Biomedical subjects

N Arai

Publications and source records attributed to N Arai.

At least 37 records · Page 2Linked to original sources

PubMed2001

[Clinical significance of measurement of urinary leukotriene E4 in asthmatic patients without attack].

To evaluate clinical significance of measurement of urinary leukotriene E4 (LTE4) in asthmatic patients without attack, we measured urinary LTE4 in 68 asthmatic patients without attack and investigated its correlation with severity of asthma, % FEV1, bronchial hyperresponsiveness and peripheral eosinophil counts. Values of urinary LTE4 were significantly higher in the asthmatic patients (113.6 +/- 9.7 pg/mg.cr) than in healthy control subjects (67.8 +/- 4.7, n = 31), and the level of urinary LTE4 was in proportion to the severity of disease. Urinary LTE4 showed significant negative correlation with % FEV1 in atopic patients (Rs = -0.43, p = 0.025, n = 28), which was not recognized in non-atopic patients. Urinary LTE4 showed no significant correlation with bronchial hyperresponsiveness and peripheral eosinophil counts. Our findings suggested that basal LTE4 in urine reflected chronic airway inflammation of asthma.

Adult↗

PubMed2001

[A case of multiple emphysematous bullae treated with living-donor lung transplantation from identical twin brothers].

A 30-year-old man with multiple emphysematous bullae and bronchiectasis was admitted to Toyama Medical and Pharmaceutical University Hospital because of exertional dyspnea and fever. His chest radiograph and CT scan revealed multiple large bullae in the right lung and infiltrative shadows in the left middle lung field. Pseudomonas aeruginosa was isolated from his sputum culture. Although standard therapies including various antibiotics were administered, his respiratory condition was exacerbated, accompanied with the enlargement of bullae in the right lung and the consequent shift of the mediastinum to the left. The patient and his family proposed lung transplantation, and we concluded that lung transplantation would be an appropriate treatment for his disease. We transported the patient to Osaka University Hospital. Living-donor lung transplantation from the patient's identical twin brothers was successfully performed.

Adult↗

PubMed2001

[A case with left mesial temporal lobe epilepsy characterized by abnormal massive salivation].

A 26-year-old woman was admitted because of a 12-year history of intractable epileptic seizures. Every seizure began with an upper abdominal discomfort, and often followed by massive salivation. Whenever the epileptic salivation happened, the patient lost consciousness, and sometimes she developed generalized convulsions. In terictal sphenoidal EEG recordings revealed abnormal discharges in the left mesial temporal region. MRI demonstrated left hippocampal atrophy. Since her seizures were medically intractable, left temporal lobectomy was performed. Neuropathologic examination revealed hippocampal sclerosis. After the operation, she became completely seizure-free with no episode of massive salivation. From the literature, epileptic salivation can originates from the rolandic area; fronto-orbital cortex & cingulate gyrus; insula & operculum; and mesial temporal structures. The abnormal massive salivation in our patient might be attributable to the activation of frontal limbic system triggered by hippocampal abnormal firing during the ictal period of TLE.

Adult↗

PubMed2000

Cutting edge: chromatin remodeling at the IL-4/IL-13 intergenic regulatory region for Th2-specific cytokine gene cluster.

During the differentiation of naive Th cells into Th2 effector cells, the entire IL-4/IL-13 locus is remodeled into an accessible chromatin conformation. Here we show that ectopic expression and activation of Stat6 or GATA-3 in Th cells developing under Th1-polarizing conditions lead to the induction of chromatin remodeling not only at the flanking regions of the IL-4 and IL-13 genes but also at the IL-4/IL-13 intergenic regulatory region for the IL-4/IL-13/IL-5 gene cluster. Furthermore, we demonstrate that GATA-3 and another Th2-specific, inducible protein complex interact with the IL-4/IL-13 intergenic DNase I hypersensitive region specifically in Th2 cells.

Animals↗

PubMed2000

The Hairy and Enhancer of Split homologue-1 (HES-1) mediates the proliferative effect of 17beta-estradiol on breast cancer cell lines.

