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Aoi W.,Kyoto Prefectural University | Naito Y.,Kyoto Prefectural University of Medicine | Takagi T.,Kyoto Prefectural University of Medicine | Tanimura Y.,Kyoto Prefectural University of Medicine | And 12 more authors.
Gut | Year: 2013

Objective: Several epidemiological studies have shown that regular exercise can prevent the onset of colon cancer, although the underlying mechanism is unclear. Myokines are secreted skeletal muscle proteins responsible for some exercise-induced health benefits including metabolic improvement and anti-inflammatory effects in organs. The purpose of this study was to identify new myokines that contribute to the prevention of colon tumorigenesis. Methods: To identify novel secreted muscle-derived proteins, DNA microarrays were used to compare the transcriptome of muscle tissue in sedentary and exercised young and old mice. The level of circulating secreted protein acidic and rich in cysteine (SPARC) was measured in mice and humans that performed a single bout of exercise. The effect of SPARC on colon tumorigenesis was examined using SPARC-null mice. The secretion and function of SPARC was examined in culture experiments. Results: A single bout of exercise increased the expression and secretion of SPARC in skeletal muscle in both mice and humans. In addition, in an azoxymethane-induced colon cancer mouse model, regular low-intensity exercise significantly reduced the formation of aberrant crypt foci in wild-type mice but not in SPARC-null mice. Furthermore, regular exercise enhanced apoptosis in colon mucosal cells and increased the cleaved forms of caspase-3 and caspase-8 in wild-type mice but not in SPARC-null mice. Culture experiments showed that SPARC secretion from myocytes was induced by cyclic stretch and inhibited proliferation with apoptotic effect of colon cancer cells. Conclusions: These findings suggest that exercise stimulates SPARC secretion from muscle tissues and that SPARC inhibits colon tumorigenesis by increasing apoptosis.

Fujita S.,Louis Pasteur Center for Medical Research
Neuroscience Research | Year: 2014

In 1960s, histological study on developing CNS led us to a novel finding that the periventricular layer ("Matrix" of W. His) of fetal neocortex is composed solely of the matrix cells. Application of 3H-thymidine autoradiography revealed "elevator movement" of the matrix cells. Following the stage of pure matrix cell proliferation (Stage I), stage of neuron production (Stage II) ensues, and when Stage II is over, stage of gliogenesis (Stage III) follows immediately; first, glioblasts, then astrocytes, oligodendrocytes and microglia differentiate, in sequence.As for the mechanism of the switching, recent progress in molecular research on dynamism of the chromatin and transcription-factors revealed the irreversible epigenetic changes controlling the switch. In Stage I of cytogenesis, axial ectodermal cells escape from irreversible differentiation into epidermis, and change into matrix cells composing the neural plate. In Stage II, some matrix cells, in which proneural genes are activated, exit cell cycle to become neurons. When Stage II ends, the neural-repressor REST/NRSBF is up regulated and occupies RE-1 silencer region to irreversibly inactivate neuron-specific genes including the type II Na+ channel, thereby matrix cells can now only produce non-excitable cells, i.e., glial cells. This is the Stage III of cytogenesis of the CNS. © 2014 Published by Elsevier Ireland Ltd.

Nagata K.,Kyoto Prefectural University of Medicine | Maruyama K.,Kyoto Prefectural University of Medicine | Uno K.,Louis Pasteur Center for Medical Research | Shinomiya K.,Kyoto Prefectural University of Medicine | And 7 more authors.
Investigative Ophthalmology and Visual Science | Year: 2012

