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N Terada

Publications and source records attributed to N Terada.

At least 37 records · Page 2Linked to original sources
PubMed2001

Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase.

Elongation factor 2 kinase (eEF2k) phosphorylates and inactivates eEF2. Insulin induces dephosphorylation of eEF2 and inactivation of eEF2 kinase, and these effects are blocked by rapamycin, which inhibits the mammalian target of rapamycin, mTOR. However, the signalling mechanisms underlying these effects are unknown. Regulation of eEF2 phosphorylation and eEF2k activity is lost in cells in which phosphoinositide-dependent kinase 1 (PDK1) has been genetically knocked out. This is not due to loss of mTOR function since phosphorylation of another target of mTOR, initiation factor 4E-binding protein 1, is not defective. PDK1 is required for activation of members of the AGC kinase family; we show that two such kinases, p70 S6 kinase (regulated via mTOR) and p90(RSK1) (activated by Erk), phosphorylate eEF2k at a conserved serine and inhibit its activity. In response to insulin-like growth factor 1, which activates p70 S6 kinase but not Erk, regulation of eEF2 is blocked by rapamycin. In contrast, regulation of eEF2 by stimuli that activate Erk is insensitive to rapamycin, but blocked by inhibitors of MEK/Erk signalling, consistent with the involvement of p90(RSK1).

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2001

The kinetics of allergen-induced eotaxin level in nasal lavage fluid: its key role in eosinophil recruitment in nasal mucosa.

Eotaxin (CCL11) is a potent eosinophil chemoattractant belonging to the C-C chemokine. To evaluate the role of eotaxin in eosinophilic inflammation in nasal mucosa, we investigated the levels of eosinophil chemoattractants in nasal lavage fluids obtained after antigen challenge, compared with eosinophil counts and eosinophil protein X (EPX) levels. In subjects with allergic rhinitis, allergen challenge led to parallel increases in eosinophil counts, levels of EPX, and eotaxin concentrations in nasal lavage fluid. The levels of eotaxin in lavage samples showed strong correlation with lavage levels of eosinophil counts and EPX. Normal subjects had few, if any, eosinophils and EPX as well as the measured parameters in their nasal lavage fluids before and after antigen challenge. In our experiments of eosinophil endothelial transmigration (TEM) assay using the nasal microvascular endothelial cells, eotaxin showed the most potent effect among various eosinophil chemoattractants. In addition, treatment of eosinophils with anti-CCR-3 mAb significantly blocked eosinophil TEM induced by homogenate of nasal mucosa. These results indicate that eotaxin has an important role in eosinophil-dependent inflammation in nasal mucosa and suggest that blocking eotaxin or CCR-3 might be useful for new therapeutic tools of allergic rhinitis.

Allergens↗
PubMed2001

p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD.

Cytokines often deliver simultaneous, yet distinct, cell growth and cell survival signals. The 70-kDa ribosomal protein S6 kinase (p70S6K) is known to regulate cell growth by inducing protein synthesis components. We purified membrane-based p70S6K as a kinase responsible for site-specific phosphorylation of BAD, which inactivates this proapoptotic molecule. Rapamycin inhibited mitochondrial-based p70S6K, which prevented phosphorylation of Ser-136 on BAD and blocked cell survival induced by insulin-like growth factor 1 (IGF-1). Moreover, IGF-1-induced phosphorylation of BAD Ser-136 was abolished in p70S6K-deficient cells. Thus, p70S6K is itself a dual pathway kinase, signaling cell survival as well as growth through differential substrates which include mitochondrial BAD and the ribosomal subunit S6, respectively.

Animals↗
PubMed2001

Cardioprotective effect afforded by transient exposure to phosphodiesterase III inhibitors: the role of protein kinase A and p38 mitogen-activated protein kinase.

