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Biomedical subjects

H Nawata

Publications and source records attributed to H Nawata.

At least 127 records · Page 7Linked to original sources
PubMed1999

Minute gastric carcinoma of differentiated type with special reference to the significance of intestinal metaplasia, proliferative zone, and p53 protein during tumor development.

BACKGROUND: The differentiated type of minute gastric carcinoma (MGC), measuring less than 5 mm in greatest dimension, has been considered to represent the incipient phase of gastric carcinoma. To determine the clinicopathologic features of MGCs, the authors examined tissues from MGCs with a view to clarifying their histopathologic diversity. The immunohistochemistry of these tissues was determined using monoclonal antibody against p53 and Ki-67, and their mucin-histochemical types were determined with reference to the presence of intestinal metaplasia (IM) within their surrounding mucosa. METHODS: One hundred three specimens were obtained from 93 patients with MGCs. Each lesion was evaluated both macroscopically and histologically, and the degree of IM was assessed. All sections were examined mucin-histochemically with Con A, GOS, and HID-AB, and stained with commercially available monoclonal antibodies, PAb 1801 and Ki-67. Additional nonminute carcinomas present within the same stomachs were used as controls. RESULTS: Macroscopically, most lesions were depressed. IM was noted in the surrounding mucosa of 85 MGCs (82.5%). Immunohistochemically, 25 MGCs (24.2%) showed p53 overexpression, although the rate of p53 overexpression was increased to 34.6% in other nonminute carcinomas from the same stomachs. Twenty-four MGCs were associated with a proliferative zone, demonstrated by Ki-67 positive cells. Statistically significant differences in the rate of p53 overexpression were observed between MGCs with a proliferative zone and those without. Mucin phenotypes of MGCs tended to imitate their own surrounding mucosa. CONCLUSIONS: The MGCs, which represent the incipient phase of early gastric carcinoma, have various histologic, immunohistochemical, and mucin-histochemical features. It would seem that p53 expression is more closely related to the progression of MGCs than to their carcinogenesis.

Adult↗
PubMed1999

Nicotinamide potentiates TSHR and MHC class II promoter activity in FRTL-5 cells.

Here we show that nicotinamide modulates the promoter activity of rat thyrotropin (TSHR) and major histocompatibility complex (MHC) class II genes in rat FRTL-5 thyroid cells, and have identified a novel mechanism for its action. TSHR and MHC class II, are potentiated through reduced expression of a common repressor of these two genes, TSEP-1 (TSHR suppressor element binding protein-1)/YB-1. Thus we show that TSHR mRNA is increased and TSHR promoter activity was concentration-dependently activated from 0 to 40 mM nicotinamide. The promoter lengths of TSHR and MHC class II containing TSEP/YB-1 binding sites were enhanced by 40 mM nicotinamide, but not the ones deleted of these binding sites. TSEP-1/YB-1 binding to the recognition sites in both TSHR and MHC class II promoters was reduced in nicotinamide-treated FRTL-5 nuclear extracts. Nicotinamide reduced the expression of TSEP-1/YB-1 mRNA and TSEP-1/YB-1 protein in the nucleus.

Animals↗
PubMed1999

Novel germline mutations of the MEN1 gene in Japanese patients with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroid glands, the pancreatic islet cells, and the anterior pituitary. Germline mutations of the MEN1 gene in three independent Japanese cases with MEN1 were analyzed. Case 1 has revealed a 2-bp (TA) insertion at nucleotide position 341 (341insTA) in exon 2, which shifts the reading frame such that the mutant protein has a completely different amino acid sequence from codon 78 to the premature stop codon at 119. In case 2, a nucleotide substitution, i.e., TAG in place of TGG, which encodes tryptophan at codon 198 was identified (nonsense mutation). These mutations were heterozygously present and have not been reported previously. Case 3 showed no mutations in the protein-coding exons and exon-intron junctions of the MEN1 gene by single-strand conformation polymorphism or direct sequencing of the polymerase chain reaction (PCR) fragments. We confirmed the finding that patients with MEN1 carry heterozygous germline mutations in the MEN1 gene, which is compatible with the idea that the MEN1 gene is a tumor suppressor gene. The reason why mutations in the coding region of the MEN1 gene could not be detected by PCR-based analysis in some of the MEN1 patients, e.g. case 3, needs to be clarified further.

