Lung gene therapy for cystic fibrosis disease has not been successful due to several challenges such as the absence of an appropriate vector. Therefore, optimal delivery of emerging therapeutics to ...airway epithelial cells demands suitable non-viral systems. In this work, we describe the formulation and the physicochemical investigation of biocompatible and biodegradable polymeric nanoparticles (NPs), including PLGA and chitosan (animal and non-animal), as novel methods for the safe and efficient delivery of CFTR-specific locked nucleic acids (LNAs).
Oxidation chemistry using enzymes is approaching maturity and practical applicability in organic synthesis. Oxidoreductases (enzymes catalysing redox reactions) enable chemists to perform highly ...selective and efficient transformations ranging from simple alcohol oxidations to stereoselective halogenations of non‐activated C−H bonds. For many of these reactions, no “classical” chemical counterpart is known. Hence oxidoreductases open up shorter synthesis routes based on a more direct access to the target products. The generally very mild reaction conditions may also reduce the environmental impact of biocatalytic reactions compared to classical counterparts. In this Review, we critically summarise the most important recent developments in the field of biocatalytic oxidation chemistry and identify the most pressing bottlenecks as well as promising solutions.
Oxidoreductases enable highly selective and efficient transformations, ranging from simple alcohol oxidations to stereoselective halogenations of non‐activated C−H bonds. This Review summarises the most important recent developments in the field of biocatalytic oxidation chemistry and identifies the most pressing bottlenecks as well as promising solutions.
Background
Because of the COVID‐19 pandemic, health care systems worldwide are working under challenging conditions. Patients, who are seriously ill, require intensive care admission. In fighting ...COVID‐19, nurses are frontline health care workers and, as such, have a great responsibility providing needed specialized patient care in intensive care units (ICU). However, working conditions and emotional factors have an impact on the quality of the care provided.
Aim
The purpose of the present study was to explore and describe the experiences and perceptions of nurses working in an ICU during the COVID‐19 global pandemic.
Study design
Qualitative research was undertaken, using an empirical approach and inductive content analysis techniques.
Methods
The selected population consisted of ICU nurses from a tertiary teaching hospital in Spain. Data were obtained via semi‐structured videocall interviews from Apr 12th to Apr 30th, 2020. Subsequently, transcribed verbatims were analysed using the template analysis model of Brooks.
Findings
A total of 17 nurses comprised the final sample after data saturation. Four main themes emerged from the analysis and 13 subthemes: “providing nursing care,” “psychosocial aspects and emotional lability,” “resources management and safety” and “professional relationships and fellowship.”
Conclusion
Providing health care by intensive care nursing professionals, during the COVID‐19 pandemic, has shown both strong and weak points in the health care system. Nursing care has been influenced by fear and isolation, making it hard to maintain the humanization of the health care.
Relevance to clinical practice
Implications for practice include optimizing resource management (human and material), providing psychological support, and adequate training for ICU nurses, as well as high‐quality protocols for future emergency situations.
Retinal diseases linked to inflammation are often accompanied by macrophage/microglial cells activation. However, the dynamics between M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization of ...microglia during diabetic retinopathy (DR) has not been investigated and it might be therapeutically useful. We assessed microglia polarization in retinas from db/db mice and human diabetic donors and also the microglia-mediated anti-inflammatory effects of the bicyclic nojirimycin derivative (1R)-1-dodecylsulfinyl-5N,6O-oxomethylidenenojirimycin (R-DS-ONJ). Visual function in mice was evaluated by electroretinogram (ERG). Expression of pro- and anti-inflammatory markers in the retina was analyzed by immunofluorescence, Western-blot and quantitative real-time PCR. Lipopolysaccharide (LPS)-mediated polarization profile was studied in Bv.2 microglial cells in the absence or presence of anti-inflammatory cytokines (IL4/IL13) or R-DS-ONJ. At 5weeks of age, reduced ERG amplitude values of rod and mixed waves were detected in db/db compared to db/+ mice that correlated with elevated circulating endotoxemia and pro-inflammatory cytokines. At this early stage of DR, the marker of activated microglia Iba-1 co-localized with the M2 marker arginase-1 in the retina. Conversely, in retinas from 8weeks old db/db mice Iba-1-colocalized with active caspase-1, a key component of the inflammasome, reflecting an opposite pattern of microglia polarization. Markers of activated microglia were detected in retinas of diabetic donors. Treatment of Bv.2 cells with LPS and IL4/IL13 or R-DS-ONJ switched the M1 response towards M2. In retinal explants from db/db mice, R-DS-ONJ induced a M2 response. In conclusion, the modulation of microglia polarization dynamics towards a M2 status at early stages of DR offers novel therapeutic interventions.
•Neuroinflammation precedes neurodegeneration during DR progression.•During early stages of DR microglia displays a M2 phenotype.•Microglia-M2 phenotype switches towards M1 phenotype in advances stage of DR.•Modulation of microglia polarization is a new target against neuroinflammation in DR.
