Biomedical subjects

Ken Takeda

Publications and source records attributed to Ken Takeda.

At least 37 records · Page 2Linked to original sources

PubMed2004

Tumor-promoting activity and mutagenicity of 5 termiticide compounds.

The tumor-promoting activities of 5 commercial compounds used in termiticides were measured by a cell-transformation assay employing Bhas 42 cells. Their initiating activities were also measured by the microsuspension assay employing S. typhimurium TA98 and TA100 strains. The results of the transformation assay confirmed the tumor-promoting activities of fenitrothion, silafluofen and bifenthrin. Furthermore, the mutagenicity of S-421 and fenitrothion were also confirmed. Consideration of 2-stage carcinogenesis suggests that concurrent use of and long-term exposure to these compounds that have tumor-promoting and initiator activity, and compounds exhibiting either type of activity individually should be avoided as much as possible.

Biotransformation↗

PubMed2004

Relationships between radiosensitivity and microvascular density in esophageal carcinoma: significance of hypoxic fraction.

PURPOSE: The prognosis and the radiosensitivity of macroscopically infiltrative type of esophageal carcinoma are worse than those of the localized type of esophageal carcinoma treated with irradiation. The aim of this study was to investigate the cause of differences in radiosensitivity and prognosis of esophageal carcinoma according to macroscopic type from the viewpoint of tumor angiogenesis. METHODS AND MATERIALS: A total of 40 surgically resected esophageal carcinoma tissues with good material remaining were selected at random from macroscopically localized type (n = 20) and infiltrative type (n = 20) of esophageal carcinoma. The highest intratumoral microvascular density (h-MVD), average intratumoral microvascular density (a-MVD), Ki67 labeling index, and expression of vascular endothelial growth factor (VEGF) in each section were estimated. RESULTS: h-MVD was significantly (p = 0.0006) greater in the infiltrative type than in the localized type, whereas a-MVD (p = 0.0014) and Ki67 labeling index (p = 0.022) were significantly lower in the infiltrative type than in the localized type. The expression level of VEGF was significantly (p < 0.0001) higher in the infiltrative type. CONCLUSIONS: The generally underdeveloped vascular densities with low proliferation activities (suggesting increase of hypoxic fraction) seemed to be one of the reasons for unfavorable radiosensitivities of infiltrative type of esophageal carcinoma. The infiltrative type of esophageal carcinoma shows a high level of VEGF expression and high activity of tumor angiogenesis. The locally enhanced neovascularization, which occurs frequently in hematogenous metastasis seemed to be one of the reasons for the unfavorable prognosis of the infiltrative type of esophageal carcinoma.

Aged↗

PubMed2004

Equol, a metabolite of daidzein, inhibits bone loss in ovariectomized mice.

Soybean isoflavones have structures similar to that of estrogen and have received attention as alternatives to hormone replacement therapy for the prevention of postmenopausal osteoporosis. Daidzein, a major isoflavone found in soybean, is metabolized to equol by gut microflora, and the metabolite exhibits a stronger estrogenic activity than daidzein. However, there is no direct evidence that equol affects bone metabolism. In this study, we examined the effect of equol on the inhibition of bone loss in ovariectomized (OVX) mice. Female mice (8 wk old) were assigned to 5 groups as follows: sham-operated (sham), OVX, OVX + 0.1 mg/d equol administration (0.1 Eq), OVX + 0.5 mg/d equol administration (0.5 Eq), and OVX + 0.03 microg/d 17beta-estradiol administration (E(2)). Equol and E(2) were administered s.c., using a mini-osmotic pump. At 4 wk after the intervention, uterine weight was less in the OVX mice than in sham-operated mice (P < 0.05). The weight was maintained in the E(2) group. In contrast, administration of equol at doses used in this study did not affect uterine atrophy in OVX mice. Bone mineral density (BMD) for the whole body in the OVX group measured by dual-energy X-ray absorptiometry was lower than that in the sham group, whereas administration of 0.5 mg/d Eq as well as E(2) maintained the BMD. The BMD of the femur and lumbar spine in the OVX group was also lower than those in the sham group, and treatment with 0.5 mg/d Eq maintained it. Notably, the BMD of the proximal femur in the 0.5 Eq group was the same as that of the sham group. E(2) inhibited bone loss from all regions induced by OVX. These results suggest that equol, a major metabolite of daidzein, inhibits bone loss apparently without estrogenic activity in the reproductive organs of OVX mice.