Adult↗
PubMed1999

Grasping forceps assisted endoscopic resection of large pedunculated GI polypoid lesions.

BACKGROUND: Endoscopic resection of pedunculated polyps with heads 1 cm or greater in diameter is technically complex. To facilitate removal of such polyps, we developed grasping forceps assisted endoscopic resection in which we use a detachable snare to prevent polypectomy-related bleeding and evaluated the usefulness and safety of the procedure. METHODS: Ten patients with pedunculated polyps with heads 1 cm or greater in diameter were treated with this technique. A two-channel endoscope, grasping forceps, electrosurgical snare, and detachable snare are needed for the procedure. RESULTS: All lesions were easily and safely resected. During this procedure, a two-channel endoscope with grasping forceps proved to be satisfactory for handling the detachable snare and the electrosurgical snare and for accurate recognition of the stalk under good visual control. No hemorrhage, perforation, or other complication occurred as a result of use of this new technique. CONCLUSIONS: Grasping forceps assisted endoscopic resection of polyps with a detachable snare is an effective method for the prevention of polypectomy-associated bleeding. This technique makes it technically easier to resect large pedunculated polypoid lesions of the GI tract.

Aged↗
PubMed1999

Induction of apoptosis in rat hepatic stellate cells by disruption of integrin-mediated cell adhesion.

Cell-matrix adhesion is recognized as a physiologic determinant of cell growth and survival. Integrin occupancy seems to be a primary role. We sought to investigate the signal transduction pathways for integrin effects on cell survival in hepatic stellate cells. Integrin function was antagonized by the soluble integrin recognition sequence pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) in primary cultures of rat hepatic stellate cells. Integrin antagonism with GRGDS peptide induced apoptosis. To investigate signal transduction mechanisms for the effect of integrins on cell survival in hepatic stellate cells, the expression of p53, Bcl-2, and Bax was analyzed. Incubation with soluble GRGDS peptide resulted in increased expression of p53 and decreased the Bcl-2/Bax ratio. In conclusion, these findings indicate that the abrogation of cell adhesion with soluble GRGDS peptide plays a critical role in the induction of apoptosis of rat hepatic stellate cells.

Animals↗
PubMed1999

Role of Rho small GTP binding protein in the regulation of actin cytoskeleton in hepatic stellate cells.

BACKGROUND/AIMS: In the fibrotic response to liver injury, hepatic stellate cells are activated, leading to the myofibroblastic cell shape, with actin cytoskeletal reorganization and increased extracellular matrix production. The reorganization of actin cytoskeleton suggests that the small GTP binding protein Rho might modulate the process of this myofibroblastic change. The aim of this study was to investigate the role of Rho in the phenotypic changes of hepatic stellate cells. METHODS: The phenotypic changes were investigated by the overexpression of Rho regulator, Rho GDI or dominant negative mutant of Rho in mouse hepatic stellate cell line, GRX cells. In activated rat hepatic stellate cells, the effects of microinjection of Botulinus toxin C3, which is the specific inhibitor for Rho, were analyzed. Furthermore, the effect of C3 on the type I collagen accumulation in hepatic stellate cells was investigated. RESULTS: Overexpression of Rho GDI or the dominant negative mutant of Rho caused the shrinkage cell shape and suppressed stress fiber formation. Microinjection of toxin C3 caused a markedly distorted cell shape and the disappearance of stress fibers in rat stellate cells. In addition, C3 strongly suppressed collagen accumulation in activated stellate cells. CONCLUSIONS: These results suggest that Rho regulates the actin cytoskeletal reorganization, and may be implicated in the collagen accumulation in activated stellate cells. These findings provide evidence for the role of Rho in the myofibroblastic phenotype in hepatic stellate cells.

