of molecular fluids explicitly considering the molecular orientation.

We implemented an interaction site model integral equation for rigid molecules based on a density-functional theory where the molecular orientation is explicitly considered. In this implementation of the integral equation, multiple integral of the degree of freedom of the molecular orientation is performed using efficient quadrature methods, so that the site-site pair correlation functions are evaluated exactly in the limit of low density. We apply this method to Cl(2), HCl, and H(2)O molecular fluids that have been investigated by several integral equation studies using various models. The site-site pair correlation functions obtained from the integral equation are in good agreement with the one from a simulation of these molecules. Rotational invariant coefficients, which characterize the microscopic structure of molecular fluids, are determined from the integral equation and the simulation in order to investigate the accuracy of the integral equation.

Journal Article↗

PubMed2006

Enhanced spontaneous metastasis in bikunin-deficient mice.

Previously, we showed that bikunin, a Kunitz-type protease inhibitor, inhibits invasion and metastasis in several types of cancer cells possibly through suppression of upregulation of urokinase-type plasminogen activator (uPA) expression. Bikunin corresponds to a light chain of the inter-alpha inhibitor. To explore critical role of endogenous bikunin, we used bikunin knockout (Bik-/-) mice. Here, we show that 1) higher frequency of spontaneous 3LL lung metastasis was observed in Bik-/- mice compared to Bik+/+ mice, suggesting that bikunin deficiency increases the sensitivity of mice to lung metastasis; 2) administration of exogenous bikunin caused a significant reduction of lung metastasis in Bik-/- and Bik+/+ mice; 3) primary and metastatic tumors significantly upregulated uPA and PAI-1 expression in Bik-/- mice relative to Bik+/+ mice at least through phosphorylation of ERK1/2 and 4) exogenous bikunin suppressed phosphorylation of ERK1/2 and upregulation of uPA and PAI-1 expression in 3LL cells in response to G-CSF. These data allow us to conclude that the increased sensitivity of Bik-/- mice to lung metastasis in vivo is due to a lack of circulating proteins of the inter-alpha inhibitor family, especially bikunin.

Animals↗

PubMed2005

Entropy- or enthalpy-driven collapse of strongly charged polymer chains in a one-component charged fluid of counterions or coions.

We applied a simulation method [T. Sumi and H. Sekino, J. Chem. Phys. 122, 194910 (2005)] to an infinitely dilute polyelectrolyte immersed in one-component charged fluids in order to investigate salt effects on its collapse. In this model system, the degree of freedom of the counterion (or the coion) is considered using a density-functional theory for polymer-solvent admixtures, while the oppositely charged ions are treated as a structureless background having the opposite charge. Results obtained by these simulations show that not only the counterion but also the coion makes the polymer chain collapsed. The effects by the coion are stronger than that by the counterion. Temperature variation of the gyration radius of the polymer chain immersed in the counterion is opposite to that in the coion: while the radius of gyration decreases as the temperature decreases in the case of the counterion, it decreases as the temperature increases in the case of the coion. From these results we conclude that the former is interpreted as an enthalpy-driven collapse caused by the screening effects of the counterion, whereas the latter is interpreted as an entropy-driven one due to the translational entropy of the coion.

Journal Article↗

PubMed2005

Nonlinear optical property calculations by the long-range-corrected coupled-perturbed Kohn-Sham method.

The long-range correction (LC) scheme for the exchange functional of density-functional theory (DFT) was combined with the coupled-perturbed Kohn-Sham (CPKS) method to calculate nonlinear optical response properties. By using this LC-CPKS method, we calculated the hyperpolarizabilities of typical molecules and the dipole moments, polarizabilities, and hyperpolarizabilities of push-pull pi-conjugated systems: p-nitroaniline, 4-amino-4'-nitrostilbene, and alpha,omega-nitroaminopolyenes. It was found that the LC scheme clearly improved the calculation of these optical properties for all of these systems, which have been significantly overestimated by conventional DFTs. We therefore concluded that the long-range exchange interaction played an important role in calculating the optical properties using the DFT formalism.

Journal Article↗

PubMed2005

Bikunin down-regulates heterodimerization between CD44 and growth factor receptors and subsequently suppresses agonist-mediated signaling.

