Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of Substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Activation of the mixed lineage kinase and c-Jun N-terminal kinase (JNK) has been reported in models of PD. Our focus was to discern whether distinct pathways were activated in cell-specific manner within the SNpc. We now demonstrate the selective phosphorylation of p38 MAP kinase within the dopaminergic neurons, whereas JNK activation occurs predominantly in the microglia. p38 activation results in downstream phosphorylation of p53 and increased p53 mediated transcription of Bax and Puma in the ventral midbrain. Treatment with p38 inhibitor, SB239063 protected primary dopaminergic neurons derived from human progenitor cells from MPP+ mediated cell death and prevented the downstream phosphorylation of p53 and its translocation to the nucleus in vivo, in the ventral midbrain. The increased staining of phosphorylated p38 in the surviving neurons of SNpc in human brain sections from patients with PD and in MPTP treated mice but not in the ventral tegmental area provides further evidence suggesting a role for p38 in the degeneration of dopaminergic neurons of SNpc. We thus demonstrate the cell specific activation of MAP kinase pathways within the SNpc after MPTP treatment emphasizing the role of multiple signaling cascades in the pathogenesis and progression of the disease. Selective inhibitors of p38 may therefore, help preserve the surviving neurons in PD and slow down the disease progression

Evaluation of Tensile Bond Strength of Zinc Containing and Zinc Free Denture Adhesives on Different Denture Base Resin Materials: An in Vitro Study

Background and aim: Denture adhesives augment the retention and stability of the complete denture. The included studies have not directly compared tensile bond strength between zinc and zinc-free denture adhesives. This study compared the tensile bond strength of zinc-containing and zinc-free denture adhesives on different denture base resin materials at various intervals.Material and methods: Four groups of denture base resin materials (Acralyn H, Lucitone199- DB1, SR Ivocap-DB2, Polytray-DB3) were fabricated using different polymerization techniques. Each group had ten specimens. The control group consisted of resin cylinders coated with artificial saliva, while the test groups had denture adhesive applied between the test and control cylinders. Tensile bond strength was measured using a universal testing machine.Results: The tensile bond strength values of Fixodent with DBI &DB3 and DB2 &DB3 at 5 min (P < 0.01), 3 hours (P < 0.01), and 6 hours (P < 0.061 and P < 0.020) alongside with DB1 & DB2, DBI & DB3, and DB2 & DB3 at 12 hours (P < 0.01) were found to be statistically significant. The tensile bond strengths variations of Fittydent with DB1 & DB3 and DB2 & DB3 at 3 hours (P =0.013, P =0.012) and 6 hours (P < 0.01), and DB2 & DB3 at 12 hours (P=0.015), was statistically significant at 0.05 level.Conclusions: The zinc-containing and zinc-free denture adhesives exhibited a significant increase in tensile bond strength compared to the control group (artificial saliva) at all time intervals

Editorial: Mitochondria and Endoplasmic Reticulum Dysfunction in Parkinson's Disease

Producción CientíficaNo abstract availabl

MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model

Activation of apoptosis signal regulating kinase 1 (ASK1)-p38 MAPK death signaling cascade is irn plicated in the death of dopaminergic neurons in substantia nigra in Parkinson's disease (PD). We investigated upstream activators of ASK1 using an MPTP mouse model of parkinsonism and assessed the temporal cascade of death signaling in ventral midbrain (VMB) and striatum (ST). MPTP selectively activated ASK1 and downstream 1)38 MAPK in a time dependent manner in VMB alone. This occurred through selective protein thiol oxidation of the redox-sensitive thiol disulfide oxidoreductase, thiorcdoxin (Trxl), resulting in release of its inhibitory association with ASK1, while glutathione-S-transferase ji 1 (GSTM1) remained in reduced form in association with ASK1. Levels of tumor necrosis factor (TNF), a known activator of ASK1, increased early after MPTP in VMB. Protein ovariation netvvork analysis (PCNA) using protein states as nodes revealed TNF to be an important node regulating the ASK1 signaling cascade. In confirmation, blocking MPTP-mecliated TNF signaling through intrathecal administration of TNFneutralizing antibody prevented Trxl oxidation and downstream ASK1-p38 MAPK activation. Averting an early increase in TNF, which leads to protein thiol oxidation resulting in activation of ASK1-p38 signaling, may be critical for neuroprotection in PD. Importantly, network analysis can help in understanding the cause/effect relationship within protein networks in complex disease states. (C) 2015 Published by Elsevier Inc

Author Correction: PV plasticity sustained through D1/5 dopamine signaling required for long-term memory consolidation