BACKGROUND: Phosphodiesterase III inhibitors (PDEIII-Is) improve the hemodynamic status of heart failure via inotropic/vasodilatory effects attributable to the increase in intracellular cAMP level. Direct cardioprotection by PDEIII-Is and its underlying mechanisms, however, have not been identified. We tested the infarct size-limiting effect of PDEIII-Is and the roles of cAMP, protein kinase (PK) A, PKC, and mitogen-activated protein kinase (MAPK) families in open-chest dogs. Methods and Results-- Milrinone, olprinone (PDEIII-Is), or dibutyryl-cAMP (db-cAMP) was injected intravenously 30 minutes before 90-minute ischemia, followed by 6 hours of reperfusion. Olprinone was also examined with an intracoronary cotreatment with a PKA inhibitor (H89), a PKC inhibitor (GF109203X), an extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059), or a p38 MAPK inhibitor (SB203580) throughout the preischemic period. Either PDEIII-Is or db-cAMP caused substantial hemodynamic changes, which returned to control levels in 30 minutes. Collateral flow and percent risk area were identical for all groups. Both PDEIII-Is and db-cAMP increased myocardial p38 MAPK activity during the preischemic period, which was blocked by H89, but not by GF109203X. Both PDEIII-Is and db-cAMP reduced infarct size (19.1+/-4.1%, 17.5+/-3.3%, and 20.3+/-4.8%, respectively, versus 36.1+/-6.2% control, P<0.05 each). Furthermore, the effect of olprinone was blunted by either H89 (35.5+/-6.4%) or SB203580 (32.6+/-5.9%), but not by GF109203X or PD98059. H89, GF109203X, PD98059, or SB203580 alone did not influence infarct size. CONCLUSIONS: Pretreatment with PDEIII-Is has cardioprotective effects via cAMP-, PKA-, and p38 MAPK-dependent but PKC-independent mechanisms in canine hearts.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Histamine N-methyltransferase regulates histamine-induced phosphoinositide hydrolysis in guinea pig cerebellum.

We report here that the dose-response curve of the histamine-stimulated phosphoinositide hydrolysis in the guinea pig cerebellar slices was shifted to the left when the slices were pretreated with SKF 91488 (100 microM), a specific inhibitor of histamine N-methyltransferase (HMT). In contrast, the pretreatment of the cerebellar slices with aminoguanidine (100 microM - 1 mM), an inhibitor of diamine oxidase, had no effect on histamine-induced phosphoinositide hydrolysis. HMT mRNA was expressed abundantly in cerebellum, especially in Purkinje cells. These observations suggest that HMT regulates histaminergic neurotransmission in guinea pig cerebellum more predominantly than diamine oxidase in histamine degradation.

Animals↗
PubMed2001

Hepatic maturation in differentiating embryonic stem cells in vitro.

We investigated the potential of mouse embryonic stem (ES) cells to differentiate into hepatocytes in vitro. Differentiating ES cells expressed endodermal-specific genes, such as alpha-fetoprotein, transthyretin, alpha 1-anti-trypsin and albumin, when cultured without additional growth factors and late differential markers of hepatic development, such as tyrosine aminotransferase (TAT) and glucose-6-phosphatase (G6P), when cultured in the presence of growth factors critical for late embryonic liver development. Further, induction of TAT and G6P expression was induced regardless of expression of the functional SEK1 gene, which is thought to provide a survival signal for hepatocytes during an early stage of liver morphogenesis. The data indicate that the in vitro ES differentiation system has a potential to generate mature hepatocytes. The system has also been found useful in analyzing the role of growth factors and intracellular signaling molecules in hepatic development.

Animals↗
PubMed2001

Interleukin-18 up-regulates osteoprotegerin expression in stromal/osteoblastic cells.

Osteoprotegerin (OPG) and osteoclast differentiation factor (ODF) are crucial regulators of osteoclastogenesis. To determine the biological role of interleukin (IL)-18 produced by stromal/osteoblastic cells in osteoclastogenesis, we examined the effects of IL-18 on the OPG and ODF mRNA levels in these cells. When bone marrow stromal ST2 cells, osteoblastic MC3T3-E1 cells, and mouse calvarial osteoblasts were stimulated with IL-18, the expression of OPG mRNA, but not ODF mRNA, was transiently increased, its expression reaching a maximal level at 3 h after the beginning of the culture. In accordance with this observation, all these cells expressed the mRNAs of two IL-18 receptor components and MyD88, an adapter molecule involved in IL-18 signaling. Moreover, in these cells, mitogen-activated protein kinase was phosphorylated after stimulation with IL-18. These results suggest that stromal/osteoblastic cells are IL-18-responsive cells and that IL-18 may inhibit osteoclastogenesis by up-regulating OPG expression, without stimulation of ODF production, in stromal/osteoblastic cells.

