Esteban C Gabazza

Mie University, Tu, Mie, Japan

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Publications (263)1093.22 Total impact

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    ABSTRACT: Eosinophils and mast cells play critical roles in the pathogenesis of bronchial asthma. Activation of both cells leads to the release of pro-inflammatory mediators in the airway of asthmatic patients. Recently, we have shown that inhaled thrombomodulin inhibits allergic bronchial asthma in a mouse model. In the present study, we hypothesize that thrombomodulin can inhibit the activation of eosinophils and mast cells. The effect of thrombomodulin on the activation and release of inflammatory mediators from eosinophils and mast cells was evaluated. Thrombomodulin inhibited the eotaxin-induced chemotaxis, upregulation of CD11b and degranulation of eosinophils. Treatment with thrombomodulin also significantly suppressed the degranulation and synthesis of inflammatory cytokines and chemokines in eosinophils and mast cells. Mice treated with a low-dose of inhaled thrombomodulin have decreased number of eosinophils and activated mast cells and Th2 cytokines in the lungs compared to untreated mice. The results of this study suggest that thrombomodulin may modulate allergic responses by inhibiting the activation of both eosinophils and mast cells. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cellular Immunology 12/2014; 293(1):34-40. · 1.87 Impact Factor
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    ABSTRACT: Background Alcohol consumption is a major cause of liver injury but the mechanisms are not completely understood. Protein S (PS) is an anticoagulant glycoprotein with multiple functions. The role of PS in liver injury is unknown.Objectives This study investigated the role of PS in acute alcoholic hepatitis.MethodsA mouse overexpressing human PS (hPS-TG) was generated in which acute hepatitis was induced by intraperitoneal injection of ethanol.ResultsThe levels of serum liver enzymes, liver tissue inflammatory cytokines and the degree of hepatic steatosis were significantly increased in hPS-TG mice treated with ethanol compared with ethanol-treated wild type (WT) mice. Cell expansion, activation and inhibition of apoptosis were significantly augmented in natural killer T (NKT) cells from hPS-TG mice compared to WT mice. Liver mononuclear cells from hPS-TG mice express higher levels of inflammatory cytokines than those from WT mice after stimulation with a specific stimulant of NKT cells in vitro. In a co-culture system of hepatocytes and NKT cells, the effects of PS on ethanol-mediated cell injury were suppressed by a CD1d neutralizing antibody. Alcoholic liver injury was significantly improved in mice pre-treated with PS siRNA and anti-protein S antibody compared to control mice. Patients with alcoholic hepatitis showed significantly increased plasma PS levels and enhanced liver expression of PS and CD1d compared to controls.Conclusions The results of this study suggest that PS exacerbates acute alcoholic hepatitis by inhibiting apoptosis of activated NKT cells.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 11/2014; · 6.08 Impact Factor
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    ABSTRACT: Therapy with monoclonal antibodies to tumor necrosis factor (TNF)-α and the interleukin (IL)-12/23 p40 subunit has significantly improved the clinical outcome of patients with psoriasis. These antibodies inhibit the effects of the target cytokines and thus the major concern during their use is the induction of excessive immunosuppression. Recent studies evaluating the long-term efficacy and safety of biologic therapy in psoriasis have shown no significant appearance of serious adverse effects including infections and malignancies. However, the immunological consequence and the mechanism by which the blockade of a single cytokine by biologics can successfully control the activity of psoriasis remain unclear. In the current study, we investigated the effect of biologic therapy on cytokine production of various lymphocytes and on the activity of monocytes and neutrophils in psoriatic patients. Neutrophils, monocytes and T cells were purified from heparinized peripheral venous blood by Ficoll density gradient centrifugation, and γ-interferon, TNF-α and IL-17 production from lymphocytes was measured by flow cytometer. The activation maker of neutrophils and the activated subsets of monocytes were also analyzed. Biologic therapy induced no significant changes in the cytokine production by lymphocytes from the skin and gut-homing T cells. However, neutrophil activity and the ratio of activated monocyte population increased in severely psoriatic patients were normalized in psoriatic patients receiving biologic therapy. The present study showed that biologic therapy ameliorates clinical symptoms and controls the immune response in patients with psoriasis.
