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Biomedical subjects

Yutaka Shimada

Publications and source records attributed to Yutaka Shimada.

At least 37 records · Page 2Linked to original sources
PubMed2006

Keishibukuryogan (gui-zhi-fu-ling-wan), a Kampo formula, decreases disease activity and soluble vascular adhesion molecule-1 in patients with rheumatoid arthritis.

An increasing death rate due to cardiovascular disease in patients with rheumatoid arthritis (RA) has been reported. Keishibukuryogan (KBG) is a traditional Chinese/Japanese (Kampo) formula that has been administered to patients with blood stagnation, e.g. thrombotic disease and atherosclerosis. The objective of this study was to evaluate the efficacy of KBG on disease activity and endothelial dysfunction in RA patients. Sixteen RA patients were enrolled and administered KBG (12 g per day) for 12 weeks in addition to continuing other drugs. The disease activity of RA was assessed by modified disease activity scores for 28 joints (DAS(28)). Plasma levels of adhesion molecules, soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were evaluated. C-reactive protein (CRP), inflammatory cytokines (IL-1beta, IL-6 and TNF-alpha) and lipid peroxide (LPO) were also evaluated. Fourteen patients completed the study. The disease activity of RA, tender joint count, swollen joint count and DAS(28) decreased significantly. Among adhesion molecules, only sVCAM-1 decreased significantly. LPO also decreased significantly, whereas CRP and inflammatory cytokines remained unchanged. These results suggest that KBG has insufficient anti-inflammatory or immunomodulating effect but does have a beneficial effect on articular symptoms and a protective effect against endothelial dysfunction in RA patients.

Journal Article↗
PubMed2006

Macrophage-mediated inhibitory effect of Zingiber officinale Rosc, a traditional oriental herbal medicine, on the growth of influenza A/Aichi/2/68 virus.

The inhibitory effect of Zingiber officinale Rosc (ZOR), an Oriental traditional herbal medicine, on the growth of influenza A/Aichi/2/68 (Aichi) virus was investigated in Madin-Darby canine kidney (MDCK) cells. Direct addition of ZOR (0.1 approximately 100 microg/ml) to the infected cells did not have any inhibitory effect. However, the ZOR-induced conditioned medium (ZOR-CM) of RAW cells, a murine macrophage (Mphi) cell line, exhibited an apparent inhibitory effect on MDCK cells without cytotoxicity. In accordance with the time-dependent inhibitory effect of ZOR-CM, it has been demonstrated that tumor necrosis factor (TNF)-alpha was gradually accumulated in ZOR-CM by the induction of TNF-alpha mRNA expression in ZOR-stimulated RAW cells. Conversely, the inhibitory effect of ZOR-CM was reduced significantly by the removal of TNF-alpha after the formation of an immune complex with anti-TNF-alpha monoclonal antibody. These data suggested that ZOR itself has no inhibitory effect on the growth of influenza virus, but could exert its effect via macrophage activation leading to production of TNF-alpha.

Animals↗
PubMed2006

Vitreous Chemokines and Sho (Zheng in Chinese) of Chinese-Korean-Japanese medicine in patients with diabetic vitreoretinopathy.

We examined the levels of vitreous chemokines and Sho (Zheng in Chinese) of Chinese-Korean-Japanese medicine in diabetic patients. Patients undergoing vitrectomy were classified into Group 1 (no diabetic retinopathy), Group 2 (diabetic retinopathy with no or a few new vessels), and Group 3 (diabetic retinopathy with many new vessels). The levels of IL-8, MCP-1, MIP-1alpha, MIP-1beta, and RANTES in the vitreous fluid were measured using cytometric bead array method. Sho was determined by the standard diagnostic method of Chinese-Korean-Japanese medicine. Vitreous levels of IL-8 and MCP-1 in Groups 2 and 3 were higher than those in Group 1. MIP-1alpha, MIP-1beta, and RANTES levels in Groups 2 and 3 were almost the same as those in Group 1. The percentage of patients with Keishibukuryo-gan (Guizhifuling-wan in Chinese) sho in Group 3 was higher than that in Group 1. In conclusion, vitreous levels of IL-8 and MCP-1 were high in patients with diabetic vitreoretinopathy. Keishibukuryo-gan sho may be associated with diabetic vitreoretinopathy.

