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Biomedical subjects

M Toyoda

Publications and source records attributed to M Toyoda.

At least 127 records · Page 7Linked to original sources
PubMed1998

Involvement of MAP kinase-independent protein kinase C signaling pathway in the EGF-induced p21(WAF1/Cip1) expression and growth inhibition of A431 cells.

Previous studies have revealed that the growth inhibition of A431 cells overexpressing epidermal growth factor (EGF) receptors by a high concentration of EGF is mainly due to the expression of cycline dependent kinase (CDK) inhibitor p21(WAF1/Cip1). However, the signal transduction mechanism from the activated EGF receptor to the induction of p21(WAF1/Cip1) gene is still poorly understood. We investigated which signaling pathway plays an important role in p21(WAF1/Cip1) expression and growth inhibition by using specific inhibitors of the signaling molecules. A broad PKC inhibitor, PKC delta inhibitor, but not the conventional PKC inhibitor suppressed the EGF-induced p21(WAF1/Cip1) expression and the growth inhibition of A431 cells. These inhibitors did not alter either the activation of EGF receptor or the stimulation of MAP kinase at detectable levels. Furthermore, we found that the induction of p21(WAF1/Cip1) at the early phase (within 12 hr after stimulation) by a high concentration of EGF was independent of the MAP kinase activation by using dominant negative Ras. These results suggest that PKC, especially PKC delta plays a crucial role in the EGF-induced p21(WAF1/Cip1) expression, resulting in the growth inhibition of A431 cells.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1998

Differential inhibition of fluid accumulation and tumor growth in two mouse ascites tumors by an antivascular endothelial growth factor/permeability factor neutralizing antibody.

In the accompanying paper (Luo et al., Cancer Res., 58: 2652-2660, 1998), we demonstrated that vascular endothelial growth factor (VEGF), also designated vascular permeability factor (VPF), significantly accumulated in all mouse malignant ascites tested, suggesting its fundamental role in ascites tumors. Removal of VEGF may inhibit the development of ascites tumors. In this study, using a goat antimouse VEGF-neutralizing antibody, we tested this hypothesis with two well-defined syngeneic mouse ascites tumors: MM2 breast adenocarcinoma and OG/Gardner lymphoma 6C3HED (expressing moderate and low levels of VEGF, respectively). This antibody significantly inhibited MM2 and OG cell-free ascites fluid-induced hyperpermeability of mouse peritoneal microvessels and in vitro endothelial cell growth. Mice bearing tumors were administered i.p. daily with the antibody or normal goat IgG as controls for 8 days, at doses of 20-fold (for MM2-bearing mice) or 40-fold (for OG-bearing mice) the estimated amounts of VEGF that kinetically accumulated in the ascites fluid after the tumor inoculation. The average volume of ascites fluid, number of tumor cells and leaked RBCs, and the peritoneal microvessel permeability in MM2-bearing mice that received the antibody treatment were significantly lower than those in the matched controls (P < 0.01). Unexpectedly, OG-bearing mice did not show satisfactory response to the anti-VEGF treatment. This discrepancy was not likely due to inadequate doses or different host immune responses, but it was quite possibly to the different characteristics of MM2 carcinoma and OG lymphoma tumors, the latter being strongly invasive, and/or the existence of an inflammatory mediator(s), such as bradykinin or cytokine(s) other than VEGF. In summary, our results directly demonstrated, for the first time, differential roles for VEGF in ascites tumors in vivo and suggest the potential of VEGF inhibition as a specific therapy for ascites tumors of carcinoma origin, which are the major cause of the malignant ascites in adult humans.

Animals↗
PubMed1998

Affinity maturation in Lyn kinase-deficient mice with defective germinal center formation.