    The Journal of Dermatology 08/2014; 41(8). · 2.35 Impact Factor
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    ABSTRACT: Epithelial to mesenchymal transition (EMT) is a mechanism by which eosinophils can induce airway remodeling. Montelukast, an antagonist of the cysteinyl leukotriene receptor, can suppress airway remodeling in asthma. The purpose of this study was to evaluate whether montelukast can ameliorate airway remodeling by blocking EMT induced by eosinophils. EMT induced was assessed using a co-culture system of human bronchial epithelial cells and human eosinophils or the eosinophilic leukemia cell lines, Eol-1. Montelukast inhibited co-culture associated morphological changes of BEAS-2b cells, decreased the expression of vimentin and collagen I, and increased the expression of E-cadherin. Montelukast mitigated the rise of TGF-β1 production and Smad3 phosphorylation. Co-culture of human eosinophils with BEAS-2B cells significantly enhanced the production of CysLTs compared with BEAS-2B cells or eosinophils alone. The increase of CysLTs was abolished by montelukast pre-treatment. Montelukast had similar effects when co-culture system of Eol-1 and BEAS-2B was used. This study showed that montelukast suppresses eosinophils-induced EMT of airway epithelial cells. This finding may explain the mechanism of montelukast-mediated amelioration of airway remodeling in bronchial asthma.
    Biochemical and Biophysical Research Communications 05/2014; · 2.28 Impact Factor
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    ABSTRACT: Quantitative analysis of itching in patients with itching dermatitis including atopic dermatitis (AD) is indispensable for the evaluation of disease activity and response to therapy. However, the objective evaluation system for itching is limited. We have developed a new objective and quantitative scratching behavior detection system using a wristwatch-type sound detector. The scratch sound detected on the wrist is recorded on a personal computer through a filtering, squaring and smoothing process by specific hardware. Subsequently, the data is automatically processed and judged for the scratching movement using specific software based on the periodicity and energy of the signal. Twenty-four measurements for healthy volunteers and those with AD by this system were evaluated by comparison with a simultaneously recorded video analysis system. The ratio of scratching time in sleeping time evaluated by these two systems was almost identical. The healthy subjects scratched their skin approximately 2 min during 6 h of sleeping time, while the mean scratching time of AD subjects was 24 min in their sleeping time. In contrast to the time-consuming video analysis system, this system takes only several minutes for evaluation of an overnight record. This scratch sound detection system is expected to serve as a new objective evaluation tool for itching dermatitis, namely, AD, and development of anti-itch therapies for dermatitis.
    The Journal of Dermatology 02/2014; · 2.35 Impact Factor
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    ABSTRACT: The skin is an immune organ that contains innate and acquired immune systems and thus is able to respond to exogenous stimuli producing large amount of proinflammatory cytokines including IL-1 and IL-1 family members. The role of the epidermal IL-1 is not limited to initiation of local inflammatory responses, but also to induction of systemic inflammation. However, association of persistent release of IL-1 family members from severe skin inflammatory diseases such as psoriasis, epidermolysis bullosa, atopic dermatitis, blistering diseases and desmoglein-1 deficiency syndrome with diseases in systemic organs have not been so far assessed. Here, we showed the occurrence of severe systemic cardiovascular diseases and metabolic abnormalities including aberrant vascular wall remodeling with aortic stenosis, cardiomegaly, impaired limb and tail circulation, fatty tissue loss and systemic amyloid deposition in multiple organs with liver and kidney dysfunction in mouse models with severe dermatitis caused by persistent release of IL-1s from the skin. These morbid conditions were ameliorated by simultaneous administration of anti-IL-1α and IL-1β antibodies. These findings may explain the morbid association of arteriosclerosis, heart involvement, amyloidosis and cachexia in severe systemic skin diseases and systemic autoinflammatory diseases, and support the value of anti-IL-1 therapy for systemic inflammatory diseases.
