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Biomedical subjects

H Shimura

Publications and source records attributed to H Shimura.

At least 19 recordsLinked to original sources
PubMed1998

Hepatocyte growth factor stimulates the invasion of gallbladder carcinoma cell lines in vitro.

Human gallbladder cancer is highly malignant and its prognosis is usually poor depending on the extent of surrounding tissue invasion. We examined in vitro the invasive activity of four gallbladder cancer cell lines (GB-d1, GB-h3, GB-d2 and FU-GBC-1) in the absence or presence of hepatocyte growth factor (HGF). In type 1 collagen gel culture, HGF stimulated cell proliferation and induced an invasive phenotype of arborizing structures in GB-d1, GB-h3 and GB-d2. In a Matrigel invasion assay, invasion was also induced in three of these cell lines by HGF but not in FU-GBC-1. Cellular motility was, however, stimulated by HGF in all of the four cell lines to various extents. Zymography for proteolytic enzymes demonstrated high levels of type IV collagenase and urokinase-type plasminogen activator (u-PA) activity in GB-d1, GB-h3 and GB-d2 even in the absence of HGF. In the presence of HGF, the 72 kDa type IV collagenase (MMP-2) activity of GB-h3 and u-PA activities of GB-d1, GB-h3 and GB-d2 were enhanced. In contrast, the MMPs and PAs activities of FU-GBC-1 were faint irrespective of the addition of HGF. A Western blot analysis demonstrated higher levels of 190 kDa c-MET product (HGF receptor) of GB-d1, GB-h3 and GB-d2 than that of FU-GBC-1. The invasion in the Matrigel assay stimulated by HGF was inhibited by protease inhibitors, aprotinin and FOY-305, as well as by anti-HGF antibody. These results thus suggest that, in addition to the importance of the proteolytic activity, the cellular motility induced via the HGF/HGF-receptor system is essential for the invasive progression of gallbladder carcinoma cells.

Adenocarcinoma↗
PubMed1998

Augmentation of mitochondrial reduced glutathione by S-adenosyl-L-methionine administration in ischemia-reperfusion injury of the rat steatotic liver induced by choline-methionine-deficient diet.

We examined whether warm ischemia-reperfusion (I/R) damage of the rat steatotic liver can be reduced by administration of S-adenosyl-L-methionine (SAMe). We examined the effect of SAMe on the mitochondrial reduced-glutathione (GSH) pool. Sixty minutes of partial left lobar vascular clamping followed by 2 h of reperfusion were employed for a model of hepatic warm ischemia. Either 5% dextrose or SAMe was injected intraperitoneally 2 h before I/R in steatotic rats (S-D5% or S-SAMe group). Serum liver enzyme concentrations 2 h after reperfusion were significantly lower in the S-SAMe group than in the S-D5% group. The cytosolic and mitochondrial GSH concentrations after I/R were significantly higher in the S-SAMe group than in the S-D5% group (p < 0.05). The cytosolic and mitochondrial oxidized-glutathione/GSH ratios after I/R were significantly greater in the S-D5% group than in the S-SAMe group (p < 0.01). The adenosine triphosphate concentration was higher in the S-SAMe group than in the S-D5% group (p = 0.0515). These results show that hepatocellular and mitochondrial oxidative stress after I/R in the steatotic liver can be reduced by administration of SAMe. The results also show that mitochondrial function and hepatocellular integrity can be restored by administration of SAMe in steatotic rats.

Animals↗
PubMed1998

Modulation of cholesterol metabolism affects tumor growth in hamsters.

To investigate the effects of cholesterol and cholesterol-lowering agents on cholesterol metabolism and tumor growth, 0.5% cholesterol, 2% cholestyramine, or 0.01% simvastatin was fed to hamsters with transplanted Simian virus40 transformed tumor cells. Tumor weight, tissue cholesterol and DNA concentrations, and HMG-CoA reductase activities were determined. Cholesterol or cholestyramine feeding did not affect the tumor growth, however, the tumor weight and DNA concentration were decreased and tumor HMG-CoA reductase activity was increased in the simvastatin group. In conclusion, simvastatin may inhibit the DNA synthesis and growth of the Simian virus40 transformed tumor cells possibly through the inhibition of cholesterol and isoprenoids synthesis in the hamster.