Actins↗
PubMed1999

Macrophage inflammatory protein 1alpha enhances in a different manner adhesion of hematopoietic progenitor cells from bone marrow, cord blood, and mobilized peripheral blood.

Regulatory mechanisms governing adhesion of hematopoietic progenitor cells to the stromal nische are poorly understood. Growth factors such as stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor, and thrombopoietin were reported to upregulate the adhesion of hematopoietic progenitors to immobilized fibronectin through activation of integrin alpha4beta1 and alpha5beta1. Macrophage inflammatory protein (MIP)-1alpha is a C-C chemokine that suppresses colony formation by stem/progenitor cells in vitro. We asked if MIP-1alpha would modulate the adhesive phenotype of colony-forming cells (CFCs) obtained from healthy donor bone marrow (BM), cord blood (CB), and mobilized peripheral blood (mPB) CD34+ cells, in comparison with SCF, using immobilized fibronectin. SCF significantly increased the level of adhesion of CFCs from BM, CB, and mPB. On the other hand, MIP-1alpha significantly increased the level of adhesion of CFCs from BM and CB, but less so from mPB. The effects of MIP-1alpha were inhibited by blocking antibodies to integrin alpha4, alpha5, or beta1, and polymerization plus rearrangement of F-actin were observed in affected cells by labeling with rhodamine-conjugated phalloidine. These data indicate that the effect of MIP-1alpha on the adhesive phenotype of CFCs is mediated by modulation of the organization of integrin. The amount of MIP-1alpha receptor on mPB was less than for BM or CB, which may explain the distinct characteristics in the adhesive response induced by MIP-1alpha. We suggest that hematopoietic progenitor cells from different sources may be heterogeneous with respect to maturation, integrin affinity, MIP-1alpha receptor expression, and regulation of MIP-1alpha signaling. Our data indicate that MIP-1alpha may affect migration, homing, and mobilization of hematopoietic progenitors by modulating the adhesive phenotype of these cells.

Actins↗
PubMed1999

Soluble Arg-Gly-Asp peptides reduce collagen accumulation in cultured rat hepatic stellate cells.

Hepatic stellate cells play a central role in the pathogenesis of liver fibrosis, both via production of extracellular matrix proteins and through secretion of matrix metalloproteinases. In this study, effects of soluble cell adhesion peptides on collagen type I accumulation and on expression of matrix metalloproteinases were analyzed. First, we revealed the expression of alpha5-integrin on hepatic stellate cells by immunostaining. Treatment with 100 microg/ml of soluble Arg-Gly-Asp (RGD) peptides was found to reduce accumulation of type I collagen without any effects on its transcriptional level in rat hepatic stellate cells, whereas a control peptide Gly-Arg-Gly-Glu-Ser (GRGES) had no such effect. Soluble RGD peptides also increased the secretion of collagenase by stellate cells. These data suggested that reduced accumulation of type I collagen caused by the RGD peptide ligation to integrins on hepatic stellate cells was partly due to stimulated expression of collagenase by stellate cells.

Animals↗
PubMed1999

Thapsigargin-induced endothelium-dependent triphasic regulation of vascular tone in the porcine renal artery.