    PLoS ONE 01/2014; 9(8):e104479. · 3.53 Impact Factor
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    ABSTRACT: Background: Thrombomodulin treatment modulates the properties of dendritic cells (DCs) converting them from immunogenic to tolerogenic and inducing its own expression on DCs. Thrombomodulin binds to the inflammatory mediator, high mobility group protein B1 (HMGB1), antagonizing signalling through its receptor, receptor for advanced glycation end products (RAGE). Methods: To test if soluble thrombomodulin could antagonize HMGB1 signaling via RAGE on DCs. DCs were prepared from mouse bone marrow cells or human monocytes. In some experiments dendritic cells were sorted into thrombomodulin+ and thrombomodulin- populations. Expression of surface maturation markers was determined by flow cytometry following treatment with thrombomodulin in the presence or absence of HMGB1. Results: Thrombomodulin+ dendritic cells secrete less HMGB1 into the medium. HMGB1 reduces the effects of thrombomodulin on expression of DC maturation markers. Treatment with thrombomodulin reduces the expression of maturation markers such as CD80 and CD86 and increases the expression of thrombomodulin on the DC surface. Treatment of DCs with neutralizing anti-HMGB1 antibody acted synergistically with thrombomodulin in increasing thrombomodulin expression on DCs. Treatment with thrombomodulin can still reduce the expression of surface markers on DCs derived from mice that are deficient in RAGE showing that thrombomodulin can affect DCs by an alternative mechanism. Conclusions: The results of this study show that thrombomodulin modulates DCs both by antagonizing the interaction of HMGB1 with RAGE and by an independent mechanism.
    Allergology International 12/2013;
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    ABSTRACT: IL-10 plays a critical role in the induction of specific T cell tolerance. To date, whether IL-10 induction by antigen application is dose- or time-dependent remains unclear. In this study, IL-10 induction by allergen exposure was investigated in the several schedules. Oxazolone was repeatedly applied to mouse ear, and mRNA of inflammatory cytokines in lesional skins was measured. The results indicated that continuous high-dose antigen exposure induces IL-4 as well as abundant IL-10 production. Monocytes/ dendritic cells and T cells are major source of IL-10. Allergen-specific immunotherapy is resumed before antigen scattering: pre-season. We evaluated safe-loading dose of allergens in pre-seasonal therapy focusing Tr1 induction. Re-starting immunotherapy with high dose effectively augmented IL-10 expression accompanied with further induction of IL-4 and inflammatory cytokines. Therefore, the protocol re-starting with low-dose antigen is preferential to obviate the risk of exacerbation or anaphylaxis. This article is protected by copyright. All rights reserved.
    Experimental Dermatology 12/2013; · 4.12 Impact Factor
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    ABSTRACT: Background. Optimal empiric therapy for hospitalized healthcare-associated pneumonia (HCAP) patients is uncertain. Methods. We prospectively applied a therapeutic algorithm, based on the presence of risk factors for multidrug-resistant (MDR) pathogens in a multicenter- cohort study of 445 pneumonia patients, including both community-acquired pneumonia (CAP, n=124) and HCAP (n=321). Results. MDR pathogens were more common (15.3% vs 0.8%, p<0.001) in HCAP patients than in CAP patients, including Staphylococcus aureus (11.5% vs 0.8%, p<0.001) ; methicillin-resistant Staphylococcus aureus (MRSA) (6.9% vs 0%, p=0.003); Enterobacteriaceae (7.8% vs 2.4%, p=0.037); and Pseudomonas aeruginosa (6.9% vs 0.8%, p=0.01). Using the proposed algorithm, HCAP patients with>2 MDR risks, one of which was severity of illness (n=170), vs. HCAP with 0-1 risk (n=151) had a significantly higher frequency of MDR pathogens (27.1% vs 2%, p<0.001). 93.1% of HCAP patients were treated according to the therapy algorithm, with only 53% receiving broad-spectrum empiric therapy, yet 92.9% received appropriate therapy for the identified pathogen. 30-day HCAP mortality was significantly higher than for CAP (13.7% vs. 5.6%, p=0.017), but among HCAP patients with 0-1 MDR risks, mortality was lower than with ≥2 MDR risks (8.6% vs. 18.2%, p=0.012). In multivariate analysis, initial treatment failure, but not inappropriate empiric antibiotic therapy, was a mortality risk factor (odds ratio 72.0). Conclusions. Basing empiric HCAP therapy on its severity and the presence of risk factors for MDR pathogens is a potentially useful approach that achieves good outcomes without excessive use of broad-spectrum antibiotic therapy.
