Katsutoshi Nakayama

Publications (43)192.42 Total impact

• Article: Apoptosis inhibitor of macrophage (AIM) expression in alveolar macrophages in COPD.

  Jun Kojima, Jun Araya, Hiromichi Hara, Saburo Ito, Naoki Takasaka, Kenji Kobayashi, Satoko Fujii, Chikako Tsurushige, Takanori Numata, Takeo Ishikawa, [......], Noriki Kamiya, Jun Hirano, Makoto Odaka, Toshiaki Morikawa, Hiroshi Hano, Satoko Arai, Toru Miyazaki, Yumi Kaneko, Katsutoshi Nakayama, Kazuyoshi Kuwano
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  ABSTRACT: Marked accumulation of alveolar macrophages (AM) conferred by apoptosis resistance has been implicated in pathogenesis of chronic obstructive pulmonary disease (COPD). Apoptosis inhibitor of macrophage (AIM), has been shown to be produced by mature tissue macrophages and AIM demonstrates anti-apoptotic property against multiple apoptosis-inducing stimuli. Accordingly, we attempt to determine if AIM is expressed in AM and whether AIM is involved in the regulation of apoptosis in the setting of cigarette smoke extract (CSE) exposure. Immunohistochemical evaluations of AIM were performed. Immunostaining was assessed by counting total and positively staining AM numbers in each case (n = 5 in control, n = 5 in non-COPD smoker, n = 5 in COPD). AM were isolated from bronchoalveolar lavage fluid (BALF). The changes of AIM expression levels in response to CSE exposure in AM were evaluated. Knock-down of anti-apoptotic Bcl-xL was mediated by siRNA transfection. U937 monocyte-macrophage cell line was used to explore the anti-apoptotic properties of AIM. The numbers of AM and AIM-positive AM were significantly increased in COPD lungs. AIM expression was demonstrated at both mRNA and protein levels in isolated AM, which was enhanced in response to CSE exposure. AIM significantly increased Bcl-xL expression levels in AM and Bcl-xL was involved in a part of anti-apoptotic mechanisms of AIM in U937 cells in the setting of CSE exposure. These results suggest that AIM expression in association with cigarette smoking may be involved in accumulation of AM in COPD.
  Respiratory research 01/2013; 14:30. · 3.36 Impact Factor
• Article: Insufficient autophagy in idiopathic pulmonary fibrosis.

  Jun Araya, Jun Kojima, Naoki Takasaka, Saburo Ito, Satoko Fujii, Hiromichi Hara, Haruhiko Yanagisawa, Kenji Kobayashi, Chikako Tsurushige, Makoto Kawaishi, Noriki Kamiya, Jun Hirano, Makoto Odaka, Toshiaki Morikawa, Stephen L Nishimura, Yoshinori Kawabata, Hiroshi Hano, Katsutoshi Nakayama, Kazuyoshi Kuwano
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  ABSTRACT: Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type specific manner and is a promising clue for understanding the pathogenesis of IPF.
  AJP Lung Cellular and Molecular Physiology 10/2012; · 3.66 Impact Factor
• Article: Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease.

