Grape seed proanthocyanidin extract induces apoptotic and autophagic cell death in rheumatoid arthritis fibroblast-like synoviocytes.

Objectives: In this study, we aimed to evaluate the association between grape seed proanthocyanidin extract (GSPE) and rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLSs) and to investigate whether GSPE induces cell death in RA-FLSs. Materials and methods: The FLSs were isolated from RA synovial tissues. Cell viability and cell cycle staging were analyzed using a hemocytometer and flow cytometry. Caspase 3 and poly (ADP-ribose) polymerase (PARP) proteins were analyzed using Western blotting with z-VAD-fmk. Protein LC3 and polyubiquitin-binding protein p62 that were degraded by autophagy were evaluated using Western blotting with 3-methyladenine and chloroquine. Reactive oxygen species (ROS) were also evaluated. Results: When RA-FLSs were treated with GSPE, cell viability decreased, the number of cells in sub-G1 and G2/M phases increased, and the expression of pro-PARP and pro-caspase 3 proteins decreased in a concentration-dependent manner. This result was offset, when the cells were co-treated with the pan-caspase inhibitor z-VAD-fmk. The reduced cell viability, increased expression of LC3-II protein, and reduced expression of p62 protein with GSPE treatment were offset, when RA-FLSs were co-treated with GSPE and autophagy inhibitors 3-methyladenine and chloroquine. The level of ROS in RA-FLSs treated with GSPE was significantly lower than treatment with N-acetyl-cysteine, a ROS inhibitor. Conclusion: Our study results show that GSPE induces apoptotic and autophagic cell death and inhibites reactive oxygen species in RA-FLSs.

Near-Infrared-Active Copper Bismuth Oxide Electrodes for Targeted Dissociation of Alzheimer's ß-Amyloid Aggregates.

The abnormal accumulation of ß-amyloid (Aß) aggregates in the brain is a major pathological hallmark of Alzheimer's disease. We report a near-infrared (NIR)-active CuBi2O4-based photocathodic platform that can target intact Aß aggregates and dissociate them into nontoxic species. Because of its relatively narrow band gap, CuBi2O4 exhibits strong absorption of NIR light, which allows for deeper tissue penetration and causes less photodamage to tissues compared to visible light. Furthermore, its high stability in aqueous media, biocompatibility, and robustness against photocorrosion make CuBi2O4 an ideal material for medical applications. For the targeted clearance of Aß aggregates, we have conjugated the KLVFF peptide which specifically recognizes and captures Aß aggregates on the surface of silver-doped CuBi2O4 (Ag:CuBi2O4). Upon illumination of NIR light under a cathodic bias, the KLVFF-immobilized Ag:CuBi2O4 (KLVFF-Ag:CuBi2O4) effectively dissociated ß-sheet-rich, long, and entangled Aß fibrillary aggregates into small fragmented, soluble species through photo-oxygenation. We also verified that the KLVFF-Ag:CuBi2O4 photocathode is biocompatible and effective in reducing Aß aggregate-induced neurotoxicity. Our work demonstrates the potential of the KLVFF-Ag:CuBi2O4 platform for the targeted disassembly of cytotoxic, robust Aß aggregates with the aid of NIR energy and cathodic bias.