    Clinical Infectious Diseases 09/2013; · 9.42 Impact Factor
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    ABSTRACT: Previously we have shown in a mouse model of bronchial asthma that thrombomodulin can convert immunogenic conventional dendritic cells into tolerogenic dendritic cells while inducing its own expression on their cell surface. Thrombomodulin(+) dendritic cells are tolerogenic while thrombomodulin(-) dendritic cells are pro-inflammatory and immunogenic. Here we hypothesized that thrombomodulin treatment of dendritic cells would modulate inflammatory gene expression. Murine bone marrow-derived dendritic cells were treated with soluble thrombomodulin and expression of surface markers was determined. Treatment with thrombomodulin reduces the expression of maturation markers and increases the expression of TM on the DC surface. Thrombomodulin treated and control dendritic cells were sorted into thrombomodulin(+) and thrombomodulin(-) dendritic cells before their mRNA was analyzed by microarray. mRNAs encoding pro-inflammatory genes and dendritic cells maturation markers were reduced while expression of cell cycle genes were increased in thrombomodulin-treated and thrombomodulin(+) dendritic cells compared to control dendritic cells and thrombomodulin(-) dendritic cells. Thrombomodulin-treated and thrombomodulin(+) dendritic cells had higher expression of 15-lipoxygenase suggesting increased synthesis of lipoxins. Thrombomodulin(+) dendritic cells produced more lipoxins than thrombomodulin(-) dendritic cells, as measured by ELISA, confirming that this pathway was upregulated. There was more phosphorylation of several cell cycle kinases in thrombomodulin(+) dendritic cells while phosphorylation of kinases involved with pro-inflammatory cytokine signaling was reduced. Cultures of thrombomodulin(+) dendritic cells contained more cells actively dividing than those of thrombomodulin(-) dendritic cells. Production of IL-10 is increased in thrombomodulin(+) dendritic cells. Antagonism of IL-10 with a neutralizing antibody inhibited the effects of thrombomodulin treatment of dendritic cells suggesting a mechanistic role for IL-10. The surface of thrombomodulin(+) dendritic cells supported activation of protein C and procarboxypeptidase B2 in a thrombomodulin-dependent manner. Thus thrombomodulin treatment increases the number of thrombomodulin(+) dendritic cells, which have significantly altered gene expression compared to thrombomodulin(-) dendritic cells in key immune function pathways.
    PLoS ONE 08/2013; 8(8):e72392. · 3.53 Impact Factor
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    ABSTRACT: Apart from its role in the coagulation system, thrombin plays an important role in the inflammatory response through its protease-activated receptor(PAR)s. However, the role of thrombin in the immune response is not clear. We evaluated if thrombin has a modulatory role in allergic bronchial asthma. Bronchial asthma was induced in mice by intraperitoneal sensitization and inhalation challenge with ovalbumin. Thrombin or its inhibitors were administered by inhalation before each allergen challenge. Mice with low but sustained coagulation activation had reduced allergic inflammation and allergic asthma was inhibited by low doses but worsened by high doses of thrombin. Allergic asthma was worsened by antithrombin, argatroban, hirudin and anti-thrombomodulin antibody. Mice with an increased concentration of an inhibitor of both thrombin and activated protein C had worsened disease. Heterozygous PAR-1 mice had less allergic inflammation but PAR-1 agonist worsened it. Allergic bronchial inflammation was worsened in mice that received adoptive transfer of PAR-1 agonist-treated Th2 cells compared to controls. Low concentrations of thrombin suppressed but high-dose of it enhanced maturation and secretion of cytokines in dendritic cells. The effects of thrombin on allergic asthma are dose-dependent with detrimental effects at high dose and protective ones at low dose. These data demonstrate that thrombin modulates the outcome in allergic bronchial asthma. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 08/2013; · 6.08 Impact Factor
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    ABSTRACT: The number of elderly patients undergoing surgery for lung cancer is increasing. In this study, we assessed the usefulness of three-dimensional computed tomographicangiography (3D-CTA) for the detection of coronary disease in the elderly before surgical intervention for lung cancer. One hundred twenty patients admitted to our institution for lung cancer resection were enrolled in the study. 3D-CTA was performed in all 120 patients. Seventy-one patients had normal findings, and forty-nine patients showed coronary stenosis on 3D-CTA examination. Among the latter 49 patients, 24 with slight stenosis underwent lung tumor resection, 23 had coronary angiography for severe stenosis before lung surgery and 2 were not eligible for lung resection because of very severe coronary stenosis. The diagnostic value of 3D-CTA was better than conventional CT. This study suggests the usefulness of 3D-CTA for the preoperative diagnosis of coronary ischemic disease in elderly lung cancer patients.