The mechanism behind hormone dependent growth of breast cancer is presently not well understood. We show that the HES-1 protein level in the breast cancer cell lines T47D and MCF-7 is down regulated by 17beta-estradiol treatment. This regulation could be reversed by addition of the anti-estrogens 4OH tamoxifen, raloxifen and Imperial Chemical Industries (ICI) 182,780. In T47D cells with inducible exogenous HES-1 expression, induced expression of HES-1 protein prevented the proliferative effect of 17beta-estradiol and subsequent up regulation of proliferating cell nuclear antigen (PCNA). An inverse correlation between the HES-1 and PCNA protein levels respectively was found in colon cancer cell lines. These findings point to a potential role of HES-1 as a tumor suppressor in epithelial cells, and as a mediator of 17beta-estradiols proliferative effect on breast cancer cells.

Basic Helix-Loop-Helix Proteins↗

PubMed2000

Difference in effective dosage of genistein on bone and uterus in ovariectomized mice.

Phytoestrogen including soybean isoflavones has structural similarity to estrogen and exhibits beneficial effects on bone tissue to protect against bone loss under estrogen-deficient conditions. Recent studies also indicate a possible action of isoflavones as endocrine disrupters in reproductive tissues. In this study, we administered various dosages of genistein to ovariectomized (OVX) mice, and compared the effective dosages of genistein on bone and uterus. Treatment with genistein at 0.7 mg/day prevented trabecular bone loss in OVX mice without hypertrophic effects on the uterus, while administration of 5 mg/day of genistein induced uterine hypertrophy. The serum levels of genistein in OVX mice treated with 0.7 mg/day and 5 mg/day were 3-fold (1.3 nmol/ml) and 50-fold (20.4 nmol/ml) higher than that in OVX mice. These results suggest that there is a marked difference between genistein dosages that protect against bone loss and those that induce uterine hypertrophy.

Animals↗

PubMed2000

GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells.

Committed T helper type 1 (Th1) and Th2 effector cells, resulting from chronic antigenic stimulation in interleukin (IL)-12 and IL-4, are implicated in the pathology of autoimmune and allergic diseases. Committed Th1 cells cannot be induced to change their cytokine profiles in response to antigenic stimulation and Th2 cytokine-inducing conditions. Here, we report that ectopic expression of GATA-3 induced Th2-specific cytokine expression not only in developing Th1 cells but also in otherwise irreversibly committed Th1 cells and a Th1 clone, HDK1. Moreover, cAMP, an inhibitor of cytokine production by Th1 cells, markedly augmented Th2 cytokine production in GATA-3-expressing Th1 cells. Ectopic expression of GATA-3 in developing Th1 cells, but not in Th1 clone HDK1, induced endogenous GATA-3, suggesting an autoregulatory mechanism for maintenance of GATA-3 expression in Th2 cells. Structure-function analyses of GATA-3 revealed that the NH(2)-terminal transactivation domain and the COOH-terminal zinc finger domain of GATA-3 were critical, whereas the NH(2)-terminal zinc finger domain was dispensable for the induction of IL-4. Both zinc fingers, however, were required for IL-5 induction. A Th2-specific DNaseI-hypersensitive site of the IL-4 locus was detected in GATA-3-expressing Th1 cells. Thus, GATA-3 can change the phenotype of committed Th1 cells, previously considered to be irreversible.

Animals↗

PubMed2000

NFATz: a novel rel similarity domain containing protein.

Nuclear Factor of Activated T cell (NFAT) is a family of transcription factors that are important for the coordinate expression of various cytokines and immunoregulatory cell surface molecules in T cells and other types of cells in the immune system. In addition, analysis of gene disrupted mice revealed that some members of NFAT family are important for the development of myocardium, myocardial hypertrophy, and mesenchymal stem cells. NFAT family proteins have two conserved domains, the NFAT Homology Domain (NHD) and the Rel Similarity Domain (RSD). The RSD is DNA binding and AP-1 interacting domain which has structural similarity to the Rel Homology Region, the DNA binding domain of Rel family proteins. The NHD is a regulatory domain required for the Ca regulated translocation of NFAT. We report here the isolation and initial characterization of a novel RSD containing protein designated NFATz. NFATz has a RSD but no NHD. NFATz protein is localized in the nucleus without Ca signal. There is no detectable binding to a typical NFAT site even in the presence of AP-1, and it is not capable of activating transcription through the NFAT site. The chromosomal location determined by FISH revealed that NFATz and NFATx genes are in the same region.

Amino Acid Sequence↗

PubMed2000

Successive expression and activation of NFAT family members during thymocyte differentiation.

