Desmond D Mascarenhas, Bhaumik Patel, Puja Ravikumar, Edward Amento, Ajay Bhargava
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引用次数: 0
Abstract
Immodulins are synthetic peptides that efficiently utilize iron-mediated cellular uptake, importin-mediated nuclear translocation and binding to retinoid X receptor to mediate transcriptional effects. The possible use of side-chain derivatized immodulins (SCDI) as tunable therapeutic agents is explored in this work. Rat biodistribution studies show that, when applied transdermally to rats using a nanoemulsion, immodulin peptides rapidly partition to skin tissue resulting in a 9X enrichment in skin relative to plasma, even at skin locations distant from the site of application. We show that optimized side-chain derivatization of immodulins with selected ligands of RXR heterodimeric partners can stimulate by one to three orders of magnitude: [a] CD169+CCL22+ macrophage differentiation (RARα/β ligand); [b] IL-19, IL-22 and IL-24 production by HaCaT keratinocytes (RARγ agonist); and [c] FGF7/KGF-1, TGFβ and COL1A1 by dermal fibroblasts (partial PPARγ ligand); all p<0.01. Differentiated CD169+ macrophages, in turn, drive the conversion of FoxP3 CD4+Tcells into iTregs (>4-fold, p<0.01) while reducing IL-17 levels >4-fold (p<0.01). In addition, myoblast differentiation is stimulated >10X by a PPARα ligand (p<0.01). These processes resemble key features of paracrine circuitry in skin known to be involved in wound healing. Versatile SCDI scaffolds hold promise for the rapid and inexpensive development of safe, targeted, self-administered therapeutic agents for skin.
期刊介绍:
Cellular and Molecular Biology publishes original articles, reviews, short communications, methods, meta-analysis notes, letters to editor and comments in the interdisciplinary science of Cellular and Molecular Biology linking and integrating molecular biology, biophysics, biochemistry, enzymology, physiology and biotechnology in a dynamic cell and tissue biology environment, applied to human, animals, plants tissues as well to microbial and viral cells. The journal Cellular and Molecular Biology is therefore open to intense interdisciplinary exchanges in medical, dental, veterinary, pharmacological, botanical and biological researches for the demonstration of these multiple links.