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 microgliamediated 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 5 weeks 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 8 weeks 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.
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.
Superball! Ein dodekavalentes Iminozucker‐Derivat mit einem Fulleren‐Kern (siehe Bild) zeigt in Versuchen zur Glycosidase‐Inhibition eine um bis zu drei Größenordnungen bessere Bindung als der entsprechende monovalente Ligand. Dies ist der erste Beleg für einen signifikanten Multivalenzeffekt bei der Glycosidase‐Inhibition.
Inhibition of type 1 fi mbriae-mediated Escherichia coli adhesion and biofi lm formation by trimeric cluster thiomannosides conjugated to diamond nanoparticles Trimeric thiosugar clusters, conveniently obtained through a thiol-ene "click" strategy, have been effi ciently conjugated to alkynyl-functionalized nanodiamonds (NDs) using a Cu(I)-catalysed "click" reaction. These tri-thiomannoside clusterconjugated NDs (ND-Man 3 ) are shown to be potent inhibitors of type 1 fi mbriae-mediated E. coli adhesion to yeast and T24 bladder cells and moreover to inhibit E. coli-mediated biofi lm formation. This latter feature has only rarely been reported in the past for analogues featuring such simple multivalent glycosidic motifs and would constitute a useful additional characteristic of any anti-adhesive drug lead. anti-adhesive nanoparticles displaying activity against biofilms. In this work, trimeric thiomannoside clusters conjugated to nanodiamond particles (ND) were targeted for investigation. NDs have attracted attention as a biocompatible nanomaterial and we were curious to see whether the high mannose glycotope density obtained upon grouping monosaccharide units in triads might lead to the corresponding NDconjugates behaving as effective inhibitors of E. coli type 1 fimbriae-mediated adhesion as well as of biofilm formation. The required trimeric thiosugar clusters were obtained through a convenient thiol-ene "click" strategy and were subsequently conjugated to alkynyl-functionalized NDs using a Cu(I)-catalysed "click" reaction. We demonstrated that the tri-thiomannoside cluster-conjugated NDs (ND-Man 3 ) show potent inhibition of type 1 fimbriae-mediated E. coli adhesion to yeast and T24 bladder cells as well as of biofilm formation. The biofilm disrupting effects demonstrated here have only rarely been reported in the past for analogues featuring such simple glycosidic motifs. Moreover, the finding that the tri-thiomannoside cluster (Man 3 N 3 ) is itself a relatively efficient inhibitor, even when not conjugated to any ND edifice, suggests that alternative mono-or multivalent sugar-derived analogues might also be usefully explored for E. coli-mediated biofilm disrupting properties.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.