Animals↗

PubMed2004

Complementary DNA microarray analysis in acute lung injury induced by lipopolysaccharide and diesel exhaust particles.

We have recently shown that diesel exhaust particles (DEP) synergistically enhance acute lung injury related to lipopoly-saccharide (LPS) in mice. The present study used cDNA microarray to elucidate the effects of DEP on the global pattern of LPS-related gene expression in the murine lung. The number of genes upregulated >/=2-fold as compared with their expression levels in the vehicle group was greater in the LPS group than in other groups, but treatment with DEP and LPS dramatically increased the number of the genes upregulated >/=6-fold. In particular, gene expression of metallothionein-1 and -2, S100 calcium-binding protein A9, lipocalin 2, and small inducible cytokine B family member 10 was higher by >/=20-fold in the DEP + LPS group than in the vehicle group. These results were concomitant with those obtained by real-time reverse transcription-polymerase chain reaction analysis in the overall trend. Our findings suggest that intense, focused expression of genes such as S100 calcium-binding protein A9, lipocalin 2, and small inducible cytokine B family member 10 relates to the synergistic aggravation of acute lung injury by LPS and DEP rather than weak, broad expression of various genes by exposure of LPS alone.

Animals↗

PubMed2004

Brain stem hypertensive encephalopathy evaluated by line scan diffusion-weighted imaging.

Hypertensive encephalopathy rarely presents with predominant involvement of the brain stem and relative sparing of the supratentorial regions. We describe the MR imaging features in a patient with reversible brain stem hypertensive encephalopathy. Extensive hyperintensity was predominantly seen in brain stem regions on fluid-attenuated inversion-recovery and T2-weighted images. These lesions showed an increased apparent diffusion coefficient with the use of line scan diffusion-weighted imaging. The clinical findings and MR imaging abnormalities resolved with control of hypertension.

Aged↗

PubMed2004

Endocrine-disrupting activity of chemicals in diesel exhaust and diesel exhaust particles.

Diesel exhaust (DE) is known as the main cause of air pollution. DE is a complex mixture of particulate and vapor-phase compounds. The soluble organic fraction of the particulate materials in DE contains thousands of compounds including a variety of polycyclic aromatic hydrocarbons and heavy metals. To clarify the endocrine-disrupting activities of DE, we have reviewed the reports about the effects of DE on the reproductive and brain-nervous systems, and the endocrine-disrupting action of diesel exhaust particles (DEP). In utero exposure to low levels (0.1 mg DEP/m3) of DE from day 2 postcoitum (p.c.) until day 13 p.c. reduced the expression level of Ad4BP/SF-1 mRNA and thereby might affect the development of gonads. Low levels of DE also reduced the expression of several genes known to play key roles in gonadal development, including an enzyme necessary for testosterone synthesis. Mature male rats exposed to DE during the fetal period showed an irreversible decrease in daily sperm production due to an insufficient number of Sertoli cells. DE exposure during the fetal period influenced the brain tissue in newborn mice. In the 3 mg DEP/m3 exposure group at 10 weeks of age, a significant reduction in performance was observed in the passive avoidance learning test in both male and female mice. In addition, the fetal exposure of mice to DE affected the emotional behaviors associated with the serotonergic and dopaminergic systems in the mouse brain. In toluidine blue-stained specimens from the DE-exposed group, edema around the vessels where fluorescent granular perithelial (FGP) cells exist and degenerated granules within the FGP cytoplasm were observed; similar findings were obtained by electron microscopic examination. DEP contain many substances that stimulate Ah receptors, such as the polycyclic aromatic hydrocarbon containing benzo[a]pyrene. DEP also contain substances with estrogenic, antiestrogenic and antiandrogenic activities. The neutral substance fraction of DEP has the causal substance that reduces estrogen receptor mRNA expression. Evaluating the influence of these chemicals present in the environment on human health is an important task.