  Satoko Fujii, Hiromichi Hara, Jun Araya, Naoki Takasaka, Jun Kojima, Saburo Ito, Shunsuke Minagawa, Yoko Yumino, Takeo Ishikawa, Takanori Numata, Makoto Kawaishi, Jun Hirano, Makoto Odaka, Toshiaki Morikawa, Stephen Nishimura, Katsutoshi Nakayama, Kazuyoshi Kuwano
  [show abstract] [hide abstract]
  ABSTRACT: Tobacco smoke-induced accelerated cell senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cell senescence is accompanied by the accumulation of damaged cellular components suggesting that in COPD, inhibition of autophagy may contribute to cell senescence. Here we look at whether autophagy contributes to cigarette smoke extract (CSE) - induced cell senescence of primary human bronchial epithelial cells (HBEC), and further evaluate p62 and ubiquitinated protein levels in lung homogenates from COPD patients. We demonstrate that CSE transiently induces activation of autophagy in HBEC, followed by accelerated cell senescence and concomitant accumulation of p62 and ubiquitinated proteins. Autophagy inhibition further enhanced accumulations of p62 and ubiquitinated proteins, resulting in increased senescence and senescence-associated secretory phenotype (SASP) with interleukin (IL)-8 secretion. Conversely, autophagy activation by Torin1, a mammalian target of rapamycin (mTOR inhibitor), suppressed accumulations of p62 and ubiquitinated proteins and inhibits cell senescence. Despite increased baseline activity, autophagy induction in response to CSE was significantly decreased in HBEC from COPD patients. Increased accumulations of p62 and ubiquitinated proteins were detected in lung homogenates from COPD patients. Insufficient autophagic clearance of damaged proteins, including ubiquitinated proteins, is involved in accelerated cell senescence in COPD, suggesting a novel protective role for autophagy in the tobacco smoke-induced senescence-associated lung disease, COPD.
  Oncoimmunology. 08/2012; 1(5):630-641.
• Source

  Available from: Keiichi Jingu

  Article: Initial evaluation of dynamic human imaging using18F-FRP170 as a new PET tracer for imaging hypoxia

  Tomohiro Kaneta, Yoshihiro Takai, Ren Iwata, Takashi Hakamatsuka, Hiroyasu Yasuda, Katsutoshi Nakayama, Yoichi Ishikawa, Shoichi Watanuki, Shozo Furumoto, Yoshihito Funaki, Eiko Nakata, Keiichi Jingu, Michihiko Tsujitani, Masatoshi Ito, Hiroshi Fukuda, Shoki Takahashi, Shogo Yamada
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  ABSTRACT: 18F-FRP170, 1-(2-fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, is a new hypoxia imaging agent for positron emission tomography. This compound was synthesized by18F-labeling of RP170, which was developed as a new hydrophilic 2-nitroimidazole analog. In the present study, we analyzed dynamic whole-body imaging in healthy volunteers and dynamic tumor imaging in three patients with lung cancer.Methods: Four healthy male volunteers and three lung cancer patients were enrolled in this study. Volunteers underwent dynamic whole-body scans just after injection of18F-FRP170 for about 90 min, while the lung cancer patients underwent dynamic tumor imaging for about 60 or 120 min. Data are expressed as standardized uptake values (SUV). Regions of interest were placed over images of each organ or tumor to generate time-SUV curves.Results: The series of dynamic whole-body scans showed rapid elimination of18F-FRP170 from the kidneys following elimination from the liver. Very low physiological uptake was observed above the diaphragm.18F-FRP170 uptake in the lung cancer lesion could be visualized clearly from early after injection. The changes of tumor SUV, tumor/blood ratio, or tumor/muscle ratio about 30 min after injection or later were small.Conclusions: Dynamic imaging using18F-FRP170 demonstrated rapid elimination from the kidney, suggesting the high hydrophilicity of this imaging agent. The background activity above the diaphragm was very low, and patients with lung cancer showed clear tumor uptake of18F-FRP170 early after injection.
  Annals of Nuclear Medicine 04/2012; 21(2):101-107. · 1.50 Impact Factor
• Article: Involvement of creatine kinase B in cigarette smoke-induced bronchial epithelial cell senescence.