Aged↗
PubMed2006

Cinnamaldehyde induces endothelium-dependent and -independent vasorelaxant action on isolated rat aorta.

The vasorelaxant effect of cinnamaldehyde, one of the major oil components in Cinnamomi Cortex, was studied using isolated rat aorta. Cinnamaldehyde at final concentrations of 1 microM to 1 mM showed dose-dependent relaxation of the rat aorta contracted by treatment with prostaglandin F2alpha, norepinephrine or KCl. In addition, cinnamaldehyde relaxed prostaglandin F2alpha-precontracted aortic rings with endothelium and without endothelium, with the latter being significantly less sensitive than the former. Relaxation induced by cinnamaldehyde with endothelium was significantly inhibited by NG-nitro-L-arginine methyl ester (L-NAME), while nonselective cyclooxygenase inhibitor (indomethacin), beta-adrenergic receptor blocker (propranolol), an inhibitor of phosphodiesterase (theophylline), a delayed rectifier K+ channel blocker (tetraethyl ammonium chloride), or an ATP-sensitive K+ channel blocker (glibenclamide) did not reduce the relaxation induced by cinnamaldehyde with endothelium treated by L-NAME. Conversely, aorta pretreatment with L-NAME and theophylline increased the relaxation by cinnamaldehyde significantly compared to aorta pretreatment with only L-NAME. Furthermore, cinnamaldehyde significantly inhibited Ca2+-induced contraction. These results suggested that the vasorelaxant effects of cinnamaldehyde were derived from both endothelium-dependent and -independent effects. Endothelium-dependent relaxation is affected by nitric oxide, and one of the mechanisms of endothelium-independent relaxation is thought to be influenced by the blocking of Ca2+ channels.

Acrolein↗
PubMed2006

Loss of function of the candidate tumor suppressor prox1 by RNA mutation in human cancer cells.

The importance of genetic mutations in carcinogenesis has been recognized, and it has been proposed that aberrant mutation of mRNA may represent a novel oncogenic principle. Here we report that the mRNA of a homeobox gene prox1, a candidate tumor suppressor, suffers adenosine-to-inosine nucleotide conversion and loses tumor-suppressive functions in a subset of human cancers. Expression of Prox1 was reduced in pancreatic cancers, and the extent of reduction correlated with progression of tumor differentiation. A-to-G base change was found in prox1 cDNA taken from human cancer cells, but not in corresponding genomic DNA. We mapped four common mutation sites in prox1 gene, and the same four sites were mutated in human clinical samples from several cancers. Tetracycline-induced wild-type (wt) Prox1 in tumor cells inhibited transforming activity and cellular proliferation. However, mutant Prox1 with the four common sites altered from A to G lost these inhibitory functions. In mice, xenografts of tumor cells with tetracycline-induced wt-Prox1 formed tumor masses significantly more slowly than control tumors, whereas mutated Prox1 had no effect. These findings may point to a pivotal role of the RNA mutation of prox1 gene in the pathogenesis of human cancer progression.

Animals↗
PubMed2005

Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury.

