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Biomedical subjects

Hirotoshi Nakamura

Publications and source records attributed to Hirotoshi Nakamura.

At least 37 records · Page 2Linked to original sources
PubMed2004

Unliganded thyroid hormone receptor-beta1 represses liver X receptor alpha/oxysterol-dependent transactivation.

The thyroid hormone receptor (TR) and liver X receptor (LXR)-alpha are members of the nuclear hormone receptor family and are ligand-dependent transcription factors. Among the promoter target genes, TR and LXR recognize the T3 response element and LXR response element (LXRE), respectively. Because T3 response elements and LXREs have similar configurations, referred to as direct repeat 4, we investigated the possibility of cross-talk between the two ligand-dependent signal transduction pathways. We found that TRbeta1, a major isoform of TR in the liver, binds and transactivates LXREs derived from the mouse mammary tumor virus long-terminal repeat and the promoter of the sterol regulatory element binding protein 1c. Moreover, unliganded TRbeta1 suppresses promoter activity driven by LXRalpha and its ligand, whereas transactivation by T3-bound TRbeta1 is not affected by LXRalpha in the presence or absence of oxysterols. Gel shift, mammalian two-hybrid, and glutathione S-transferase pull-down assays demonstrated the direct binding of TRbeta1 to these LXREs and revealed that the interaction between TRbeta1 and corepressors is important to the unliganded TR-mediated suppression of LXRalpha-transactivation. Our findings suggest that T3 and TR influence lipid metabolism regulated by oxysterol/LXRalpha at the transcriptional level.

Animals↗
PubMed2004

Thyroid-hormone-dependent negative regulation of thyrotropin beta gene by thyroid hormone receptors: study with a new experimental system using CV1 cells.

The molecular mechanism involved in the liganded thyroid hormone receptor suppression of the TSHbeta (thyroid-stimulating hormone beta, or thyrotropin beta) gene transcription is undetermined. One of the main reasons is the limitation of useful cell lines for the experiments. We have developed an assay system using non-pituitary CV1 cells and studied the negative regulation of the TSHbeta gene. In CV1 cells, the TSHbeta-CAT (chloramphenicol acetyltransferase) reporter was stimulated by Pit1 and GATA2 and suppressed by T3 (3,3',5-tri-iodothyronine)-bound thyroid hormone receptor. The suppression was dependent on the amounts of T3 and the receptor. Unliganded receptor did not stimulate TSHbeta activity, suggesting that the receptor itself is not an activator. Analyses using various receptor mutants revealed that the intact DNA-binding domain is crucial to the TSHbeta gene suppression. Co-activators and co-repressors are not necessarily essential, but are required for the full suppression of the TSHbeta gene. Among the three receptor isoforms, beta2 exhibited the strongest inhibition and its protein level was the most predominant in a thyrotroph cell line, TalphaT1, in Western blotting. The dominant-negative effects of various receptor mutants measured on the TSHbeta-CAT reporter were not simple mirror images of those in the positive regulation under physiological T3 concentration.

Animals↗
PubMed2004

Influence of fibrate treatment on malondialdehyde-modified LDL concentration.

BACKGROUND: Drug therapy is considered essential to the clinical prevention of atherosclerotic lesions in patients with diabetes mellitus (DM). METHODS: To confirm the effects of fibrate therapy, we determined low-density lipoprotein (LDL) size by gradient gel electrophoresis and malondialdehyde-modified LDL (MDA-LDL) concentrations by enzyme-linked immunosolvent assay (ELISA) and clarified the association between apolipoprotein B (apo B) and MDA-LDL during the fibrate therapy. RESULTS: Mean MDA-LDL concentrations were higher in healthy men than in healthy women. There were no significant differences in mean MDA-LDL concentrations between age groups for males or females. According to the regression equation (y = 0.063x + 10.9) obtained for apo B and MDA-LDL concentrations with fibrate treatment, the apo B concentration in those may need to be decreased to 1260 mg/l to restore the MDA-LDL concentration to the control concentration (65 +/- 25 units/l). This slope of the apoB/MDA-LDL regression line was approximately half of that with no-drug treatment (y = 0.109x - 10.8). CONCLUSIONS: Fibrate therapy had an effect on reducing serum MDA-LDL concentration in diabetic patients.