Lysosomal storage disorders (LSDs) are often caused by mutations that destabilize native folding and impair the trafficking of enzymes, leading to premature endoplasmic reticulum (ER)-associated ...degradation, deficiencies of specific hydrolytic functions and aberrant storage of metabolites in the lysosomes. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) are available for a few of these conditions, but most remain orphan. A main difficulty is that virtually all LSDs involve neurological decline and neither proteins nor the current SRT drugs can cross the blood-brain barrier. Twenty years ago a new therapeutic paradigm better suited for neuropathic LSDs was launched, namely pharmacological chaperone (PC) therapy. PCs are small molecules capable of binding to the mutant protein at the ER, inducing proper folding, restoring trafficking and increasing enzyme activity and substrate processing in the lysosome. In many LSDs the mutated protein is a glycosidase and the accumulated substrate is an oligo- or polysaccharide or a glycoconjugate, e.g. a glycosphingolipid. Although it might appear counterintuitive, substrate analogues (glycomimetics) behaving as competitive glycosidase inhibitors are good candidates to perform PC tasks. The advancements in the knowledge of the molecular basis of LSDs, including enzyme structures, binding modes, trafficking pathways and substrate processing mechanisms, have been put forward to optimize PC selectivity and efficacy. Moreover, the chemical versatility of glycomimetics and the variety of structures at hand allow simultaneous optimization of chaperone and pharmacokinetic properties. In this Feature Article we review the advancements made in this field in the last few years and the future outlook through the lessons taught by three archetypical LSDs: Gaucher disease, GM1-gangliosidosis and Fabry disease.
Selective oxyfunctionalizations of inert C−H bonds can be achieved under mild conditions by using peroxygenases. This approach, however, suffers from the poor robustness of these enzymes in the ...presence of hydrogen peroxide as the stoichiometric oxidant. Herein, we demonstrate that inorganic photocatalysts such as gold–titanium dioxide efficiently provide H2O2 through the methanol‐driven reductive activation of ambient oxygen in amounts that ensure that the enzyme remains highly active and stable. Using this approach, the stereoselective hydroxylation of ethylbenzene to (R)‐1‐phenylethanol was achieved with high enantioselectivity (>98 % ee) and excellent turnover numbers for the biocatalyst (>71 000).
Inorganic photocatalysis with Au‐TiO2 and selective enzymatic catalysis were combined for the oxyfunctionalization of inert C−H bonds. The hydroxylation of ethylbenzene to (R)‐1‐phenylethanol was thus achieved with high enantioselectivity and excellent turnover numbers.
In many human carcinomas, mucin-1 (MUC1) is overexpressed and aberrantly glycosylated, resulting in the exposure of previously hidden antigens. This generates new patient antibody profiles that can ...be used in cancer diagnosis. In the present study, we focused on the MUC1-associated Tn antigen (α-O-GalNAc-Ser/Thr) and substituted the GalNAc monosaccharide by a glycomimic to identify MUC1-based glycopeptides with increased antigenicity. Two different glycopeptide libraries presenting the natural Tn antigen or the sp2 -iminosugar analogue were synthesized and evaluated with anti-MUC1 monoclonal antibodies in a microarray platform. The most promising candidates were tested with healthy and breast cancer sera aiming for potential autoantibody-based biomarkers. The suitability of sp2 -iminosugar glycopeptides to detect anti-MUC1 antibodies was demonstrated, and serological experiments showed stage I breast cancer autoantibodies binding with a specific unnatural glycopeptide with almost no healthy serum interaction. These results will promote further studies on their capabilities as early cancer biomarkers.
Background and Purpose
Activation of astrocytes contributes to synaptic remodelling, tissue repair and neuronal survival following traumatic brain injury (TBI). The mechanisms by which these cells ...interact to resident/infiltrated inflammatory cells to rewire neuronal networks and repair brain functions remain poorly understood. Here, we explored how TLR4‐induced astrocyte activation modified synapses and cerebrovascular integrity following TBI.
Experimental Approach
To determine how functional astrocyte alterations induced by activation of TLR4 pathway in inflammatory cells regulate synapses and neurovascular integrity after TBI, we used pharmacology, genetic approaches, live calcium imaging, immunofluorescence, flow cytometry, blood–brain barrier (BBB) integrity assessment and molecular and behavioural methods.
Key Results
Shortly after a TBI, there is a recruitment of excitable and reactive astrocytes mediated by TLR4 pathway activation with detrimental effects on post‐synaptic density‐95 (PSD‐95)/vesicular glutamate transporter 1 (VGLUT1) synaptic puncta, BBB integrity and neurological outcome. Pharmacological blockage of the TLR4 pathway with resatorvid (TAK‐242) partially reversed many of the observed effects. Synapses and BBB recovery after resatorvid administration were not observed in IP3R2−/− mice, indicating that effects of TLR4 inhibition depend on the subsequent astrocyte activation. In addition, TBI increased the astrocytic‐protein thrombospondin‐1 necessary to induce a synaptic recovery in a sub‐acute phase.
Conclusions and Implications
Our data demonstrate that TLR4‐mediated signalling, most probably through microglia and/or infiltrated monocyte–astrocyte communication, plays a crucial role in the TBI pathophysiology and that its inhibition prevents synaptic loss and BBB damage accelerating tissue recovery/repair, which might represent a therapeutic potential in CNS injuries and disorders.
A method for the copper-catalyzed borylmethylation and borylation of vinyl cyclic carbonates through an SN2′ mechanism is reported. These singular reactions involve selective SN2′ allylic ...substitutions with concomitant ring opening of the cyclic carbonate and with extrusion of CO2 and formation of a useful hydroxyl functionality in a single step. The stereoselectivity of the homoallylic borylation and allylic borylation processes can be controlled, and synthetically useful unsaturated (E)-pent-2-ene-1,5-diols and (E)-but-2-ene-1,4-diols are accessed.
PDF