  Hiromichi Hara, Jun Araya, Naoki Takasaka, Satoko Fujii, Jun Kojima, Yoko Yumino, Kenichiro Shimizu, Takeo Ishikawa, Takanori Numata, Makoto Kawaishi, Keisuke Saito, Jun Hirano, Makoto Odaka, Toshiaki Morikawa, Hiroshi Hano, Katsutoshi Nakayama, Kazuyoshi Kuwano
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  ABSTRACT: Cigarette smoke induces damage to proteins and organelles by oxidative stress, resulting in accelerated epithelial cell senescence in the lung, which is implicated in chronic obstructive pulmonary disease (COPD) pathogenesis. Although the detailed molecular mechanisms are not fully understood, cellular energy status is one of the most crucial determinants for cell senescence. Creatine kinase (CK) is a constitutive enzyme, playing regulatory roles in energy homeostasis of cells. Among two isozymes, brain-type CK (CKB) is the predominant CK in lung tissue. In this study, we investigated the role of CKB in cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBECs). Primary HBECs and Beas2B cells were used. Protein carbonylation was evaluated as a marker of oxidative protein damage. Cellular senescence was evaluated by senescence-associated β-galactosidase staining. CKB inhibition was examined by small interfering RNA and cyclocreatine. Secretion of IL-8, a hallmark of senescence-associated secretary phenotype, was measured by ELISA. CKB expression levels were reduced in HBECs from patients with COPD compared with that of HBECs from nonsmokers. CSE induced carbonylation of CKB and subsequently decreased CKB protein levels, which was reversed by a proteasome inhibitor. CKB inhibition alone induced cell senescence, and further enhanced CSE-induced cell senescence and IL-8 secretion. CSE-induced oxidation of CKB is a trigger for proteasomal degradation. Concomitant loss of enzymatic activity regulating energy homeostasis may lead to the acceleration of bronchial epithelial cell senescence, which is implicated in the pathogenesis of COPD.
  American Journal of Respiratory Cell and Molecular Biology 03/2012; 46(3):306-12. · 5.13 Impact Factor
• Article: Organizing pneumonia complicated by cyst and pneumothorax formation.

  Tsukasa Kadota, Kenichiro Shimizu, Chikako Tsurushige, Makoto Kawaishi, Jun Araya, Katsutoshi Nakayama, Kazuyoshi Kuwano, Hiroshi Hano
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  ABSTRACT: We present a case of organizing pneumonia complicated by pneumothorax in association with cyst formation that developed during corticosteroid treatment. Although it has been reported that the check-valve mechanism is a plausible cause of cyst and pneumothorax formation in patients with organizing pneumonia, the details of the corresponding pathological changes that occur in air-trapping have not been elucidated. A pathological examination of lung specimens obtained with video-assisted thoracoscopic surgery suggested that granulation tissues plugging the bronchiole lumens might be a potential cause of the check-valve mechanism in this case. In this report, we also reviewed eight other cases of organizing pneumonia with pneumothorax or cyst formation.
  Internal Medicine 01/2012; 51(22):3155-8. · 0.94 Impact Factor
• Article: Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer.

  Hitomi Fujie, Toshiaki Tanaka, Masatoshi Tagawa, Niu Kaijun, Mika Watanabe, Takashi Suzuki, Katsutoshi Nakayama, Muneo Numasaki
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  ABSTRACT: The antitumor activities of type III interferon (IFN) (interleukin [IL]-28 and IL-29) and the combination of type III IFN and type I IFN (IFN-α) were evaluated using human non-small cell lung cancer (NSCLC). The expression of type III and type I receptor complexes was detected in NSCLC lines. IL-29 significantly inhibited the in vitro growth of a wide range of NSCLC lines in a dose-dependent fashion. To a lesser degree, IL-28A also displayed growth inhibitory activity. Antitumor activity of type III IFN is associated with cell cycle arrest at the G1 phase and apoptosis. IL-29 upregulated cyclin-dependent kinase inhibitor p21Waf1/Cip1 in cells sensitive, but not insensitive, to antiproliferative activity, and knockdown of p21 with small interfering RNA largely attenuated the antiproliferative effect. Intratumoral and systemic administration of IL-29 inhibited OBA-LK1 and LK-1, but not A549, tumor growth in severe combined immunodeficiency mice. Immunohistochemical analyses demonstrated marked upregulated p21 and downregulated Ki-67 expression in tumors treated with IL-29. The interferon combination of IL-29 and IFN-α displayed a more effective antiproliferative effect and a more intense p21 expression than each reagent alone in vitro. Furthermore, interferon combination therapy suppressed in vivo NSCLC growth more effectively than interferon monotherapy. These findings demonstrate that type III IFN can mediate direct antitumor activities via increased p21 expression and induction of apoptosis and cooperate with type I IFN to elicit more efficient direct antitumor activities, and suggest the possibility that type III IFN might improve the efficacy and reduce the side-effects of type I IFN cancer therapy.
  Cancer Science 08/2011; 102(11):1977-90. · 3.33 Impact Factor
• Article: Insulin-dependent phosphatidylinositol 3-kinase/Akt and ERK signaling pathways inhibit TLR3-mediated human bronchial epithelial cell apoptosis.

