The Effect of Environmental Enrichment on Glutathione-Mediated Xenobiotic Metabolism and Antioxidation in Normal Adult Mice

Olfactory bulb (OB) plays an important role in protecting against harmful substances via the secretion of antioxidant and detoxifying enzymes. Environmental enrichment (EE) is a common rehabilitation method and known to have beneficial effects in the central nervous system. However, the effects of EE in the OB still remain unclear. At 6 weeks of age, CD-1® (ICR) mice were assigned to standard cages or EE cages. After 2 months, we performed proteomic analysis. Forty-four up-regulated proteins were identified in EE mice compared to the control mice. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes Pathway demonstrated that the upregulated proteins were mainly involved in metabolic pathways against xenobiotics. Among those upregulated proteins, 9 proteins, which participate in phase I or II of the xenobiotic metabolizing process and are known to be responsible for ROS detoxification, were validated by qRT-PCR. To explore the effect of ROS detoxification mediated by EE, glutathione activity was measured by an ELISA assay. The ratio of reduced glutathione to oxidized glutathione was significantly increased in EE mice. Based on a linear regression analysis, GSTM2 and UGT2A1 were found to be the most influential genes in ROS detoxification. For further analysis of neuroprotection, the level of iNOS and the ratio of Bax to Bcl-2 were significantly decreased in EE mice. While TUNEL+ cells were significantly decreased, Ki67+ cells were significantly increased in EE mice, implicating that EE creates an optimal state for xenobiotic metabolism and antioxidant activity. Taken together, our results suggested that EE protects olfactory layers via the upregulation of glutathione-related antioxidant and xenobiotic metabolizing enzymes, eventually lowering ROS-mediated inflammation and apoptosis and increasing neurogenesis. This study may provide an opportunity for a better understanding of the beneficial effects of EE in the OB

Mechanosensitive activation of K+ channel via phospholipase C-induced depletion of phosphatidylinositol 4,5-bisphosphate in B lymphocytes

In various types of cells mechanical stimulation of the plasma membrane activates phospholipase C (PLC). However, the regulation of ion channels via mechanosensitive degradation of phosphatidylinositol 4,5-bisphosphate (PIP(2)) is not known yet. The mouse B cells express large conductance background K(+) channels (LK(bg)) that are inhibited by PIP(2). In inside-out patch clamp studies, the application of MgATP (1 mm) also inhibited LK(bg) due to the generation of PIP(2) by phosphoinositide (PI)-kinases. In the presence of MgATP, membrane stretch induced by negative pipette pressure activated LK(bg), which was antagonized by PIP(2) (> 1 microm) or higher concentration of MgATP (5 mm). The inhibition by PIP(2) was partially reversible. However, the application of methyl-beta-cyclodextrin, a cholesterol scavenger disrupting lipid rafts, induced the full recovery of LK(bg) activity and facilitated the activation by stretch. In cell-attached patches, LK(bg) were activated by hypotonic swelling of B cells as well as by negative pressure. The mechano-activation of LK(bg) was blocked by U73122, a PLC inhibitor. Neither actin depolymerization nor the inhibition of lipid phosphatase blocked the mechanical effects. Direct stimulation of PLC by m-3M3FBS or by cross-linking IgM-type B cell receptors activated LK(bg). Western blot analysis and confocal microscopy showed that the hypotonic swelling of WEHI-231 induces tyrosine phosphorylation of PLCgamma2 and PIP(2) hydrolysis of plasma membrane. The time dependence of PIP(2) hydrolysis and LK(bg) activation were similar. The presence of LK(bg) and their stretch sensitivity were also proven in fresh isolated mice splenic B cells. From the above results, we propose a novel mechanism of stretch-dependent ion channel activation, namely, that the degradation of PIP(2) caused by stretch-activated PLC releases LK(bg) from the tonic inhibition by PIP(2)

NHERF2 specifically interacts with LPA(2) receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta 3 activation

Lysophosphatidic acid (LPA) activates a family of cognate G protein-coupled receptors and is involved in various pathophysiological processes. However, it is not clearly understood how these LPA receptors are specifically coupled to their downstream signaling molecules. This study found that LPA, but not the other LPA receptor isoforms, specifically interacts with Na+/H+ exchanger regulatory factor2 (NHERF2). In addition, the interaction between them requires the C-terminal PDZ domain-binding motif of LPA(2) and the second PDZ domain of NHERF2. Moreover, the stable expression of NHERF2 potentiated LPA-induced phospholipase C-beta (PLC-beta) activation, which was markedly attenuated by either a mutation in the PDZ-binding motif of LPA(2) or by the gene silencing of NHERF2. Using its second PDZ domain, NHERF2 was found to indirectly link LPA(2) to PLC-beta3 to form a complex, and the other PLC-beta isozymes were not included in the protein complex. Consistently, LPA(2)-mediated PLC-beta activation was specifically inhibited by the gene silencing of PLC-beta3. In addition, NHERF2 increases LPA-induced ERK activation, which is followed by cyclooxygenase-2 induction via a PLC-dependent pathway. Overall, the results suggest that a ternary complex composed of LPA(2), NHERF2, and PLC-beta3 may play a key role in the LPA2-mediated PLC-beta signaling pathwayclose606