Differentiation of immature CD4(+)CD8(+) thymocytes to mature CD4(+) or CD8(+) T cells is induced by positive selection and appears to involve calcineurin-dependent activation of NFAT, a family of transcription factors. NFATx is predominantly expressed in CD4(+)CD8(+) thymocytes, whereas NFATp and NFATc are expressed at much lower levels in the thymus than in mature T cells. However, how or when each NFAT member is involved in the differentiation pathway is unclear. Using an in vitro model system where isolated CD4(+)CD8(+) thymocytes can survive and differentiate into semi-mature CD4-lineage T cells, we suggest that low calcineurin activity sustained for approximately 20 h is required for cell survival and differentiation. Accordingly, the DNA binding activity of NFAT slowly increased during the stimulation of 20 h to induce the differentiation. NFATx significantly contributed to the early rise, but the late increase was mostly due to NFATc activation. Meanwhile, the expression of NFATx mRNA decreased and that of NFATc mRNA increased. The DNA-binding activity of NFATp was detectable but low throughout the stimulation. NFATp became dominantly active after the semi-mature T cells differentiated into mature and activated CD4 T cells. These findings suggest that NFATx and NFATc successively play roles in T cell development.

Animals↗

PubMed2000

Calcineurin is activated in rat hearts with physiological left ventricular hypertrophy induced by voluntary exercise training.

BACKGROUND: Calcineurin may play a pivotal role in the signaling of cardiac hypertrophy; since this hypothesis was first put forward, controversial reports have been published using various experimental models. This study was designed to compare the physiological left ventricular hypertrophy (LVH) induced by voluntary exercise with LVH induced by aortic constriction and to determine whether calcineurin participates in the signaling of exercise-induced LVH. METHODS AND RESULTS: Wistar rats were assigned to 1 of the following 5 groups: 10 weeks of voluntary exercise (EX), a sedentary regimen, a 1-week (AC1) or 4-week (AC4) ascending aortic constriction period, or a sham operation. EX rats ran 2.4+/-0.7 km/day voluntarily in specially manufactured cages; this was associated with an increase of LV diastolic dimension and stroke volume. Myocardial calcineurin activity markedly increased in EX rats (46.4+/-8.3 versus 18.4+/-0.5 pmol. min(-1). mg(-1) in sedentary rats; P<0.001) and in AC1 rats (44.9+/-6.7 versus 22.1+/-3.7 pmol. min(-1). mg(-1) in sham-operated rats; P<0.001), but not in AC4 rats (29.0+/-3.4 pmol. min(-1). mg(-1)). Treatment with cyclosporin A completely inhibited the development of LVH in EX rats, but it only partially attenuated the development of LVH in AC4 rats. CONCLUSIONS: Calcineurin was activated in exercise-induced physiological LVH and in the developing phase of LVH (AC1), but not in decompensated pressure-overload hypertrophy (AC4). Cyclosporin therapy for the prevention of LVH may be harmful because it does not block the development of pathological hypertrophy but rather that of favorable adaptive hypertrophy.

Animals↗

PubMed2000

Estrogen receptor beta mRNA in colon cancer cells: growth effects of estrogen and genistein.

Knowledge regarding the expression of the recently cloned estrogen receptor beta (ERbeta) in colonic mucosa is limited. In this study, we demonstrated that five human colon cancer cell lines, HT29, Colo320, Lovo, SW480, and HCT116, expressed ERbeta mRNA, but lacked ERalpha mRNA. Results from a cell growth assay demonstrated that these colon cancer cells were not influenced by estrogen, while genistein possessed slight growth inhibitory effects on HT29, Colo320 and Lovo cells at 10 microM, at which concentration is stimulated the growth of ERalpha-positive human breast cancer MCF-7 cells. Tamoxifen inhibited the growth of HT29 and Colo320 cells, dose-dependently, as well as MCF-7 cells. A transfected reporter plasmid containing a vitellogenin estrogen response element could be activated by estradiol in Colo320 cells. Taken together with previous reports, these data suggest that ERalpha and ERbeta may have different biological functions in colon cells.

Base Sequence↗

PubMed2000

The molecular basis of T helper 1 and T helper 2 cell differentiation.