Adaptor Proteins, Signal Transducing↗
PubMed2001

IkappaB kinase alpha is essential for mature B cell development and function.

IkappaB kinase (IKK) alpha and beta phosphorylate IkappaB proteins and activate the transcription factor, nuclear factor (NF)-kappaB. Although both are highly homologous kinases, gene targeting experiments revealed their differential roles in vivo. IKKalpha is involved in skin and limb morphogenesis, whereas IKKbeta is essential for cytokine signaling. To elucidate in vivo roles of IKKalpha in hematopoietic cells, we have generated bone marrow chimeras by transferring control and IKKalpha-deficient fetal liver cells. The mature B cell population was decreased in IKKalpha(-/-) chimeras. IKKalpha(-/-) chimeras also exhibited a decrease of serum immunoglobulin basal level and impaired antigen-specific immune responses. Histologically, they also manifested marked disruption of germinal center formation and splenic microarchitectures that depend on mature B cells. IKKalpha(-/-) B cells not only showed impairment of survival and mitogenic responses in vitro, accompanied by decreased, although inducible, NF-kappaB activity, but also increased turnover rate in vivo. In addition, transgene expression of bcl-2 could only partially rescue impaired B cell development in IKKalpha(-/-) chimeras. Taken together, these results demonstrate that IKKalpha is critically involved in the prevention of cell death and functional development of mature B cells.

Animals↗
PubMed2001

Role of phasic dynamism of p38 mitogen-activated protein kinase activation in ischemic preconditioning of the canine heart.

Although ischemic stress, including ischemic preconditioning (IP), activates p38 mitogen-activated protein kinase (MAPK), the relationship between p38 MAPK activation and the underlying cellular mechanisms of cardioprotection by IP is not verified in vivo. We examined the effects of the selective p38 MAPK inhibition on the cardioprotective effect of IP in the open-chest dogs. The coronary artery was occluded 4 times for 5 minutes, separated by 5 minutes of reperfusion (IP) followed by 90 minutes of occlusion and 6 hours of reperfusion. We infused SB203580 into the coronary artery during IP and 1 hour of reperfusion, during IP alone, and during sustained ischemia in the IP group. p38 MAPK activity markedly increased during IP but did not additionally increase at the onset of ischemia and was even attenuated at 15 minutes of sustained ischemia, and heat-shock protein (HSP) 27 was phosphorylated and translocated from cytosol to myofibril or nucleus without affecting total protein level at the onset of ischemia compared with the control group. SB203580 treatment (1 micromol/L) only during IP blunted the infarct size limitation by IP (37.3+/-6.3% versus 7.4+/-2.1% in the IP group, P:<0.01) and attenuated either phosphorylation or translocation of HSP27 during IP. Although the SB203580 treatment throughout the preischemic and postischemic periods had no significant effect on infarct size (33.3+/-9.4%) in this model, treatment with SB203580 only during ischemia partially mimicked the infarct size limitation by IP (26.8+/-3.5%). Thus, transient p38 MAPK activation during ischemic preconditioning mainly mediates the cardioprotection followed by HSP27 phosphorylation and translocation in vivo in the canine heart.

Animals↗
PubMed2001

Volume-weighted mean nuclear volume predicts tumor biology of clinically organ-confined prostate cancer.