Adult↗
PubMed2004

Prostaglandin E2 inhibits platelet-derived growth factor-stimulated cell proliferation through a prostaglandin E receptor EP2 subtype in rat hepatic stellate cells.

Prostaglandin (PG) E2 inhibits hepatic stellate cell (HSC) mitogenesis. PGE-specific receptors are divided into four subtypes that are coupled either to Ca2+ mobilization (EP1 and EP3) or to the stimulation of adenyl cyclase (EP2 and EP4). The aims of the current study were to identify PGE receptor subtypes in cultured rat HSC and to examine which PGE receptor subtype(s) mediates the inhibitory effect of PGE2 on platelet-derived growth factor (PDGF)-stimulated proliferation. Reverse transcription-polymerase chain reaction analysis was performed to detect PGE receptor subtype mRNA expression. Cell proliferation was determined by measuring [3H]thymidine incorporation, and intracellular cyclic AMP was measured by radioimmunoassay. Cultured rat HSC expressed mRNAs for all four subtypes of PGE receptor. PGE2- and EP2-selective agonist produced dose-dependent inhibitory effects on PDGF-stimulated proliferation. Neither EP1-, EP3-, nor EP4-selective agonists showed any inhibitory effect. An adenylate cyclase inhibitor strongly blunted the inhibition of DNA synthesis elicited by PGE2 and the EP2 agonist. The EP2 agonist generated higher and more prolonged increases in intracellular cyclic AMP than the EP4 agonist. Activation of the PGE EP2 receptor has an antiproliferative effect in HSC that may be mediated by cyclic AMP-related signal transduction pathways.

Animals↗
PubMed2004

[A case of sarcoidosis with atypical high resolution CT findings].

A 36-year-old woman was referred to our hospital for investigation of erythema on the upper arms and thighs and abnormal radiological findings in the chest. A chest radiograph showed poorly defined fine nodules in both lung fields and high-resolution CT revealed fine nodular opacities with a random distribution throughout both lungs. No lymph node enlargement or peribronchovascular interstitial thickening were seen. Bronchoscopic evaluation revealed bronchial mucosal hypervascularity. Transbronchial lung biopsy and skin biopsy specimens showed noncaseating epithelioid cell granulomas. These findings confirmed the diagnosis of sarcoidosis. This is a rare case of sarcoidosis presenting with atypical high-resolution CT findings, which are difficult to differentiate from those of miliary tuberculosis or metastatic carcinoma.

Adult↗
PubMed2004

[Two cases of intralobar pulmonary sequestration associated with nontuberculous mycobacterial infection in a young patient].

We report two cases of intralobar pulmonary sequestration associated with nontuberculous mycobacterial infection. Case 1: A 28-year-old woman was hospitalized because of cough. Chest CT demonstrated multi-cystic lesions with an air-fluid level in the right lower lobe. Case 2: A 25-year-old woman was hospitalized because of fever. Chest CT demonstrated homogeneous consolidation in the right lower lobe. In both cases, aortography showed an anomalous artery supplying the right basal segment, and pulmonary sequestration was diagnosed. Furthermore, Mycobacterium avium was detected in the bronchial lavage, and a right lower lung lobectomy was performed after chemotherapy. Mycobacterium avium was cultured from the fluid in the sequestrated lung, and histological findings of the resected lobe showed epithelioid cell granulomas. We diagnosed these cases as having pulmonary sequestrations associated with nontuberculous mycobacterial infection. We concluded that pulmonary sequestration should be considered an underlying disease of secondary nontuberculous mycobacterial infections in young patients.

Adult↗
PubMed2004

[Clinical analysis of idiopathic nonspecific interstitial pneumonia with unfavorable outcome].