We provided evidence previously that bikunin, a Kunitz-type protease inhibitor, can disrupt dimerization of CD44 proteins, which may result in suppression of receptor-mediated MAP kinase signaling. However, to what extent dimerization may alter ligand-induced signaling has not been documented. Given the recent recognition that some growth factor receptors can form heterodimers with CD44, the present study was undertaken to determine whether the CD44 and growth factor receptors (e.g., EGFR, FGFR, HGFR, VEGFR, TGF-betaRI, or TGF-betaRII) can form heterodimers in cancer cells and, if so, to investigate the potential functional consequences of such heterodimerization. We also examined whether bikunin can abrogate these heterodimerizations and inhibit CD44/growth factor-dependent signaling. Here, we show direct evidence for heterodimerization of CD44-FGFR and CD44-TGF-betaRI in human chondrosarcoma HCS-2/8 cells, CD44-EGFR complex in human glioma U87MG cells, and CD44-TGF-betaRI heterodimer in human ovarian cancer HRA cells. Coupling of CD44 and growth factor receptor may be selective, depending on a cell type. Bikunin does not alter the ligand binding, whereas functionally reduces heterodimerization between CD44 and growth factor receptors. The disruption of heterodimerization substantially reduces receptor-induced tyrosine phosphorylation and ERK1/2 activation. Taken together, our data suggest that bikunin-mediated suppression of heterodimerization between CD44 and growth factors may inhibit the agonist-promoted activation of the signaling pathway.

Cell Line, Tumor↗

PubMed2005

Plasma bikunin as a favorable prognostic factor in ovarian cancer.

PURPOSE: Bikunin is a multifunctional glycoprotein, which mediates suppression of tumor cell invasion and metastasis. The measurement of bikunin levels in the tissue of patients with malignant diseases has been introduced as a new and simple diagnostic tool for the evaluation of prognosis. The high bikunin expression in ovarian cancer tissue would enable the use of soluble bikunin protein present in the circulation of ovarian cancer patients as a biomarker of disease. PATIENTS AND METHODS: We developed a double-antibody immunoassay for bikunin and detected its presence in normal human circulation. We quantified, by enzyme-linked immunosorbent assay and/or immunoblot assay bikunin in sera from 200 healthy women (controls), 200 patients with benign gynecologic diseases, and 327 patients with ovarian cancer before surgical removal of the tumor. RESULTS: When the values of bikunin corresponding to the median were used as the cutoff value (11.5 microg/mL), low plasma bikunin was strongly associated with late-stage, suboptimal debulking with large residual tumor (> 2 cm) and low response to chemotherapy. The median survival time of the patients with a high bikunin level was more than 60 months as compared with 26 months among those with low bikunin level (P = .002). This difference corresponded to a 2.2-fold increased risk of dying for the lower plasma bikunin patients (hazard ratio, 0.45; P = .023) and remained significant in multivariate analysis (hazard ratio, 0.63; P = .041). CONCLUSION: Preoperative plasma bikunin concentration is a strong and independent favorable prognostic marker for ovarian cancer.

Biomarkers, Tumor↗

PubMed2005

Bikunin suppresses lipopolysaccharide-induced lethality through down-regulation of tumor necrosis factor- alpha and interleukin-1 beta in macrophages.

BACKGROUND: Lipopolysaccharide (LPS) is the primary mediator of gram-negative sepsis; it induces the production of macrophage-derived cytokines. It has been shown that bikunin, a Kunitz-type protease inhibitor, inhibits LPS-induced cytokine expression. METHODS: To explore the role of bikunin, bikunin knockout (Bik(-/-)) mice were used for in vitro cytokine experiments and in vivo animal models. RESULTS: We show that a higher level of LPS-mediated death was induced in Bik(-/-), compared with wild-type (wt), mice; the administration of bikunin caused a significant reduction in LPS-induced lethality; LPS significantly increased tumor necrosis factor (TNF)- alpha and interleukin-1 beta levels in Bik(-/-), relative to wt, mice after LPS challenge; concomitant administration of bikunin inhibited the LPS-induced plasma levels of these cytokines; bikunin suppressed the LPS-induced up-regulation of cytokine expression through the suppression of the phosphorylation of ERK1/2, JNK, and p38 in macrophages; and LPS-induced up-regulation of TNF- alpha expression was not enhanced in Bik(-/-) macrophages without endogenous bikunin. CONCLUSIONS: These data allow us to speculate that the increased sensitivity of Bik(-/-) mice to LPS-induced death in vivo is due to a lack of circulating bikunin in plasma. Bikunin may play a role as a potent anti-inflammatory agent.

Animals↗

PubMed2005

Thalidomide inhibits tumor necrosis factor-alpha-induced interleukin-8 expression in endometriotic stromal cells, possibly through suppression of nuclear factor-kappaB activation.