BACKGROUND: Estimates of volume-weighted mean nuclear volume (MNV) are the only means by which unbiased estimates of three-dimensional parameters can be obtained from a single two-dimensional section, with stereological methods. The present study was conducted to elucidate the role of MNV in predicting tumor biology for patients treated with radical prostatectomy. METHODS: A retrospective prognostic study of 71 patients with T1/T2 disease, treated with radical prostatectomy alone, was performed. MNV was estimated using biopsy specimens based on a stereological method, and was compared with other preoperative clinical variables. For patients with prostate-specific antigen (PSA) failure, we determined the correlation of MNV with PSA doubling time (PSA DT) which was calculated using PSA values obtained with an ultrasensitive assay. RESULTS: Mean MNVs for pathologically organ-confined and non-organ-confined tumors were 198.9 and 236.3 microm3, respectively; this difference was significant (P = 0.0364). Univariate analysis showed that PSA, MNV, and Gleason score were significant predictors of prognosis (P = 0.0126, 0.0148, and 0.0375, respectively). Multivariate analysis revealed that MNV and preoperative PSA were powerful independent predictors of prognosis (P = 0.0160 and P = 0.0147, respectively), but the Gleason score was not correlated with prognosis (P = 0.4120). For patients with PSA failure, PSA DT was significantly correlated with MNV (r = -0.597, P = 0.0099). When these patients were classified using median PSA DT at 6 months into two groups, MNV was significantly greater in PSA rapid-riser group than in the slow-riser group (P = 0.0008), but no differences were observed between these groups in PSA, the Gleason score, or cancer volume. CONCLUSIONS: The findings of the present study suggest that MNV is a powerful predictor of PSA failure for patients with clinically organ-confined disease treated with radical prostatectomy. More importantly, they suggest that MNV can be a useful new parameter for prediction of tumor biology for patients with PSA failure after radical prostatectomy.

Aged↗
PubMed2001

Localization of human interleukin 13 receptor in non-haematopoietic cells.

Although the functional roles of interleukin (IL-)13 in haematopoietic cells are well investigated, those in non-haematopoietic cells remain to be addressed. IL-13 exerts its actions by binding to the IL-13 receptor (IL-13R) on target cells, which is composed of IL-13Ralpha1 and the IL-4 receptor alpha chain (IL-4Ralpha). However, there has been no study of localization of IL-13R in each tissue. To address this question, we generated monoclonal anti-IL-13Ralpha1 antibody, and performed immunohistochemistry using this antibody and anti-IL-4Ralpha antibody. Distribution of these two components was the same in all examined tissues. Staining was positive in keratinocytes, hair follicles, and sebaceous and sweat glands in skin; in ciliated respiratory epithelial cells in nasal tissue; in heart muscle cells; in foveola cells, gastric glands, and the smooth muscle layer in stomach; and in hepatocytes in liver. However, staining was undetectable in brain and bone marrow. Fibroblasts and endothelial cells were stained in some tissues. These results provide clues to elucidate the known pathological roles of IL-13 in atopic dermatitis and allergic rhinitis, as well as its unknown physiological roles.

Animals↗
PubMed2001

Immunoelectron-microscopic study of Kit-expressing cells in the jejunum of wildtype and Ws/Ws rats.

Interstitial cells of Cajal (ICC) are responsible for generating electrical slow waves in the gastrointestinal (GI) tract. Slow waves regulate the frequency of contractions of the tunica muscularis, and therefore ICC are critical for normal motility in the small intestine. ICC express Kit, the gene product of c-kit, a protooncogene that encodes a receptor tyrosine kinase. Physiological evidence demonstrating that ICC are pacemakers has come from experiments on W-mutant mice which have few Kit-positive cells at the level of the myenteric plexus (IC-MY) and also lack electrical slow waves. In the past identification of ICC required the use of electron microscopy, however the discovery that ICC express Kit has facilitated studies of the distribution of ICC in several species. Immunoelectron microscopy to relate ultrastructure to Kit expression has only been performed in a limited number of studies of mice. We examined the ultrastructure of Kit-expressing cells in the rat using immunoelectron microscopy and an anti-Kit antibody. We compared the presence and appearance of Kit-expressing ICC in wildtype and Ws/Ws rats, which carry a mutation in the white spotting locus and have a phenotype similar to W/Wv mutant mice. Kit-expressing cells could be detected in the myenteric plexus (MY) and deep muscular plexus (DMP) regions of the small intestine of wildtype animals. In Ws/Ws rats, Kit-expressing cells were not observed in the region of MY, but were observed in the DMP. The density of Kit-positive cells in the DMP of Ws/Ws rats was similar to those in wildtype rats. Electron microscopy showed that Kit-expressing cells at the level of the MY of the rat had similar ultrastructural features as IC-MY in wildtype mice. IC-DMP in the rat of both wildtype and Ws/Ws mutants were similar in structure to IC-DMP of the mouse. We conclude that wildtype rats have IC-MY and IC-DMP in the tunica muscularis of the jejunum. ICC express Kit-like immunoreactivity (Kit-LI) in the rat as in the mouse. IC-MY are absent in the small intestine of Ws/Ws rats, and this corresponds to the lack of Kit-labeling in this region. Ws/Ws rats, however, possess IC-DMP with normal ultrastructural features and Kit-LI. The absence of IC-MY of Ws/Ws rats is likely to account for the abnormal contractile activity of the GI tract observed in these mutants. The present study suggests that Ws/Ws rats could provide an interesting model to investigate the physiological significance of pacemaker activity because they manifest a defect in IC-MY.

