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Biomedical subjects

Yuji Taketani

Publications and source records attributed to Yuji Taketani.

At least 19 recordsLinked to original sources
PubMed2006

The expression and possible roles of chemokine CXCL11 and its receptor CXCR3 in the human endometrium.

IFN-gamma secreted by a human embryo and trophoblast cells during implantation is suggested to play an important role in implantation and pregnancy. In the present study, we explored expression and possible functions of CXCL11, a CXC chemokine strongly induced by IFN-gamma, and its receptor CXCR3 in the human endometrium. Secreted CXCL11 protein was not detected in cultured endometrial stromal cells (ESC) but was detected in cultured endometrial epithelial cells (EEC). IFN-gamma stimulated the protein levels of CXCL11 in a dose-dependent manner in EEC and ESC. CXCL11 secreted from EEC with 100 ng/ml IFN-gamma was 220-fold of the control, and 100-fold as compared with that secreted from ESC with the same dose of IFN-gamma. CXCR3 was expressed in EEC, ESC, and trophoblast cells. Addition of IFN-gamma to EEC increased the chemotactic activity of its culture medium to trophoblast cells and T cells, and the effect was suppressed by immunoneutralization with Abs of three CXCR3 ligands, including anti-CXCL11 Ab. CXCL11 significantly increased BrdU incorporation of ESC, which was inhibited by a p42/44 MAPK pathway inhibitor PD98059. In contrast, CXCL11 significantly decreased BrdU incorporation and increased the release of lactate dehydrogenase and the positive staining of annexin V in EEC. These findings suggest that IFN-gamma promotes implantation by stimulating EEC to produce CXCL11, which induces migration of trophoblast cells and T cells, proliferation of ESC, and apoptosis of EEC.

Apoptosis↗
PubMed2006

Treatment with paclitaxel plus carboplatin, alone or with irradiation, of advanced or recurrent endometrial carcinoma.

OBJECTIVES: The goal of this study was to evaluate the efficacy and toxicity of paclitaxel plus carboplatin in the treatment of primarily advanced or recurrent endometrial carcinoma. METHODS: Thirty-seven consecutive patients with advanced or recurrent endometrial carcinoma were enrolled in this study. Paclitaxel at a dose of 175 mg/m(2) was administered intravenously over 3 h followed by carboplatin with area under the curve of 5 to 6 over 1 h at 4-week intervals. Five patients were received 50 Gy pelvic irradiation, and 7 were received 50 Gy pelvic and 50 Gy paraaortic irradiation, after adjuvant chemotherapy with paclitaxel plus carboplatin. Eighteen patients had evaluable lesions. Responses were assessed before the use of any irradiation. RESULTS: Eleven patients (61%) achieved an objective response, including one complete response (5.6%) and 10 partial responses (56%). The most common toxicity was hematologic: grade 3 or 4 leukopenia and neutropenia occurred in 59% and 86% of patients, respectively. Three patients (8%) required granulocyte colony-stimulating factor support. One patient required a platelet transfusion, and four required blood transfusions. There was a single adverse event of anaphylaxis. CONCLUSION: The combination of paclitaxel and carboplatin appears to be an effective regimen for the treatment of patients with advanced or recurrent endometrial carcinoma with tolerable toxicity.

Adult↗
PubMed2006

Human homolog of Drosophila tumor suppressor Scribble negatively regulates cell-cycle progression from G1 to S phase by localizing at the basolateral membrane in epithelial cells.

Drosophila tumor suppressor Scribble has been identified as an apical-basolateral polarity determinant in epithelia. A human homolog of Drosophila Scribble, human Scribble (hScrib), has been identified as a protein targeted by human papillomavirus E6 for the ubiquitin-mediated degradation dependent on E6AP, a cellular ubiquitin-protein ligase. Human Scribble is classified as a LAP protein, having leucine-rich repeats (LRRs) and PDZ domains. We investigated whether hScrib, which is thought to have a role in polarity determination based on the data of its Drosophila homolog, is involved in cell-cycle regulation and proliferation control of epithelia. Transfection of hScrib inhibits cell-cycle progression from G1 to S phase, and it up- and down-regulates expression of adenomatous polyposis coli and cyclins A and D1, respectively. Knockdown of hScrib expression by siRNA leads to cell-cycle progression from G1 to S phase. We explored functional domain mapping to reveal which domains of hScrib are critical for its cellular proliferation control and localization at the basolateral membrane. We found that LRRs and PDZ domain 1 are indispensable for hScrib to inhibit cell growth by blocking cell-cycle progression and to keep its proper localization. These data indicate that basolateral membrane localization of hScrib is closely related to its proliferation control. Our findings suggest the possibility that hScrib is involved in signal transduction to negatively regulate cell proliferation by localizing at the basolateral membrane of epithelial cells through LRRs and PDZ domains.