    World Journal of Surgical Oncology 07/2013; 11(1):164. · 1.20 Impact Factor
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    ABSTRACT: IL-18 is a pro-inflammatory cytokine of the IL-1 family involved in Th1/Th2 polarization. IL-18 is produced and stored as an inactive precursor (proIL-18) in several cells including keratinocytes, and thus appropriate processing is required to release its active form. In a previous study using recombinant protein, we demonstrated that granzyme B (GrB) cleaves proIL-18 into its active forms in a similar fashion as caspase-1 and human mast cell chymase. GrB released from cytotoxic T lymphocyte (CTL) and NK cells has roles in apoptosis and cytotoxic activity. In certain inflammatory skin diseases with epidermal cell death, the epidermal keratinocytes are targets of CTL and NK cells. However, IL-18 activation during the direct interaction of CTL/NK with keratinocytes has not been described so far. We investigated the interaction between CTL and keratinocytes, and IL-18 processing by CTL-derived GrB using cultured CD8+ T cells and keratinocyte cell line HaCaT. GrB(+)/caspase-1(-) CD8+ T cells cultivated from healthy human PBMC were co-cultured with interferon(IFN)-γ-treated HaCaT cells. The expression of GrB and caspase-1 in HaCaT cells was analyzed by flow cytometry and PCR. The IL-18 concentration in the culture supernatant was measured by specific ELISA. The interaction between HaCaT cells and CTL co-culture increased the number of cytoplasmic GrB-positive HaCaT cells with limited endogenous GrB mRNA expression. The concentration of mature IL-18 levels increased in the co-culture supernatant. GrB from CTLs acts double roles to keratinocytes: a IL-18 converting enzyme and pro-apoptotic factor in the skin inflammatory diseases.
    Archives for Dermatological Research 07/2013; · 2.27 Impact Factor
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    ABSTRACT: Background: Acute lung injury (ALI) is a devastating disease with an overall mortality rate of 30~40%. The coagulation/fibrinolysis system is implicated in the pathogenesis of ALI. Thrombin-activatable fibronolysis inhibitor (TAFI) is an important component of the fibrinolysis system. Recent studies have shown that TAFIa can also regulate inflammatory responses by its ability to inhibit complement C3a and C5a, and osteopontin. Objective: We hypothesized that TAFI might have a protective role in ALI. To demonstrate this hypothesis the development of ALI was compared between wild type and TAFI-deficient mice. Methods: ALI was induced by intratracheal instillation of lipopolysaccharide (LPS). Control mice were treated with saline. Animals were sacrificed 24 hours after LPS. Results: The number of inflammatory cells and the concentration of total protein and inflammatory cytokines were significantly increased in BALF from LPS-treated TAFI-deficient mice compared to their wild type counterparts. Significantly higher concentrations of C5a were found in BALF and plasma in LPS-treated TAFI KO mice compared to wild type mice. Pre-treatment with inhaled C5a receptor antagonist blocked the detrimental effects of TAFI deficiency to levels of wild type mice. Conclusions: TAFI protects against acute lung injury, at least in part, by inhibiting the complement system.
