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S Kondo

Publications and source records attributed to S Kondo.

At least 19 recordsLinked to original sources
PubMed2007

In vitro activation of the corticosteroid ciclesonide in animal nasal mucosal homogenates.

Ciclesonide, a new corticosteroid for allergic rhinitis, is administered as an inactive parent compound that is converted by esterases to the pharmacologically active metabolite, desisobutyryl-ciclesonide (des-CIC). This study investigated the in vitro activation of ciclesonide in nasal mucosa of multiple animal species. Nasal mucosal homogenates from rats, guinea-pigs, rabbits and dogs were incubated with ciclesonide 0.5 micromol/l (0.271 microg/ml) or 5 micromol/l (2.71 microg/ml) for up to 120 min. Concentrations of ciclesonide and des-CIC were measured by high-performance liquid chromatography with tandem mass spectrometry. Ciclesonide was metabolized to des-CIC in nasal mucosal homogenates of each species. The initial velocities of des-CIC formation ranged from 0.0038 to 0.0150 nmol/min/mg protein and 0.0319 to 0.0983 nmol/min/mg protein in nasal mucosal homogenates incubated with ciclesonide 0.5 micromol/l and 5 micromol/l, respectively. Furthermore, the initial velocities of ciclesonide metabolism ranged from 0.0032 to 0.0142 nmol/min/mg protein and 0.0445 to 0.1316 nmol/min/mg protein in nasal mucosal homogenates incubated with ciclesonide 0.5 micromol/l and 5 micromol/l, respectively. This study confirms that ciclesonide is converted to des-CIC in nasal mucosal homogenates without any marked differences among animal species.

Adrenal Cortex Hormones↗
PubMed2006

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo.

Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC(50) values for WP1066 were 5.6 muM in U87-MG cells and 3.7 muM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X(L) and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (P<0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

Antineoplastic Agents↗
PubMed2006

Absence of tyrosine kinase mutations in Japanese colorectal cancer patients.

Tyrosine kinases, which are important regulators of intracellular signal-transduction pathways, have mutated forms that are often associated with oncogenesis and are attractive targets for therapeutic intervention. Recently, systematic mutational analyses of tyrosine kinases revealed that a minimum of 30% of colorectal cancer contain at least one mutation in the tyrosine kinases. To further explore these mutations, we examined all reported mutations of NTRK3, FES, KDR, EPHA3, NTRK2, JAK1, PDGFRA, EPHA7, EPHA8, ERBB4, FGFR1, MLK4 and GUCY2F genes in the 24 colorectal cancer cell lines. Unexpectedly, among 24 colorectal cancer cell lines, only two cell lines (LoVo and CaR1) harbored mutation C1408T (R470C) in MLK4 gene. The mutation rate was extremely low compared to that previously reported. Therefore, we analyzed mutations in 46 colorectal cancer samples resected from the same number of Japanese patients. Surprisingly, none of the 46 samples contained any of the mutations reported. Based on our study, we advise that a more comprehensive tyrosine kinase gene mutation assay is necessary in the future.

Aged↗
PubMed2006

Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells.

The mammalian target of rapamycin (mTOR) plays a central role in regulating the proliferation of malignant glioma cells, and mTOR-specific inhibitors such as rapamycin analogs are considered as promising therapy for malignant gliomas. However, the efficacy of mTOR inhibitors alone in the treatment of patients with malignant gliomas is only modest, potentially because these agents rather than acting as mTOR kinase inhibitors instead interfere with the function of only mTOR/raptor (regulatory-associated protein of mTOR) complex and thus do not perturb all mTOR functions. The purpose of this study was to determine whether global inhibition of the mTOR molecule enhances the antitumor effect of rapamycin on malignant glioma cells. We showed that rapamycin induced autophagy and that inhibition of autophagy by small interfering RNA (siRNA) directed against autophagy-related gene Beclin 1 attenuated the cytotoxicity of rapamycin in rapamycin-sensitive tumor cells, indicating that the autophagy was a primary mediator of rapamycin's antitumor effect rather than a protective response. Exogenous expression of an mTOR mutant interfering with its kinase activity markedly enhanced the incidence of rapamycin-induced autophagy. Moreover, silencing of mTOR with siRNA augmented the inhibitory effect of rapamycin on tumor cell viability by stimulating autophagy. Importantly, not only rapamycin-sensitive malignant glioma cells with PTEN mutations but also rapamycin-resistant malignant glioma cells with wild-type PTEN were sensitized to rapamycin by mTOR siRNA. These results indicate that rapamycin-induced autophagy is one of the agent's antitumor effects and that silencing or inhibiting mTOR kinase activity could enhance the effectiveness of rapamycin.