Epidermal growth factor (EGF) is predominantly secreted by salivary glands and activates Na(+)/H(+) exchanger-1 (NHE-1), which regulates intracellular pH (pH(i)). We investigated the roles of EGF and NHE-1 in esophageal epithelial defense against acid using human esophageal epithelial cell lines and a rat chronic esophagitis model. Esophageal epithelial cells were incubated with acidified medium in the absence or presence of EGF. Cell viability and changes in pH(i) were measured. Chronic acid reflux esophagitis was induced in rats with and without sialoadenectomy. Esophageal lesion index, epithelial proliferation, and expression of EGF receptors and NHE-1 were examined. EGF protected esophageal epithelial cells against acid in a dose-dependent manner, and the cytoprotective effect of EGF was completely blocked by treatment with NHE-1 inhibitors. Tyrosine kinase, calmodulin, and PKC inhibitors significantly inhibited cytoprotection by EGF, whereas MEK, phosphatidylinositol 3-kinase, and PKA inhibitors had no effect. EGF significantly increased pH(i) recovery after NH(4)Cl pulse acidification, and this increase in pH(i) recovery was significantly blocked by inhibitors of calmodulin and PKC. Sialoadenectomy led to an increase in the severity of chronic esophagitis but affected neither epithelial proliferation nor expression of EGF receptors. Expression of NHE-1 mRNA was increased in esophagitis and upregulated in rats with sialoadenectomy. The increasing severity of esophagitis in rats with sialoadenectomy was prevented by exogenous administration of EGF. In conclusion, EGF protects esophageal epithelial cells against acid through NHE activation via Ca(2+)/calmodulin and the PKC pathway. Deficiency in endogenous EGF is associated with increased severity of esophagitis. EGF and NHE-1 play crucial roles in esophageal epithelial defense against acid.

Animals↗
PubMed2005

GPR40 gene expression in human pancreas and insulinoma.

To assess gene expression of a membrane-bound G-protein-coupled fatty acid receptor, GPR40, in the human pancreas and islet cell tumors obtained at surgery were analyzed. The mRNA level of the GPR40 gene in isolated pancreatic islets was approximately 20-fold higher than that in the pancreas, and the level was comparable to or rather higher than that of the sulfonylurea receptor 1 gene, which is known to be expressed abundantly in human pancreatic beta cells. A large amount of GPR40 mRNA was detected in tissue extracts from two cases of insulinoma, whereas the expression was undetectable in glucagonoma or gastrinoma. The present study demonstrates that GPR40 mRNA is expressed predominantly in pancreatic islets in humans and that GPR40 mRNA is expressed solely in human insulinoma among islet cell tumors. These results indicate that GPR40 is probably expressed in pancreatic beta cells in the human pancreas.

Humans↗
PubMed2005

Expression profiles of various transporters for oligopeptides, amino acids and organic ions along the human digestive tract.

Various transporters such as H+/peptide cotransporter PEPT1 are expressed in the intestine, and play important physiological and pharmacological roles in the body. Present study was performed to examine the expression profile of 20 kinds of transporters (PEPT1 and 2, P-glycoprotein, amino acid transporters and organic ion transporters) along the human digestive tract, especially focusing on PEPT1. Using normal mucosal specimens, real-time polymerase chain reactions were carried out. Immunoblot analyses were also performed for PEPT1 expression. PEPT1 mRNA was highly expressed in the small intestine (duodenum>jejunum>ileum) compared to other tissues, and some patients showed a significant level of expression in the stomach. The expressional pattern of PEPT1 in the stomach and histological diagnosis indicated that gastric PEPT1 originated from the intestinal metaplasia. The amino acid transporters showed unique mRNA expression levels and distributions in the digestive tract. For example, the expression levels of B(0)AT1, a Na+-dependent and chloride-independent neutral amino acid transporter, were increased from the duodenum to ileum, which pattern is completely inverted to that for PEPT1. There is little expression of organic ion transporters except for organic cation/carnitine transporter OCTN2. In conclusion, PEPT1 was abundantly expressed in the small intestine, and the reciprocal expression of PEPT1 and B(0)AT1 may serve for the efficient absorption of protein digestive products.

Aged↗
PubMed2005

Clinical significance of osteopontin in esophageal squamous cell carcinoma: comparison with common tumor markers.