    American Journal of Respiratory Cell and Molecular Biology 05/2013; · 4.15 Impact Factor
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    ABSTRACT: Insulin-like growth factor 1 receptor (IGF-1R) is critical for cancer cell proliferation; however, recent clinical anti-IGF-1R trials did not show clear clinical benefit in cancer therapy. We hypothesized that IGF-1R signaling-mediated proliferative response is heterogeneous in neuroblastoma (NB) cells, and analyzed the cell growth of 31 NB cell lines cultured in 3 different media, including Hybridoma-SFM medium (with insulin) and RPMI1640 with/without 10% FBS. Three growth patterns were found. In response to IGFs and insulin, cell proliferation and Akt phosphorylation were up-regulated in 13 cell lines, and suppressed by MK2206 (Akt inhibitor) and picropodophyllin (PPP, IGF-1R inhibitor). Interestingly, 3 of these 13 cell lines showed Akt self-phosphorylation and cell proliferation in RPMI1640; their proliferation was down-regulated by anti-IGF-1 or anti-IGF-2 neutralizing antibody, suggesting the existence of autocrine loop in the IGF-1R/Akt pathway. Eighteen NB cell lines did not proliferate in RPMI1640, even though Akt phosphorylation was up-regulated by IGFs and insulin. Based on the heterogeneous response of the IGF-1R/Akt pathway, the 31 NB cell lines could be classified into group 1 (autocrine IGFs-mediated), group 2 (exogenous IGFs-mediated) and group 3 (partially exogenous IGFs-mediated) NB cell lines. Additionally, group 3 NB cell lines were different from group 1 and 2, in terms of serum starvation-induced caspase 3 cleavage and PPP-induced G2/M arrest. These results indicate that the response of the IGF-1R/Akt pathway is an important determinant of the sensitivity to IGF-1R antagonists in NBs. To our knowledge, this is the first report describing heterogeneity in the IGF-1R/Akt-mediated proliferation of NB cells. This article is protected by copyright. All rights reserved.
    Cancer Science 05/2013; · 3.53 Impact Factor
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    ABSTRACT: Eosinophilic inflammation and remodeling of the airways including subepithelial fibrosis and myofibroblast hyperplasia are characteristic pathological findings of bronchial asthma. Epithelial to mesenchymal transition (EMT) plays a critical role in airway remodelling. In this study, we hypothesized that infiltrating eosinophils promote airway remodelling in bronchial asthma. To demonstrate this hypothesis we evaluated the effect of eosinophils on EMT by in vitro and in vivo studies. EMT was assessed in mice that received intra-tracheal instillation of mouse bone marrow derived eosinophils and in human bronchial epithelial cells co-cultured with eosinophils freshly purified from healthy individuals or with eosinophilic leukemia cell lines. Intra-tracheal instillation of eosinophils was associated with enhanced bronchial inflammation and fibrosis and increased lung concentration of growth factors. Mice instilled with eosinophils pre-treated with transforming growth factor(TGF)-β1 siRNA had decreased bronchial wall fibrosis compared to controls. EMT was induced in bronchial epithelial cells co-cultured with human eosinophils and it was associated with increased expression of TGF-β1 and Smad3 phosphorylation in the bronchial epithelial cells. Treatment with anti-TGF-β1 antibody blocked EMT in bronchial epithelial cells. Eosinophils induced EMT in bronchial epithelial cells, suggesting their contribution to the pathogenesis of airway remodelling.
    PLoS ONE 05/2013; 8(5):e64281. · 3.53 Impact Factor
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    ABSTRACT: Radioisotopes and fluorescent compounds are frequently used for RNA labeling but are unsuitable for clinical studies of RNA drugs because of the risk from radiation exposure or the nonequivalence arising from covalently attached fluorophores. Here, we report a practical phosphoramidite solid-phase synthesis of (18)O-labeled RNA that avoids these disadvantages, and we demonstrate its application to quantification and imaging. The synthesis involves the introduction of a nonbridging (18)O atom into the phosphate group during the oxidation step of the synthetic cycle by using (18)O water as the oxygen donor. The (18)O label in the RNA was stable at pH 3-8.5, while the physicochemical and biological properties of labeled and unlabeled short interfering RNA were indistinguishable by circular dichroism, melting temperature and RNA-interference activity. The (18)O/(16)O ratio as measured by isotope ratio mass spectrometry increased linearly with the concentration of (18)O-labeled RNA, and this technique was used to determine the blood concentration of (18)O-labeled RNA after administration to mice. (18)O-labeled RNA transfected into human A549 cells was visualized by isotope microscopy. The RNA was observed in foci in the cytoplasm around the nucleus, presumably corresponding to endosomes. These methodologies may be useful for kinetic and cellular-localization studies of RNA in basic and pharmaceutical studies.