Nonspecific interstital pneumonia (NSIP) is associated with an excellent response to steroidal therapy. However, it was reported that some cases of NSIP might have an unfavorable outcome in spite of aggressive therapy. In this study, we explored the prognosis for 23 patients with NSIP and examined matched groups of 18 patients with treatment-responsive or naturally recovered idiopathic NSIP, and 5 patients with idiopathic NSIP who fared poorly despite therapy. The patients who had poor prognoses were, significantly, all non-smoking women. Histologic examination revealed that the cases with progressive, idiopathic NSIP were in all cases of the fibrotic type. By contrast, only 39% of those with a good prognosis, were fibrotic. No significant differences in CT appearance were noted between the two cohorts. These findings provide a potential clinical marker of therapy outcome of in idiopathic NSIP.

Adult↗
PubMed2004

[A case of adenocarcinoma of the lung presenting symptoms of choroidal metastasis as the initial clinical manifestation].

A 51-year-old woman was referred to our hospital with a complaint of disturbance in vision. Ophthalmologic examination revealed multiple choroidal tumors. High-resolution CT showed a nodular shadow in the left lower lobe. Transbronchial biopsy and right supraclavicular lymph node biopsy specimens showed a poorly-differentiated adenocarcinoma. We concluded that the choroidal tumors had metastasized from the lung. Combined chemotherapy (CDDP + CPT-11) followed by irradiation of both eyes and brain were performed. Nevertheless, she died 6 months after the initial presentation. It is important to notice ophthalmologic symptoms because lung cancer may metastasize to the choroids.

Adenocarcinoma↗
PubMed2004

The incidence and clinical characteristics of bronchiolitis obliterans organizing pneumonia syndrome after radiation therapy for breast cancer.

STUDY OBJECTIVE: Bronchiolitis obliterans organizing pneumonia (BOOP) syndrome after adjuvant radiation therapy for breast cancer has been recently recognized. However, the precise incidence of this syndrome remains to be determined. The aim of this study was to clarify the incidence and clinical characteristics of radiation-induced BOOP syndrome. METHODS: We conducted a retrospective analysis of 206 consecutive patients wit breast cancer undergoing tangential-field radiation therapy at our institution from 1992 to 2002. RESULTS: Among the patients, five (2.4%) developed BOOP syndrome. These five patients began with flu-like symptoms 2-7 months after the completion of radiation therapy. Four of them had received tamoxifen, an estrogen receptor antagonist, and the other one underwent cytotoxic chemotherapy. Their chest radiographs revealed peripheral alveolar opacities with migration outside the irradiated fields. Increased lymphocyte counts and elevated CD4/CD8 ratios were observed in the bronchoalveolar lavage fluid. Transbronchial biopsy revealed organizing pneumonia. The serum levels of KL-6, a marker of interstitial pneumonia, did not increase in any patients. Treatment with corticosteroids resulted in a rapid improvement, but two patients relapsed after the cessation of corticosteroids. CONCLUSIONS: These results suggest that BOOP syndrome after tangential-field radiation therapy for breast cancer is not rare and more attention should be directed to this condition as a radiation-induced pulmonary toxicity.

Biopsy↗
PubMed2003

Antiinflammatory roles of peroxisome proliferator-activated receptor gamma in human alveolar macrophages.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcriptional factor belonging to the nuclear receptor superfamily. PPARgamma, which is predominantly expressed in adipose tissue, plays a major regulatory role in glucose metabolism and adipogenesis. Interestingly, recent studies have demonstrated PPARgamma expression in monocytes/macrophages and its antiinflammatory activities. However, it is unclear whether alveolar macrophages (AMs) express functional PPARgamma. The present study was conducted to investigate the expression of PPARgamma by AMs and to elucidate its functional role. Using reverse transcription-polymerase chain reaction and Western blotting, we demonstrated the strong expression of PPARs messenger RNA and protein in freshly isolated human AMs. Ligands of PPARgamma, 15-deoxy-delta(12,14)prostaglandin J2, and troglitazone significantly decreased LPS-induced tumor necrosis factor-alpha production by AMs. These ligands markedly upregulated the expression of CD36, a scavenger receptor that mediates the phagocytosis of apoptotic neutrophils. Indeed, ligand-treated AMs ingested a significantly higher number of apoptotic neutrophils than untreated AMs. These data indicate that PPARgamma expressed by AMs play an antiinflammatory role through inhibiting cytokine production and increasing their CD36 expression together with the enhanced phagocytosis of apoptotic neutrophils, which is an essential process for the resolution of inflammation. This suggests the potential therapeutic application of PPARgamma ligands in inflammatory disorders of the lung.

