Diabetic retinopathy is one of the most frequent causes of blindness in adults in the Western countries. Although diabetic retinopathy is considered a vascular disease, several reports demonstrate that retinal neurons are also affected, leading to vision loss. Tauroursodeoxycholic acid (TUDCA), an endogenous bile acid, has proven to be neuroprotective in several models of neurodegenerative diseases, including models of retinal degeneration. Since hyperglycemia is considered to play a central role in retinal cell dysfunction and degeneration, underlying the progression of diabetic retinopathy, the purpose of this study was to investigate the neuroprotective effects of TUDCA in rat retinal neurons exposed to elevated glucose concentration. We found that TUDCA markedly decreased cell death in cultured retinal neural cells induced by exposure to elevated glucose concentration. In addition, TUDCA partially prevented the release of apoptosis-inducing factor (AIF) from the mitochondria, as well as the subsequent accumulation of AIF in the nucleus. Biomarkers of oxidative stress, such as protein carbonyl groups and reactive oxygen species production, were markedly decreased after TUDCA treatment as compared to cells exposed to elevated glucose concentration alone. In conclusion, TUDCA protected retinal neural cell cultures from cell death induced by elevated glucose concentration, decreasing mito-nuclear translocation of AIF. The antioxidant properties of TUDCA might explain its cytoprotection. These findings may have relevance in the treatment of diabetic retinopathy patients.

Immunoglobulin (Ig) G molecules are essential players in the human immune response against bacterial infections. An important effector of IgG-dependent immunity is the induction of complement activation, a reaction that triggers a variety of responses that help kill bacteria. Antibody-dependent complement activation is promoted by the organization of target-bound IgGs into hexamers that are held together via noncovalent Fc-Fc interactions. Here we show that staphylococcal protein A (SpA), an important virulence factor and vaccine candidate of Staphylococcus aureus, effectively blocks IgG hexamerization and subsequent complement activation. Using native mass spectrometry and high-speed atomic force microscopy, we demonstrate that SpA blocks IgG hexamerization through competitive binding to the Fc-Fc interaction interface on IgG monomers. In concordance, we show that SpA interferes with the formation of (IgG)6:C1q complexes and prevents downstream complement activation on the surface of S. aureus. Finally, we demonstrate that IgG3 antibodies against S. aureus can potently induce complement activation and opsonophagocytic killing even in the presence of SpA. Together, our findings identify SpA as an immune evasion protein that specifically blocks IgG hexamerization.

Gene delivery targeting mitochondria has the potential to transform the therapeutic landscape of mitochondrial genetic diseases. Taking advantage of the nonuniversal genetic code used by mitochondria, a plasmid DNA construct able to be specifically expressed in these organelles was designed by including a codon, which codes for an amino acid only if read by the mitochondrial ribosomes. In the present work, gemini surfactants were shown to successfully deliver plasmid DNA to mitochondria. Gemini surfactant-based DNA complexes were taken up by cells through a variety of routes, including endocytic pathways, and showed propensity for inducing membrane destabilization under acidic conditions, thus facilitating cytoplasmic release of DNA. Furthermore, the complexes interacted extensively with lipid membrane models mimicking the composition of the mitochondrial membrane, which predicts a favored interaction of the complexes with mitochondria in the intracellular environment. This work unravels new possibilities for gene therapy toward mitochondrial diseases.