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Search Results: 1 - 10 of 36696 matches for " Jun Kawanokuchi "
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GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia
Parajuli Bijay,Sonobe Yoshifumi,Kawanokuchi Jun,Doi Yukiko
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-268
Abstract: Background Microglia are resident macrophage-like cells in the central nervous system (CNS) and cause innate immune responses via the LPS receptors, Toll-like receptor (TLR) 4 and CD14, in a variety of neuroinflammatory disorders including bacterial infection, Alzheimer’s disease, and amyotrophic lateral sclerosis. Granulocyte macrophage-colony stimulating factor (GM-CSF) activates microglia and induces inflammatory responses via binding to GM-CSF receptor complex composed of two different subunit GM-CSF receptor α (GM-CSFRα) and common β chain (βc). GM-CSF has been shown to be associated with neuroinflammatory responses in multiple sclerosis and Alzheimer’s disease. However, the mechanisms how GM-CSF promotes neuroinflammation still remain unclear. Methods Microglia were stimulated with 20 ng/ml GM-CSF and the levels of TLR4 and CD14 expression were evaluated by RT-PCR and flowcytometry. LPS binding was analyzed by flowcytometry. GM-CSF receptor complex was analyzed by immunocytechemistry. The levels of IL-1β, IL-6 and TNF-α in culture supernatant of GM-CSF-stimulated microglia and NF-κB nuclear translocation were determined by ELISA. Production of nitric oxide (NO) was measured by the Griess method. The levels of p-ERK1/2, ERK1/2, p-p38 and p38 were assessed by Western blotting. Statistically significant differences between experimental groups were determined by one-way ANOVA followed by Tukey test for multiple comparisons. Results GM-CSF receptor complex was expressed in microglia. GM-CSF enhanced TLR4 and CD14 expressions in microglia and subsequent LPS-binding to the cell surface. In addition, GM-CSF priming increased LPS-induced NF-κB nuclear translocation and production of IL-1β, IL-6, TNF-α and NO by microglia. GM-CSF upregulated the levels of p-ERK1/2 and p-p38, suggesting that induction of TLR4 and CD14 expression by GM-CSF was mediated through ERK1/2 and p38, respectively. Conclusions These results suggest that GM-CSF upregulates TLR4 and CD14 expression in microglia through ERK1/2 and p38, respectively, and thus promotes the LPS receptor-mediated inflammation in the CNS.
The neuroprotective effects of milk fat globule-EGF factor 8 against oligomeric amyloid β toxicity
Endong Li, Mariko Noda, Yukiko Doi, Bijay Parajuli, Jun Kawanokuchi, Yoshifumi Sonobe, Hideyuki Takeuchi, Tetsuya Mizuno, Akio Suzumura
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-148
Abstract: The release of MFG-E8 from microglia treated with conditioned medium from neurons exposed to neurotoxic substances, glutamate or oligomeric amyloid β (oAβ) was measured by ELISA. The neuroprotective effects of MFG-E8 and MFG-E8???induced microglial phagocytosis of oAβ were assessed by immunocytochemistry. The effects of MFG-E8 on the production of the anti-oxidative enzyme hemeoxygenase-1 (HO-1) were determined by ELISA and immunocytochemisty.MFG-E8 was induced in microglia treated with conditioned medium from neurons that had been exposed to neurotoxicants, glutamate or oAβ. MFG-E8 significantly attenuated oAβ-induced neuronal cell death in a primary neuron???microglia coculture system. Microglial phagocytosis of oAβ was accelerated by MFG-E8 treatment due to increased CD47 expression in the absence of neurotoxic molecule production, such as tumor necrosis factor-α, nitric oxide, and glutamate. MFG-E8???treated microglia induced nuclear factor E(2)???related factor 2 (Nrf2)???mediated HO-1 production, which also contributed to neuroprotection.These results suggest that microglia release MFG-E8 in response to signals from degenerated neurons and that MFG-E8 protects oAβ-induced neuronal cell death by promoting microglial phagocytic activity and activating the Nrf2-HO-1 pathway. Thus, MFG-E8 may have novel roles as a neuroprotectant in neurodegenerative conditions.
Fingolimod Phosphate Attenuates Oligomeric Amyloid β–Induced Neurotoxicity via Increased Brain-Derived Neurotrophic Factor Expression in Neurons
Yukiko Doi, Hideyuki Takeuchi, Hiroshi Horiuchi, Taketo Hanyu, Jun Kawanokuchi, Shijie Jin, Bijay Parajuli, Yoshifumi Sonobe, Tetsuya Mizuno, Akio Suzumura
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061988