Animals↗
PubMed2006

Combined phospho-Akt and PTEN expressions associated with post-treatment hysterectomy after conservative progestin therapy in complex atypical hyperplasia and stage Ia, G1 adenocarcinoma of the endometrium.

Young patients with complex atypical hyperplasia (CAH) or stage Ia, G1 adenocarcinoma (IaG1) of the endometrium, who desire to preserve fertility, can select the conservative therapy by oral progestin, medroxyprogesterone acetate (MPA). However, conservative treatments involve potential risks of progression and recurrence. In an attempt to find out molecular markers for sensitivity to MPA, we performed immunohistochemical analysis of PTEN, phospho-Akt, p53, ER and PgR in MPA-treated 31 cases with CAH or IaG1. Eleven of 12 cases (92%) with CAH and 15 of 19 cases (79%) with IaG1 demonstrated an initial complete response, while five patients underwent hysterectomy due to no response. Four of 11 responders (36%) with CAH and five of 15 responders (33%) with IaG1 later developed relapse. Five of nine patients (56%) with CAH and three of 11 patients (27%) with IaG1 became pregnant after infertility treatment. Immunohistochemical analysis revealed that phospho-Akt expression was significantly decreased by MPA administration (p=0.002). Furthermore, combination of two factors, weak phosho-Akt or PTEN-null expression, was found to be significantly associated with receiving hysterectomy (p=0.04), while each factor showed a trend without statistical significance (p=0.07 and 0.2, respectively). Strong expression of both ER and PgR significantly correlated with successful pregnancy after infertility treatment following complete response to MPA (p=0.02). Our observations in vivo suggest that anti-tumor action of MPA may be mediated by dephosphorylation of Akt, and that immunohistochemical evaluation of phospho-Akt and PTEN may be able to predict the outcome of MPA therapy.

Adenocarcinoma↗
PubMed2006

FR 167653, a p38 mitogen-activated protein kinase inhibitor, suppresses the development of endometriosis in a murine model.

In various cells including endometriotic cells, p38 mitogen-activated protein kinase (MAPK) plays essential roles for inflammation, an etiological factor for endometriosis. We evaluated the effect of FR 167653, a p38 MAPK inhibitor, on the development of endometriosis using a murine model. As an endometriosis model, estradiol-treated ovariectomized BALB/c mice were injected intraperitoneally with endometrial fragments of the syngenic donor mice. The animals were injected with either 30mg/kg FR 167653 or only vehicle (control) s.c. twice a day, starting 2 days before endometrial injection. Three weeks later, the peritoneal fluids and the developed endometriotic lesions were collected. Both the weight of all the endometriotic lesions per mouse and the concentrations of interleukin-6 and monocyte chemoattractant protein-1 in the peritoneal fluid were significantly lower in the FR 167653-treated mice than in the control mice. These findings suggest that FR 167653 may inhibit the development of endometriosis possibly by suppressing peritoneal inflammatory status.

Animals↗
PubMed2006

Selective increase in high molecular weight adiponectin concentration in serum of women with preeclampsia.

Total adiponectin concentrations have been shown to increase in serum of preeclamptic women. However, variance of concentrations of different isoforms has not been studied, despite the emerging notion that high, medium and low molecular weight adiponectin exert different functions. We have determined serum concentrations of each adiponectin isoform using a newly developed enzyme immunosorbent assay. High molecular weight (HMW) adiponectin concentrations were significantly higher in women with preeclampsia (n=14; median, 11.2 microg/ml; interquartile range, 9.2-15.8) compared to normal pregnant women (n=14; 6.8 microg/ml, 5.4-10.7; P=0.04). In contrast, medium molecular weight and low molecular weight adiponectin concentrations were substantially equal between the groups. The ratio of HMW adiponectin to total adiponectin was also markedly higher in preeclamptic women (52.3%, 49.5-58.7) than control women (43.0%; 39.8-48.0; P=0.004). Taken together with other reports our findings imply a physiological feedback response to minimize endothelial damage in preeclamptic women.