OBJECTIVE: Endometriosis, a common disease among women of reproductive age, is characterized by the presence of endometrial-like tissue outside the uterus. TNF-alpha induces IL-8 production in endometriotic cells through nuclear factor-kappaB (NF-kappaB) activation. Thalidomide (Thal) inhibits inflammation by down-regulating the expression of proinflammatory cytokines in tumor cells and inflammatory cells. However, the mechanism of Thal action in human endometriotic stromal cells has not yet been elucidated. MAIN OUTCOME MEASURES: We examined whether Thal abrogates TNF-alpha-induced up-regulation of IL-8 expression in endometriotic stromal cells. RESULTS: Here, we show 1) that treatment of endometriotic stromal cells with TNF-alpha increased the expression of phosphorylated IkappaBalpha and degradation of total IkappaBalpha, which in turn activates NF-kappaB; 2) Thal significantly inhibits the TNF-alpha-induced expression of phosphorylated IkappaBalpha and degradation of IkappaBalpha; 3) TNF-alpha activation induced increased nuclear translocation of NF-kappaB, which was inhibited by pretreatment with either Thal or N-tosyl-L-phenylalanine chloromethyl ketone, an NF-kappaB inhibitor. Thal did not enhance the N-tosyl-L-phenylalanine chloromethyl ketone's action; and 4) Pretreatment with Thal reduced TNF-alpha-induced IL-8 protein production as well as mRNA expression. CONCLUSION: The current study showed for the first time that Thal treatment attenuated the expression of IL-8 by reducing TNF-alpha-induced NF-kappaB activation.

Active Transport, Cell Nucleus↗

PubMed2005

Reduced syndecan-1 expression stimulates heparin-binding growth factor-mediated invasion in ovarian cancer cells in a urokinase-independent mechanism.

The expression of syndecan-1 generally appears down-regulated in human cancers and experimental models, whereas transfectional expression of syndecan-1 in cancer cells has been shown to inhibit aspects of their malignant behavior. To clarify how reduced levels of syndecan-1 may confer enhanced invasiveness, we transfected human ovarian cancer cell line HRA with antisense (AS) syndecan-1 oligodeoxynucleotide (ODN) and compared the properties of transfected cells to those of parental cells or sense (S) syndecan-1 cells. Here, we show: 1) there was lower proliferation in the AS syndecan-1 cells compared to controls (parental HRA cells and S syndecan-1 cells) when cells were incubated with HB-GFs (HB-EGF, HGF, or FGF2); 2) transfection of HRA cells with a syndecan-1 AS ODN enhanced the increase in HB-GF-dependent invasiveness; 3) in contrast, IGF-I stimulated cell proliferation and invasion, irrespective of whether cells were transfected with the AS syndecan-1 gene; 4) IGF-I stimulated ERK1/2 activation and uPA expression in both the control and AS cells, whereas the net effect of the reduction of syndecan-1 is to shift the HB-GF dose-response curve to the right; 5) the AS cells reduced activation and up-regulation of ERK1/2 phosphorylation and uPA expression, respectively, in response to HB-GFs; and 6) in comparison with early stage ovarian cancer tissues, there was a 3-fold decrease in syndecan-1 mRNA levels in advanced stage tissues. Taken together, these data suggest that decreased syndecan-1 expression may be associated with enhanced cell invasion possibly through the uPA-independent mechanism.

Adult↗

PubMed2004

A kunitz-type protease inhibitor bikunin disrupts ligand-induced oligomerization of receptors for transforming growth factor (TGF)-beta and subsequently suppresses TGF-beta signalings.

We previously found that bikunin (bik), a Kunitz-type protease inhibitor, suppresses transforming growth factor-beta1 (TGF-beta1)-stimulated expression of urokinase-type plasminogen activator (uPA) in human ovarian cancer cells that lack endogenous bik. In the present study, we tried to elucidate the mechanism by which bik also inhibits plasminogen activator inhibitor type-1 (PAI-1) and collagen synthesis using human ovarian cancer cells. Here, we show that (a) there was an enhanced production of both uPA and PAI-1 in HRA cells in response to TGF-beta1; (b) the overexpression of bik in the cells or exogenous bik results in the inhibition of TGF-beta1 signaling as measured by phosphorylation of the downstream signaling effector Smad2, nuclear translocation of Smad3, and production of PAI-1 and collagen; (c) bik neither decreased expression of TGF-beta receptors (TbetaRI and TbetaRII) in either cell types nor altered the specific binding of 125I TGF-beta1 to the cells, indicating that the effects of bik in these cells are not mediated by ligand sequestration; (d) TbetaRI and TbetaRII present on the same cells exclusively form aggregates in TGF-beta1-stimulated cells; (e) co-treatment of TGF-beta1-stimulated cells with bik suppresses TGF-beta1-induced complex formation of TbetaRI and TbetaRII; and (f) a chondroitin-4-sulfate side chain-deleted bik (deglycosylated bik) does not inhibit TGF-beta1 signaling or association of type I/type II receptor. We conclude that glycosylated bik attenuates TGF-beta1-elicited signaling cascades in cells possibly by abrogating the coupling between TbetaRI and TbetaRII and that this probably provides the mechanism for the suppression of uPA and PAI-1 expression.