OBJECTIVE: Osteopontin (OPN) is a secreted integrin-binding glycophosphoprotein that may have a role in head and neck squamous cell carcinoma (SCC). To evaluate the clinical significance of OPN in esophageal squamous cell carcinoma (ESCC), we compared plasma OPN levels with those of common tumor markers. METHODS: Preoperative plasma OPN levels were measured by enzyme immunoassay in 103 ESCC patients. Serum SCC antigen, Cyfra 21-1, and carcinoembryonic antigen (CEA) levels were also measured routinely at admission by radioimmunoassay. RESULTS: Plasma OPN levels ranged from 82.8 to 1,980 ng/ml. High OPN level was associated with lymph node metastasis (p = 0.05), but not with tumor histology or depth of invasion. The overall survival of the patients with high OPN levels was worse than that of those with low OPN levels (p = 0.02). SCC antigen and Cyfra 21-1 levels were associated with the depth of tumor invasion, the tumor diameter, lymph node metastasis, and the overall survival, but CEA was not associated with these clinicopathological factors. Combined evaluation of OPN plus Cyfra 21-1 or OPN plus SCC antigen was useful as an independent prognostic indicator. CONCLUSION: Measurement of the plasma OPN level, as well as serum SCC antigen and Cyfra 21-1, may help to predict the progression of ESCC.

Aged↗
PubMed2005

Prediction of survival in patients with esophageal carcinoma using artificial neural networks.

BACKGROUND: Accurate estimation of outcome in patients with malignant disease is an important component of the clinical decision-making process. To create a comprehensive prognostic model for esophageal carcinoma, artificial neural networks (ANNs) were applied to the analysis of a range of patient-related and tumor-related variables. METHODS: Clinical and pathologic data were collected from 418 patients with esophageal carcinoma who underwent resection with curative intent. A data base that included 199 variables was constructed. Using ANN-based sensitivity analysis, the optimal combination of variables was determined to allow creation of a survival prediction model. The accuracy (area under the receiver operator characteristic curve [AUR]) of this ANN model subsequently was compared with the accuracy of the conventional statistical technique: linear discriminant analysis (LDA). RESULTS: The optimal ANN models for predicting outcomes at 1 year and 5 years consisted of 65 variables (AUR = 0.883) and 60 variables (AUR = 0.884), respectively. These filtered, optimal data sets were significantly more accurate (P < 0.0001) than the original data set of 199 variables. The majority of ANN models demonstrated improved accuracy compared with corresponding LDA models for 1-year and 5-year survival predictions. Furthermore, ANN models based on the optimal data set were superior predictors of survival compared with a model based solely on TNM staging criteria (P < 0.0001). CONCLUSIONS: ANNs can be used to construct a highly accurate prognostic model for patients with esophageal carcinoma. Sensitivity analysis based on ANNs is a powerful tool for seeking optimal data sets.

Diagnosis, Computer-Assisted↗
PubMed2005

Prognostic significance of fascin overexpression in human esophageal squamous cell carcinoma.

PURPOSE: Fascin, an actin bundling protein, induces membrane protrusions and increased cell motility in various transformed cells. The expression of fascin in epithelial neoplasms has been described only recently, and the role of fascin in esophageal squamous cell carcinoma (ESCC) is still unknown. EXPERIMENTAL DESIGN: Paraffin sections of 200 patients with ESCC were immunohistochemically investigated. The expression levels of fascin mRNA in 20 ESCC tissues were compared with that in corresponding normal esophageal epithelium by semiquantitative reverse transcription-PCR. We also examined fascin protein expression in 33 ESCC cell lines. The role of fascin in cell motility and invasiveness in ESCC cells was assessed by the vector-based small interfering RNA. RESULTS: In immunohistochemical study, the intensity of fascin expression was usually increased in the tumor compared with that in normal epithelium. Fascin overexpression was significantly associated with a poor prognosis (immunoreactive rate, P = 0.033; immunoreactive intensity, P = 0.031). The fascin immunoreactive rate was associated with extent of the tumor (P = 0.002) and lymph node metastasis (P = 0.003). Multivariate analysis showed that fascin expression intensity was an independent prognostic factor, but the immunoreactive rate was not. In addition, up-regulation of fascin mRNA was found in 60% (12 of 20) of patients. In vitro study revealed that all 33 ESCC cell lines expressed fascin protein at a certain level. KYSE170, one of the fascin-overexpressed cells, decreased its motile and invasive properties after down-regulation of fascin expression. CONCLUSION: Our findings suggest that fascin overexpression may play an important role in the progression of ESCC.

