PDRN, a natural bioactive compound, blunts inflammation and positively reprograms healing genes in an “in vitro” model of oral mucositis
Giacomo Picciolo, Federica Mannino, Natasha Irrera, Domenica Altavilla, Letteria Minutoli, Mario Vaccaro, Vincenzo Arcoraci, Violetta Squadrito, G Picciolo, Francesco Squadrito, Giovanni Pallio
Abstract
Oral mucositis is a side effect hard to treat following high dose chemotherapy or radiotherapy. Adenosine A 2A receptor stimulation blocks NF-B and boosts the Wnt/-catenin signaling, thus blunting inflammation and triggering growth factor codifying genes. Polydeoxyribonucleotide (PDRN) is a registered drug that activates the A 2A receptor. Therefore, the aim of this study was to evaluate PDRN effects in an "in vitro" model of oral mucositis induced by prompting an inflammatory phenotype in human gingival fibroblasts (GF) and human oral mucosal epithelial cells (EC). GF and EC were stimulated with LPS (2 g/ml) alone or in combination with i) PDRN (100 g/ml); ii) PDRN plus ZM241385 (1 M) as an A 2AR antagonist; iii) CGS21680 (1 M) as an A 2AR agonist. LPS boosted NF-B, TNF- and IL-6 expression, decreased IL-10 levels and downregulated both Wnt/ -catenin, VEGF and EGF expression. PDRN reverted the LPS-induced phenotype as well as CGS21680. Coincubation with ZM241385 abolished PDRN effects, thus confirming A 2A receptor involvement in PDRN mechanism of action. These results suggest that PDRN efficacy may be due to a "dual mode" of action: NF-B inhibition and Wnt/-catenin signaling activation. However, these interesting findings need to be confirmed by animal and clinical studies.