Lyn kinase-deficient (lyn-/-) mice show several abnormalities such as reduced numbers of circulating B cells, hyper-IgM, and low proliferative responses induced by CD40 ligand. Lyn-/- mice also develop splenomegaly, produce autoreactive Abs with age, and finally develop glomerulonephritis. Another abnormality observed in lyn-/- mice is that their disability to form germinal centers (GCs). It has been considered that GCs play an important role in affinity maturation and differentiation to B cell memory upon immunization with thymus-dependent Ag. Since Lyn kinase has been thought to be downstream of the signals from the B cell Ag receptor as well as CD40, we studied whether or not lyn-/- mice could exhibit normal Ag-specific class switching and affinity maturation following somatic hypermutation. The mice were immunized with (4-hydroxy-3-nitrophenyl)acetyl-chicken gamma-globulin (NP-CG). Production of NP-specific IgG1 Abs was slightly reduced but clearly detectable. The affinity of Abs produced was comparable to that in wild-type mice. Furthermore, somatic hypermutation occurred in the heavy-chain variable region at the same level as that in wild-type mice. Therefore, we conclude that isotype switching and affinity maturation occur normally in lyn-/- mice without the formation of GCs. The results lead to a speculation that Lyn may not play a role in induction of isotype switching or affinity maturation, despite being downstream of the signals from the B cell Ag receptor complex and CD40, and that GC architecture may not be absolutely essential for affinity maturation.

Amino Acid Sequence↗
PubMed1998

Simple spectrophotometric analysis of passive and active ear cutaneous anaphylaxis in the mouse.

Homologous passive cutaneous anaphylaxis (PCA) and active cutaneous anaphylaxis (ACA) to ovalbumin and DNP-hapten were studied in the ears of female BALB/c mice by means of assessing Evans blue dye leakage. For the quantitative evaluation of PCA and ACA, a hand-held spectrophotometer and the conventional colorimetric method were used to detect the amount of extravasated dye. The value of deltaE*ab (a numerical expression of color) obtained with the hand-held spectrophotometer and the amount of extravasated dye showed a good correlation. In the mouse ear, the sensitivity of PCA reaction was comparable to that of PCA in the rat, and deltaE*ab in the PCA and ACA reactions correlated well with the dilutions of sera and of the antigen, respectively. Thus, using a hand-held spectrophotometer is a simple, quantitative and sensitive method for ascertaining the extent of immediate-type hypersensitivity in the mouse.

Anaphylaxis↗
PubMed1998

Fluctuation correlation in the sliding movement generated by protein motors in vitro.

The fluctuation in the sliding distance of cytoskeletal filaments driven to move by protein motors in vitro does not depend on the filament length. This is in sharp contrast to the case of Brownian movement of filamentous particles in their longitudinal directions, in which the positional fluctuation is proportional to the inverse of the length (L) of filaments. This latter 1/L dependence is a direct consequence of the central limit theorem: the statistical independence and randomness of the solvent molecule collisions with filaments, the collisions of which cause the random Brownian movement. The above length-independence in the sliding distance fluctuation found in the in vitro motility indicates the presence of correlation in the fluctuation. A possible explanation for the correlation is to assume that there is an extended time-correlation in the sliding movement, a correlation which could be produced by the actions on a sliding filament of protein motors with their heads randomly oriented in the in vitro motility assay system. We have checked this possibility by using long myosin thick filaments of molluscan smooth muscles, on which myosin heads are uniformly oriented, and have found that even with such myosin filaments with oriented myosin heads, the positional fluctuation of actin sliding distance does not depend on the actin filament length. This result thus indicates that the actions of protein motors on a sliding filament are not statistically independent or random, so that the positional fluctuation of filaments in the motor-generated sliding movement does not depend on the filament length.

Actins↗
PubMed1998

Cardenolide glycosides from seeds of Corchorus olitorius.

Three new cardenolide glycosides were isolated from the seeds of Corchorus olitorius L. On the basis of chemical and spectroscopic evidence, their structures were established as cannogenol 3-O-beta-D-glucopyranosyl-(1-->4)-O-beta-D-boivinopyranoside, periplogenin 3-O-beta-D-glucopyranosyl-(1-->4)-O-beta-D-digitoxopyranoside and digitoxigenin 3-O-beta-D-glucopyranosyl-(1-->6)-O-beta-D-glucopyranosyl-(1-->4)-O-beta - D-digitoxopyranoside.

Carbohydrate Sequence↗
PubMed1998

Pre-transplant donor-specific transfusions induce allograft rejection and IL-2 gene expression in the WKY-->F344 functional tolerance model of rat lung transplantation.