    Nucleic Acids Research 04/2013; · 8.81 Impact Factor
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    ABSTRACT: The current mainstay of therapy for chronic obstructive pulmonary disease (COPD) is long-acting bronchodilators. To date, the effect of indacaterol, a β2-agonist, on activities of daily living in COPD patients is not well understood. The aim of this study was to evaluate the efficacy of indacaterol with regard to activities of daily living in patients with COPD. In this nonrandomized open-label study, 23 patients with COPD were instructed to carry an accelerometer for 4 weeks without indacaterol therapy and then for another period of 4 weeks while receiving indacaterol therapy. The number of steps, duration of moderate or greater physical activity, and energy expenditure were significantly increased after treatment with indacaterol compared with baseline data in all patients with COPD; the metabolic equivalent of task was also significantly enhanced after treatment with indacaterol. This study provides early evidence that indacaterol improves daily physical activity in patients with COPD.
    International Journal of COPD 01/2013; 8:1-5.
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    ABSTRACT: Long-term supplementation with branched-chain amino acids (BCAA) is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05). The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver.
    PLoS ONE 01/2013; 8(7):e70309. · 3.53 Impact Factor
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    ABSTRACT: Ustekinumab is a fully human IgG1κ monoclonal antibody targeting interleukin (IL)-12/23 p40 subunit. The role of IL-12/23-mediated pathway in the mechanism of various inflammatory disorders especially psoriasis has been well recognized. Recently the long-term efficacy and safety of ustekinumab in patients with moderate-to-severe psoriasis has been evaluated in phase 2/3 clinical trials, and the results showed no significant risk for serious adverse effects, infections, or malignancies. Ustekinumab inhibits the function of the IL-12/23 p40 subunit, and therefore it is believed that inhibition of IL-12 p40 pathway decreases IFN-γ production. The major concern for the use of ustekinumab is the possibility of increased immunosuppression due to low IFN-γ production. However, the effects of ustekinumab on CD4(+) T cell function have not been fully investigated so far. In this study, we explored changes in cytokine production by memory CD4(+) T cells as well as in the differentiation of naïve T cells to helper T cell (Th) 1, Th2, or Th17 cells in psoriasis patients treated with ustekinumab. The effect of the treatment on T cell receptor repertoire diversity was also evaluated. The results showed that ustekinumab improves clinical manifestation in patients with psoriasis without affecting cytokine production in memory T cells, T cell maturation, or T cell receptor repertoire diversity. Although the number of patients is limited, the present study suggests that T cell immune response remains unaffected in psoriasis patients treated with ustekinumab.
    PLoS ONE 12/2012; 7(12):e51819. · 3.53 Impact Factor

Publication Stats

4k Citations
1,093.22 Total Impact Points


  • 1991–2014
    • Mie University
      • • Graduate School of Medicine
      • • Department of Dermatology
      • • Department of Immunology
      • • Department of Gastroenterology and Hepatology
      • • Third Department of Internal Medicine
      • • Department of Molecular and Laboratory Medicine
      Tu, Mie, Japan
  • 2013
    • Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
      Shanghai, Shanghai Shi, China
  • 2012
    • Mie-chuo Medical Center
      Matsusaka, Mie, Japan
  • 2009
    • Osaka City University
      Ōsaka, Ōsaka, Japan
    • Suzuka University of Medical Science
      Kambe, Mie, Japan
  • 2008
    • Shiga University of Medical Science
      • Department of Otorhinolaryngology
      Ōtu, Shiga, Japan
  • 2003
    • Sungkyunkwan University
      • Department of Pediatrics
      Sŏul, Seoul, South Korea
    • University of Occupational and Environmental Health
      • Department of Biochemistry
      Kitakyūshū, Fukuoka, Japan
  • 2002
    • Red Cross
      Washington, Washington, D.C., United States