Cytokines such as interleukin 12 (IL-12) and IL-4 are dominant factors in driving the development of T helper 1 (Th1) and Th2 cells, respectively, through specific signalling pathways. In addition, it has been demonstrated more recently that T helper-cell-specific transcription factors exist that determine the commitment of Th1 and Th2 cells for the production of distinct profiles of cytokines. In addition to the expression of distinct cytokine genes and transcription factors, the molecular basis for commitment to a Th1 or Th2 phenotype can probably be explained by multiple mechanisms, including differential cytokine signalling, exclusive cytokine receptor expression, differential expression of transcription factors and/or differential chromatin remodelling of Th1- and Th2-specific genes.

Animals↗

PubMed2000

Bradykinin stimulates IL-6 and IL-8 production by human lung fibroblasts through ERK- and p38 MAPK-dependent mechanisms.

Bradykinin (BK) is a major kinin with well-documented pharmacological properties including vascular leakage and induction of a variety of cytokines. However, the intracellular signalling mechanisms by which BK induced proinflammatory cytokine production have not been fully elucidated. This study investigated the role of the extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in the BK-induced interleukin (IL)-6 and IL-8 production by human lung fibroblasts. Lung fibroblasts were stimulated with BK in the presence or in the absence of PD98059, a specific MAPK/ERK kinase-1 inhibitor, or SB203580, a specific p38 MAPK inhibitor, and IL-6 or IL-8 production and their gene expression was examined. BK-induced ERK 1/2 or p38 MAPK phosphorylation was also analysed by Western blot analysis. BK at nanomolar concentrations stimulated lung fibroblasts to produce IL-6 and IL-8 along with increased ERK 1/2 and p38 MAPK phosphorylation. BK-induced IL-6 and IL-8 synthesis was inhibited by a B2-type BK receptor antagonist. Furthermore, PD98059 or SB203580 significantly suppressed BK-induced IL-6 and IL-8 production and their gene expression. These results indicate that bradykinin-induced interleukin-6 and interleukin-8 production are at least partly mediated through the extracellular signal-related protein kinase 1/2 and p38 mitogen-activated protein kinase pathway-dependent activation in human lung fibroblasts, and suggest that bradykinin appears to be involved in the inflammatory reaction leading to acute lung injury through stimulating interleukin-6 and interleukin-8 production by lung fibroblasts.

Blotting, Northern↗

PubMed2000

Presence of human herpesvirus 6 and herpes simplex virus detected by polymerase chain reaction in surgical tissue from temporal lobe epileptic patients.

We investigated the presence of human herpesvirus 6 (HHV-6) and herpes simplex virus (HSV) in surgical tissue from temporal lobe epileptic patients. A total of 17 cases were studied, including eight males and nine females. The mean age was 24.9 +/- 11.1 years and the mean age of onset was 11.1 +/- 5.4 years. Five patients were diagnosed as encephalitis/meningitis and another three had a history of suspected encephalitis/meningitis, but no patient showed any obvious neurological symptom or mental handicap. Mesial and lateral temporal tissues were examined by polymerase chain reaction. Among six patients positive for HHV-6 (35%), the mesial temporal lobe was positive in four and the lateral temporal lobe was positive in three. Herpes simplex virus was positive in only one patient. Three of the six patients positive for HHV-6 did not show any apparent causes. Mild encephalitis/meningitis induced by HHV-6, a condition sometimes not recognized as encephalitis/meningitis, may be one of the most frequent causes of temporal lobe epilepsy.

Adult↗

PubMed2000

Regulation of nuclear factor of activated T-cell family transcription factors during T-cell development in the thymus.

BACKGROUND: T lymphocytes undergo a series of developmental events in the thymus, and signaling through the T-cell antigen receptor is crucial in this differential program. The nuclear factor of activated T cells (NFATs) may be involved in transcriptional induction of cytokine genes and other immunoregulatory genes in T cells. OBJECTIVES: We have examined the distribution of 3 NFAT family members (NFAT1, NFATc, and NFATx) in human fetal thymocytes, by using semiquantitative RT-PCR and electrophoretic mobility shift assay. RESULTS: The messenger RNA of NFATx was expressed in all T-lymphocyte subsets tested, and expression was highest in CD4(+)CD8(+) thymocytes. Conversely, mRNA of NFAT1 was preferentially expressed in mature CD4(+) single-positive cells. NFATc mRNA was present at low levels in all subsets but was strongly induced by treatment with phorbol ester plus calcium ionophore. Using electrophoretic mobility shift assay, we observed stimulation-dependent NFAT-DNA binding in CD4(+)CD8(+) thymocytes, which was largely dependent on NFATx protein. This DNA-binding activity was inhibited by cyclosporin A, which indicated that NFATx nuclear translocation in CD4(+)CD8(+) thymocytes was regulated by calcineurin phosphatase. In contrast, NFAT1 and NFATc (and to some extent NFATx) were responsible for NFAT DNA binding in the CD4(+) cells. CONCLUSIONS: Expression of NFAT family members is differentially regulated during T-cell development, and NFATx may be involved in T-cell antigen receptor/calcineurin-dependent signaling in CD4(+)CD8(+) thymocytes.