Adiponectin↗
PubMed2006

Elevated serum bisphenol A levels under hyperandrogenic conditions may be caused by decreased UDP-glucuronosyltransferase activity.

This study was performed to investigate the effect of androgen on the metabolism of bisphenol A (BPA), an endocrine disruptor, in order to clarify the mechanism of the higher levels of serum BPA in men and hyperandrogenemic women compared with normal women. Castrated female rats (OVX) were subcutaneously injected with testosterone propionate (TP) (0.01, 0.1, and 1 mg) every day for 2 weeks. Serum BPA concentrations in OVX rats showed a TP dose-dependent increase and were significantly higher at 0.1 and 1.0 mg of TP. The enzyme reaction of BPA glucuronidation in the rat liver microsomes showed that the ratio of glucuronide in the OVX rats was significantly reduced in a TP dose-dependent manner. Analysis of the mRNA expression of UDP-glucuronosyltransferase 2B1 (UGT2B1) by real-time quantitative RT-PCR revealed that the relative expression level of UGT2B1 mRNA showed a TP dose-dependent decrease. The results of enzyme analyses demonstrated that the ratio of BPA glucuronidation and the expression level of UGT2B1 mRNA were significantly lower under the hyperandrogenemic conditions. The clearance of BPA may be slowed in a TP dose-dependent manner, resulting in an increase of serum BPA concentration under hyperandrogenemic conditions.

Animals↗
PubMed2006

Expression of adiponectin receptors and its possible implication in the human endometrium.

Adiponectin, a pleiotropic cytokine, exerts its effects via the specific receptors AdipoR1 and AdipoR2. Whereas circulating adiponectin concentrations decrease in women with endometriosis and endometrial cancer, possible effects of adiponectin and the presence of the receptors in the endometrium have not been determined. In this study, we examined the expression of adiponectin receptors AdipoR1 and AdipoR2 in the human endometrium and assessed effects of adiponectin in endometrial cells. Expression of AdipoR1 and AdipoR2 in endometrial tissues was evaluated by real-time quantitative PCR, in situ hybridization, and Western blotting. The effects of adiponectin on phosphorylation of AMP-activated protein kinase, a regulator of energy homeostasis, in cultured endometrial stromal cells (ESCs) and epithelial cells (EECs) were studied by Western blotting. The effects of adiponectin on IL-1beta-induced secretion of IL-6, IL-8, and monocyte chemoattractant protein 1 from cultured ESCs were determined using specific ELISAs. The expression of AdipoR1 and AdipoR2 was detected in the endometrium. The expression of both genes was increased in the midluteal phase, the period of embryo implantation. In situ hybridization revealed that both AdipoR1 and AdipoR2 appeared to be equally expressed in the epithelial cells and in the stromal cells. Adiponectin increased phosphorylation of AMP-activated protein kinase in ESCs and EECs. Adiponectin decreased IL-1beta-induced secretion of IL-6, IL-8, and monocyte chemoattractant protein 1 from ESCs. These findings suggest that adiponectin exerts energy-homeostatic and antiinflammatory effects in the endometrium, and these effects might be relevant to pathological and physiological endometrium-related events such as implantation and endometriosis.

AMP-Activated Protein Kinases↗
PubMed2006

Inhibitory cis-element-mediated decay of human papillomavirus type 16 L1-transcript in undifferentiated cells.

Production of human papillomavirus type 16 major capsid protein L1 in undifferentiated cells is negatively regulated by several yet unidentified cis-acting inhibitory RNA elements, among which a major element is located within the first 514 nucleotides of the L1-mRNA. By Northern blotting we examined effect of the major element on the steady-state level of mRNA transiently transcribed in 293T cells from the firefly luciferase (Fluc) gene combined with the L1 DNA fragment encoding the major element. As reported previously, the element down-regulated steady-state level of the mRNA. The most efficient down-regulation was achieved by insertion of the element near the 5' end of mRNA, resulting in an undetectable level of the mRNA. The longer the distance from the 5' end of the mRNA to the element, the weaker the down-regulation. The half-life of the mRNA having the element was similar to that of normal Fluc-mRNA. When the element near the 5' end was removed by splicing, the steady-state level of the resultant mRNA was raised to a readily detectable level. The steady-state level of RNA synthesized by RNA polymerase-I was not influenced by the presence of the element. Taken together, it is suggested that DNA region encoding the major inhibitory element does not disturb transcription and that the pre-mRNA is degraded by an RNA element-mediated mechanism after the splicing step in the course of mRNA maturation.