Animals↗

PubMed2003

Induction of plasminogen activator inhibitor-2 is associated with suppression of invasive activity in TPA-mediated differentiation of human prostate cancer cells.

We previously reported that 12-O-tetra-decanoylphorbol-13-acetate (TPA) induces microglia-like differentiation and decreases malignancy in human prostate cancer TSU-Pr1 cells. To investigate the mechanism underlying differentiation and decrease of malignancy in TSU-Pr1 cells treated with TPA, we attempted to identify genes expressed differentially during the differentiation using differential display. We successfully detected plasminogen activator inhibitor type-2 (PAI-2) as one gene up-regulated by TPA treatment. The change in expression of PAI-2 by TPA was blocked by treatment with protein kinase C or mitogen-activated protein kinase inhibitors. We also found that secretion of PAI-2 protein was increased by TPA treatment. Moreover, we demonstrated that suppression of invasive activity of TSU-Pr1 cells by TPA treatment was blocked by co-treatment with anti-PAI-2 antibody. These results suggest that induction of PAI-2 is associated with suppression of invasive activity in TSU-Pr1 cells treated with TPA.

Cell Differentiation↗

PubMed2003

ERK 1/2- and JNKs-dependent synthesis of interleukins 6 and 8 by fibroblast-like synoviocytes stimulated with protein I/II, a modulin from oral streptococci, requires focal adhesion kinase.

Protein I/II, a pathogen-associated molecular pattern from oral streptococci, is a potent inducer of interleukin-6 (IL-6) and IL-8 synthesis and release from fibroblast-like synoviocytes (FLSs), cells that are critically involved in joint inflammation. This synthesis implicates ERK 1/2 and JNKs as well as AP-1-binding activity and nuclear translocation of NF-kappaB. The mechanisms by which protein I/II activates MAPKs remain, however, elusive. Because focal adhesion kinase (FAK) was proposed to play a role in signaling to MAPKs, we examined its ability to contribute to the MAPKs-dependent synthesis of IL-6 and IL-8 in response to protein I/II. We used FAK-/- fibroblasts as well as FAK+/+ fibroblasts and FLSs transfected with FRNK, a dominant negative form of FAK. The results demonstrate that IL-6 and IL-8 release in response to protein I/II was strongly inhibited in both protein I/II-stimulated FAK-/- and FRNK-transfected cells. Cytochalasin D, which inhibits protein I/II-induced phosphorylation of FAK (Tyr-397), had no effect either on activation of ERK 1/2 and JNKs or on IL-6 and IL-8 release. Taken together, these results indicate that IL-6 and IL-8 release by protein I/II-activated FLSs is regulated by FAK independently of Tyr-397 phosphorylation.

Active Transport, Cell Nucleus↗

PubMed2003

A novel support system for patient immobilization and transportation for daily computed tomographic localization of target prior to radiation therapy.

PURPOSE: To develop a method for quick and smooth transportation of patients from a computed tomography (CT) table to a linear accelerator (linac) table for confirming tumor center before radiation therapy. MATERIALS AND METHODS: We developed a system using a subtable for patient immobilization that is transported via a customized stretcher. The patient lies on the subtable and is immobilized by a vacuum cushion and thermoplastic body cast. The subtable stretcher is used to carry the subtable from the CT table to the linac table. During transportation, the subtable is kept flat and shock to the subtable is carefully avoided. Between August 2001 and September 2002, a total of 9 patients with solitary upper lung tumors (superior to carina) were treated using this system. RESULTS: Intrafractional tumor motion along the x (left-right), y (anterior-posterior), and z axis (superior-inferior) ranged from -2 mm to 2 mm, -2 mm to 2 mm, and -5 mm to 3 mm, respectively. The standard deviation of intrafractional tumor motion along the x, y, and z axis ranged from 0.5 mm to 1.5 mm, 0 mm to 1.7 mm, and 0.6 mm to 3.5 mm, respectively. Interfractional setup errors along the x, y, and z axis ranged from -5 mm to 4 mm, -6 mm to 8 mm, and -6 mm to 6 mm, respectively, and we could reduce interfractional setup errors in the majority of treatment sessions. CONCLUSIONS: We developed a system that allows patients to be immobilized and transported to verify tumor location on a daily basis. This system is highly useful for reducing setup errors.

