Liver X receptor-dependent inhibition of microglial nitric oxide synthase 2

Background The nuclear receptor liver X receptor (LXR) exerts transcriptional control over lipid metabolism and inflammatory response in cells of the myeloid lineage, suggesting that LXR may be a potential target in a number of chronic neuroinflammatory and neurodegenerative diseases where persistent microglial activation has been implicated in the pathogenesis. Methods The effect of LXR activation on microglia and central nervous system (CNS) inflammation was studied using a synthetic LXR agonist in cultured microglia, a microglial cell line and experimental allergic encephalomyelitis (EAE), an animal model of CNS inflammation. Results LXR activation inhibited nitric oxide synthase 2, inducible (Nos2) expression and nitric oxide production in lipopolysaccharide (LPS)-stimulated microglia. Inhibition of microglial activation in response to interferon-γ was less reliable. In LPS-stimulated cells, LXR activation did not inhibit nuclear translocation of NF-kappaB1 p50. Instead, LXR-dependent Nos2 repression was associated with inhibition of histone 4 acetylation and inhibition of NF-kappaB1 p50 binding at the Nos2 promoter. Histone acetylation and NF-kappaB1 p50 binding were mechanistically linked, and histone deacetylase (HDAC) activity appeared to be important for LXR-dependent transcriptional repression of Nos2. Analysis of CNS gene expression in animals undergoing EAE showed that the expressions of Lxr and LXR-dependent genes were downregulated during CNS inflammation. Nevertheless, administration of LXR agonist GW3965 during the effector phase of EAE delayed the onset of clinical disease and reversed the diminished expression of LXR-dependent reverse cholesterol transport genes. However, the CNS expressions of Nos2 and other inflammatory genes were not significantly inhibited by LXR activation in EAE, and clinical disease severity was comparable to vehicle controls at later time points in LXR agonist treated animals. Conclusions LXR can be targeted to modulate microglial activation. LXR-dependent repression of inflammatory genes may be stimulus-dependent and impaired by HDAC inhibition. Endogenous LXR activity does not appear to modulate CNS inflammation, but LXR activity can be partially restored in the CNS by administration of exogenous LXR agonist with an impact on clinical disease severity at early, but not late, time points in EAE

Enhancing Cognition in Older Persons with Depression or Anxiety with a Combination of Mindfulness-Based Stress Reduction (MBSR) and Transcranial Direct Current Stimulation (tDCS): Results of a Pilot Randomized Clinical Trial.

OBJECTIVES: Individuals with subjective memory complaints and symptoms of depression and/or anxiety are at high risk for further cognitive decline, and possible progression to dementia. Low-burden interventions to help slow or prevent cognitive decline in this high-risk group are needed. The objective of this study is to assess the feasibility of combining Mindfulness-Based Stress Reduction (MBSR) with transcranial direct current stimulation (tDCS) to increase putative benefits of MBSR for cognitive function and everyday mindfulness in depressed or anxious older adults with subjective cognitive decline. METHODS: We conducted a two-site pilot double-blind randomized sham-controlled trial, combining active MBSR with either active or sham tDCS. The intervention included weekly in-class group sessions at the local university hospital and daily at-home practice. Anodal tDCS was applied for 30 min during MBSR meditative practice, both in-class and at-home. RESULTS: Twenty-six individuals with subjective cognitive complaints and symptoms of depression and/or anxiety were randomized to active (n = 12) or sham tDCS (n = 14). The combination of MBSR and tDCS was safe and well tolerated, though at-home adherence and in-class attendance were variable. While they were not statistically significant, the largest effect sizes for active vs. sham tDCS were for everyday mindfulness (d = 0.6) and social functioning (d = 0.9) (F (1,21) = 3.68, p = 0.07 and F (1,21) = 3.9, p = 0.06, respectively). CONCLUSIONS: Our findings suggest that it is feasible and safe to combine tDCS with MBSR in older depressed and anxious adults, including during remote, at-home use. Furthermore, tDCS may enhance MBSR via transferring its meditative learning and practice into increases in everyday mindfulness. Future studies need to improve adherence to MBSR with tDCS. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03653351 and NCT03680664). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12671-021-01764-9

A Poly(cobaloxime)/Carbon Nanotube Electrode: Freestanding Buckypaper with Polymer-Enhanced H2-Evolution Performance.

