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Biomedical subjects

Shuji Toda

Publications and source records attributed to Shuji Toda.

At least 19 recordsLinked to original sources
PubMed2006

Hypopharyngeal squamous cell carcinoma bordering ectopic gastric mucosa "inlet patch" of the cervical esophagus.

OBJECTIVE: Ectopic gastric mucosa of the cervical esophagus, referred to as inlet patch (IP), is considered to be a common development abnormality of the esophagus. We report here a case of hypopharyngeal squamous cell carcinoma bordering on IP of the cervical esophagus. METHODS: A 44-year-old female underwent partial pharyngectomy, total laryngectomy, cervical esophagectomy, and bilateral neck dissection under the diagnosis of hypopharyngeal carcinoma. RESULTS: Resected specimens of the hypopharynx revealed a well-differentiated squamous cell carcinoma in the ulcerative tumorous lesion (3.5 cm x 0.5 cm). A brown patch (2 cm x 1.5 cm) bordering the anal aspect of the tumor comprised ectopic gastric mucosa of fundic type epithelium. Immunohistochemistry revealed the surface mucosal cells of this lesion were strongly positive for human gastric mucin (HGM) and the fundic cells were positive for gastrin. CONCLUSION: The hypopharyngeal squamous cell carcinoma likely developed in association with chronic irritation due to gastric acid from the IP. To our knowledge, this is the first reported case of squamous cell carcinoma related to IP.

Adult↗
PubMed2006

Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals.

BACKGROUND: Subepithelial fibrosis is a cardinal feature of bronchial asthma. Collagen I, III, and V; fibronectin; and tenascin-C are deposited in the lamina reticularis. Extensive evidence supports the pivotal role of IL-4 and IL-13 in subepithelial fibrosis; however, the precise mechanism remains unclear. We have previously identified the POSTN gene encoding periostin as an IL-4/IL-13-inducible gene in bronchial epithelial cells. Periostin is thought to be an adhesion molecule because it possesses 4 fasciclin I domains. OBJECTIVE: We explore the possibility that periostin is involved in subepithelial fibrosis in bronchial asthma. METHODS: We analyzed induction of periostin in lung fibroblasts by IL-4 or IL-13. We next analyzed expression of periostin in patients with asthma and in ovalbumin-sensitized and ovalbumin-inhaled mice. Furthermore, we examined the binding ability of periostin to other extracellular matrix proteins. RESULTS: Both IL-4 and IL-13 induced secretion of periostin in lung fibroblasts independently of TGF-beta. Periostin colocalized with other extracellular matrix proteins involved in subepithelial fibrosis in both asthma patients and ovalbumin-sensitized and ovalbumin-inhaled wild-type mice, but not in either IL-4 or IL-13 knockout mice. Periostin had an ability to bind to fibronectin, tenascin-C, collagen V, and periostin itself. CONCLUSION: Periostin secreted by lung fibroblasts in response to IL-4 and/or IL-13 is a novel component of subepithelial fibrosis in bronchial asthma. Periostin may contribute to this process by binding to other extracellular matrix proteins. CLINICAL IMPLICATIONS: Periostin induced by IL-4/IL-13 shows promise in inhibiting subepithelial fibrosis in bronchial asthma.

Adolescent↗
PubMed2006

Expression of new human inorganic pyrophosphatase in thyroid diseases: its intimate association with hyperthyroidism.

Inorganic pyrophosphatase (PPase) controls the level of inorganic pyrophosphate produced by biosynthesis of protein, RNA, and DNA. Thus, PPase is essential for life. PPase expression is unclear in the thyroid. We cloned a new human PPase, phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPPase), and established a rabbit polyclonal anti-LHPPase antibody. This is the first study to determine the PPase expression by immunohistochemistry and Western blot. Intranuclear LHPPase expression of thyrocytes was enhanced most prominently in Graves' disease and autonomously functional thyroid nodule. To estimate a regulating factor of subcellular localization of LHPPase, we examined its expression of Graves' disease-derived thyrocytes in vitro with the disease-originated serum. Nuclear expression of LHPPase was lost in cultured thyrocytes even with the serum, while its cytoplasmic expression was retained. The data suggest that increased expression of LHPPase is associated with hyperthyroidism. Intranuclear expression of LHPPase may not be regulated by Graves' disease-derived serum factors.