Animals↗
PubMed2001

Hip-shelf procedure in the treatment of osteonecrosis of the transpositioned acetabulum after rotational acetabular osteotomy.

Necrosis of the transpositioned acetabulum after rotational acetabular osteotomy (RAO) is a major complication characteristic of this procedure. This complication, although rare, has been thought difficult to treat. We report a patient with acetabular osteonecrosis and subsequent collapse after RAO that was effectively treated with a shelf operation, providing satisfactory remodeling of the hip joint. A 16-year-old female had undergone RAO for the treatment of developmental acetabular dysplasia. Postoperative radiography showed that the osteotomized acetabular fragment was unusually thin, and that the osteotome entered the hip joint during the surgery. Five months after the RAO, X-rays revealed significant collapse of the transpositioned acetabulum, and femoral head subluxation caused by postoperative osteonecrosis. Seven months after the RAO, the patient underwent a hip-shelf procedure. The remaining acetabular fragment was used in this procedure, according to the Spitzy method. Seven years after the second operation, favorable remodeling of the hip joint was observed; however, early osteoarthritic changes, including slight joint space narrowing, bone sclerosis of the new acetabulum, and bone cysts within the femoral head, were seen.

Acetabulum↗
PubMed2001

Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal.

It has recently been proposed that gastrointestinal stromal tumors (GISTs) originate from stem cells that differentiate toward a phenotype of interstitial cells of Cajal (ICCs). Nestin is a newly identified intermediate filament protein, and is predominantly expressed in immature cells, such as neuroectodermal stem cells and skeletal muscle progenitor cells, and tumors originating from these cells. In this study, we examined, using immunohistochemistry, the nestin expression in GISTs and ICCs to clarify the origin of GISTs. Strong immunoreactivity for nestin was observed in all 18 GISTs, and its expression was confirmed by Western blot and Northern blot analyses. In contrast, three leiomyomas and a schwannoma that developed in the gastrointestinal tract showed no apparent immunoreactivity for nestin. Among 17 mesenchymal tumors (seven leiomyosarcomas, five malignant peripheral nerve sheath tumors, and five fibrosarcomas) that occurred in sites other than the gastrointestinal tract, only two malignant peripheral nerve sheath tumors were moderately immunoreactive for nestin. Furthermore, with fluorescence double immunostaining of the normal small intestine, nestin expression was demonstrated in ICCs. These results show that nestin may be a useful marker for diagnosis of GISTs, and support the current hypothesis that GISTs are tumors of stem cells that differentiate toward an ICC phenotype.

Adult↗
PubMed2001

Microwave thermotherapy for benign prostatic hyperplasia with the Dornier Urowave: response durability and variables potentially predicting response.