Animals↗
PubMed1997

HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor.

We prepared a specific antagonist for hepatocyte growth factor (HGF) and designated it HGF/NK4. HGF/NK4 is composed of N-terminal 447 amino acids of the alpha-chain of HGF, thus contains the N-terminal hairpin domain and subsequent four kringle domains. HGF/NK4 competitively inhibited the specific binding of HGF to the receptor. Importantly, HGF/NK4 neither stimulated DNA synthesis of primary cultured rat hepatocytes (mitogenesis) nor induced cell scattering (motogenesis) and branching tubulogenesis (morphogenesis) of MDCK renal epithelial cells, however, HGF/NK4 almost completely inhibited the mitogenic, motogenic, and morphogenic activities of HGF. HGF/NK4 also suppressed tyrosine phosphorylation of the c-Met/HGF receptor induced by HGF. Apparently this is the first documentation of a specific antagonist which abrogates the mitogenic, motogenic, and morphogenic activities of HGF.

Animals↗
PubMed1997

Allopurinol reduced hepatic ischemia-reperfusion injury exacerbated by inhalation of high-concentration oxygen in rats.

Exposure to high-concentration oxygen (O2) increases lipid peroxidation of the cellular membrane, leading to tissue injury which may involve hepatic ischemia-reperfusion (I/R) injury. We examined the effects of inhaling high-concentration O2 on hepatic I/R injury with allopurinol, which is a xanthine oxidase inhibitor. Partial hepatic ischemia was performed in rats with or without allopurinol under 21 or 100% O2 inhalation. Levels of lipid peroxide, serum liver enzymes, and hepatocellular oxidative stress in the 100% O2 group were significantly higher than in the 21% O2. Administration of allopurinol significantly inhibited those changes in the 100% O2 group. Severe degeneration of mitochondria were noted in the 100% O2 group, but appeared to be reduced by allopurinol. Results suggest that inhalation of high-concentration O2 during liver surgery may increase lipid peroxidation and exacerbate hepatic I/R injury, but those changes may be prevented by allopurinol.

Alanine Transaminase↗
PubMed1997

Iodide uptake and experimental 131I therapy in transplanted undifferentiated thyroid cancer cells expressing the Na+/I- symporter gene.

131I therapy is a widely accepted treatment for differentiated thyroid cancers which can accumulate iodide. We evaluated the efficiency of 131I therapy against tumors which are transfected with the Na+/I- symporter (NIS) gene. We transfected the rat NIS cDNA expression vector into malignantly transformed rat thyroid cells (FRTL-Tc) which do not concentrate iodide. The resultant cell line (Tc-rNIS) accumulated 125I 60-fold in vitro. The FRTL-Tc cells formed solid tumors after injection of cells into subcutaneous tissues of Fischer 344 rats. Tumors formed with Tc-rNIS cells accumulated up to 27.3% of total 125I administered, and concentrated 125I 11 to 27-fold in the tumors. Extracorporeal measurement of radioactivity in the tumors revealed that 125I accumulation peaked at 90 min, and decreased to half levels 6 h after the injections. To investigate the effect of 131I administration on the tumor growth, we injected Na131I 2 and 3 weeks after the transplantation of the cells. The Na131I did not change the tumor volume significantly in either the FRTL-Tc or the Tc-rNIS-induced tumors. The short (6 h) effective half life of 131I in the tumors diminished the radiation dose to the tumor cells. However, this approach may prove beneficial in the treatment of radiosensitive cancers, and could be employed diagnostically.

Animals↗
PubMed1997

Regulation of thyrotropin receptor gene expression in 3T3-L1 adipose cells is distinct from its regulation in FRTL-5 thyroid cells.