Antibodies↗
PubMed2006

Spindle epithelial tumor with thymus-like differentiation (SETTLE): youngest reported patient.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare thyroid tumor. It is one of a family of tumors arising either from ectopic thymus or remnants of branchial pouches that retain the potential to differentiate along the thymic line. Herein is reported a case of SETTLE in a 2-year-old girl. The patient underwent right thyroid lobectomy for a tumor of the right thyroid lobe. The resected specimen of this tumor revealed a whitish and solid mass. On microscopy, the tumor exhibited an area of spindle cells, glandular epithelium, and mucinous cystic lesions. The following findings were obtained on immunohistochemistry: the spindle cell area was diffusely positive for cytokeratin AE1/3 and vimentin, and partially positive for alpha-smooth muscle-specific actin. The glandular structures consisted of columnar cells and the cystic area was also positive for cytokeratin AE1/3. All three components of the tumor were negative for thyroglobulin, thyroid transcription factor-1, S-100 protein, carcinoembryonic antigen, somatostatin, synaptophysin, and chromogranin A. On the basis of the aforementioned findings, SETTLE was diagnosed. The patient remains disease free to date, 2 years after surgery with no additional treatment. To the best of the authors' knowledge the present SETTLE patient is the youngest yet reported.

Carcinoma↗
PubMed2006

T cell deficiency leads to liver carcinogenesis in azoxymethane-treated rats.

There is an increasing amount of evidence suggesting that T cell deficiency contributes to tumor development. However, it is unclear whether T cell deficiency leads to liver and colon carcinogenesis. The aim of this study was to investigate the role of T cells on liver and colon carcinogenesis. Athymic F344/N Jcl-rnu/- (nu/nu) rats and euthymic F344/N Jcl-rnu/+(nu/+) rats were administered the carcinogen azoxymethane (AOM) at a dose of 15 mg/kg body wt once a week for 2 weeks. At 48 weeks after the second carcinogen treatment, the rats were sacrificed, and livers and colons were examined. Apoptosis and cell proliferation were evaluated by DNA fragmentation and proliferating cell nuclear antigen assays, respectively. Wild-type p53 and members of the Jun and Fos oncogene families were detected by Western blotting. AOM treatment induced 100% liver tumor and 63.6% colon tumor incidence in T cell-deficient nu/nu rats, compared with 0% and 38.5% incidence in nu/+ rats. T cell deficiency promoted the inhibitory action of AOM on apoptosis in both liver and colon at 48 weeks. In contrast, T cell deficiency increased cell proliferation after AOM treatment in both tissues. Wild-type p53 was reduced in both tissues of T cell-deficient rats. AOM treatment induced c-Jun and c-Fos expressions in the liver but increased only Fos B in the colon, whereas T cell deficiency enhanced c-Jun overexpression in the liver. These results suggest that T cell deficiency leads to liver carcinogenesis partly by a reduction in wild-type p53 and increasing c-Jun expression in AOM-treated rats.

Animals↗
PubMed2006

Merkel cell-nerve cell interaction undergoes formation of a synapse-like structure in a primary culture.

Merkel cells have been assumed to guide nerve fibers to the skin. However, there has been little in vitro evidence that supports this hypothesis, because there is no suitable established culture system of Merkel cells. Here we show that Merkel cells isolated from rat footpad skin were successfully cultured in a monolayer with keratinocytes. Keratinocytes did not affect any structural changes in Merkel cells. When nerve cells (NG108-15 or PC12) were added to the culture system, both nerve fibers and cytoplasmic processes of Merkel cells outgrew and cooperatively organized synapse-like structures at their contact points. Nerve cells promoted Merkel cell survival, compared with keratinocytes only. Merkel cell proliferation was not detected in all conditions, even with nerve growth factor, neurotrophin-3, interleukin-6 and tumor necrosis factor-alpha. The data suggest, firstly, that Merkel cells may guide nerve fibers to the skin by interacting with nerve cells; and, secondly, that nerve cells, but not keratinocytes, may produce some survival factors other than the cytokines above for Merkel cells, although Merkel cells may be a terminally differentiated cell type. Our method could open a way to study Merkel cell biology.