Aged↗

PubMed2003

Radiation therapy combined with cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for untreated and recurrent esophageal cancer.

From January 1999 to November 2000, a total of 24 esophageal cancer patients (17 untreated and 7 recurrent cases) were treated with radiation therapy (60-70 Gy) combined with cis-diammine-glycolatoplatinum (Nedaplatin) (80-120 mg/body) and 5-fluorouracil (5-FU) (500-1,000 mg/body/24 h, continuous infusion for 5 days). Grade III leukocytopenia was observed in 6 (25%) of the patients. Grade III and IV thrombocytopenia was observed in one patient each. The 1-year and 2-year survival rates for definitively irradiated patients were 59% and 39%, respectively, and for patients with postoperative recurrence 69% and 69%, respectively. High-dose radiation combined with Nedaplatin and 5-FU is a safe and effective method for treating esophageal cancer.

Adult↗

PubMed2003

Molecular mechanism of nuclear translocation of an orphan nuclear receptor, SXR.

The steroid and xenobiotic receptor (SXR) is an orphan nuclear receptor that plays a key role in the regulation of xenobiotic response by controlling the expression of drug metabolizing and clearance enzymes. We observed that pregnane X receptor (PXR), the mouse ortholog of SXR, was retained in the cytoplasm of hepatic cells of untreated mice, whereas PXR was translocated to the nucleus after administration of a ligand, pregnenolone 16 alpha-carbonitrile. To understand the molecular mechanisms underlying the xenochemical-dependent nuclear translocation of SXR, we identified the signal sequence of SXR that regulates its nuclear translocation; using an in vitro expression system, we allocated the nuclear localization signal (NLS) to amino acid residues 66 to 92 within the DNA binding domain of SXR. The NLS of SXR is characterized as the bipartite type, and is recognized by the three molecular species of importin alpha: Rch1 (PTAC58), NPI1, and Qip1, in the presence of PTAC97 of importin beta to target the nuclear pore. The nuclear translocation of SXR was observed as an essential regulatory event for transcription of its target genes such as CYP3A4. These results strongly suggest that the molecular mechanism of the nuclear import of SXR was different from that of another xenosensor, the constitutively active receptor, whose translocation into the nucleus is mediated by a leucine-rich xenochemical response signal in its ligand binding domain.

Active Transport, Cell Nucleus↗

PubMed2003

IRAS is an anti-apoptotic protein.

Active cell death, also known as apoptosis, has been implicated in the pathophysiology of diseases such as cancer, heart failure and neurodegenerative disorders. We report the anti-apoptotic function of IRAS, which was previously shown to bind imidazoline ligands. The amino acid sequence of human IRAS (hIRAS) is unrelated to known proteins, except for rat IRAS and a mouse homologue named nischarin, which binds the alpha5 integrin subunit of the fibronectin receptor. When stably transfected into PC12 cells, hIRAS localizes to the cytosol as a 167 kDa immunoreactive protein. Clonal PC12 cell lines expressing hIRAS displayed normal serum growth responses. However, hIRAS expression led to prolonged cell survival against known apoptotic stimuli: serum starvation or thapsigargin or staurosporine treatments. The apoptotic population of hIRAS-expressing cells was significantly reduced, and this protection was achieved by a decrease in caspase-3 activity, phosphatidylserine translocation, and nuclear fragmentation. Similar protective effect was obtained in COS7 cells transiently transfected with hIRAS. A partial activation of the PI3 kinase pathway is possibly implicated in the anti-apoptotic effect of IRAS. Thus, IRAS appears to represent a previously unknown anti-apoptotic protein involved in the regulation of cell survival.

Animals↗

PubMed2003

Alterations of gene expression in adult male rat testis and pituitary shortly after subacute administration of the antiandrogen flutamide.