Our previous studies have shown that a spontaneous functional tolerance develops in a rat model of lung transplantation (WKY-->F344). The tolerance observed in this model may be due to the minor histocompatible differences in this combination, however, the possibility of a tolerogenic effect related specifically to the lung allograft must be considered. To further examine this model, the effect of pre-transplant donor-specific spleen cell transfusions (DSTs) was examined on the functional tolerance state seen in this model. F344 rats received WKY spleen cells on days -45 and -30 before lung transplantations. Control F344 rats received lung transplants without DSTs. Recipients in both groups were killed on day 7, 14, 21 and 49 post-transplant, and allograft rejection (AR) was graded histologically (stage 0-IV). Intragraft cytokine gene transcripts were examined on day 7 and 14 post-transplant using reverse transcriptase-polymerase chain reaction (RT-PCR) techniques to investigate the underlying immunological events occurring in each group. In addition, allogeneic (WKY) and third party (BN) skin grafts were placed on lung recipients at day 35 post-transplant to evaluate the development of systemic tolerance. It was seen that control animals showed moderate to severe lymphocytic infiltrations (stage II-III AR) in the first 3 weeks followed by spontaneous recovery with stage I-II AR on day 49. In marked contrast, DST-treated animals showed more aggressive AR with severe lymphocytic infiltration and haemorrhagic infarction (stage III-IV AR) by day 14-21, without any evidence of recovery on day 49. WKY skin grafts showed prolonged survival in control animals, but were promptly rejected in DST-treated animals. Intragraft cytokine gene expression in control animals was characterized by no or weak expression of IL-2 and high IL-10, while DST-treated animals showed high levels of IL-2 transcripts. IL-2:IL-10 and IL-2:IL-4 ratios were significantly increased in DST-treated animals compared with controls on day 7 post-transplant. It was concluded that pre-transplant DSTs did not enhance allograft survival, but actually induced AR and ablated any immunological benefit of the lung allograft on induction of tolerance in the WKY-->F344 lung transplant model. It was found that the DST-induced AR was associated with a deviation of cytokine immune responses from a predominant Th2 to Th1 profile characterized by increased IL-2 gene expression in the allografts. We also conclude that factors other than the degree of histocompatibility matching, such as the route and timing of alloantigen exposure, and the amount or nature of alloantigens associated specifically with lung allografts, are involved in deviating native immune responses toward acceptance or rejection of lung allografts in this model of lung transplantation.

Animals↗
PubMed1998

Morphological alterations of epidermal melanocytes in photoageing: an ultrastructural and cytomorphometric study.

To examine pathological changes of melanocytes in photodamaged skin, we performed a comparative cytomorphometric analysis and a qualitative observation of melanocytes from sun-exposed and sun-protected facial skin at the electron microscopic level. The characteristic ultrastructural features of melanocytes in photodamaged skin included a statistically significant increase in their number, a marked nuclear heterogeneity, signs of cell activation, close apposition to photodamaged degenerate keratinocytes, degenerative changes represented by large intracytoplasmic vacuoles, and frequent direct contacts with Langerhans cells. Cytomorphometric analysis revealed significant decreases in cell and nuclear sizes, increases in cell and nuclear perimeters accompanied by irregular contours, and higher degrees of nuclear ellipticity in sun-exposed melanocytes. This study demonstrates that there are remarkable differences in the morphology of melanocytes between photoaged and intrinsically aged facial skin, and supports the concept that photoageing processes contribute to cytological alterations in melanocytes.

Aged↗
PubMed1998

Morphological assessment of the effects of cyclosporin A on mast cell--nerve relationship in atopic dermatitis.

There is considerable clinical and experimental evidence that cyclosporin A has powerful therapeutic effects on severe, therapy-resistant atopic dermatitis. To further clarify the mechanism of beneficial action of cyclosporin A for atopic dermatitis, we assessed its effects on mast cell morphology and on the topographical relationship between mast cells and cutaneous nerves in lesional skin of atopic dermatitis. The ultrastructural features of mast cell-specific granules in cyclosporin A-treated skin compared with those in the pretreated skin included an increase in the stable granule population and the disappearance of signs of granule exocytosis. The close apposition of mast cells to peripheral nerve fibres in the upper dermis and an invasion of mast cells into nerve bundles in the lower dermis were immunohistochemically noted, and an intimate association between mast cells and unmyelinated dermal nerves or Schwann cells was observed ultrastructurally in the pretreated lesional skin. After cyclosporin A therapy, the close interrelation of mast cells and cutaneous nerves was not seen. These findings suggest that cyclosporin A may exert its therapeutic efficacy by inhibiting mast cell activation, and by affecting the interaction between mast cells and nerves, which may explain the beneficial therapeutic action of cyclosporin A in the management of the disease.

