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.

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). N-(2-mercaptopropionyl)glycine (tiopronin)-capped silver (Ag@tiopronin) nanoparticles of a narrow sized distribution ( approximately 5 nm) were synthesized and characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, Raman, (1)H-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. Ag@tiopronin nanoparticles have a narrow size distribution ( approximately 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 microg/10(6) 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. 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.

Tannic acid nanoparticles targeted to the epidermal growth factor receptor allows selective delivery of this promising chemotherapeutic agent to tumoral cells.