Apoptosis↗
PubMed2003

Beta-catenin/Tcf-1-mediated transactivation of cyclin D1 promoter is negatively regulated by thyroid hormone.

Cyclin D1 is an oncogenic cyclin frequently over-expressed in cancer. To examine the effect of thyroid hormone (T3) and its receptor (TR) on the transcription of cyclin D1 gene, we co-transfected the chloramphenicol acetyl-transferase (CAT) reporter plasmid containing cyclin D1 promoter together with the expression plasmids for TRbeta1 and wild-type or mutant beta-catenin (SA) into 293T cells. In the presence of T3, beta-catenin-dependent transactivation of cyclin D1 promoter was suppressed by co-transfection of TRbeta1. The suppression by T3/TRbeta1 was in a dose-dependent manner. The CAT reporter gene in which Tcf/Lef-1 sites were fused to heterologous promoter was also suppressed by T3/TRbeta1. Furthermore, inhibition of endogenous wild-type beta-catenin by T3/TRbeta1 was observed in SW480 colon carcinoma cells with mutation of the adenomatous polyposis coli gene. These results indicate that the T3-bound TR inhibits the transcription of cyclin D1 through the Tcf/Lef-1 site, which is positively regulated by the Wnt-signaling pathway.

Cells, Cultured↗
PubMed2003

High expression of Cks1 in human non-small cell lung carcinomas.

Enhanced degradation of cyclin-dependent kinase (CDK) inhibitor p27(Kip1) is known to be a powerful prognostic marker in many types of human cancers. Human CDK subunit 1 (Cks1) and S-phase kinase associated protein 2 (Skp2) are components of the SCF(Skp2) complex, which acts as a ubiquitin ligase for p27(Kip1). There are no reports about the involvement of Cks1 in the pathogenesis of human cancer. Here we show high expression of Cks1 in non-small cell lung cancers (NSCLCs) using Western blotting and quantitative real-time RT-PCR. The Skp2 mRNA expression level was high in squamous cell carcinomas and was inversely related with the p27(Kip1) protein level in individual clinical samples. In contrast, Cks1 mRNA expression had no such relationship with p27(Kip1), although Cks1 mRNA was significantly elevated in adenocarcinomas. These results suggest that high expression of Skp2 and Cks1 may be involved in the pathogenesis of NSCLCs via different mechanisms.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Elevated complement C3a in plasma from patients with severe acute asthma.

BACKGROUND: Complement component C3a, an anaphylatoxin, provokes acute inflammatory responses, including smooth muscle contraction, mucus hypersecretion, increase in vascular permeability, and recruitment of inflammatory cells. Thus C3a may be related to airway inflammation and bronchoconstriction in acute asthma exacerbation. OBJECTIVE: We sought to determine whether plasma C3a is elevated in patients presenting for emergency treatment of acute asthma exacerbations and to correlate C3a concentrations with response to therapy. METHODS: Plasma C3a and serum eosinophil cationic protein were measured in 52 patients with acute asthma with peak expiratory flow of < or =50% the predicted value. Control subjects were 42 patients with stable chronic asthma. Patients with severe acute asthma were classified into 2 groups (admitted and discharged), according to how effective inhaled bronchodilators and systemic corticosteroids were in the first 2 hours of treatment. RESULTS: Concentrations of C3a in plasma from subjects in the admitted group (median, 256 ng/mL; range, 94 to 454) were significantly higher than those in the discharged group (197 ng/mL; 72 to 300) or those in patients with stable chronic asthma (166 ng/mL; 89 to 254; P <.0001). Elevated plasma C3a concentrations in admitted asthmatic patients decreased significantly by 7 days after admission (P =.0005). No significant difference was evident in serum eosinophil cationic protein concentration between the admitted group (33.1 microg/L; 6.3 to 143) and the discharged group (32.7 microg/L; 14.6 to 160; P =.99). CONCLUSIONS: Concentrations of C3a, which can induce airway inflammation and bronchoconstriction, were associated with differences in response to emergency treatment of severe asthma exacerbation.

Acute Disease↗