Animals↗
PubMed2005

Air-liquid interface promotes invasive growth of laryngeal squamous cell carcinoma with or without hypoxia.

Air-liquid interface (ALI) is a microenvironment of aerodigestive tract. In our previous study, ALI promoted invasive growth of laryngeal squamous cell carcinoma (SCC); but its mechanism was unclear. Hypoxia is also related to cancer spread. Here we show that ALI with or without hypoxia accelerated invasive growth of laryngeal SCC cells, using collagen gel invasion assay. Submerged condition (SMC) without ALI did not induce the invasion with or without hypoxia. ALI enhanced expression of the following growth-, invasion-, and motility-related molecules in the cells with or without hypoxia more greatly than SMC: c-Met, Ras, mitogen-activated protein kinase cascade proteins (Raf-1, MEK-1, and ERK-1/2), matrix metalloproteinase-1, and filamin A. The data indicate that ALI promotes invasive growth of SCC cells by enhancement of the invasive growth-related molecules above, through mechanisms that differ from hypoxia, suggesting that ALI microenvironment should be taken into account for the study of cancer biology.

Air↗
PubMed2005

A new in vitro model for analyzing the biological behavior of well-differentiated squamous cell carcinoma.

A suitable model analyzing the behavior of well-differentiated squamous cell carcinoma has not yet been established. We tried to establish such a system using a reconstructed oral mucosa, in which T3M-1 squamous cell carcinoma cells were cultured on 3T3 fibroblast-containing collagen gel. Fibroblasts promoted the stratification and keratinization of T3M-1 cells. During growth, the Ki-67 index of T3M-1 cells with fibroblasts was higher than that of T3M-1 cells alone. Fibroblasts increased the expression of involucrin, a differentiating marker of keratinocytes, in T3M-1 cells. They also promoted the invasion of T3M-1 cells into the gel. When T3M-1 cells alone were cultured in a fibroblast-conditioned (FC) medium, the fibroblast-induced phenomena mentioned above were almost replicated. In addition, epidermal growth factqr (EGF) promoted T3M-1 cells growth, but not the invasion. cDNA microarray analysis showed that FC medium increased the expression of EGF receptor and several other mRNAs of T3M-1 cells. The data suggest that T3M-1 cells, under cancer-stromal fibroblast interaction, undergo invasive growth with their well-differentiated squamous phenotype, and that this interaction may be mediated partly by soluble molecules (e.g., EGF) in an autocrine or paracrine pathway. Our system will probably provide a useful model for analyzing the biological behavior of well-differentiated squamous cell carcinoma.

3T3 Cells↗
PubMed2005

Apoptosis in rat jejunal mucosa is regulated partly through the central nervous system, which controls feeding behavior.

AIM: The aim of this study was to investigate whether central nervous system-related feeding behavior regulates mucosal apoptosis in rat small intestines. METHODS: The test solutions used in this study were an H(1) receptor antagonist (chlorpheniramine maleate), 2-deoxy-D-glucose, leptin, and 1-deoxy-D-glucosamine (2-amino-1,5-anhydro-2-deoxy-D-glucitol). Test solutions were injected into the third cerebroventricles of rats. Feeding behavior and jejunal apoptosis were evaluated both with and without truncal vagotomy. Intestinal apoptosis was evaluated by percentage fragmented DNA, electrophoresis, and TUNEL staining. RESULTS: Chlorpheniramine and 2-deoxy-D-glucose elicited feeding, whereas leptin and 1-deoxy-D-glucosamine suppressed feeding. The test solutions, which elicited feeding (0.24 and 24 micromol/rat of chlorpheniramine and 2-deoxy-D-glucose, respectively), suppressed mucosal apoptosis in the rat jejunum 1 h after cerebroventricular infusion. In contrast, the test solutions, which suppressed feeding (8 and 24 micromol/rat of leptin and 1-deoxy-D-glucosamine, respectively), induced jejunal mucosal apoptosis 3 h after infusion. The effects of the test solutions on feeding behavior and changes in apoptosis were not affected by truncal vagotomy. CONCLUSION: The central nervous system, which regulates feeding behavior, might control intestinal function through the regulation of intestinal apoptosis.