  Takanori Numata, Jun Araya, Satoko Fujii, Hiromichi Hara, Naoki Takasaka, Jun Kojima, Shunsuke Minagawa, Yoko Yumino, Makoto Kawaishi, Jun Hirano, Makoto Odaka, Toshiaki Morikawa, Stephen L Nishimura, Katsutoshi Nakayama, Kazuyoshi Kuwano
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  ABSTRACT: TLR3, one of the TLRs involved in the recognition of infectious pathogens for innate and adaptive immunity, primarily recognizes viral-associated dsRNA. Recognition of dsRNA byproducts released from apoptotic and necrotic cells is a recently proposed mechanism for the amplification of toxicity, suggesting a pivotal participation of TLR3 in viral infection, as well as in lung diseases where apoptosis plays a critical role, such as asthma and chronic obstructive pulmonary disease. In addition to metabolic control, insulin signaling was postulated to be protective by inhibiting apoptosis. Therefore, we explored the role of insulin signaling in protecting against TLR3-mediated apoptosis of human bronchial epithelial cells. Significant TLR3-mediated apoptosis was induced by polyinosinic-polycytidylic acid, a dsRNA analog, via caspase-8-dependent mechanisms. However, insulin efficiently inhibited TLR3/polyinosinic-polycytidylic acid-induced human bronchial epithelial cell apoptosis via PI3K/Akt and ERK pathways, at least in part, via upregulation of cellular FLIPs and through protein synthesis-independent mechanisms. These results indicate the significance of TLR3-mediated dsRNA-induced apoptosis in the pathogenesis of apoptosis-driven lung disease and provide evidence for a novel protective role of insulin.
  The Journal of Immunology 07/2011; 187(1):510-9. · 5.79 Impact Factor
• Article: A new strategy with proton pump inhibitors for the prevention of acute exacerbations in COPD.

  Takahiko Sasaki, Katsutoshi Nakayama, Hiroyasu Yasuda, Mutsuo Yamaya
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  ABSTRACT: Acute exacerbations of chronic obstructive pulmonary disease (COPD), an acute worsening of respiratory symptoms, generally result in a poor prognosis. Successful prevention and management of such exacerbations is thus important for patient care. Viral infection, primarily with rhinovirus (RV), is the foremost cause of exacerbations in COPD patients. Proton pump inhibitors (PPIs) have been reported to inhibit RV infection in human airway epithelial cells in vitro. Furthermore, clinical trials of PPIs in patients with COPD resulted in a reduction in rates of both common cold and COPD exacerbations. In this review, we discuss the significance of COPD exacerbations, summarize a published trial of the effect of low-dose PPIs on COPD exacerbations, and postulate a mechanism for this effect.
  Therapeutic Advances in Respiratory Disease 02/2011; 5(2):91-103.
• Article: Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells.

  Shunsuke Minagawa, Jun Araya, Takanori Numata, Satoko Nojiri, Hiromichi Hara, Yoko Yumino, Makoto Kawaishi, Makoto Odaka, Toshiaki Morikawa, Stephen L Nishimura, Katsutoshi Nakayama, Kazuyoshi Kuwano
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  ABSTRACT: Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of IPF, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin (SIRT) family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in IPF lung. Senescence-associated β-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-β-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1β expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In IPF lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-β induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-β also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-β-induced senescence via proteasomal degradation of p21. TGF-β-induced senescent HBEC secreted increased amounts of IL-1β, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6.
  AJP Lung Cellular and Molecular Physiology 12/2010; 300(3):L391-401. · 3.66 Impact Factor
• Article: Procaterol inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells.