Capsid Proteins↗
PubMed2006

Osteopontin deficiency suppresses high phosphate load-induced bone loss via specific modulation of osteoclasts.

Phosphate (Pi) plays a critical role in the maintenance of mineralized tissues and signaling in the intracellular environment. Although extracellular phosphate concentration is maintained at fixed levels, physiological machineries involved in phosphate homeostasis in bone, which is the largest phosphate storage site, have not yet been fully elucidated. Here we examined the role of osteopontin (OPN) in a high-Pi diet load-induced bone loss. A high-Pi diet significantly reduced bone mineral density as well as bone mass in wild type. In contrast, OPN deficiency totally prevented reduction in bone mineral density and bone mass. Analyses of bone turnover-related components revealed that bone formation parameters (bone formation rate and mineral apposition rate) were enhanced by high-Pi diet load similarly in wild-type and OPN-deficient mice. In sharp contrast, bone resorption parameters (osteoclast number and osteoclast surface) were enhanced by high-Pi diet load in wild type but not at all in OPN-deficient mice. Bone marrow cell cultures revealed no major effects of OPN deficiency on high-Pi diet modulation of mineralized nodule formation in culture. On the other hand, tartrate-resistant acid phosphatase-positive multinucleated cell development in cultures were enhanced by high-Pi diet load in wild-type cells, but such effects of high Pi-diet were totally abolished in the absence of OPN. These data indicated that OPN is needed for osteoclastic activity to resorb bone on high phosphate loading.

Animals↗
PubMed2006

Expression patterns of lectin-like natural killer receptors, inhibitory CD94/NKG2A, and activating CD94/NKG2C on decidual CD56bright natural killer cells differ from those on peripheral CD56dim natural killer cells.

The balance of inhibitory and activating natural killer (NK) receptors on maternal decidual NK cells, most of which are CD56bright, is thought to be crucial for the proper growth of trophoblasts in placenta. A lectin-like NK receptor, CD94/NKG2, is the receptor for human leukocyte antigen (HLA)-E, which is expressed on trophoblasts. To clarify the mechanism regulating the activity of decidual NK cells during pregnancy, we investigated the expression patterns of inhibitory NK receptor, CD94/NKG2A, and activating receptor, CD94/NKG2C, on decidual NK cells in an early stage of normal pregnancy and compared them with those on peripheral NK cells, most of which are CD56dim. The rate of NKG2A-positive cells was significantly higher for decidual CD56bright NK cells than for peripheral CD56dim NK cells, but the rates of NKG2C-positive cells were comparable between the two cell types. Interestingly, peripheral CD56dim NK cells reciprocally expressed inhibitory NKG2A and activating NKG2C, but decidual CD56bright NK cells that expressed activating NKG2C simultaneously expressed inhibitory NKG2A. The co-expression of inhibitory and activating NKG2 receptors may fine-tune the immunoregulatory functions of the decidual NK cells to control the trophoblast invasion in constructing placenta.

CD56 Antigen↗
PubMed2006

IgG antibodies to HPV16, 52, 58 and 6 L1-capsids and spontaneous regression of cervical intraepithelial neoplasia.

To identify the predictive markers for spontaneous regression of cervical intraepithelial neoplasia (CIN), we examined whether IgG antibody responses to common human papillomavirus (HPV) L1-capsids correlate with CIN regression. In a cohort study, a total of 116 Japanese women with CIN grade I/II were tested for cervical HPV DNA and serum IgG antibodies to HPV16/52/58/6 L1-capsids. Our data suggest that baseline IgG reactivities to HPV L1-capsids do not serve as a predictive marker of CIN regression, in contrast to histological CIN grades and HPV DNA status.

Antibodies, Viral↗
PubMed2006

Involvement of a cellular ubiquitin-protein ligase E6AP in the ubiquitin-mediated degradation of extensive substrates of high-risk human papillomavirus E6.

