Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy.
Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy.
Biomed Pharmacother. 2021 Jun;138:111538. doi: 10.1016/j.biopha.2021.111538. Epub 2021 Mar 31.
Oral mucositis is a side effect hard to treat following high dose chemotherapy or radiotherapy. Adenosine A receptor stimulation blocks NF-κB and boosts the Wnt/β-catenin signaling, thus blunting inflammation and triggering growth factor codifying genes. Polydeoxyribonucleotide (PDRN) is a registered drug that activates the A 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 μg/ml) alone or in combination with i) PDRN (100 μg/ml); ii) PDRN plus ZM241385 (1 μM) as an A antagonist; iii) CGS21680 (1 μM) as an A agonist. LPS boosted NF-κB, TNF-α and IL-6 expression, decreased IL-10 levels and downregulated both Wnt/β-catenin, VEGF and EGF expression. PDRN reverted the LPS-induced phenotype as well as CGS21680. Co-incubation with ZM241385 abolished PDRN effects, thus confirming A receptor involvement in PDRN mechanism of action. These results suggest that PDRN efficacy may be due to a "dual mode" of action: NF-κB inhibition and Wnt/β-catenin signaling activation. However, these interesting findings need to be confirmed by animal and clinical studies.
口腔黏膜炎是大剂量化疗或放疗后难以治疗的副作用。腺苷 A 受体刺激可阻断 NF-κB 并增强 Wnt/β-catenin 信号通路，从而减轻炎症并触发生长因子编码基因。聚脱氧核糖核苷酸（PDRN）是一种激活 A 受体的注册药物。因此，本研究旨在评估 PDRN 在人牙龈成纤维细胞（GF）和人口腔黏膜上皮细胞（EC）中诱导的口腔黏膜炎“体外”模型中的作用。单独或联合使用 LPS（2μg/ml）刺激 GF 和 EC：i）PDRN（100μg/ml）；ii）PDRN 加 ZM241385（1μM）作为 A 拮抗剂；iii）CGS21680（1μM）作为 A 激动剂。LPS 可增强 NF-κB、TNF-α 和 IL-6 的表达，降低 IL-10 水平，并下调 Wnt/β-catenin、VEGF 和 EGF 的表达。PDRN 可逆转 LPS 诱导的表型，以及 CGS21680。与 ZM241385 共孵育可消除 PDRN 的作用，从而证实 A 受体参与 PDRN 的作用机制。这些结果表明，PDRN 的疗效可能归因于“双重作用模式”：NF-κB 抑制和 Wnt/β-catenin 信号通路激活。然而，这些有趣的发现需要通过动物和临床研究来证实。