Abstract: The neurodegenerative processes that underlie Alzheimer's disease are mediated, in part, by soluble oligomeric amyloid β, a neurotoxic protein that inhibits hippocampal long-term potentiation, disrupts synaptic plasticity, and induces the production of reactive oxygen species. Here we show that the sphingosine-1-phosphate (S1P) receptor (S1PR) agonist fingolimod phosphate (FTY720-P)-a new oral drug for multiple sclerosis-protects neurons against oligomeric amyloid β-induced neurotoxicity. We confirmed that primary mouse cortical neurons express all of the S1P receptor subtypes and FTY720-P directly affects the neurons. Treatment with FTY720-P enhanced the expression of brain-derived neurotrophic factor (BDNF) in neurons. Moreover, blocking BDNF-TrkB signaling with a BDNF scavenger, TrkB inhibitor, or ERK1/2 inhibitor almost completely ablated these neuroprotective effects. These results suggested that the neuroprotective effects of FTY720-P are mediated by upregulated neuronal BDNF levels. Therefore, FTY720-P may be a promising therapeutic agent for neurodegenerative diseases, such as Alzheimer's disease.
Blockade of Gap Junction Hemichannel Suppresses Disease Progression in Mouse Models of Amyotrophic Lateral Sclerosis and Alzheimer's Disease
Hideyuki Takeuchi, Hiroyuki Mizoguchi, Yukiko Doi, Shijie Jin, Mariko Noda, Jianfeng Liang, Hua Li, Yan Zhou, Rarami Mori, Satoko Yasuoka, Endong Li, Bijay Parajuli, Jun Kawanokuchi, Yoshifumi Sonobe, Jun Sato, Koji Yamanaka, Gen Sobue, Tetsuya Mizuno, Akio Suzumura
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021108
Abstract: Background Glutamate released by activated microglia induces excitotoxic neuronal death, which likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. Although both blockade of glutamate receptors and inhibition of microglial activation are the therapeutic candidates for these neurodegenerative diseases, glutamate receptor blockers also perturbed physiological and essential glutamate signals, and inhibitors of microglial activation suppressed both neurotoxic/neuroprotective roles of microglia and hardly affected disease progression. We previously demonstrated that activated microglia release a large amount of glutamate specifically through gap junction hemichannel. Hence, blockade of gap junction hemichannel may be potentially beneficial in treatment of neurodegenerative diseases. Methods and Findings In this study, we generated a novel blood-brain barrier permeable gap junction hemichannel blocker based on glycyrrhetinic acid. We found that pharmacologic blockade of gap junction hemichannel inhibited excessive glutamate release from activated microglia in vitro and in vivo without producing notable toxicity. Blocking gap junction hemichannel significantly suppressed neuronal loss of the spinal cord and extended survival in transgenic mice carrying human superoxide dismutase 1 with G93A or G37R mutation as an amyotrophic lateral sclerosis mouse model. Moreover, blockade of gap junction hemichannel also significantly improved memory impairments without altering amyloid β deposition in double transgenic mice expressing human amyloid precursor protein with K595N and M596L mutations and presenilin 1 with A264E mutation as an Alzheimer's disease mouse model. Conclusions Our results suggest that gap junction hemichannel blockers may represent a new therapeutic strategy to target neurotoxic microglia specifically and prevent microglia-mediated neuronal death in various neurodegenerative diseases.
Complete Convergence of Weighted Sums for Asymptotically Almost Negatively Associated Sequences  [PDF]
Jun An
Applied Mathematics (AM) , 2017, DOI: 10.4236/am.2017.811120
For weighted sums of asymptotically almost negatively associated (AANA) random variables sequences, we use the Rosenthal type moment inequalities and prove the Marcinkiewicz-Zygmund type complete convergence and obtain the complete convergence rates. Our results extend some known ones.
Sleep, Serotonin, and Suicide  [PDF]
Jun Kohyama
Journal of Behavioral and Brain Science (JBBS) , 2012, DOI: 10.4236/jbbs.2012.24055
Abstract: The author hypothesizes that sleep loss associated with a decrease in serotonergic activity plays a significant role in attempted suicide. Recent research has emphasized the role of the economic recession on the occurrence of suicide, but with no attention paid to possible biological aspects. In this brief review, the association between sleep, the serotonergic system, and suicide is initially introduced. Then, with consideration of recent research, a hypothesis regarding the oc- currence of suicide is proposed. Finally, based on that hypothesis, three factors possibly germane to reducing suicides (sufficient sleep duration, activation of the serotonergic system, and activation of the prefrontal cortex) are discussed.
Remodeling of living human nasal cavity under the assistance of acoustic rhinometry technique  [PDF]
Jun Zhang
Journal of Biosciences and Medicines (JBM) , 2013, DOI: 10.4236/jbm.2013.12007