In the version of this article initially published, the right panel in Fig. 2b was duplicated from the corresponding panel in Fig. 2c, and some data points in Fig. 3b were duplicated from Fig. 3a. None of the conclusions in the paper are affected. The errors have been corrected in the HTML and PDF versions of the article, and source data have been posted for the revised panels. The original and corrected figures are shown in the accompanying Author Correction

Glutaredoxin1 Diminishes Amyloid Beta-Mediated Oxidation of F-Actin and Reverses Cognitive Deficits in an Alzheimer's Disease Mouse Model

Aims: Reactive oxygen species (ROS) generated during Alzheimer's disease (AD) pathogenesis through multiple sources are implicated in synaptic pathology observed in the disease. We have previously shown F-actin disassembly in dendritic spines in early AD (34). The actin cytoskeleton can be oxidatively modified resulting in altered F-actin dynamics. Therefore, we investigated whether disruption of redox signaling could contribute to actin network disassembly and downstream effects in the amyloid precursor protein/presenilin-1 double transgenic (APP/PS1) mouse model of AD. Results: Synaptosomal preparations from 1-month-old APP/PS1 mice showed an increase in ROS levels, coupled with a decrease in the reduced form of F-actin and increase in glutathionylated synaptosomal actin. Furthermore, synaptic glutaredoxin 1 (Grx1) and thioredoxin levels were found to be lowered. Overexpressing Grx1 in the brains of these mice not only reversed F-actin loss seen in APP/PS1 mice but also restored memory recall after contextual fear conditioning. F-actin levels and F-actin nanoarchitecture in spines were also stabilized by Grx1 overexpression in APP/PS1 primary cortical neurons, indicating that glutathionylation of F-actin is a critical event in early pathogenesis of AD, which leads to spine loss. Innovation: Loss of thiol/disulfide oxidoreductases in the synapse along with increase in ROS can render F-actin nanoarchitecture susceptible to oxidative modifications in AD. Conclusions: Our findings provide novel evidence that altered redox signaling in the form of S-glutathionylation and reduced Grx1 levels can lead to synaptic dysfunction during AD pathogenesis by directly disrupting the F-actin nanoarchitecture in spines. Increasing Grx1 levels is a potential target for novel disease-modifying therapies for AD

A beta mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease

Dendritic spine loss is recognized as an early feature of Alzheimer's disease (AD), but the underlying mechanisms are poorly understood. Dendritic spine structure is defined by filamentous actin (F-actin) and we observed depolymerization of synaptosomal F-actin accompanied by increased globular-actin (G-actin) at as early as 1 month of age in a mouse model of AD(APPswe/PS1 Delta E9, male mice). This led to recall deficit after contextual fear conditioning (cFC) at 2 months of age in APPswe/PS1 Delta E9 male mice, which could be reversed by the actin-polymerizing agent jasplakinolide. Further, the F-actin-depolymerizing agent latrunculin induced recall deficit after cFC in WT mice, indicating the importance of maintaining F-/G-actin equilibrium for optimal behavioral response. Using direct stochastic optical reconstruction microscopy (dSTORM), we show that F-actin depolymerization in spines leads to a breakdown of the nano-organization of outwardly radiating F-actin rods in cortical neurons from APPswe/PS1 Delta E9 mice. Our results demonstrate that synaptic dysfunction seen as F-actin disassembly occurs very early, before onset of pathological hallmarks in AD mice, and contributes to behavioral dysfunction, indicating that depolymerization of F-actin is causal and not consequent to decreased spine density. Further, we observed decreased synaptosomal F-actin levels in postmortem brain from mild cognitive impairment and AD patients compared with subjects with normal cognition. F-actin decrease correlated inversely with increasing AD pathology (Braak score, A beta load, and tangle density) and directly with performance in episodic and working memory tasks, suggesting its role in human disease pathogenesis and progression

Versatile self-cleaning coating production through sol–gel chemistry

Power, A ORCiD: 0000-0002-7119-8486The performance of optical devices is dependent on their optical transparency (OT). This is evident when such devices are exposed to environmental conditions that can reduce OT. The development of a robust, transparent and self-cleaning coating is highly desirable, for applications likeoptical windows and solar panels. This work reports the design of such coatings based on a hydrophobic thin film fabricated using a sol-gel process. Coating properties were optimised by modification of the surface topography of the coatings, achieved by the incorporation of silica nanoparticles(NPs). The coating was characterised by water contact angle(WCA), scanning electron microscopy(SEM) and white light interferometry (WLI). The efficacy and robustness of the coating foroptical application was assessed