In the course of profiling alterations of gene expression in the male reproductive system induced by anti-androgenic agents, 28 genes expressed in the testis or pituitary of adult rats were examined shortly after subacute administration of the well-known anti-androgen, flutamide (FM). FM (25 mg/kg/day) was orally administered to male rats for six days. On day 8 (D8) after the first dose of FM, intratesticular testosterone (T) levels had dramatically increased, but daily sperm production on D36 was significantly decreased. The mRNA levels of testicular and pituitary genes on D8 were measured by semiquantitative RT-PCR. Among the six testicular steroidogenic enzyme genes, the mRNAs of the P450 side chain cleavage, P450 17 alpha/C(17-20) lyase, and 3beta-hydroxysteroid dehydrogenase type I (3betaHSD) genes significantly increased, whereas 17beta-hydroxysteroid dehydrogenase type III slightly decreased. Among the three steroid receptors examined, androgen receptor (AR) and glucocorticoid receptor (GR) mRNAs were significantly down-regulated (29% and 35%, respectively) in the testis, but there was no change in estrogen receptor alpha. There were no clear changes in expression of the gonadotropin receptors and Sertoli cell specific genes, but a slight increase was observed in expression of the lactose dehydrogenase-c mRNA, a germ cell specific gene. Among the three immediate early genes, c-myc mRNA was increased approximately 1.4-fold. In the pituitary, on the other hand, mRNAs for LHbeta and FSHbeta subunits and gonadotropin releasing hormone receptor had increased significantly. These results show that subacute FM administration first affected hypothalamus/pituitary hormone gene expression, then altered gonadotropin secretion, and subsequently induced over-expression of testicular steroidogenic enzyme genes. However, the significant up-regulation of 3betaHSD and down-regulation of AR mRNAs, despite the higher level of intratesticular T, might be explained by an antagonistic action of hydroxyflutamide retained in the testis. The profiles of alterations in gene expression observed will provide important information for the screening of adult male animals for anti-androgenic chemicals.

3-Hydroxysteroid Dehydrogenases↗

PubMed2003

Effects of vinclozolin administration on sperm production and testosterone biosynthetic pathway in adult male rat.

The effect of vinclozolin (VCZ), used as a fungicide and known to have anti-androgenic effects on spermatogenesis and gene expression in the male rat testis was investigated. In Experiment 1, VCZ (100 mg/kg/day) or flutamide (FM, 25 mg/kg/day) was orally administered to male Holzman rats for six days. 8 days after the last administration (D8), a drastic increase in intratesticular testosterone was detected in FM (4.2-fold over control) but not in VCZ treated animals, whereas on D36 post-administration, both groups showed similar levels. Significant decreases in daily sperm production were seen in both VCZ and FM-treated rats on D36. Semiquantitative RT-PCR analysis with testicular and pituitary mRNAs on D8 revealed that LHbeta and FSHbeta mRNAs were increased in the pituitary by VCZ, as well as by FM. Among the four testicular steroidogenic enzyme genes, cytochrome P450 side chain cleavage (P450scc) and cytochrome P450 17alpha/C(17-20) lyase (P450c17) mRNAs were significantly increased, whereas 17beta-hydroxysteroid dehydrogenase type III (17betaHSD) mRNA was not changed. A significant increase in 3beta-hydroxysteroid dehydrogenase type I (3betaHSD) and a decrease in androgen receptor (AR) mRNA were observed only in FM treated rats. Immunohistochemistry demonstrated intense staining of P450scc in the interstitial cells of VCZ-treated testis on D8. In Experiment 2, hormone levels were measured at 1, 3, 6, 12 and 24 hours after VCZ (100 mg/kg) administration to Sprague-Dawley rats. Serum LH level remained constant for the first 3 hours and started to increase at 6 hrs. In contrast, serum and intratesticular testosterone levels increased 2-fold at 1 hr and maintained the level until 24 hrs. P450c17 mRNA level was 2-fold increased at all periods, whereas no obvious changes were detected in the other steroidogenic enzyme genes. Although not statistically significant, AR mRNA level increased 2-fold, 3 hrs after VCZ administration. These results indicate that VCZ affects the pituitary in a similar manner as FM, but functions differently on testicular gene expression.

Androgen Antagonists↗

PubMed2003

Results of radiation therapy for uterine cervical cancer using high dose rate remote after loading system.