Acoustic rhinometry could numerically describe up- per airway condition of air draft by drawing a graph plotting the distance from the nostril vs. the cross-sectional area. Some decreases on the graph correspond to the typical anatomic structures of human nasal cavity. The 3-dimensional, computing fluid dynamic model of the same person was developed based on computed tomography scans. The veracity of the CFD model was valued by contrasting the relevant areas of stenosis site between the model and the AR graph. The aim in this study is to make clear how to use an AR to help improve and enrich the CFD model with the information of graph acquired from the measurement. The combination of AR and CT can be used to establish a living human nasal cavity model with higher significant information content.

Characteristic size research of human nasal cavity and the respiratory airflow CFD analysis  [PDF]
Jun Zhang
Journal of Biosciences and Medicines (JBM) , 2013, DOI: 10.4236/jbm.2013.12006

To study the airflow distribution in human nasal cavity during respiration and the characteristic parameters for nasal structure, thirty three-dimensional, anatomically accurate representations of adult nasal cavity models were reconstructed based on processed tomography images collected from normal people. The airflow fields in nasal cavities were simulated using the fluid dynamics with the finite element software ANSYS. The results showed that the difference of human nasal cavity structure led to varying airflow distribution in the nasal cavities and the main airflow passed through the common nasal meatus. The nasal resistance in the regions of nasal valve and nasal vestibule accounted for more than a half of overall resistance. The characteristic model of nasal cavity was extracted based on the characteristic points and dimensions deducted from the original models. It showed that either the geometric structure or the air-flow field of the two kinds of model was similar. The characteristic dimensions were the characteristic parameters of nasal cavity that properly represented the original model in research for nasal cavity.

Capacity Limitations of Medical Services Provided by Pediatricians in Japan  [PDF]
Jun Kohyama
Open Journal of Pediatrics (OJPed) , 2014, DOI: 10.4236/ojped.2014.41014

The shortage of pediatricians has been identified as one of the largest social problems in Japan. This study aimed to compare the assumed ideal nighttime working conditions of pediatric hospitalists in Japan with the actual current situation. By using available data on the age-related numbers of pediatricians in Japan, we described the ideal working conditions for pediatric hospitalists in Japan. The ideal situation was then compared with the existing actual working conditions. Compared with the assumed ideal condition, current pediatric hospitalists are working in many hospitals with a few colleagues. To solve the current supply-demand mismatch on medical care for children during night, an involvement of non-pediatric physicians in the medical care of children during the night is indispensable. Also, parents in Japan need to know the limitations relating to the available capacity of pediatricians, and accept that their children can be cared for adequately by non-pediatric physicians, who have been trained to provide primary medical care to children.

H-Singular Value of a Positive Tensor  [PDF]
Jun He
Advances in Linear Algebra & Matrix Theory (ALAMT) , 2015, DOI: 10.4236/alamt.2015.51002

In this paper we study properties of H-singular values of a positive tensor \"\" and present an iterative algorithm for computing the largest H-singular value of the positive tensor. We prove that this method?converges for any positive tensors.

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