Novel Sulfated Polysaccharides Disrupt Cathelicidins, Inhibit RAGE and Reduce Cutaneous Inflammation in a Mouse Model of Rosacea

Rosacea is a common disfiguring skin disease of primarily Caucasians characterized by central erythema of the face, with telangiectatic blood vessels, papules and pustules, and can produce skin thickening, especially on the nose of men, creating rhinophyma. Rosacea can also produce dry, itchy eyes with irritation of the lids, keratitis and corneal scarring. The cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37.We tested a new class of non-anticoagulant sulfated anionic polysaccharides, semi-synthetic glycosaminoglycan ethers (SAGEs) on key elements of the pathogenic pathway leading to rosacea. SAGEs were anti-inflammatory at ng/ml, including inhibition of polymorphonuclear leukocyte (PMN) proteases, P-selectin, and interaction of the receptor for advanced glycation end-products (RAGE) with four representative ligands. SAGEs bound LL-37 and inhibited interleukin-8 production induced by LL-37 in cultured human keratinocytes. When mixed with LL-37 before injection, SAGEs prevented the erythema and PMN infiltration produced by direct intradermal injection of LL-37 into mouse skin. Topical application of a 1% (w/w) SAGE emollient to overlying injected skin also reduced erythema and PMN infiltration from intradermal LL-37.Anionic polysaccharides, exemplified by SAGEs, offer potential as novel mechanism-based therapies for rosacea and by extension other LL-37-mediated and RAGE-ligand driven skin diseases

Highly efficient organic photocatalysts discovered via a computer-aided-design strategy for visible-light-driven atom transfer radical polymerization

Organocatalysed photoredox-mediated atom transfer radical polymerization (O-ATRP) is a very promising polymerization method as it eliminates concerns associated with transition-metal contamination of polymer products. However, reducing the amount of catalyst and expanding the monomer scope remain major challenges in O-ATRP. Herein, we report a systematic computer-aided-design strategy to identify powerful visible-light photoredox catalysts for O-ATRP. One of our discovered organic photoredox catalysts controls the polymerization of methyl methacrylate at sub-ppm catalyst loadings (0.5 ppm-a very meaningful amount enabling the direct use of polymers without a catalyst removal process); that is, 100-1,000 times lower loadings than other organic photoredox catalysts reported so far. Another organic photoredox catalyst with supra-reducing power in an excited state and high redox stability facilitates the challenging polymerization of the non-acrylic monomer styrene, which is not successful using existing photoredox catalysts. This work provides access to diverse challenging organic/polymer syntheses and makes O-ATRP viable for many industrial and biomedical applications