Adult↗
PubMed1998

Benign sebaceous neoplasm with prominent epidermal component.

A 65-year-old woman presented with a solitary nodule within an erythematous plaque in her right groin. Histopathologic examination showed central lobular proliferation of basaloid cells admixed with mature sebaceous cells and a lateral extensive intraepidermal component composed mostly of lobules of mature sebocytes consistent with intraepidermal epithelioma with sebaceous differentiation and focal invasion. Although various cutaneous neoplasms may show an intraepidermal growth pattern, extensive sebaceous differentiation in such a neoplasm, as seen in this case, has not been described. Electron-microscopic study revealed that the basaloid cells have features of pluripotential cells. This observation supports the previously reported concept that intraepidermal epithelioma may be composed of a group of heterogeneous tumors with various degrees and lines of differentiation. Additionally, sebaceous epithelioma/adenoma should be considered in the differential diagnosis of the cutaneous neoplasms with an intraepidermal growth pattern.

Aged↗
PubMed1998

Solitary basaloid follicular hamartoma.

We present a case of solitary basaloid follicular hamartoma of 8 years' duration on the nose of a 55-year-old Japanese man. Clinical examination revealed a solitary, asymptomatic, smooth-surfaced, black papule. Histologically, the lesion showed multifocal proliferation of basaloid cells forming islands, branching cords and anastomosing strands that were continuous with the basal layer of the epidermis. Individual hair follicles were replaced by these undifferentiated basaloid proliferating cells. Some abortive hair follicle-like structures composed of follicular bulbs and contiguous rudimentary dermal papillae were observed. This solitary papular type of basaloid follicular hamartoma is quite rare; our case is clearly distinguished from other neoplasms with hair follicle differentiation as well as from infundibulocystic basal cell carcinoma, which have been the most problematic differential diagnoses in the recent dermatopathologic literature.

Basal Cell Carcinoma↗
PubMed1998

An overview of topical antibiotics for acne treatment.

Topical use of antibiotics is currently a widely accepted effective and safe treatment for acne. A review of the articles published in the past 30 years revealed that topical application of antibiotics such as erythromycin, clindamycin or tetracycline showed clinical effectiveness for mild to moderate inflammatory acne, especially when they are combined with zinc, tretinoin or benzoyl peroxide, while they showed little influence on noninflammatory acne. The main mechanism of action of topical antibiotics for acne treatment is inhibition of inflammation caused by bacteria rather than a direct bactericidal effect. The adverse reactions of topical antibiotics are mostly minor and negligible, while special attention should be given to the risk of development of resistant strains of Propionibacterium acnes. The development of new antibiotics is promising and will provide a wider range of therapeutic options for refractory cases.

Acne Vulgaris↗
PubMed1998

Inhibitory effects of apple polyphenol on induced histamine release from RBL-2H3 cells and rat mast cells.

The anti-allergic activities of polyphenol fractions extracted from immature fruits of apple (Rosaceae, Malus sp.) were evaluated by in vitro assays. A crude apple polyphenol (CAP) fraction, which had been obtained from the juice of immature apples by reverse-phase column chromatography, was further purified by LH-20 column chromatography to obtain an apple condensed tannin (ACT) fraction consisting of linear oligomeric epicatechins from the dimer to pentadecamer. ACT strongly inhibited the release of histamine from rat basophilic leukemia (RBL-2H3) cells stimulated by the antigen-stimulation and from rat peritoneal mast cells stimulated by compound 48/80. The IC50 values for histamine release were 30 micrograms/ml and 25 micrograms/ml, respectively. ACT also inhibited hyaluronidase activity and the increase in intracellular free calcium concentration in RBL-2H3 cells stimulated with the antigen. These results suggest that ACT affected early signal transduction including the calcium influx.

Animals↗
PubMed1998

Electron microscopic characterization of filiform papillae in the normal human tongue.