  Mutsuo Yamaya, Hidekazu Nishimura, Yukimasa Hatachi, Motoki Yoshida, Hidenori Fujiwara, Masanori Asada, Katsutoshi Nakayama, Hiroyasu Yasuda, Xue Deng, Takahiko Sasaki, Hiroshi Kubo, Ryoichi Nagatomi
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  ABSTRACT: β(2) agonists reduce the frequency of exacerbations in patients with bronchial asthma and chronic obstructive pulmonary disease caused by respiratory virus infection. β(2) agonists reduce the production of pro-inflammatory cytokines. However, the inhibitory effects of β(2) agonists on the infection of rhinovirus, the major cause of exacerbations, have not been well studied. To examine the effects of a β(2) agonist, procaterol, on rhinovirus infection and rhinovirus infection-induced airway inflammation, human tracheal epithelial cells were infected with a major group rhinovirus, type 14 rhinovirus. Rhinovirus infection increased viral titers and the content of pro-inflammatory cytokines, including interleukin-1β and interlukin-6, in supernatant fluids and rhinovirus RNA in the cells. Procaterol reduced rhinovirus titers and RNA, cytokine concentrations, and susceptibility to rhinovirus infection. Procaterol reduced the expression of intercellular adhesion molecule-1 (ICAM-1), the receptor for type 14 rhinovirus, and the number of acidic endosomes in the cells from which rhinovirus RNA enters into the cytoplasm. Procaterol inhibited the activation of nuclear factor kappa-B (NF-κB) proteins including p50 and p65 in the nuclear extracts, while it increased the cytosolic amount of the inhibitory kappa B-α and intracellular cyclic AMP (cAMP) levels. A selective β(2)-adrenergic receptor antagonist ICI 118551 [erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol] reversed the inhibitory effects of procaterol on rhinovirus titers and RNA, susceptibility to rhinovirus infection, pro-inflammatory cytokines production, ICAM-1 expression, acidic endosomes, and NF-κB. ICI 118551 also reversed the effects of procaterol on cAMP levels. Procaterol may inhibit rhinovirus infection by reducing ICAM-1 and acidic endosomes as well as modulate airway inflammation in rhinovirus infection.
  European journal of pharmacology 10/2010; 650(1):431-44. · 2.59 Impact Factor
• Article: Low serum 1,25-dihydroxyvitamin D level and risk of respiratory infections in institutionalized older people.

  Takaaki Asamura, Takashi Ohrui, Katsutoshi Nakayama, Mei He, Miyako Yamasaki, Takae Ebihara, Satoru Ebihara, Katsutoshi Furukawa, Hiroyuki Arai
  Gerontology 01/2010; 56(6):542-3. · 2.78 Impact Factor
• Chapter: Therapeutic Applications of Nitric Oxide for Malignant Tumor in Animal Models and Human Studies

  Hiroyasu Yasuda, Kazuhiro Yanagihara, Katsutoshi Nakayama, Tadashi Mio, Takahiko Sasaki, Masanori Asada, Mutsuo Yamaya, Masanori Fukushima
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  ABSTRACT: In cancer science, nitric oxide (NO) has been mainly discussed as an oncogenic molecule over the past decades. However, NO has recently been noted in cancer biology to be associated with cancer cell apoptosis, cancer cell cycle, cancer progression and metastasis, cancer angiogenesis, cancer chemoprevention, and a modulator for chemo/radio/immunotherapy. NO is produced and released from three different isoforms of NO synthase (NOS) and from exogenously administered NO donors in vivo. Over-expression of inducible NOS (iNOS) in cancer tissues is associated with an increase in microvascular density in tumor tissues and poor prognosis in patients with cancers. Recently, NO donors and iNOS transfer have been demonstrated to enhance the effects of cancer therapy including chemotherapy, radiotherapy, and immunotherapy for solid cancers, resulting in a prolonged survival time. In this chapter, we to discuss the recent animal experiments and clinical trials to develop these investigations for clinical applications. KeywordsNitric oxide-Nitric oxide synthase-Cancer biology-Cancer progression-Metastasis-Apoptosis-Cell cycle-Proliferation-Chemoprevention-Chemotherapy-Radiotherapy-Immunotherapy-Animal experiment-Clinical trial
  12/2009: pages 419-441;
• Article: Macrolide antibiotics inhibit respiratory syncytial virus infection in human airway epithelial cells.