1. To elucidate the role of thapsigargin-induced Ca2+ entry in endothelial cells in the regulation of vascular tone, changes in Ca2+ and force of smooth muscle were simultaneously monitored in fura-2-loaded strips of porcine renal artery. 2. During phenylephrine-induced sustained contraction, thapsigargin caused an endothelium-dependent triphasic response; an initial relaxation, a subsequent transient contraction, and a sustained relaxation. The initial relaxation and the contraction were associated with a decrease and an increase in [Ca2+]i, respectively. There was no apparent [Ca2+]i decrease during the sustained relaxation. Thapsigargin-induced responses were observed at 10-8 M and higher concentrations, with the maximum response observed at 10-6 M. 3. The transient contraction was inhibited by a cyclo-oxygenase inhibitor (10-5 M indomethacin), a thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor antagonist (10-5 M ONO-3708), and a TXA2 synthase inhibitor (10-5 M OKY-046). 4. During the phenylephrine-induced contraction in the presence of indomethacin, thapsigargin caused an initial, but not a sustained relaxation, in the presence of Nomega-nitro-L-arginine methylester (L-NAME). During the contraction induced by phenylephrine plus 40 mM K+-depolarization in the presence of indomethacin, thapsigargin induced both a transient and a sustained relaxation. However, these relaxations were completely abolished in the presence of L-NAME. 5. Thapsigargin caused a large Ca2+ elevation in cultured endothelial cells of the renal artery. The concentration-response relation was thus similar to that for force development in the arterial strips. 6. In conclusion, thapsigargin-induced Ca2+ entry in endothelial cells led to triphasic changes in the tone of the porcine renal artery. The endothelium-dependent contraction was mediated mainly by TXA2. Nitric oxide and hyperpolarizing factor are both involved in the initial relaxation. However, a sustained relaxation was observed which mainly depended on nitric oxide.

Animals↗
PubMed1999

Effect of pancreastatin on cerulein-stimulated pancreatic blood flow and exocrine secretion in anaesthetized rats.

BACKGROUND: Pancreastatin (PST) is an inhibitor of pancreatic exocrine secretion in vivo but not in vitro, which suggests that the inhibitory effect of PST is indirect, that is, not mediated by a specific receptor on pancreatic acinar cells. In this study, we investigated the effects of PST on pancreatic exocrine secretion and local pancreatic blood flow in anaesthetized rats to elucidate the participation of PST in indirect regulation of pancreatic exocrine function through blood supply. METHODS: Pancreastatin (100, 200 or 500 pmol/kg per h) was administered intravenously under background infusion of cerulein (0.5 microg/kg per h), a cholecystokinin analogue. Pancreatic exocrine secretion was monitored by volume and protein output of the pancreatic juice and local pancreatic blood flow was measured by the hydrogen gas clearance method. RESULTS: Pancreastatin significantly reduced cerulein-induced local pancreatic blood flow in a dose-dependent manner. Pancreatic exocrine secretion was also reduced significantly by PST dose-dependently. Pancreastatin did not change systemic blood pressure. These results suggested that the reduction of pancreatic blood flow is associated with the reduction of pancreatic exocrine secretion. CONCLUSIONS: We conclude that the mechanism of PST-induced inhibition of pancreatic exocrine secretion is, at least, partly mediated by the reduction of local pancreatic blood flow through blockade, caused by the action of cerulein on pancreatic blood flow.

Animals↗
PubMed1999

Thiazolidinedione induces apoptosis and monocytic differentiation in the promyelocytic leukemia cell line HL60.

Thiazolidinedione (TZD) is known to be a potent activator of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor that constitutes a heterodimer with retinoid X receptor (RXR). Since a considerable amount of PPARgamma is expressed in various hematopoietic cells, the present study was undertaken to examine the effect of TZD in the absence or presence of LG100268, an RXR-selective ligand, on a cultured promyelocytic leukemia cell line, HL60. Treatment with TZD (25-50 microM troglitazone or pioglitazone) markedly suppressed cell proliferation of HL60. A cell cycle analysis revealed that the suppressive effect of troglitazone on HL60 cell proliferations was caused by G0/G1 cell cycle arrest as well as by an apoptotic effect. Treatment with the same concentration of troglitazone also induced the monocytic differentiation of HL60 cells. The apoptotic or the differentiating effect of TZD on HL60 cells was synergistically enhanced by the combined treatment with 1 microM LG100268, while LG100268 alone neither had an apoptotic nor a differentiating effect on HL60 cells. These results suggest that these actions are mediated through the nuclear receptor system constituted by the PPARgamma: RXR heterodimer.

Antineoplastic Agents↗
PubMed1999

Dax-1 as one of the target genes of Ad4BP/SF-1.