OBJECTIVES: To evaluate the clinical efficacy and durability of transurethral microwave thermotherapy (TUMT) in the treatment of benign prostatic hyperplasia. The clinical variables useful in predicting outcome were identified. METHODS: From October 1996 to March 2000, 58 patients with symptomatic benign prostatic hyperplasia were treated with TUMT using the Urowave device. Treatment outcome was evaluated by the International Prostate Symptom Score (IPSS), quality-of-life assessment score, and urodynamic investigation. The patients were divided into those having a good and poor response on the basis of the degree of IPSS decrease at 3 months. RESULTS: The mean IPSS significantly decreased from 19.2 at baseline to 13.3 at 3 months (P <0.0001). The mean quality-of-life score changed from 4.6 at baseline to 2.9 at 3 months (P <0.0001). No statistically significant differences in peak flow rate, postvoid residual volume, Schäfer's obstruction scale, or detrusor pressure at peak flow were noted before or after TUMT. The pretreatment IPSS of the good response group was significantly higher than that of the poor response group (P=0.017). A more significant difference was obtained for the obstructive score (P = 0.002), and no difference was observed in the irritative score (P = 0.631). The Schäfer grading scale score of the good response group was significantly smaller than that of the poor response group (P = 0.047). CONCLUSIONS: TUMT with the Urowave was effective in eliminating symptoms associated with benign prostatic hyperplasia, but did not markedly improve the objective voiding parameters. Patients with urodynamically less obstructive symptoms but subjectively more obstructive symptoms are therefore probably good candidates for TUMT.

Aged↗
PubMed2001

Expression of osteopontin by exudate macrophages in inflammatory tissues of the middle ear: a possible association with development of tympanosclerosis.

Tympanosclerosis is a condition leading to a calcification process in the middle ear, and often develops after chronic inflammation of the middle ear. Since osteopontin (OPN) has been shown to participate in the pathological calcification, we here investigated whether OPN is involved in the process of calcification in tympanosclerosis. The tympanic membrane and middle ear mucosa, obtained from patients of tympanosclerosis and chronic otitis media, were histologically classified depending on the calcification degree. In hyalinized tissues with macroscopic calcification and fibrous tissues with microscopic calcification, OPN was immunohistochemically found in the calcification sites. In inflammatory tissues with microscopic calcification, OPN was also found in the calcifying foci, and many OPN mRNA-expressing cells, determined by in situ hybridization, located around their foci. Moreover, immunohistochemical double staining of OPN and CD68 showed that the OPN-expressing cells were CD68-positive, indicating these cells were macrophages. In inflammatory tissues without calcification, immunohistochemistry of CD68 and in situ hybridization of OPN mRNA revealed that most OPN mRNA-expressing cells were CD68-positive. The expression of OPN mRNA in inflammatory tissues was also shown by reverse transcriptase polymerase chain reaction. These results suggest that OPN secreted by exudate macrophages might be an important regulator in the calcification of tympanosclerosis.

Adolescent↗
PubMed2001

Malignant portal venous obstructions treated by stent placement: significant factors affecting patency.

PURPOSE: To identify factors affecting stent occlusion after stent placement in the portal vein in patients with malignant portal vein invasion. MATERIALS AND METHODS: Forty patients were studied. Twenty-three patients had hepatocellular carcinoma, nine patients had pancreatic cancer, and eight patients had bile duct cancer. Stents were placed in the portal venous system across stenotic (n = 28) or obstructive (n = 12) lesions after percutaneous transhepatic portography. Bare stents were used in 33 patients and covered stents were used in seven patients. Twenty-two variables were analyzed with use of univariate and multivariate analyses to identify significant factors affecting stent occlusion. RESULTS: Stents remained patent during a mean follow-up period of 11.9 months (range, 2-61 mo) in 60% of the patients. Stent occlusion was found in 40% of the patients, with a mean period until occlusion of 3.7 months (range, 0.2-16 mo). In the univariate analysis, the following five factors were significantly associated with a higher probability of stent occlusion: (i) splanchnic vein involvement, (ii) Child-Pugh class C, (iii) obstruction of the portal venous system, (iv) pancreatic cancer, and (v) lack of anticancer treatment after stent placement. In the multivariate analysis, the first three factors were found to have independent value for stent occlusion. CONCLUSIONS: Splanchnic vein involvement, severe hepatic dysfunction, and obstruction of the portal venous system are the most important factors affecting stent occlusion in patients with malignant portal vein invasion.

Adult↗