  Masanori Asada, Motoki Yoshida, Tomoko Suzuki, Yukimasa Hatachi, Takahiko Sasaki, Hiroyasu Yasuda, Katsutoshi Nakayama, Hidekazu Nishimura, Ryoichi Nagatomi, Hiroshi Kubo, Mutsuo Yamaya
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  ABSTRACT: To examine the effects of macrolide antibiotics on RS virus infection in airways, human tracheal epithelial cells were pre-treated with bafilomycin A(1) and clarithromycin, and infected with RS virus. Viral titers in supernatant fluids and RNA of RS virus, and concentrations of cytokines in supernatant fluids, including interleukin-6 increased with time after infection. Bafilomycin A(1) and clarithromycin reduced viral titers in supernatant fluids of RS virus, RNA of RS virus, the susceptibility to RS virus infection, and concentrations of cytokines induced by virus infection. N-acetyl-S-geranylgeranyl-L-cysteine, an inhibitor for a small GTP binding protein of RhoA, isoform A of the Ras-homologus (Rho) family, an active form of which is associated with RS virus infection via binding to its fusion protein (F protein), reduced viral titers in supernatant fluids and RNA of RS virus. Bafilomycin A(1) and clarithromycin inhibited RhoA activation induced by lysophosphatidic acid in the cells. Fasudil, an inhibitor of Rho kinase, also reduced viral titers in supernatant fluids and RNA of RS virus. These findings suggest that macrolide antibiotics may inhibit RS virus infection, partly through the reduced expression of F protein receptor, activated RhoA, and the inhibition of subsequent Rho kinase activation in human airway epithelial cells.
  Antiviral research 09/2009; 83(2):191-200. · 3.61 Impact Factor
• Article: Carbocisteine inhibits oxidant-induced apoptosis in cultured human airway epithelial cells.

  Motoki Yoshida, Katsutoshi Nakayama, Hiroyasu Yasuda, Hiroshi Kubo, Kazuyoshi Kuwano, Hiroyuki Arai, Mutsuo Yamaya
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  ABSTRACT: Increased oxidant levels have been associated with exacerbations of COPD, and L-carbocisteine, a mucolytic agent, reduces the frequency of exacerbations. The mechanisms underlying the inhibitory effects of L-carbocisteine on oxidant-induced COPD exacerbations were examined in an in vitro study of human airway epithelial cells. In order to examine the antioxidant effects of L-carbocisteine, human tracheal epithelial cells were treated with L-carbocisteine and exposed to hydrogen peroxide (H(2)O(2)). Cell apoptosis was assessed using a cell death detection ELISA, and the pathways leading to cell apoptosis were examined by measurement of caspase-3 and caspase-9 by western blot analysis with fluorescent detection. The proportion of apoptotic cells in human tracheal epithelium was increased in a concentration- and time-dependent manner, following exposure to H(2)O(2). Treatment with L-carbocisteine reduced the proportion of apoptotic cells. In contrast, H(2)O(2) did not increase the concentration of LDH in supernatants of epithelial cells. Exposure to H(2)O(2) activated caspase-3 and caspase-9, and L-carbocisteine inhibited the H(2)O(2)-induced activation of these caspases. L-carbocisteine activated Akt phosphorylation, which modulates caspase activation, and the inhibitors of Akt, LY294002 and wortmannin, significantly reversed the inhibitory effects of L-carbocisteine on H(2)O(2)-induced cell apoptosis. These findings suggest that in human airway epithelium, L-carbocisteine may inhibit cell damage induced by H(2)O(2) through the activation of Akt phosphorylation. L-carbocisteine may have antioxidant effects, as well as mucolytic activity, in inflamed airways.
  Respirology 09/2009; 14(7):1027-34. · 2.42 Impact Factor
• Article: A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients.