Autophagy↗
PubMed2006

Multiple activation of mitogen-activated protein kinases by purified independent CCN2 modules in vascular endothelial cells and chondrocytes in culture.

CCN2 consists of 4 distinct modules that are conserved among various CCN family protein members. From the N-terminus, insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C repeat (VWC), thrombospondin type 1 repeat (TSP1) and C-terminal cysteine-knot (CT) modules are all aligned tandem therein. The multiple functionality of CCN2 is thought to be enabled by the differential use of these modules when interacting with other molecules. In this study, we independently prepared all 4 purified module proteins of human CCN2, utilizing a secretory production system with Brevibacillus choshinensis and thus evaluated the cell biological effects of such single modules. In human umbilical vascular endothelial cells (HUVECs), VWC, TSP and CT modules, as well as a full-length CCN2, were capable of efficiently activating the ERK signal transduction cascade, whereas IGFBP was not. In contrast, the IGFBP module was found to prominently activate JNK in human chondrocytic HCS-2/8 cells, while the others showed similar effects at lower levels. In addition, ERK1/2 was modestly, but significantly activated by IGFBP and VWC in those cells. No single module, but a mixture of the 4 modules provoked a significant activation of p38 MAPK in HCS-2/8 cells, which was activated by the full-length CCN2. Therefore, the signals emitted by CCN2 can be highly differential, depending upon the cell types, which are thus enabled by the tetramodular structure. Furthermore, the cell biological effects of each module on these cells were also evaluated to clarify the relationship among the modules, the signaling pathways and biological outcomes. Our present results not only demonstrate that single CCN2 modules were potent activators of the intracellular signaling cascade to yield a biological response per se, while also providing new insight into the module-wise structural and functional relationship of a prototypic CCN family member, CCN2.

Blotting, Western↗
PubMed2006

Transcriptional targeting of adenovirus vectors with the squamous cell carcinoma-specific antigen-2 promoter for selective apoptosis induction in lung cancer.

Squamous cell carcinoma antigens SCCA1 and SCCA2 are highly homologous serine proteinase inhibitors which have been widely utilized as serological markers for squamous cell cancers, but it has recently been demonstrated that only SCCA2 is truly specific for certain forms of lung cancer. Using a construct containing the 5'-flanking region of the SCCA2 gene between -460 and +0 bp and the luciferase reporter gene, SCCA2 promoter activity was detected in SCCA2-producing SCC cell lines (LK-2, LC-1), but not in SCCA2-nonproducing lung adenocarcinoma cell lines (A549, ABC-1, and RERF-LC-MS) or normal cells (WI-38, SAEC, and NHEK-Adult). Infection with a recombinant adenovirus vector, Ad-SCCA2-DsRed, resulted in cell-specific expression of the SCCA2 promoter-driven DsRed marker gene only in LK-2 and LC-1 cells. The same strategy was used for SCCA2-driven expression of a proapoptotic gene, (KLAKLAK)2, which can cause mitochondrial disruption by triggering mitochondrial permeabilization and swelling, resulting in the release of cytochrome c and induction of apoptosis. Infection with Ad-SCCA2-KLAKLAK2 specifically reduced the growth of the two human lung SCC cell lines compared to the SCCA2 nonproducing cell lines both in vitro and in vivo, suggesting that the SCCA2 promoter had a tumor-specific effect. These results suggest that transduction of SCCA2 promoter-controlled suicide genes by adenoviral vectors can confer transcriptionally targeted cytotoxicity in SCCA2-producing lung SCC cells, and represents a novel strategy for gene transfer specifically targeted to SCC in the lung.

Adenoviridae↗
PubMed2006

Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway.

