Gaucher disease (GD) is caused by mutations in the GBA1 gene, which encodes lysosomal β-glucocerebrosidase. Homozygosity for the L444P mutation in GBA1 is associated with high risk of neurological manifestations which are not improved by enzyme replacement therapy. Alternatively, pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the mutant enzyme represent promising alternative therapies.Here, we report on how the L444P mutation affects mitochondrial function in primary fibroblast derived from GD patients. Mitochondrial dysfunction was associated with reduced mitochondrial membrane potential, increased reactive oxygen species (ROS), mitophagy activation and impaired autophagic flux.Both abnormalities, mitochondrial dysfunction and deficient β-glucocerebrosidase activity, were partially restored by supplementation with coenzyme Q10 (CoQ) or a L-idonojirimycin derivative, N-[N’-(4-adamantan-1-ylcarboxamidobutyl)thiocarbamoyl]-1,6-anhydro-L-idonojirimycin (NAdBT-AIJ), and more markedly by the combination of both treatments. These data suggest that targeting both mitochondria function by CoQ and protein misfolding by PCs can be promising therapies in neurological forms of GD.
Aims: Capped silver nanoparticles that can be coupled to a variety of molecules and biomolecules are of great interest owing to their potential applications in biomedicine. However, there are no data about their toxicity or functional effects on a key innate immune response, such as IL-6 secretion, after the engagement of the main group of pathogen-associated molecular patterns receptors, that is, the Toll-like receptors (TLRs). Materials & methods: N-(2-mercaptopropionyl)glycine (tiopronin)-capped silver (Ag@tiopronin) nanoparticles of a narrow sized distribution (∼5 nm) were synthesized and characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, Raman, 1H–NMR and total correlation spectroscopy. Cytotoxicity was determined by lactate deshidrogenase and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium assays in Raw 264.7 macrophages. IL-6 was measured by ELISA. Results & discussion: Ag@tiopronin nanoparticles have a narrow size distribution (≈5 nm), high solubility and stability in aqueous environment with no cytotoxicity in terms of mitochondrial function or plasma-membrane integrity at concentrations as high as 200 µg/106 cells. Ag@tiopronin nanoparticles were not proinflammatory agents, but remarkably they specifically impaired the IL-6 secretion mediated by TLR2, TLR2/6, TLR3 or TLR9 stimulation in co-treatment experiments. However, in pretreatment experiments, nanoparticles enhanced the susceptibility of macrophages to inflammatory stimulation mediated by TLR2/1 and TLR2/6 specific ligands while severely impairing the IL-6 secretion activated by the TLR3 or TLR9 ligands. Conclusions: Contrary to what is found for bare silver nanoparticles, Ag@tiopronin nanoparticles are noncytotoxic to macrophages. Ag@tiopronin nanoparticles showed differential effects on TLR signaling of a high degree of specificity, without proinflammatory effects by themselves. These effects have to be borne in mind when using bioconjugates of Ag@tiopronin nanoparticles for future medical applications.
Infrared spectra (IR) of a great variety of zeolite frameworks in the limit of pure silica composition are calculated by molecular dynamics and also recorded experimentally. This enables us to study and assess the effect of three flexible force fields from the literature developed for zeolites in reproducing the IR spectra: the force fields by Demontis (J. Phys. Chem. 1988, 92, 867), Nicholas (J. Am. Chem. Soc. 1991, 113, 4792), and Hill (J. Phys. Chem. 1995, 99, 9536). On one side, a qualitative comparison is undertaken; on the other, a similarity index is introduced to perform a quantitative assessment of the similarity of spectra. It is applied to experimental spectra and enables us to arrange the frameworks in three different sets. It can also be applied to study the agreement of the spectra obtained with the three force fields with experimental spectra on a quantitative basis. The force field by Nicholas performs best, followed by the force field by Demontis. Frameworks are therefore analyzed purely theoretically with the Nicholas force field to investigate the dependency on frameworks. This yields a new classification in sets, which is found to be related to the topology of the frameworks. Surprisingly, these sets do not agree with the sets obtained with experimental spectra. As a consequence, it is found that none of the force fields is good enough to enable the identification of frameworks based on their experimental spectra. In a comparison of spectra generated by different force fields, it is found that the Nicholas and Hill force fields generate the most similar IR spectra. ■ INTRODUCTIONZeolites are a class of compounds of great industrial and natural importance made of frameworks of high regularity and beauty. When trying to understand and model these frameworks in order to reproduce some of their physicochemical properties, they are normally considered rigid for simplicity and for reasons of computational cost. However, these frameworks vibrate, giving rise to IR and Raman spectra, 1 where some of the bands are sensitive to details of the structure and to the Si/Al ratio. Therefore, IR and Raman techniques are often used in the characterization of the structures under study. But flexibility is also important in the industrially important diffusion processes, since it favors intermittent opening of the windows. 2ab And from the computational point of view, IR spectroscopy is a good probe to validate force fields that are intended at reproducing changes in phase of the host molecules or other structural changes.Siliceous zeolites, although consisting of only two types of atoms and a single type of bond (the Si−O single bond), exhibit nevertheless a surprising variety of frameworks. These differ in their symmetry properties, both locally through the choice and combination of so-called Secondary Building Units (SBUs) and in their space groups, the dimensionality of channels for suitable host molecules, their overall porosity and pore size, etc. The frameworks selected in this study are representative m...
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