Adult↗
PubMed2005

The clinical significance of Aurora-A/STK15/BTAK expression in human esophageal squamous cell carcinoma.

PURPOSE: Aurora-A/STK15/BTAK (Aurora-A) encodes a Serine/Threonine kinase associated with chromosomal distribution, and its up-regulation induces chromosomal instability thereby leading to aneuploidy and cell transformation in several types of cancer. In this study, we investigated the role of Aurora-A in human esophageal squamous cell carcinoma (ESCC). EXPERIMENTAL DESIGN: The expression levels of Aurora-A mRNA were compared in 33 ESCC tissues with that in corresponding normal esophageal epithelium by semiquantitative reverse transcription-PCR, and the distribution patterns and expression levels of Aurora-A protein were immunohistochemically investigated in the ESCC tumors of 142 patients. The results were then separately compared with the clinicopathologic findings of the patients, and the expression of Aurora-A was examined in nine ESCC cell lines and a normal esophageal epithelial cell line using Western blot analysis. RESULTS: The up-regulation of Aurora-A mRNA was found in 30% (10 of 33) of the tumors by semiquantitative reverse transcription-PCR, and protein up-regulation was found in 53% (75 of 142) of the patients by immunohistochemistry. mRNA and protein up-regulation of Aurora-A were correlated with distant lymph node metastasis (P = 0.05 and P = 0.04, respectively), and patients with Aurora-A mRNA or protein up-regulation had a poorer prognosis (P = 0.003 and P = 0.0009, respectively). Furthermore, multivariate analysis revealed that up-regulation of the Aurora-A protein was an independent prognostic factor. In addition, Aurora-A expression in all ESCC cell lines was higher than that in a normal esophageal epithelial cell line. CONCLUSIONS: The up-regulation of Aurora-A expression may reflect the malignant behavior of ESCC and may prove useful information as a prognostic factor for ESCC patients.

Aged↗
PubMed2005

A strategy for determining which thoracic esophageal cancer patients should undergo cervical lymph node dissection.

BACKGROUND: There is controversy about performing cervical lymph node dissections in all middle and lower thoracic esophageal squamous cell carcinoma patients. The purpose of this study was to evaluate whether intraoperative examination of thoracic paratracheal lymph node by real-time reverse transcription-polymerase chain reaction was worthwhile for selecting patients for cervical lymph node dissection. METHODS: Under informed consent, 30 middle and lower thoracic esophageal squamous cell carcinoma patients were examined for thoracic paratracheal lymph node metastasis intraoperatively by hematoxylin-eosin staining and real-time reverse transcription-polymerase chain reaction for messenger RNA encoding squamous cell carcinoma antigen. When thoracic paratracheal lymph node metastasis was found, cervical lymph node dissection was performed. If the patients had no thoracic paratracheal lymph node metastasis, a randomized study for selection of cervical lymph node dissection was performed. RESULTS: Eleven of 30 patients with middle or lower third thoracic esophageal squamous cell carcinoma had thoracic paratracheal lymph node metastasis. Five of these 11 patients had cervical lymph node metastasis. Nineteen patients who had no metastasis in the thoracic paratracheal lymph nodes were enrolled in a randomized study. Eight of the 19 patients received cervical lymph node dissection and they were found not to have cervical lymph node metastasis. The other 11 patients did not receive cervical lymph node dissection, and there was no cervical lymph node recurrence. CONCLUSIONS: The intraoperative diagnosis of metastasis in the thoracic paratracheal lymph node may be used as an indicator for cervical lymph node dissection in middle and lower thoracic esophageal cancer patients.