We previously have demonstrated that rat adipose tissue expresses TSH receptor (TSHR) messenger RNAs (mRNAs) at levels approaching those detected in the thyroid. Furthermore, we recently reported that TSHR mRNA is detected in fibroblast-like 3T3-L1 cells after their hormone-induced differentiation into adipocytes. TSH induces cAMP formation and lipolysis in differentiated 3T3-L1 cells. We now show that, in Northern blot analyses, TSH-induced down-regulation of TSHR mRNA levels, which can be duplicated by forskolin and dibutylyl cAMP, i.e. which is cAMP-mediated. We also have demonstrated that a beta-adrenergic stimulant, which stimulates cAMP formation in adipocytes, induces a down-regulation of TSHR mRNA levels in 3T3-L1 adipocytes. Nuclear run-on assays show that the ability of TSH/cAMP to decrease TSHR mRNA levels in 3T3-L1 cells reflects transcriptional regulation. This report also demonstrates that TSHR gene expression in 3T3-L1 adipocytes is regulated in a manner distinct from that observed in thyroid cells. Thus, in fully differentiated 3T3-L1 adipocytes, TSH-induced down-regulation of TSHR mRNA levels is evident within 1 h and is near maximum within 4 h after addition of TSH. A transient increase of TSHR gene expression, which has been demonstrated in FRTL-5 thyroid cells, was not observed in 3T3-L1 adipocytes. The down-regulation of TSHR gene expression induced by TSH/cAMP in 3T3-L1 cells is cycloheximide-insensitive, suggesting that continuous protein synthesis is not required for this process. In contrast, the down-regulation of TSHR gene expression observed in FRTL-5 cells is sensitive to cycloheximide. In both FRTL-5 thyroid cells and 3T3-L1 adipocytes, insulin or serum increased TSHR mRNA levels. Although insulin or serum was required for the TSH-induced down-regulation of TSHR mRNA levels in FRTL-5 thyroid cells, neither insulin nor serum was required for TSHR down-regulation in 3T3-L1 adipocytes. These findings demonstrate that TSH/cAMP regulates TSHR mRNA levels in adipocytes via a regulatory system distinct from that used in FRTL-5 cells. This report further demonstrates that adipose cells do not express thyroid transcription factor-1, which interacts with the TSHR promoter region in FRTL-5 cells, and that 3T3-L1 nuclear extracts exhibit a different binding activity to the cAMP-response element-like element in the TSHR promoter region compared with extracts from FRTL-5 cells.

3T3 Cells↗
PubMed1997

Total excision of mesenteric cysts by laparoscopic surgery: report of two cases.

Mesenteric cysts are relatively rare tumors, and most patients present nonspecific abdominal symptoms until developing larger cysts. We report two cases of mesenteric cysts that were totally excised during laparoscopic surgery. The cysts of both patients were located in the mesenterium of the cecum or ascending colon. Under laparoscopy, the cyst was punctured to collect the cystic fluid for cytology and then completely removed without bowel resection. Histological examination revealed cystic lymphangiomas with endothelial cell lining. The postoperative course was uneventful. Laparoscopic treatment of benign abdominal cysts is an alternative safe and less invasive operation.

Aged↗
PubMed1997

Xanthogranulomatous cholecystitis versus gallbladder cancer: clinical differentiating factors.

Xanthogranulomatous cholecystitis (XC) is occasionally difficult to differentiate from gallbladder cancer and mandates efforts to avoid extensive operations. We studied the clinical factors to differentiate XC from cancer. Subjects were a consecutive series of 10 patients with XC and 10 with carcinoma, all of whom radiologically showed thickened gallbladder walls. As opposed to cancer, XC was typified by invisible gallbladders on cholangiography (1), the presence of cholelithiasis (P = 0.01) (2), and, intraoperatively, an aspirate of pus or nothing (P < 0.01) (3). To diagnose XC against gallbladder cancer, (1) and (2) in combination and (3) demonstrated an accuracy of 82.4% and 85.0 per cent, respectively. Clinically, XC can be distinguished from gallbladder cancer by cholangiography, calculous findings, and a gallbladder aspirate of pus or nothing.

Aged↗
PubMed1997

A case of Meckel's diverticulum complicated by stenosis of the colon.