Animals↗
PubMed2004

Bone marrow stromal cells, preadipocytes, and dermal fibroblasts promote epidermal regeneration in their distinctive fashions.

Mesenchymal cell types, under mesenchymal-epithelial interaction, are involved in tissue regeneration. Here we show that bone marrow stromal cells (BMSCs), subcutaneous preadipocytes, and dermal fibroblasts distinctively caused keratinocytes to promote epidermal regeneration, using a skin reconstruction model by their coculture with keratinocytes. Three mesenchymal cell types promoted the survival, growth, and differentiation of keratinocytes, whereas BMSCs and preadipocytes inhibited their apoptosis. BMSCs and preadipocytes induced keratinocytes to reorganize rete ridge- and epidermal ridge-like structures, respectively. Keratinocytes with fibroblasts or BMSCs expressed the greatest amount of interleukin (IL)-1alpha protein, which is critical for mesenchymal-epithelial cross-talk in skin. Keratinocytes with or without three mesenchymal supports displayed another cross-talk molecule, c-Jun protein. Without direct mesenchymal-epithelial contact, the rete ridge- and epidermal ridge-like structures were not replicated, whereas the other phenomena noted above were. DNA microarray analysis showed that the mesenchymal-epithelial interaction affected various gene expressions of keratinocytes and mesenchymal cell types. Our results suggest that not only skin-localized fibroblasts and preadipocytes but also BMSCs accelerate epidermal regeneration in complexes and that direct contact between keratinocytes and BMSCs or preadipocytes is required for the skin-specific morphogenesis above, through mechanisms that differ from the IL-1alpha/c-Jun pathway.

Adipocytes↗
PubMed2004

Venous congestion induces mucosal apoptosis via tumor necrosis factor-alpha-mediated cell death in the rat small intestine.

BACKGROUND: Tissue and organic venous congestion is a common pathophysiologic phenomenon. However, it is unclear whether venous congestion induces small-intestinal mucosal apoptosis. The aim of this study was to investigate whether venous congestion, or congestion followed by re-outflow, induced small-intestinal mucosal apoptosis, and whether tumor necrosis factor-alpha is involved in this apoptosis. METHODS: Small-intestinal venous congestion was induced in rats by occlusion of the superior mesenteric vein with a micro-bulldog clamp. At the end of the congestive period, the clamp was released to facilitate congestion followed by re-outflow. The rats were injected with a neutral anti-tumor necrosis factor-alpha antibody (0.15 mg/kg) via the jugular vein for 30 min before venous congestion or congestion followed by re-outflow. Intestinal mucosal apoptosis was evaluated and tumor necrosis factor-alpha was assayed. The amounts of caspase-8, caspase-3, and cytochrome c were determined by Western blot analysis. RESULTS: Our results showed that venous congestion and congestion followed by re-outflow significantly increased mucosal apoptosis, the amount of mucosal tumor necrosis factor-alpha, and the levels of caspase-8 cleavage and caspase-3 activation, but did not induce cytochrome c release from mitochondria to the cytosol. Pretreatment with an anti-tumor necrosis factor-alpha antibody significantly reduced mucosal apoptosis after intestinal congestion or congestion followed by re-outflow. CONCLUSIONS: The present results support the view that venous congestion and congestion followed by re-outflow induce mucosal apoptosis in the rat small intestine, and show that the apoptosis occurs partly via tumor necrosis factor-alpha-mediated cell death.

Animals↗
PubMed2004

Ischemic preconditioning attenuates ischemia-reperfusion-induced mucosal apoptosis by inhibiting the mitochondria-dependent pathway in rat small intestine.