A substantial number of neural stem cells (NSCs) continue to proliferate and generate neurons in the central nervous system throughout life. Ionizing radiation, an important adjuvant therapy for glioma patients, may damage NSCs and cause neuronal deficits, such as cognitive dysfunction and memory impairment. However, the precise mechanism of radiation effects on death and differentiation of NSCs remains largely unknown. Here, we found that radiation induced apoptosis in NSCs via the mitochondrial pathway, upregulating the ratio of Bax to Bcl-2 and releasing cytochrome c into the cytoplasm. Radiation also inhibited neuronal differentiation of NSCs by 50%. Of the three stress-associated mitogen-activated protein kinases (MAPKs), only c-Jun NH(2)-terminal kinase (JNK) was activated in NSCs after radiation. Interestingly, JNK inhibition by the specific inhibitor SP600125 rescued NSCs from apoptosis and improved neuronal differentiation. Furthermore, we examined whether radiation directly inhibits neuronal differentiation or not. Radiation did not affect the promoter activity of NeuroD, a basic helix-loop-helix transcription factor that regulates the expression of neuronal differentiation markers. Radiation induced more apoptosis in NeuroD-positive cells than NeuroD-negative cells. We concluded that radiation activates JNK and induces apoptosis, especially in neural progenitor cells, resulting in the inhibition of neurogenesis. Our findings raise the possibility that JNK inhibition has therapeutic potential in protecting NSCs from the adverse effects of radiation.

Animals↗
PubMed2006

Hypoxic regulation of stability of connective tissue growth factor/CCN2 mRNA by 3'-untranslated region interacting with a cellular protein in human chondrosarcoma cells.

Connective tissue growth factor (CTGF/CCN2) can be induced by various forms of stress such as exposure to high glucose, mechanical load, or hypoxia. Here, we investigated the molecular mechanism involved in the induction of ctgf/ccn2 by hypoxia in a human chondrosarcoma cell line, HCS-2/8. Hypoxia increased the ctgf/ccn2 mRNA level by altering the 3'-untranslated region (UTR)-mediated mRNA stability without requiring de novo protein synthesis. After a series of extensive analyses, we eventually found that the cis-repressive element of 84 bases within the 3'-UTR specifically bound to a cytoplasmic/nuclear protein. By conducting a UV crosslinking assay, we found the cytoplasmic/nuclear protein to be a 35 kDa molecule that bound to the cis-element in a hypoxia-inducible manner. These results suggest that a cis-element in the 3'-UTR of ctgf/ccn2 mRNA and trans-factor counterpart(s) play an important role in the post-transcriptional regulation by determining the stability of ctgf/ccn2 mRNA.

3' Untranslated Regions↗
PubMed2006

Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma.

The purpose of this study was to clarify the relationship between the number of tumour-infiltrating T lymphocytes and the clinicopathological features and clinical outcome in patients with non-small-cell lung cancer (NSCLC). Tissue specimens from 109 patients who underwent surgical resection for NSCLC were immunohistochemically analysed for CD4 and CD8 expression. Patients were classified into two groups according to whether their tumours exhibited a 'high' or 'low' level of CD8(+) or CD4(+) lymphocyte infiltration. Although the level of infiltration by CD8(+) T cells alone had no prognostic significance, the survival rate for patients with both 'high' CD8(+) and 'high' CD4(+) T-cell infiltration was significantly higher than that for the other groups (log-rank test, P=0.006). Multivariate analysis indicated that concomitant high CD8(+) and high CD4(+) T-cell infiltration was an independent favourable prognostic factor (P=0.0092). In conclusion, the presence of high levels of both CD8(+) T cells and CD4(+) T cells is a significant indicator of a better prognosis for patients with NSCLC, and cooperation between these cell populations may allow a significantly more potent antitumour response than either population alone.

Adult↗
PubMed2006

Estimation of photon dose generated by a short pulse high power laser.

The authors obtain a new equation to estimate the forward component of a photon dose generated through the interaction between a target and a short pulse high power laser. As the equation is quite simple, it is useful for calculating the photon dose. The equation shows that the photon dose is proportional to the electron temperature in the range>3 MeV and proportional to the square of the electron temperature in the range<3 MeV. The dose estimated with this method is roughly consistent with the result of Monte Carlo simulation. With some assumptions and corrections, it can reproduce experimental results obtained and the dose result calculated at other laboratories.