PURPOSE. Levels of some cytokines are significantly higher in the vitreous fluid of patients with acute uveitis than in normal vitreous fluid. The authors sought to determine which proinflammatory cytokines were upregulated in the vitreous fluid of patients with ocular sarcoidosis. METHODS. Samples of vitreous fluid were collected from patients with sarcoid uveitis and from nonsarcoid control patients with idiopathic epiretinal membrane. The levels of 27 proinflammatory cytokines were measured with a multiplex beads array system. Postvitrectomy macular thickness was also measured by using spectral domain optical coherence tomography (SD-OCT). To assess the relationship between cytokine levels and disease stage, the authors divided patients into three groups based on macular thickness 1 month after operation. RESULTS. The vitreous levels of 17 cytokines were significantly higher in patients with ocular sarcoidosis than in nonsarcoid controls. Serum levels of interferon γ-induced protein 10 (IP- 10) were also higher in ocular sarcoidosis patients than in nonsarcoid controls. Conversely, serum levels of interleukin (IL) 15 in ocular sarcoidosis patients were lower than in the control group. Analysis of cytokine levels and macular thickness revealed that IL-1ra, IL-4, IL-8, IFN-γ, IP-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1β, and regulated on activation, normal T-cell expressed and secreted (RANTES) were significantly upregulated in patients with thin cystoid macular edema group. CONCLUSIONS. Patients with ocular sarcoidosis had elevated levels of proinflammatory cytokines in vitreous fluids. Different cytokines might contribute to different stages of macular edema. © 2012 The Association for Research in Vision and Ophthalmology, Inc.

Aihara K.,Kyoto University | Oga T.,Kyoto University | Chihara Y.,Kyoto University | Harada Y.,Kyoto University | And 6 more authors.
Sleep and Breathing | Year: 2013

Purpose: The presence of both systemic and airway inflammation has been suggested in obstructive sleep apnea (OSA) by increased levels of inflammatory biomarkers in the circulation and respiratory specimens. We aimed to investigate the relationship between systemic and airway inflammation in OSA. Methods: This study was conducted by simultaneously measuring various biomarkers both in serum and induced sputum of 43 patients. We compared the relationships of these biomarker levels with polysomnographic data and obesity measurements and also investigated their interrelationships between systemic and local compartments. We also assessed the relation of inflammatory markers with proximal airway resistance measured by impulse oscillometry. Results: In multiple regression analyses, each measured serum biomarker [leptin, interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF)] significantly correlated with waist circumference or fat area determined by computed tomography. In contrast, regarding airway inflammation, sputum IL-6, IL-8, TNF-α, and VEGF significantly correlated with OSA severity as indicated by the respiratory disturbance index or oxygen desaturation indices. Sputum IL-6, IL-8, TNF-α, and VEGF were significantly related to sputum neutrophil number, and sputum IL-8 and TNF-α were related to proximal airway resistance independently of body mass index. There were no significant interrelationships between the same biomarkers in serum and induced sputum. Conclusions: Systemic and airway inflammation in OSA might be differently regulated by OSA itself and comorbid obesity, depending on the type of cytokine. Although we did not find apparent interrelationships between systemic and local compartments, further studies are needed to clarify this concept. © 2012 Springer-Verlag.

Okuno K.,Kinki University | Uno K.,Louis Pasteur Center for Medical Research
Asian Pacific Journal of Cancer Prevention | Year: 2011

This study investigated the influence of Lentinula edodes mycelia extract (LEM), an oral immunomodulator, on immune function and adverse events from chemotherapy. Subjects comprised 1 gastric and 7 colorectal cancer patients. The first course of treatment was chemotherapy alone and the second was chemotherapy plus concomitant administration of LEM. Adverse events and interferon (IFN)-γ production by CD4+ T, CD8+ T and CD56+ NK/NKT cells were evaluated at the end of each course. Grade 1 or 2 adverse events were observed at the end of the first course for 6 of 8 patients. In comparison, no patients displayed any adverse events at the end of the second course. Tendencies toward improved IFN-γ production by CD4+ T, CD8+ T and CD56+ NK/NKT cells were also seen. These results suggest that concomitant use of LEM with chemotherapy can decrease the incidence of adverse effects from cancer chemotherapy among patients with advanced cancer.

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