Ischemic preconditioning provides a way of protecting organs from damage inflicted with prolonged ischemia-reperfusion. In this study, we investigated the mechanism of ischemic preconditioning involved in inhibition of prolonged ischemia-reperfusion-induced mucosal apoptosis in rat small intestine. Ischemic preconditioning was triggered by a transient occlusion of the superior mesenteric artery followed by reperfusion. Ischemia-reperfusion was induced by 60-min occlusion of the superior mesenteric artery followed by 60-min reperfusion in the small intestine. Ischemia-reperfusion alone induced mucosal apoptosis and mitochondrial respiratory dysfunction via promoted reactive oxygen species generation, reduced mitochondrial glutathione oxidation, increased mitochondrial lipid peroxidation, reduced mitochondrial membrane potential, and enhanced release of cytochrome c from mitochondria to activate caspase-9 and caspase-6 in the small intestine. Pretreatment with 20-min ischemia followed by 5-min reperfusion significantly inhibited the prolonged ischemia-reperfusion-induced mucosal apoptosis by 30%. Ischemic preconditioning ameliorated mitochondrial respiratory dysfunction by 50%, reduced reactive oxygen species generation by 38%, and suppressed mitochondrial lipid peroxidation by 36%, resulting in improvement of the mitochondrial membrane potential and prevention of cytochrome c release as well as caspase-6 activation. Results suggest that ischemic preconditioning attenuated ischemia-reperfusion-induced mucosal apoptosis partly by inhibiting the reactive oxygen species-mediated mitochondria-dependent pathway in the rat small intestine.

Animals↗
PubMed2004

Dietary corn oil promotes colon cancer by inhibiting mitochondria-dependent apoptosis in azoxymethane-treated rats.

How dietary corn oil is involved in colon carcinogenesis and cancer development is poorly understood. The aim of this study was to investigate whether long-term dietary corn oil promotes colon cancer by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis in azoxymethane (AOM)-treated rats. Male Sprague-Dawley rats were injected with AOM or with saline and fed on a basal diet or basal diet supplemented with 10% corn oil for 48 weeks. Colonic aberrant crypt foci (ACF) and tumors, including adenomas and carcinomas, were examined. Colonic apoptosis and cell proliferation were evaluated. Wild type (wt) p53 was analyzed using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. In addition, Bcl-2, Bcl-xL, Bax, and Bak localized in the mitochondria were detected. Long-term dietary corn oil increased ACF in AOM-treated rats at 12 weeks and promoted colon cancer invasion at 48 weeks. Cancer invasion was not observed in the AOM-treated rats without dietary corn oil, although colon adenomas and cancers were detected. Apoptosis was decreased and cell proliferation was increased in the AOM-treated rats with dietary corn oil, compared with the AOM-treated rats with dietary basal diet. In these rats, mitochondrial wt p53 was significantly inhibited through decreased mitochondrial localization of wt p53 and increased cytosolic p53, resulting in the upregulation of Bcl-2 and Bcl-xL and the downregulation of Bak in the mitochondria. Results suggest that long-term dietary corn oil promotes AOM-induced colon cancer development partly by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis.

Animals↗
PubMed2004

Immunohistochemical analysis of bcl-2, Bax and Bak expression in thyroid glands from patients with Graves' disease.

In order to clarify the role of apoptosis and the expression of Bcl-2 family proteins in the pathology of Graves' disease (GD), we evaluated the apoptosis by in situ end-labeling of fragmented DNA and the expression of Bcl-2, Bax and Bak by immunohistochemistry in thyroid tissues from 20 patients with GD and in normal thyroid tissues from 6 patients with follicular adenoma (N). Apoptotic nuclei were found in thyrocytes and in germinal center of lymphoid follicles. Bcl-2 was strongly expressed in both GD and N thyrocytes. Bax was not expressed in either GD or N thyrocytes. Bak was expressed in thyrocytes from 5 of 20 patients with GD, while it was detected in all N thyrocytes. In lymphoid follicles Bcl-2 was expressed in the mantle zone, while Bax and Bak were both expressed in the germinal center. The percentage of apoptotic nuclei in GD thyrocytes was low (0~3.6%), and negatively correlated with the weight of the thyroid glands resected (rs = -0.43, P<0.05). It was greater in Bak-positive GD thyrocytes than in Bak-negative ones (mean +/- SD; 1.7 +/- 0.7% vs. 0.7 +/- 0.9%, P<0.05). These findings suggest that the differential expression of Bcl-2 family proteins in both thyrocytes and lymphoid follicles may be involved in the pathology of GD.