Electrons↗
PubMed2006

Probiotics in the treatment of Japanese cedar pollinosis: a double-blind placebo-controlled trial.

BACKGROUND: Probiotic bacteria may be effective in the treatment of allergic inflammation and food allergy, but efficacy and underlying mechanisms remain unclear. OBJECTIVE: The present study investigated the effects of probiotic strain Bifidobacterium longum BB536 in the treatment of Japanese cedar pollinosis (JCPsis). METHODS: In a randomized, double-blind, placebo-controlled trial, 44 JCPsis subjects received BB536 or placebo for 13 weeks during the pollen season. Subjective symptoms and self-care measures were recorded daily and blood samples were taken before and during intervention to measure blood levels of parameters related to JCPsis. RESULTS: BB536 intake was associated with a significant reduction in number of subjects prematurely terminated due to severe symptoms and pollinosis medication (P=0.0057 vs. placebo group). Comparison of subjective symptom scores indicated significant decreases in rhinorrhea, nasal blockage and composite scores in the BB536 group compared with the placebo group. Comparison of medical scores showed marked improvements in all symptoms on BB536 intake. A T-helper type 2 (Th2)-skewed immune response occurring along with pollen dispersion was observed. BB536 significantly suppressed increases in plasma thymus- and activation-regulated chemokine and tended to suppress elevations of Japanese cedar pollen (JCP)-specific IgE. CONCLUSION: These results suggest the efficacy of BB536 in relieving JCPsis symptoms, probably through the modulation of Th2-skewed immune response.

Adult↗
PubMed2006

Salvage of a massive esophago-tracheal fistula resulting from a stenting treatment.

We report the successful surgical resolution of a case of massive esophago-tracheal fistula (ETF) caused by a stenting treatment for stricture of an esophago-gastric anastomosis. A 54-year-old man was admitted to our hospital due to serious pneumonia secondary to ETF. He had previously received esophagectomy and post-operative chemo-radiation therapy for esophageal cancer, followed by stenting treatments for a benign stricture of the esophago-gastric anastomosis. For surgical treatment of the resulting ETF, serial operations were required. The first operation, performed under percutaneous cardiopulmonary support, included removal of the stents followed by tracheotomy, were with the coverage of the tracheal defect achieved using both major pectoral muscle flaps. A salivary fistula was also generated and an enteral nutrition tube was placed. Six months after the first operation, a pedicled ileocolic interposition was performed in order to effect reconstruction of the digestive tube, with an additional microvascular anastomosis of the ileocolic and internal thoracic artery and vein. After the second operation, the patient's ability to ingest food was restored, and he was discharged from the hospital. Thus, ETF was successfully treated by successive surgical operations with delicate intra- and post-operative respiratory management.

Anastomosis, Surgical↗
PubMed2006

Immunohistochemical analysis of nuclear survivin expression in esophageal squamous cell carcinoma.

Despite advances in the treatment of esophageal carcinoma, the prognosis for this disease remains poor. Therefore, it is important to obtain a better understanding of the molecular basis of esophageal carcinogenesis. The purpose of this study was to clarify the roles of survivin in esophageal squamous cell carcinoma (ESCC). One hundred 22 ESCC surgical specimens resected from 1989 to 1999 were examined. Survivin expression was assessed by immunohistochemistry. Tumor cells were considered survivin-positive if the immunoreactivity was confined to the nucleus, and a scoring method was applied. Survivin-positive immunostaining was detected in 68 patients (56%). There was a significant association between survivin expression and pN (P = 0.0472). Moreover, the overall survival rate was worse in patients with survivin-positive tumors than in patients with survivin-negative tumors (P = 0.0189). The overexpression of survivin was associated with the overall survival rate and poor prognosis in patients with ESCC. Survivin may be targeted during cancer therapy because of its selective expression in malignant tissue.

Aged↗
PubMed2006

Successful treatment of hepatitis B virus-associated membranous nephropathy with lamivudine.