A freestanding H2-evolution electrode consisting of a copolymer-embedded cobaloxime integrated into a multiwall carbon nanotube matrix by π-π interactions is reported. This electrode is straightforward to assemble and displays high activity towards hydrogen evolution in near-neutral pH solution under inert and aerobic conditions, with a cobalt-based turnover number (TON(Co)) of up to 420. An analogous electrode with a monomeric cobaloxime showed less activity with a TON(Co) of only 80. These results suggest that, in addition to the high surface area of the porous network of the buckypaper, the polymeric scaffold provides a stabilizing environment to the catalyst, leading to further enhancement in catalytic performance. We have therefore established that the use of a multifunctional copolymeric architecture is a viable strategy to enhance the performance of molecular electrocatalysts.We acknowledge support by the Christian Doppler Research Association (Austrian Federal Ministry of Science, Research and Economy and National Foundation for Research, Technology and Development), the OMV Group, the EPSRC, the BBSRC (Grant BB/K010220/1) and the Woolf Fisher Trust in New Zealand and the Cambridge Trusts. We also thank the National EPSRC XPS User’s Service (NEXUS) at Newcastle University, UK.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/anie.20151137

Supramolecular electrode assemblies for bioelectrochemistry

For more than three decades, the field of bioelectrochemistry has provided novel insights into the catalytic mechanisms of enzymes, the principles that govern biological electron transfer, and has elucidated the basic principles for bioelectrocatalytic systems. Progress in biochemistry, bionanotechnology, and our ever increasing ability to control the chemistry and structure of electrode surfaces has enabled the study of ever more complex systems with bioelectrochemistry. This feature article highlights developments over the last decade, where supramolecular approaches have been employed to develop electrode assemblies that increase enzyme loading on the electrode or create more biocompatible environments for membrane enzymes. Two approaches are particularly highlighted: the use of layer-by-layer assembly, and the modification of electrodes with planar lipid membranes

Protective matrices for hydrogenases and bio-inspired catalysts

In dieser Arbeit werden polymere Matrizen entworfen, um Hydrogenasen und bioinspirierte Katalysatoren auf Elektrodenoberflächen zu stabilisieren und vor Inaktivierung zu schützen. Durch den Einbau der Hydrogenasen in einen Redoxhydrogelfilm bleibt deren Aktivität unter oxidativen Bedingungen erhalten. Der Elektronentransfer zwischen den redoxaktiven Spezies des Polymers kontrolliert das Potential, welches an die Hydrogenase angelegt wird. Somit ist das Enzym vor Inaktivierung durch hohe Potentiale geschützt. Unter Katalysebedingungen induzieren Elektronen, die von der Wasserstoffoxidationsreaktion geliefert werden, eine viologen-katalysierte O$_2$-Reduktion an der Polymeroberfläche. Auf diese Weise entsteht ein Schutz vor O$_2$. Eine andere Strategie wird verwendet, um bioinspirierte O$_2$-empfindliche Nickel-katalysatoren zu stabilisieren. Sie werden in einer hydrophoben redox-inaktiven-Polymermatrix dispergiert, was zu einer erhöhten Stabilität der H$_2$-Oxidation und höherer O$_2$-Toleranz führt.In this thesis, polymeric matrices are designed to stabilize hydrogenases and bioinspired catalysts on an electrode surface and to provide protection from inactivation factors. When incorporated into a redox hydrogel film, hydrogenases can sustain activity under oxidative conditions. The electron transfer between the redox-active species (viologen moieties) controls the potential applied to the active site of the hydrogenase and thus insulates the enzyme from excessive oxidative stress. Under turnover conditions, electrons provided from the hydrogen oxidation reaction, induce viologen catalyzed O$_2$ reduction at the polymer surface, thus providing a self-activated protection from O$_2$. A different strategy is used to stabilize nickel bio-inspired O$_2$ sensitive catalysts. They were dispersed in a hydrophobic redox silent polymer matrix that provides enhanced stability for H$_2$ oxidation as well as O$_2$ tolerance