Adolescent↗
PubMed2003

The negative-feedback regulation of the IL-13 signal by the IL-13 receptor alpha2 chain in bronchial epithelial cells.

Bronchial asthma is a complex disease characterized by airway inflammation involving Th2 cytokines. Among Th2 cytokines, the significance of IL-13 in the pathogenesis of bronchial asthma has recently emerged. Particularly, the direct action of IL-13 on bronchial epithelial cells (BECs) is critical for generation of airway hyperresponsiveness. IL-13 has two binding units; the IL-13 receptor alpha1 chain transduces the IL-13 signal comprising a heterodimer with the IL-4R alpha chain, whereas the IL-13 receptor alpha2 chain (IL-13Ralpha2) is thought to act as a decoy receptor. However, it remains obscure how expression of these molecules is regulated in each cell. In this article, we analyzed the expression of these components in BECs. Either IL-4 or IL-13 induced intracellular expression of IL-13Ralpha2 in BECs, which was STAT6-dependent and required de novo protein synthesis. IL-13Ralpha2 expressed on the cell surface as a monomer inhibited the STAT6-dependent IL-13 signal. Furthermore, expression of IL-13Ralpha2 was induced in lung tissues of ovalbumin-induced asthma model mice. Taken together, our results suggested the possibility that IL-13Ralpha2 induced by its ligand is transferred to the cell surface by an unknown mechanism, and it down-regulates the IL-13 signal in BECs, which functions as a unique negative-feedback system for the cytokine signal.

Animals↗
PubMed2003

Thyrocytes, but not C cells, actively undergo growth and folliculogenesis at the periphery of thyroid tissue fragments in three-dimensional collagen gel culture.

In the thyroid, new follicle formation from preexisting follicles (mother follicle-derived folliculogenesis) has been poorly understood. To address this issue, we analyzed mother follicle-derived folliculogenesis, using a thyroid tissue-organotypic culture that retains three-dimensional follicles with both thyrocytes and C cells over a long period. Three types of mother follicle-derived folliculogenesis occurred only at the periphery of the tissue fragments embedded in collagen gel: (1) solid nest, (2) budding and (3) lumen-dividing types. Immunohistochemistry showed that neogenic follicles rarely had calcitonin-positive C cells. Electron microscopy showed that their component thyrocytes expressed normal polarity. In growth, bromodeoxyuridine uptake of thyrocytes at the tissue periphery was about 5 times the uptake that occurred at the center. C cells had no uptake. Thyrotropin (TSH, 10 mU/ml) and free calcium (0.17~1.95 mM), which are associated with the biological behavior of thyrocytes and C cells, respectively, did not affect the events described above. The data indicate that thyrocytes, but not C cells, actively undergo growth and three types of mother follicle-derived folliculogenesis at the tissue periphery in a TSH- or free calcium-independent manner. This suggests that the tissue periphery, which may escape from contact inhibition of cell growth, is the regenerative site.

Animals↗
PubMed2003

Mast cells and angiogenesis.

There is much evidence that angiogenesis is related to mast cells. Mast cells accumulate in many angiogenesis-dependent situations, including tumor growth, rheumatoid arthritis, ovulation, would healing, and tissue repair. Several mast cell mediators are angiogenic and regulate endothelial cell proliferation and function. Stem cell factor, vascular endothelial growth factor, epidermal growth factor, basic fibroblast growth factor, and platelet-derived growth factor induce chemotactic migration of mast cells to sites of neovascularization. Mast cell products such as tryptase also degrade connective tissue matrix to provide space for neovascular sprouts. Angiogenesis has been proposed as a target for anticancer therapy and for treatment of inflammatory disorders such as rheumatoid arthritis. Future studies on the cascade of angiogenic events, including mast cell-target cell interaction, and various intracellular signaling pathways are indicated to provide a new approach for the treatment of cancer and inflammatory disorders and for tissue repair.

Growth Substances↗