Meckel's diverticulum is a common anomaly of the GI tract that is known to cause small intestinal obstruction. A 17-yr-old male who had no history of previous surgery was admitted with intermittent abdominal pain. A barium enema showed extraintestinal compression of the ascending colon, suggesting the existence of a congenital band. Laparoscopy revealed that the ascending colon was lifted up and compressed by the intestinal end of a Meckel's diverticulum with a fibrous band connecting to the umbilicus. The portion of the ileum including the Meckel's diverticulum was resected. This is the first case of stenosis of the colon caused by a Meckel's diverticulum.

Adolescent↗
PubMed1996

Functional expression of thyrotropin receptor in differentiated 3T3-L1 cells: a possible model cell line of extrathyroidal expression of thyrotropin receptor.

Thyrotropin receptor (TSHR) in extrathyroidal tissue, especially fat tissue, is supposed to have important roles in the development of extrathyroidal manifestations of Graves' disease. However, the molecular mechanism of TSHR expression is not known. Expression of TSHR mRNA and TSH-dependent cAMP production were observed in differentiated but not in undifferentiated 3T3-L1 cells. Maximal expression was obtained when the cells were differentiated in the presence of insulin, dexamethasone, and isobutylmethylxanthine (IBMX). Dexamethasone and IBMX were indispensable for the first three days. On the other hand, after day 4, insulin was indispensable for the expression of TSHR. 3T3-L1 cell is the first non-thyroidal cell line reported that expresses TSHR and whose expression can be induced. 3T3-L1 cell can be a good model to investigate the mechanism of expression of TSHR and extrathyroidal manifestations of Graves' disease.

1-Methyl-3-isobutylxanthine↗
PubMed1996

In vitro analysis of peritoneal adhesions in peritonitis.

Peritoneal adhesions due to peritonitis make surgery more difficult and may cause complications. Clarifying the formation mechanism of peritoneal adhesions could help identify methods useful for their prevention. We cultured mesothelial monolayers on plates and microcarriers to simulate the parietal and visceral peritoneum, respectively. We then investigated the effects of lipopolysacchride (LPS) and tumor necrosis factor (TNF) on the homologous adhesion of these mesothelial monolayers. There was no adhesion of mesothelial monolayers in the control medium. When monolayers were cultured with endotoxin (LPS), approximately 90% of the microcarriers adhered to the mesothelial microplate. Adhesions occurred at LPS concentrations of 10 ng/ml and increased linearly in a dose-dependent manner. Kinetic studies revealed that the mesothelial adhesion appeared at 12 hr, and that 90% of the microcarriers were adherent after 24 hr. Open intercellular spaces were observed after a 24-hr treatment with LPS. Scanning electron microscopy revealed that the mesothelial cells adhered to the naked glass. LPS also caused increased permeability of the mesothelial monolayer. TNF did not cause any significant adhesion. Through our experiments we were able to develop an in vitro model of peritoneal adhesion using peritoneal mesothelial cell culture. Endotoxin caused an increase in homologous adhesion of peritoneal mesothelial monolayers, which may correspond to the initial stage of peritoneal adhesion formation in peritonitis.

Dose-Response Relationship, Drug↗
PubMed1996

Semi-quantitative analysis of telomerase in pancreatic ductal adenocarcinoma.

Using a polymerase chain reaction-based amplification assay, we measured telomerase activity in surgically resected pancreatic ductal carcinomas (n = 16 cases) and normal ducts (n = 6), comparing findings with the telomerase activity of a human pancreatic cancer cell line, MIA PaCa-2, as a standard, i.e., relative telomerase activity was determined. Telomerase activity was expressed as the equivalent telomerase intensity of the number of cells of MIA PaCa-2 per microgram protein of tissue samples. The median value for telomerase activity in normal pancreatic ducts was 0.13 and the 25th and 75th percentile were 0.01 and 0.76. The median value for telomerase activity in pancreatic ductal adenocarcinoma was 34.7 (25th percentile, 4.98; and 75th percentile, 296), significantly higher than that of normal ducts (P < 0.001). When the cut-off value was set at 1.0 and 3.0, the telomerase positivity rate of pancreatic ductal adenocarcinomas was 100% and 81.3%, respectively. Telomerase may be specific marker for pancreatic ductal carcinomas.