The DAX-1 (also known as AHC) gene encodes an unusual member of the nuclear hormone receptor superfamily. DAX-1 plays a critical role during gonadal and adrenal differentiation since mutations of the human DAX-1 gene cause X-linked adrenal hypoplasia congenita associated with hypogonadotropic hypogonadism. In recent studies, DAX-1 was reported to function as a transcriptional suppressor of Ad4BP/SF-1, a critical transcription factor in gonadal and adrenal differentiation. With respect to implication of Ad4BP/SF-1 in the transcriptional regulation of the DAX-1 gene, inconsistent findings have been previously reported. We investigated the upstream region of the mouse Dax-1 (also known as Ahch) gene and identified a novel Ad4/SF-1 site by transient transfection and electrophoretic mobility shift assays. In addition, immunohistochemical analyses with a specific antibody to Dax-1 indicated the presence of immunoreactive cells in steroidogenic tissues, pituitary gland, and hypothalamus. Although the distributions of Dax-1 and Ad4BP/SF-1 were very similar, they were not completely identical. The expression of Dax-1 was significantly impaired in knock-out mice of the Ftz-f1 gene, which encodes Ad4BP/ SF-1. Taken together, our findings indicate that Ad4BP/SF-1 controls the transcription of the Dax-1 gene.

Adrenal Cortex Neoplasms↗
PubMed1999

Pre-operative staging of ampullary tumours by endoscopic ultrasound.

Ampullary carcinomas have a significantly higher resectability rate and better prognosis than other periampullary carcinomas, although the prognosis is poor with advanced disease. Accurate tumour staging is therefore important in surgical planning. Our objective was to evaluate the usefulness of, and problems associated with, endoscopic ultrasound (EUS) in the pre-operative staging of ampullary tumours. 35 patients with ampullary tumours were pre-operatively examined with EUS. The imaging results were compared with histopathological findings of the resected specimen according to the TNM staging classification. The overall accuracy of tumour (T) staging was 74% (26/35) for all tumours, and 67% (6/9), 71% (10/14) and 83% (10/12) respectively for T1, T2 and T3 tumours. The overall accuracy of nodal (N) staging was 63%. In diagnosing pancreatic invasion, EUS had an accuracy of 86% (30/35), a sensitivity of 83% (10/12), and a specificity of 87% (20/23). In conclusion, EUS provides an accurate method of evaluating the stage of ampullary tumours, especially infiltration into the pancreas. This modality is useful to surgeons in deciding on an appropriate therapeutic approach and in giving a prognosis.

Aged↗
PubMed1999

Telomerase activity in myeloma cells is closely related to cell cycle status, but not to apoptotic signals induced by interferon-alpha.

Telomeres, G-rich structures at the ends of chromosomes are essential for maintaining chromosomal integrity. Most tumor cells contain telomerase, a ribonucleoprotein that elongates telomeric repeats, and it plays an essential role in indefinite proliferation. To better understand regulatory mechanisms of telomerase, in relationship with apoptosis and the cell cycle, we examined telomerase activity in PCM6, an interleukin-6 (IL-6)-responsive, interferon-alpha (IFN-alpha)-sensitive multiple myeloma cell line, using a PCR-based assay. When PCM6 cells were cultured in serum-free media, the addition of IFN-alpha resulted in apoptosis of the cells, but with no influence on telomerase activity. When IFN-alpha was added to the culture with serum plus rIL-6 after serum deprivation, G1-S transition was inhibited and telomerase activity was lower compare to findings in culture with no IFN-alpha. Dose response experiments of rIL-6 and IFN-alpha, and the measurement of telomerase activity of sorted cells in S-phase using CD71, demonstrated a higher activity of telomerase in the samples which contained a larger proportion of cells in S-phase. These data indicate that regulation of telomerase activity is closely related to cell cycle status, in particular cells in S-phase have an high telomerase activity. While telomeres play an important role in cellular senescence, the regulation of telomerase is independent from apoptotic signals induced by IFN-alpha in myeloma cells.

Apoptosis↗