  Takahiko Sasaki, Katsutoshi Nakayama, Hiroyasu Yasuda, Motoki Yoshida, Takaaki Asamura, Takashi Ohrui, Hiroyuki Arai, Jun Araya, Kazuyoshi Kuwano, Mutsuo Yamaya
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  ABSTRACT: To investigate whether proton pump inhibitor (PPI) therapy reduces the frequency of common colds and exacerbations in patients with chronic obstructive pulmonary disease (COPD). Twelve-month, randomized, observer-blind, controlled trial. A university hospital and three city hospitals in Miyagi prefecture in Japan. One hundred patients with COPD (mean age +/- SD 74.9 +/- 8.2) participated. They were all ex-smokers and had received conventional therapies for COPD, including smoking cessation and bronchodilators. Patients with gastroesophageal reflux disease or gastroduodenal ulcer were excluded. Patients were randomly assigned to conventional therapies (control group) or conventional therapies plus PPI (lansoprazole 15 mg/d; PPI group) and observed for 12 months. Frequency of common colds and COPD exacerbations. The number of exacerbations per person in a year in the PPI group was significantly lower than that in the control group (0.34 +/- 0.72 vs 1.18 +/- 1.40; P<.001). The adjusted odds ratio with logistic regression for having exacerbation (> or =once/year) in the PPI group compared with the control group was 0.23 (P=.004). In contrast, there was no significant difference in the numbers of common colds per person per year between the PPI group and the control group (1.22 +/- 2.09 vs 2.04 +/- 3.07; P=.12). PPI therapy significantly reduced the risk of catching frequent common colds (> or =3 times/year), the adjusted odds ratio of which was 0.28 (P=.048). In this single-blind, nonplacebo-controlled trial, lansoprazole was associated with a significant decrease in COPD exacerbations. More definitive clinical trials are warranted.
  Journal of the American Geriatrics Society 06/2009; 57(8):1453-7. · 3.74 Impact Factor
• Article: Nitric oxide and cancer immunity in solid tumor tissues.

  Hiroyasu Yasuda, Katsutoshi Nakayama, Takahiko Sasaki, Kazuhiro Yanagihara
  Immunotherapy 05/2009; 1(3):338. · 1.85 Impact Factor
• Article: Dual antibody plus chemotherapy in metastatic colorectal cancer.

  Hiroyasu Yasuda, Katsutoshi Nakayama, Takahiko Sasaki, Kazuhiro Yanagihara
  Immunotherapy 05/2009; 1(3):339-40. · 1.85 Impact Factor
• Article: Fas signal and cancer progression.

  Hiroyasu Yasuda, Katsutoshi Nakayama, Takahiko Sasaki, Kazuhiro Yanagihara
  Immunotherapy 05/2009; 1(3):337-40. · 1.85 Impact Factor
• Article: [A case of pericardial malignant mesothelioma accompanied by primary lung adenocarcinoma].

  Satoko Nojiri, Yoko Yumino, Keita Sato, Reiri Onodera, Katsutoshi Nakayama, Kazuyoshi Kuwano
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  ABSTRACT: A 63-year-old man was admitted to Jikei University Hospital, with anasarca, and dyspnea in May, 2004. Echocardiograms and CT scans showed massive pericardial effusion, nodules on the pericardium and a tumor in the lower lobe of the left lung. Pathological examination of the punctured pericardial effusions yielded a diagnosis of pericardial malignant mesothelioma. However, no pathogen or malignant cells were identified from multiple biopsy specimens of the lung tumor, which were obtained by brochoscopic techniques. Since he worked as a fisherman in a diesel-powered fishing boat, he was possibly exposed to asbestos. On autopsy, the lung tumor was diagnosed as a primary lung adenocaricinoma. Exposure to asbestos is an important risk factor for both mesothelioma and lung cancer. However, pericardial malignant mesothelioma in itself is rare among mesothelioma. This is only the second report of malignant mesothelioma with primary lung adenocarcinoma, to date.
  Nihon Kokyūki Gakkai zasshi = the journal of the Japanese Respiratory Society. 03/2009; 47(2):104-9.