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Shimizu Y.,Gunma University | Shimizu Y.,Jobu Hospital for Respiratory Diseases | Dobashi K.,Gunma University | Fueki N.,Jobu Hospital for Respiratory Diseases | And 5 more authors.
Journal of Biological Regulators and Homeostatic Agents | Year: 2011

Omalizumab is an anti-IgE monoclonal antibody that was proven effective for the treatment of severe asthma. IgE plays a central role in allergic asthma, and an anti-allergic effect of omalizumab has been confirmed in terms of its impact on Th2 cytokines. The objective of the present study is to determine the influence of omalizumab on clinical parameters and circulating immuoregulatory cytokines. Patients with severe allergic asthma were enrolled and given four months of omalizumab therapy. Changes of symptoms and other parameters were assessed, including the asthma control test (ACT) score, morning peak expiratory flow (PEF), peripheral eosinophil count, total serum IgE, and pulmonary function tests. The use of corticosteroids and short-acting bronchodilators, as well as the number of unscheduled hospital visits, were monitored. Circulating levels of cytokines were analyzed with a multiplex cytokine immunoassay in patients with or without omalizumab therapy. Asthma symptoms (evaluated by the ACT score and morning PEF) improved with omalizumab treatment, while total IgE was elevated. Use of corticosteroids and short-acting bronchodilators and the number of unscheduled hospital visits for exacerbation of asthma were all reduced by omalizumab treatment. The level of macrophage inflammatory protein 1-δ (MIP1-δ) was significantly reduced after omalizumab therapy and was high in patients without omalizumab. IL-16 also tended to decrease with omalizumab therapy. Both MIP1-δ and IL-16 decreased as asthma improved over the 4-month period of omalizumab therapy. These findings suggest that omalizumab may act via IgE-mediated immunoregulation of MIP1-δ and IL-16. Copyright © by BIOLIFE, s.a.s.


Saito T.,Gunma University | Okada S.,Gunma University | Shimoda Y.,Gunma University | Tagaya Y.,Gunma University | And 8 more authors.
Cellular Signalling | Year: 2016

Expression of adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1 (APPL1) promoted glucose transporter 4 (GLUT4) translocation and glucose uptake in adipose and muscle tissues in response to stimulation with insulin, adiponectin, or exercise. In response to mechanical stretch, knockdown of APPL1 in C2C12 myotubes suppressed glucose uptake. APPL1-induced increased glucose uptake was mediated by protein kinase C (PKC) ζ but not AKT, AMPK, or calmodulin-dependent protein kinase. In myotubes overexpressing APPL1, PKCζ was phosphorylated and translocated to the plasma membrane (PM) in response to mechanical stretch. Phosphorylated PKCζ co-immunoprecipitated with protein phosphatase 2A (PP2A) under basal conditions, but dissociated upon myotube stretching. Moreover, stretch-induced phosphorylated PKCζ co-immunoprecipitated with non-muscle myosin IIa. Blebbistatin, an inhibitor of myosin II ATPase activity, suppressed APPL1-mediated stretch-induced glucose uptake and PKCζ translocation. Taken together these data demonstrate that in response to mechanical stretch, APPL1 enhances glucose uptake by modulating the activation and localization of PKCζ, as well as its functional interaction with both PP2A and myosin IIa. These findings support a new function for non-muscle myosin IIa in differentiated myotubes. © 2016 Elsevier Inc.


PubMed | Jobu Hospital for Respiratory Diseases and Gunma University
Type: Journal Article | Journal: Journal of physical therapy science | Year: 2016

[Purpose] The purpose of this study was to examine the effect of 12-month rehabilitation with low loading program on chronic respiratory disease. [Subjects and Methods] Twelve patients with chronic respiratory disease participated in this study, in which the effect of long-term rehabilitation for 12 months was assessed. Nine patients had chronic obstructive pulmonary disease, two had asthma, and one had interstitial pneumonia. In all patients, symptoms, lower-extremity strength, walking distance, activities of daily living, and quality of life were investigated to examine the effect of respiratory rehabilitation. [Results] After 12 months, the isometric knee extension strength and weight-bearing index both showed a significant increase. [Conclusion] The findings of this study suggested that improvement in lower-limb muscle strength can be achieved through long-term intervention, and indicated the validity of repetitive standing and walking exercises.


Hagiya Y.,Keio University | Kamata S.,Keio University | Mitsuoka S.,Keio University | Okada N.,Keio University | And 9 more authors.
Toxicology and Applied Pharmacology | Year: 2015

The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs+/- or Cth+/-) and homozygous (Cth-/-) knockout mice. At 4h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth-/- mice at 150mg/kg dose, and also in Cbs+/- or Cth+/- mice at 250mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth-/- mice but not wild-type mice, although glutamate-cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth-/- mice with lower Km values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150mgacetaminophen/kg into Cth-/- mice; the profiles were similar to 1000mgacetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200-300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities. © 2014 Elsevier Inc.


PubMed | Jobu Hospital for Respiratory Diseases, University of Tsukuba, Akita University and Keio University
Type: Journal Article | Journal: Toxicology and applied pharmacology | Year: 2015

The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine -synthase (CBS) and cystathionine -lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs(+/-) or Cth(+/-)) and homozygous (Cth(-/-)) knockout mice. At 4 h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth(-/-) mice at 150 mg/kg dose, and also in Cbs(+/-) or Cth(+/-) mice at 250 mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth(-/-) mice but not wild-type mice, although glutamate-cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth(-/-) mice with lower Km values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150 mg acetaminophen/kg into Cth(-/-) mice; the profiles were similar to 1000 mg acetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200-300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities.


Kuwabara H.,Jobu Hospital for Respiratory Diseases | Kuwabara H.,National Hospital Organization Numata National Hospital | Yamaoka N.,Jobu Hospital for Respiratory Diseases | Oomaki J.,Jobu Hospital for Respiratory Diseases | Suzuki M.,Jobu Hospital for Respiratory Diseases
Kitakanto Medical Journal | Year: 2015

Background: To know actual conditions and a balance between food intake and energy expenditure of each of the elderly in the super-aged society is very important. Aim: To determine the resting energy expenditure (REE) of the elderly residing in the "Roken". Methods: For Study 1, REEs of 47 elderly people in the Roken were measured. For Study 2, REEs of 22 patients who were admitted to a general hospital were measured. Results: In Study 1, REE of the elderly people in the Roken ranged from 523 to 1,628 kcal/day/body; the mean value was 909 ± 239 kcal/day/body(mean± SD) and 21.6 ± 4.5 kcal/kg/day. A discrepancy between REE and dietary energy intake was observed. In Study 2, REE of patients in the hospital widely ranged from 589 to 2,549 kcal/day/body;the mean value was 1391 ± 459 kg/day/body(mean ± SD). Conclusions: The mean value of REE of the elderly in the Roken was 74% lower than that of the healthy individuals in previous reports. The observed discrepancy between REE and dietary energy intake suggested the need for improvement in the effective absorption of nutrients from the digestive system, which may be more important than food intake.

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