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Cross-linked poly(vinylidene fluoride-cohexafluoropropene) (PVDF-co-HFP) gel polymer electrolyte for flexible li-ion battery integrated with organic light emitting diode (OLED)

Here, we fabricate poly(vinylidene fluoride-co-hexafluoropropene) (PVDF-co-HFP) by electrospinning for a gel polymer electrolyte (GPE) for use in flexible Li-ion batteries (LIBs). As a solvent, we use N-methyl-2-pyrrolidone (NMP), which helps produce the cross-linked morphology of PVDF-co-HFP separator, owing to its low volatility. The cross-linked PVDF-co-HFP separator shows an uptake rate higher than that of a commercialized polypropylene (PP) separator. Moreover, the PVDF-co-HFP separator shows an ionic conductivity of 2.3 × 10-3 S/cm at room temperature, comparable with previously reported values. An LIB full-cell assembled with the PVDF-co-HFP-based GPE shows capacities higher than its counterpart with the commercialized PP separator, confirming that the cross-linked PVDF-co-HFP separator provides highly efficient ionic conducting pathways. In addition, we integrate a flexible LIB cell using the PVDF-co-HFP GPE with a flexible organic light emitting diode (OLED), demonstrating a fully flexible unit of LIB and OLED. © 2018 by the author

Cross-linked poly(vinylidene fluoride-cohexafluoropropene) (PVDF-co-HFP) gel polymer electrolyte for flexible li-ion battery integrated with organic light emitting diode (OLED)

Here, we fabricate poly(vinylidene fluoride-co-hexafluoropropene) (PVDF-co-HFP) by electrospinning for a gel polymer electrolyte (GPE) for use in flexible Li-ion batteries (LIBs). As a solvent, we use N-methyl-2-pyrrolidone (NMP), which helps produce the cross-linked morphology of PVDF-co-HFP separator, owing to its low volatility. The cross-linked PVDF-co-HFP separator shows an uptake rate higher than that of a commercialized polypropylene (PP) separator. Moreover, the PVDF-co-HFP separator shows an ionic conductivity of 2.3 × 10-3 S/cm at room temperature, comparable with previously reported values. An LIB full-cell assembled with the PVDF-co-HFP-based GPE shows capacities higher than its counterpart with the commercialized PP separator, confirming that the cross-linked PVDF-co-HFP separator provides highly efficient ionic conducting pathways. In addition, we integrate a flexible LIB cell using the PVDF-co-HFP GPE with a flexible organic light emitting diode (OLED), demonstrating a fully flexible unit of LIB and OLED. © 2018 by the author

Li3BO3-Li2CO3: Rationally Designed Buffering Phase for Sulfide All Solid-State Li-Ion Batteries

Most inorganic solid electrolytes (SEs) suffer from narrow intrinsic electrochemical windows and incompatibility with electrode materials, which results in the below par electrochemical performances of all-solid-state Li-ion or Li batteries (ASLBs). Unfortunately, in-depth understanding on the interfacial evolution and interfacial engineering via scalable protocols for ASLBs to mitigate these issues are at an infancy stage. Herein, we report on rationally designed Li3BO3-Li2CO3 (LBO-LCO or Li3-xB1-xCxO3 (LBCO)) coatings for LiCoO2 in ASLBs employing sulfide SE of Li6PS5Cl. The new aqueous-solution-based LBO-coating protocol allows us to convert the surface impurity on LiCoO2 and Li2CO3, into highly Li+-conductive LBCO layers (6.0 x 10(-7) S cm(-1) at 30 degrees C for LBCO vs 1.4 x 10(-9) S cm(-1) at 100 degrees C for Li2CO3 or 1.4 x 10(-9) S cm(-1) at 30 degrees C for LBO), which also offer interfacial stability with sulfide SE. By applying these high-surface-coverage LBCO coatings, significantly enhanced electrochemical performances are obtained in terms of capacity, rate capability, and durability. It is elucidated that the LBCO coatings suppress the evolution of detrimental mixed conducting interphases containing Co3S4 and effectively passivate the interfaces by the formation of alternative interface phases