Cell Division↗

PubMed2004

Transforming growth factor-beta1-dependent activation of Smad2/3 and up-regulation of PAI-1 expression is negatively regulated by Src in SKOV-3 human ovarian cancer cells.

The net balance between urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) has been implicated in tumor cell invasion and metastasis. To elucidate the mechanism of the transforming growth factor-beta1 (TGF-beta1)-dependent up-regulation of PAI-1 expression, we investigated which signaling pathway transduced by TGF-beta1 is responsible for this effect. Here, we show (1) nontoxic concentrations of TGF-beta1 up-regulates uPA expression in HRA and SKOV-3 human ovarian cancer cells, (2) TGF-beta1 activates Smads (phosphorylation of Smad2 and nuclear translocation of Smad3) and subsequently up-regulates PAI-1 expression in HRA cells, whereas TGF-beta1 neither activates Smads nor up-regulates PAI-1 in SKOV-3 cells, (3) pharmacological Src inhibitor PP2 or antisense (AS) c-Src oligodeoxynucleotide (ODN) treatment significantly induces TGF-beta1-dependent activation of Smads, leading to PAI-1 synthesis, compared with controls, in SKOV-3 cells, (4) combination of TGF-beta1 and PP2, which activates PAI-1 expression and reduces uPA expression in SKOV-3, results in decreased invasiveness, (5) pharmacological inhibitors for mitogen-activated protein kinase (MAPK) (PD98059) and phosphoinositide-3-kinase (PI3K) (LY294002 and wortmannin) or AS-PI3K ODN transfection do not affect TGF-beta1-induced Smad signaling and up-regulation of PAI-1 expression in SKOV-3 cells pretreated with PP2, and (6) the induction of PAI-1 protein was partially inhibited by an inhibitor of Sp1-DNA binding, mithramycin, implicating, at least in part, Sp1 in the regulation of this gene by TGF-beta1. In conclusion, TGF-beta1-dependent activation of Smad2/3, leading to PAI-1 synthesis, may be negatively regulated by Src, but not its downstream targets MAPK and PI3K in SKOV-3 cells. These data also reflect the complex biological effect of uPA-PAI-1 system.

DNA-Binding Proteins↗

PubMed2004

A density-functional study for the liquid-vapor coexistence curve of nitrogen fluid.

We have used a density-functional theory based on the interaction site model to predict the liquid-vapor coexistence curve of nitrogen fluid. The pressure and chemical potential were calculated from thermodynamic integrations. The different paths of thermodynamic integration provide slightly different predictions for the liquid-vapor coexistence curve. However, these critical points and coexistence curves evaluated by the theory are in qualitative agreement with the experimental data. The theoretical coexistence curves scaled to critical constants agree with the experimental data quantitatively.

Journal Article↗

PubMed2004

A path integral influence functional for excess electron in fluids: Density-functional formulation.

In this paper, we propose a path integral influence functional from a solvent to determine a self-correlation function of a quantum particle in classical simple fluid. It is shown that the influence functional is related to a grand potential functional of the pure solvent under a three-dimensional external field arising from a classical isomorphic polymer, on which the quantum particle is mapped. The influence functional can be calculated from the self-correlation function, the solute-solvent and the solvent-solvent pair correlation function. The obtained equation of the self-correlation function is applied to an excess electron problem in fluid helium. The Fourier path-integral Monte Carlo method is employed to perform the path integral of the electron. The solute-solvent pair correlation function is estimated from a reference interaction site model integral equation. These results obtained form our proposed influence functional and from that proposed by Chandler, Singh, and Richardson are compared with those provided by a path integral Monte Carlo simulation with the explicit helium solvent.

Journal Article↗

PubMed2004

Bikunin inhibits lipopolysaccharide-induced tumor necrosis factor alpha induction in macrophages.

Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-alpha) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-alpha expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-alpha protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 microM). (iii) Inhibition by bikunin of TNF-alpha induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-alpha target molecules interleukin-1beta (IL-1beta) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-alpha release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-alpha production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

Animals↗