Human scribble (hScrib), which was identified as substrate of human papillomavirus (HPV) E6 for ubiquitin-mediated degradation dependent on ubiquitin-protein ligase E6AP, is a human homolog of Drosophila neoplastic tumor suppressor scribble, in which mutation causes loss of polarity and overgrowth of epithelia. Drosophila discs large (Dlg) is one of neoplastic tumor suppressors, which genetically links to scribble. E6 also targets human Dlg (hDlg) for ubiquitin-mediated degradation. Ubiquitin-protein ligase involved in this process has not been identified thus far. Here we investigated mechanism underlying degradation of three target proteins of E6, hScrib, hDlg, and p53 by using eighteen HPV 16 E6 mutants with single amino acid substitution. In vitro degradation ability of each E6 mutant was equivalent for these tumor suppressors. We investigated whether E6AP is involved in ubiquitin-mediated degradation of hDlg. In vitro binding assay revealed that hDlg formed ternary complex with E6-E6AP complex. The ability of E6 mutants to degrade these tumor suppressors was correlated with their ability to interact with E6AP. Furthermore, hDlg was targeted for in vitro ubiquitination in the presence of both E6 and E6AP. These data revealed that E6AP is extensively involved in the ubiquitin-mediated degradation of E6-dependent substrates as a cellular E3 ubiquitin-protein ligase.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Changes in umbilical arterial blood flow by an intraamniotic distilled water infusion.

OBJECTIVES: The purpose is to investigate how umbilical arterial blood flow changes by an intraamniotic distilled water infusion and to determine whether the changes in umbilical circulation have any relationship with fetal cardiovascular status and osmolality in amniotic fluid and fetal plasma. METHODS: Eleven chronically catheterized pregnant sheep were used in this study. After a 1-hour control period, 1.5 L of warmed sterile distilled water was injected over 10 minutes into the amniotic cavity. Fetal heart rate and carotid arterial pressure, blood flow of the umbilical and fetal carotid arteries were continuously measured. Fetal arterial blood sampled twice during the control period and then at 30, 60, 90, 120, 180, 240, 300, and 360 minutes after the start of the infusion, was analyzed for blood gases, pH, plasma electrolytes, and osmolality. RESULTS: Data obtained from seven sheep with normoxemic fetuses were studied statistically. Umbilical arterial blood flow decreased significantly from 229.5 +/- 3.83 mL/min in the control to 167.4 +/- 11.1 mL/min at 30 minutes after water infusion (P < .001). Umbilical arterial vascular resistance increased rapidly and reached its peak at approximately 60 minutes after infusion and then showed a gradual recovery to the control level (P < .001). Amniotic fluid osmolality had a high degree of correlation with umbilical arterial blood flow and vascular resistance, while fetal arterial blood pressure and heart rate had only little correlation with umbilical blood flow. CONCLUSION: A distilled water infusion into the amniotic cavity in near-term pregnant sheep led to an acute drop in umbilical arterial blood flow. The changes in umbilical flow were closely correlated with those in amniotic fluid osmolality. Hemolysis in the capillary networks in the fetal membranes seems to be one of the main causes of umbilical vasoconstriction. It is speculated that the fetal membranes, including capillary networks, intramembranous pathway, and amnion epithelial cells, sense the changes in amniotic fluid osmolality, which leads to a fetal adaptation to the hypotonic environment.

Amniotic Fluid↗
PubMed2006

Human scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli.

Recently, we have identified human scribble (hScrib), human homolog of the Drosophila tumor suppressor Scribble, as a substrate of human papillomavirus E6 oncoproteins for ubiquitin-mediated degradation dependent on ubiquitin-protein ligase E6AP. Human Scribble, classified as a LAP protein containing leucine-rich repeats and PDZ domains, interacts with E6 through its PDZ domains and C-terminal PDZ domain-binding motif of E6 protein. Interaction between human Discs Large (hDlg), which is a substrate of E6 for the ubiquitin-mediated degradation, and adenomatous polyposis coli (APC) has been shown. Here, we investigated whether hScrib and APC interact with each other in vitro and in vivo. Interaction between hScrib and APC is mediated by the PDZ domains 1 and 4 of hScrib and C-terminal PDZ domain-binding motif of APC. Human Scribble co-localized with APC at the synaptic sites of hippocampal neuron and at the tip of membrane protrusion in the epithelial cell line. Interference of the interaction between hScrib and APC caused disruption of adherens junction. Knockdown of hScrib expression by RNAi disrupts localization of APC at the adherens junction. These data suggest that hScrib may participate in the hDlg-APC complex through its PDZ domains and regulate cell cycle and neural function by associating with APC.

Adenomatous Polyposis Coli Protein↗