Antibodies↗

PubMed2000

Chromatin remodeling and T helper subset differentiation.

The T helper subsets Th1 and Th2 regulate specific types of immune responses by producing distinct sets of cytokines. Differentiation of the T helper subsets from their common precursors, naive CD4+ T cells, is induced by antigen stimulation and controlled by various other conditions. Of these conditions, the contributions of the cytokine environment have been the best characterized. The presence of interleukin-4 (IL-4) directs the differentiation towards Th2 cells, whereas IL-12 induces Thl differentiation. The Th2 signature cytokine genes encoding IL-4, IL-13, and IL-5 are clustered, and noncoding regions such as the intergenic region of the IL-4 and IL-13 genes are highly conserved from mice to humans. Alteration of the chromatin structure of this Th2 cytokine cluster region is detected as nuclease-accessible regions specific to Th2 cells. Activation of STAT6 promotes Th2 differentiation by inducing Th2-specific transcription factors, including GATA3. Expression of GATA3 induces Th2 differentiation and enhances the Th2 cell-specific chromatin accessibility, indicating that GATA3 is a key protein that regulates differentiation through chromatin remodeling. T helper subset differentiation provides a good system to study gene expression regulation at the chromatin level.

Alleles↗

PubMed2000

Interleukin-18 in combination with IL-2 enhances natural killer cell activity without inducing large amounts of IFN-gamma in vivo.

Interleukin-18 (IL-18) is known to synergistically enhance murine natural killer (NK) cell activity in vitro when combined with either IL-12 or IL-2. However, it has also been demonstrated that simultaneous administration of IL-18 and IL-12 to mice induces extraordinarily large amounts of interferon-gamma (IFN-gamma) in the serum. In this study, we examined the effects of a combination of IL-18 and IL-2 on in vivo NK cell activation in parallel with the induction of toxicity. In contrast to the IL-18 and IL-12 combination, the combined administration of IL-18 and IL-2 to BALB/c mice for 3 days induced neither high levels of IFN-gamma production nor other visible side effects. When compared with treatment with IL-18 or IL-2 alone, the combined treatment resulted in a significant increase in the number of DX-5 (pan-NK cells marker)-positive cells in spleens and a marked enhancement of splenic NK activity, as determined by standard cytotoxicity assays. Enhanced splenic cytotoxicity generated in the mice treated with both IL-18 and IL-2 was also observed against syngeneic Colon 26 adenocarcinoma cells. Consistent with this in vitro observation, combined treatment produced a significantly stronger inhibitory effect on the pulmonary metastases following i.v. injection of Colon 26 tumor cells than treatment with either cytokine alone. These results suggest that IL-18 combined with IL-2 potentiates in vivo NK cell activity and contributes to inhibition of tumor metastasis without inducing significant toxicity.

Animals↗

PubMed2000

Cortical dysplasia with ossification.

We present the first case of cortical dysplasia with extensive intracerebral ossification. An eight-year-old epilepsy patient with a calcified lesion was successfully treated by surgical intervention. Pathological examination revealed a number of bizarre dysplastic cells in the whole lesion, which consisted of an epileptogenic cerebral cortex and a nonepileptogenic hamartomatous lesion with adipose tissue, vascular tissue, calcification, and ossification. The patient was diagnosed as having cortical dysplasia with ossification. Our findings support the notion that cortical dysplasia has a multipotentiality of cellular differentiation, including various hamartomatous tissues. We suggest that cortical dysplasia should be considered as a potential cause for epileptogenicity of a hamartomatous lesion even when magnetic resonance imaging (MRI) fails to disclose cortical dysplasia.

Brain Diseases↗