Carcinoma, Squamous Cell↗
PubMed2005

The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53.

Gankyrin is an ankyrin repeat oncoprotein commonly overexpressed in hepatocellular carcinomas. Gankyrin interacts with the S6 proteasomal ATPase and accelerates the degradation of the tumor suppressor Rb. We show here that gankyrin has an antiapoptotic activity in cells exposed to DNA damaging agents. Downregulation of gankyrin induces apoptosis in cells with wild-type p53. In vitro and in vivo experiments revealed that gankyrin binds to Mdm2, facilitating p53-Mdm2 binding, and increases ubiquitylation and degradation of p53. Gankyrin also enhances Mdm2 autoubiquitylation in the absence of p53. Downregulation of gankyrin reduced amounts of Mdm2 and p53 associated with the 26S proteasome. Thus, gankyrin is a cofactor that increases the activities of Mdm2 on p53 and probably targets polyubiquitylated p53 into the 26S proteasome.

Animals↗
PubMed2005

Juzentaihoto, a Kampo medicine, enhances IL-12 production by modulating Toll-like receptor 4 signaling pathways in murine peritoneal exudate macrophages.

Juzentaihoto (TJ-48), a Kampo medicine, has been reported to affect the immune system. Although toll-like receptors (TLRs) have been identified as receptors of innate immunity, the effects of TJ-48 on TLR signaling pathways have not been thoroughly investigated. Here we evaluated the effects of TJ-48 on TLR4 signaling pathways. Peritoneal exudate macrophages (PEMs) isolated from mice orally administered TJ-48 for 11 days were stimulated with lipopolysaccharide (LPS), a ligand of TLR4, in vitro. Production of IL-12 p40 was significantly augmented in TJ-48-treated PEMs compared with that in vehicle PEMs, without affecting the surface expression of TLR4. Treatment with chemical inhibitors of NF-kappa B and p38 mitogen-activated protein kinases (MAPKs) in vitro inhibited LPS-induced IL-12 production, whereas JNK and ERK inhibitors increased IL-12 production. Immunoblotting with phosphorylation-state specific antibodies demonstrated that TJ-48 differentially affected LPS-induced phosphorylation of NF-kappa B and MAPKs. In PEMs treated with TJ-48, LPS-induced phosphorylation of p65 NF-kappa B and p38 MAPK was augmented, while that of JNK and ERK was attenuated compared with those in vehicle PEMs. These results suggest that selective modulation of the TLR4 signaling pathways by TJ-48 is involved in enhanced production of IL-12 in PEMs.

Administration, Oral↗
PubMed2005

Reduction of perception of chronic fatigue in an observational study of patients receiving 12 weeks of Kampo therapy.

OBJECTIVE: The aim of this study was to observe the influence of Kampo therapy on latent chronic fatigue of patients with chronic diseases. SUBJECTS: One hundred and seventy-three (173) consecutive patients with chronic diseases came to our department for the first time. DESIGN: This was a prospective study. Patients were divided into two groups: a chronic fatigue group (CFG) and a nonchronic fatigue group (NCFG). Based on Kampo diagnosis, both groups were prescribed Kampo formulae as an extract or decoction for 12 weeks. OUTCOME MEASURES: By using questionnaires, patients were assessed concerning their physical and mental types of fatigue, their sleep situation, and their attitude toward work or housekeeping, both before and after 12 weeks of treatment, according to Kampo diagnosis. RESULTS: The mental fatigue, physical fatigue, and sleep scores of both groups, and the work score of CFG, were decreased. The rate of reduction of the fatigue score was significantly greater in CFG than in NCFG. The factor responsible for this difference in fatigue score was physical fatigue. CONCLUSIONS: A reduction of the perception of chronic fatigue was observed in patients receiving 12 weeks of Kampo therapy.

Adolescent↗