Biomarkers, Tumor↗
PubMed1996

Acquisition of invasive phenotype in gallbladder cancer cells via mutual interaction of stromal fibroblasts and cancer cells as mediated by hepatocyte growth factor.

Growth and motility of carcinoma cells are regulated through their interactions with host stromal cells, i.e., tumor-stromal interactions. Hepatocyte growth factor (HGF), a ligand for c-Met tyrosine kinase, is a stromal-derived regulator of growth, motility, and morphogenesis. HGF stimulated proliferation and motility of GB-d1 gallbladder carcinoma cells from a patient with gallbladder cancer. HGF induced in vitro invasion of GB-d1 cells into a collagen gel matrix, and this potent, invasive effect was not seen with epidermal growth factor, transforming growth factor-beta 1, basic fibroblast growth factor, or platelet-derived growth factor. Although GB-d1 did not produce HGF, the cells did produce a factor which enhances HGF production in human skin fibroblasts, and this factor proved to be interleukin-1 beta (IL-1 beta). When GB-d1 cells were co-cultured with fibroblasts such that a collagen gel matrix was layered between the GB-d1 cells and fibroblasts, GB-d1 cells invaded the gel, but invasion of the cells in the co-culture system was inhibited by antibodies against HGF and partially inhibited by antibodies against IL-1 beta. Thus, GB-d1 cell-derived IL-1 beta stimulates HGF production in stromal fibroblasts and HGF up-regulated in the fibroblasts induces invasion of GB-d1 cells. The looped interaction of carcinoma cells and stromal fibroblasts mediated by HGF and a HGF-inducer such as IL-1 beta may be one mechanism which would explain the acquisition of malignant phenotype through tumor-stromal interactions.

Cell Communication↗
PubMed1996

Experimental correspondence between spore dosimetry and spectral photometry of solar ultraviolet radiation.

The biologically effective dose of solar UV radiation was estimated from the inactivation of UV-sensitive Bacillus subtilis spores. Two types of independent measurements were carried out concurrently at the Aerological Observatory in Tsukuba: one was the direct measurement of colony-forming survival that provided the inactivation dose per minute (ID/min) and the other was the measurement of the spectral irradiance by a Brewer spectrophotometer. To obtain the effective spectrum, the irradiance for each 1 nm wavelenght interval from 290 to 400 nm was multiplied with the efficiency for inactivation derived from the inactivation action spectrum of identically prepared spore samples. Integration of the effective spectrum provided the estimate for ID/min. The observed values of ID/min were closely concordant with the calculated values for the data obtained in four afternoons in 1993. The average ratio (+/- SD) between them was 1.24 (+/- 0.16) for 14 data points showing high inactivation rates (> 0.05 ID/min). Considering difficulties in the absolute dosimetry of UV radiation, the concordance was satisfactory and improved credibility of the two types of monitoring systems of biologically effective dose of solar UV radiation.

Bacillus subtilis↗
PubMed1996

Differentiation of rat preadipocytes is accompanied by expression of thyrotropin receptors.

To investigate the regulation of expression of the TSH receptor (TSHR) in extrathyroidal tissues, the level of TSHR messenger RNA (mRNA) and TSH-dependent signal transduction were determined in isolated rat adipocytes and cultured preadipocytes. The epididymal, sc, and perirenal, but not the interscapular brown adipose tissues, possessed TSHR mRNA and increased cAMP responses to TSH and were thus used as the source of preadipocytes. Morphological analysis revealed that the combination of insulin and T3 most effectively caused the differentiation of rat preadipocytes. These differentiated preadipocytes exhibited increased cAMP production in response to TSH. The addition of FCS to the culture medium inhibited the differentiation of rat preadipocytes as well as TSH-stimulated production of cAMP. The stimulation of differentiation was associated with an increased expression of TSHR mRNA levels, whereas the inhibition of differentiation was associated with a decreased expression of TSHR mRNA, as detected by Northern blot analysis. The results indicate that the expression and function of the TSHR in cultured rat preadipocytes are closely related to cellular differentiation. Cultured rat preadipocytes appear to provide a useful system for studying the mechanism of extrathyroidal expression of TSHR.

Adipocytes↗