In Japan, radiotherapy with high dose rate remote after loading system (HDR-RALS) for intracavitary brachytherapy is the standard treatment for more than 30 years. This report showed the usefulness of HDR-RALS for uterine cervical cancer. From 1980 through 1999, 442 patients with uterine cervical cancers (stage I: 66, stage II: 161, stage III: 165, stage IV: 50) were treated. Radiotherapy was performed both external teletherapy and HDR-RALS. Overall survival rate at 5 years was 60.2%. The 5-year actuarial incidence of all complications was 16.4%. The 5-year actuarial incidence of all complications in cases treated with the sum doses of whole pelvic irradiation (without central shield) and RALS up to 49 Gy, 50 to 59 Gy or larger doses were 7.5%, 11.0% and 25.2%, respectively. Radiation therapy using HDR-RALS was very effective. While the dose of whole pelvic irradiation was increased, the actuarial incidence of all complications was increased.

Actuarial Analysis↗

PubMed2002

Involvement of diverse protein kinase C isoforms in the differentiation of ML-1 human myeloblastic leukemia cells induced by the vitamin D3 analogue KH1060 and the phorbol ester TPA.

We reported previously that diverse combination of the vitamin D(3) analogue KH1060 together with 12-O-tetradecanoylphorbol-13-acetate (TPA) synergistically induces the differentiation of ML-1 cells into mature macrophages. To investigate the mechanism involved in their interaction, we examined the role of protein kinase C (PKC) in the differentiation of ML-1 cells to mature macrophages. We found that the specific PKC inhibitor GF109203 suppressed the morphological change and the alpha-naphthyl acetate esterase activity induced in ML-1 cells by treatment with KH1060 plus TPA. This treatment increased the translocation of PKC alpha, PKC epsilon, and PKC theta from cytosol to membranes. ML-1 cells treated with KH1060 alone increased translocation of PKC theta, whereas cells treated with TPA alone increased translocation of PKC alpha and PKC epsilon. These data showed that in human myeloblastic leukemia cells, diverse isoforms of PKC, including PKC alpha, epsilon, and theta, participate in the regulation of cell differentiation.

Calcitriol↗

PubMed2002

Staurosporine enhances the expression of tissue inhibitor of metalloproteinase-1 in human prostate cancer cells.

We reported previously that human prostate cancer cell line TSU-Pr1 can differentiate into neuronal cells by staurosporine treatment. In this process, reduction of invasive abilities was observed in staurosporine treated TSU-Pr1 cells. In the present study, we investigated the effect of staurosporine on tissue inhibitor of metalloproteinases (TIMPs) in prostate cancer cells. We show that treatment of TSU-Pr1 cells with staurosporine results in induction of TIMP-1 mRNA and protein secretion. The induction of TIMP-1 mRNA expression by staurosporine is likely to be caused by increased transcriptional activity and this mechanism is indirect. Furthermore, recombinant human TIMP-1 reduces the invasive activity of TSU-Pr1 cells. We are the first to report that mRNA expression and protein secretion of TIMP-1 are enhanced by staurosporine treatment in prostate cancer cells. These findings suggest that enhancement of TIMP-1 is associated with suppression of invasive activity caused by staurosporine treatment.

Base Sequence↗

PubMed2002

Lung expression of cytochrome P450 1A1 as a possible biomarker of exposure to diesel exhaust particles.

Polycyclic aromatic hydrocarbons (PAH) and reactive oxygen species (ROS) derived from diesel exhaust particles (DEP) are implicated in the pathophysiology of respiratory diseases. Cytochrome P450 (Cyp) 1A1 can be induced by several kinds of PAH and produce ROS. We determined whether acute inhalation exposure to DEP induced the expression of Cyp 1A1 in murine lung. Intratracheal instillation of DEP dose-dependently increased the lung expression of Cyp 1A1 at the levels of both mRNA and protein, whereas DEP decreased expression in the lung of aryl hydrocarbon receptors in a dose-dependent manner. In contrast, charcoal particles as the control did not affect the expression of these molecules. These results suggest that the lung expression of Cyp 1A1 can be a biomarker of acute inhalation exposure to DEP and may be implicated in an accelerated production of ROS and the subsequent aggravation of lung injury.

Animals↗