We present a case of chronic hepatitis B with membranous nephropathy, that was improved by lamivudine treatment. A 37-year-old man was admitted to our hospital for the evaluation of proteinuria. He was diagnosed as having chronic glomerulonephritis associated with chronic hepatitis B. Histopathological findings of the renal biopsy specimen indicated membranous nephropathy. He suffered from nephrotic syndrome associated with leg edema, which was parallel to the exacerbation of hepatitis. Lamivudine was started for the treatment of hepatitis, which caused the disappearance of serum hepatitis B virus DNA and the normalization of ALT level in 4 weeks. Additionally, proteinuria disappeared 120 weeks after the treatment was started. Lamivudine treatment may remit HBV-associated nephropathy.

Adult↗
PubMed2006

Effect of probiotic Bifidobacterium longum BB536 [corrected] in relieving clinical symptoms and modulating plasma cytokine levels of Japanese cedar pollinosis during the pollen season. A randomized double-blind, placebo-controlled trial.

Probiotic microorganisms have been shown to be effective in the treatment of allergic inflammation and food allergy, but their efficacy remains controversial. This study tested the effect of a yogurt supplemented with a probiotic strain Bifidobacterium longum BB536 in the treatment of Japanese cedar pollinosis (JCPsis). Forty subjects with a clinical history of JCPsis were given yoghurt either containing BB536 (BB536 yoghurt) or without BB536 (placebo yoghurt) at 2 X 100 g per day for 14 weeks, in a randomized, double-blind, placebo-controlled trial. Subjective symptoms and self-care measures were recorded daily and blood samples were taken before and during the intervention (at weeks 4, 9, and 14) to measure the blood parameter levels related to JCPsis. Yoghurt supplemented with BB536 significantly alleviated eye symptoms compared with placebo yoghurt (odds ratio 0.31; 95% confidence interval 0.10-0.97; p = 0.044). Although no statistically significant differences were detected, nasal symptoms such as itching, rhinorrhea, and blockage, as well as throat symptoms tended to be relieved with the BB536 yoghurt. BB536 tended to suppress the decreasing blood levels of interferon-gamma (IFN-y) and the increasing blood eosinophil rates; a significantly higher IFN-gamma level was observed for the difference from baseline at week 4. A decreased trend in the difference from baseline levels of JCP-specific IgE levels was also observed at week 4 in the BB536 group compared with the placebo group. In conclusion, these results suggest that intake of BB536-supplemented yoghurt may relieve JCPsis symptoms, probably through a modulating effect on Th balance.

Adult↗
PubMed2005

Dynamics of magnetic defects in heavy fermion LiV2O4 from stretched exponential 7Li NMR relaxation.

7Li NMR measurements on LiV2O4 from 0.5 to 4.2 K are reported. A small concentration of magnetic defects within the structure drastically changes the nuclear magnetization relaxation versus time from a pure exponential as in pure LiV2O4 to a stretched exponential, indicating glassy behavior of the magnetic defects. The stretched exponential function is described as arising from a distribution of 7Li nuclear spin-lattice relaxation rates and we present a model for the distribution in terms of the dynamics of the magnetic defects. Our results explain the origin of recent puzzling 7Li NMR literature data on LiV2O4 and our model is likely applicable to other glassy systems.

Journal Article↗
PubMed2005

Induction of the metabolism of etizolam by carbamazepine in humans.

OBJECTIVE: To examine the effect of carbamazepine on the single oral dose pharmacokinetics of etizolam. METHODS: Eleven healthy male volunteers received carbamazepine 200 mg/day or placebo for 6 days in a double-blind, randomized, crossover manner, and on the sixth day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured using high-performance liquid chromatography. RESULTS: Carbamazepine treatment significantly decreased the peak plasma concentration (17.5+/-4.1 ng/ml versus 13.9+/-4.1 ng/ml; P<0.05), total area under the plasma concentration-time curve (194.8+/-88.9 ng h/ml versus 105.9+/-33.0 ng h/ml; P<0.001), and elimination half-life (11.1+/-4.6 h versus 6.8+/-2.8 h; P<0.01) of etizolam. No significant change was induced by carbamazepine in the two pharmacodynamic parameters. CONCLUSIONS: The present study suggests that carbamazepine induces the metabolism of etizolam.

Administration, Oral↗