The fine structure of filiform papillae on the normal human tongue was examined level by level, from the basal layer to the surface, in specimens taken from the dorsal side of the lingual body. Human lingual epithelia showed three distinct regions: epithelia on the anterior and on the posterior sides of filiform papillae and an interpapillary epithelium. While the basal and the squamous cell layers were similar throughout these three regions, differences were noted in the granular and the horny layers. The interpapillary epithelium actually lacked both the granular and the horny layers. The epithelium on the anterior side of filiform papillae was characterized by alternating layers of granular cells and of cornified cells. Granular cells possessed three types of keratohyaline-like granules within their cytoplasm: uniformly electron dense, relatively less electron dense, and a heterogeneous type. While the number of the keratohyaline-like granules was remarkably diminished in the epithelium on the posterior side of filiform papillae, a considerable amount of tonofibrils was present in the cytoplasm. In the uppermost portion of the anterior side of filiform papillae, coherence between adjacent epithelial cells depended mainly on the interlocking of cytoplasmic villi and poorly developed desmosomes on villi. On the other hand, epithelial cells on the posterior side of filiform papillae appeared to be more tightly adhesive compared with those on the anterior side. This was due to focal thickening of the plasma membrane and to desmosomes at the interface between the granular and cornified cells, and to the formation of a marginal band and increased intercellular cement presumably derived from lamellar bodies in the horny layer. These findings demonstrate distinct differences between the anterior and the posterior sides of filiform papillae in the human tongue with respect to keratinization patterns, structures associated with cell-to-cell adhesion and the strength of cellular cohesion in the uppermost portion, and the turnover of cornified cells. These differences may contribute to the formation of the unique external configurations of filiform papillae.

Adult↗
PubMed1998

An autopsy case of systemic hemangiomatosis with honeycomb-like liver and focal splenic sarcomatoid changes.

An unusual autopsy case of systemic hemangiomatosis associated with honeycomb-like liver and splenic sarcomatoid changes is presented. The patient suffered from high-output ventricular heart failure secondary to hepatic arteriovenous shunting with hepatic failure, ending fatally due to disseminated intravascular coagulation and pulmonary bleeding. Postmortem examination revealed the characteristic distribution of vasoformative tumors presenting in the hematopoietic system including the liver, bone marrow, and spleen, with the liver appearing characteristically honeycomb-like. While these vasoformative tumors were mostly benign-appearing, partial shifts toward sarcomatoid change were observed in the splenic lesions.

Angiomatosis↗
PubMed1998

Immunomodulatory actions of intravenous immunoglobulin (IVIG): potential applications in solid organ transplant recipients.

Intravenous gammaglobulin (IVIG) products are known to have powerful immunomodulatory and anti-inflammatory functions in vitro and in vivo. In addition, IVIG has shown benefit in the treatment of many human autoimmune and inflammatory disorders. One potential mechanism of action responsible for these beneficial effects is the down-regulation of deleterious autoantibody titers through idiotypic-anti-idiotypic networks. Until recently, few data were available on the use of IVIG in the management of alloimmune disorders. In this review, we will discuss current data on the use of pooled human gammaglobulin as an agent with potential to regulate undesirable alloimmune responses and allosensitization through similar idiotypic-anti-idiotypic circuits and how this therapy could be of benefit in the management of highly sensitized patients both pre- and post-transplant. We will also discuss other potential anti-inflammatory and immunoregulatory mechanisms induced by IVIG treatment and how these may be applied to improve transplantability and outcomes in human transplantation.

Adjuvants, Immunologic↗
PubMed1998

[Immunohistochemical study on the progression of colorectal cancer--with respect to apoptotic index, expression of apoptosis-related gene products, and labeling index of proliferating cell nuclear antigen (PCNA)].

To clarify the biological changes in the development and progression of colorectal cancer, immunohistochemical examination was performed with a particular focus on the activity of apoptosis, the expression of apoptosis-related gene products and cell proliferation activity, assessed by the labeling index of proliferating cell nuclear antigen (PCNA). Seventy-six resected specimens of colorectal cancer were used to investigate the expression of apoptosis-related gene products, Bcl-2 protein and PCNA labeling index, as well as the apoptotic index using the TUNEL method. Seventy-five percent of 60 advanced cancer specimens was negative for Bcl-2 protein, and the proportion was higher than that in early cancer specimens. The apoptotic index (AI) in the advanced cancers was significantly higher than in the early stage of cancers. Meanwhile, the percentage of PCNA-positive cells for the advanced cancers was significantly higher than for early cancer. This study demonstrated a decrease in Bcl-2 protein expression, an increase in tumor cell apoptosis, and opposite an increase of cellular proliferation activity in the progression of colon cancer from early to the advanced stage of the disease.

Apoptosis↗