Impact of activation of the Nrf2 pathway by methyl dimethyl fumarate on periodontal ligament fibroblast activity

Abstract

Oxidative stress, defined as the imbalance between the production of reactive oxygen species (ROS) and antioxidant mechanisms, has been correlated with the pathogenesis of a number of inflammatory diseases, including periodontal disease. The exaggerated production of ROS can increase the oxidative damage of proteins in the periodontium and contribute to tissue destruction. The production of antioxidant enzymes, necessary to counterbalance the harmful effects of oxidative stress, is in part regulated by the Nrf2 (nuclear factor erythroid 2 related factors 2) signaling pathway. In addition to acting on the activation of antioxidant factors, Nrf2 can inhibit the activation of inflammatory cytokines and chemokines, matrix metalloproteinases, and transcription factors involved in the modulation of pro-inflammatory cytokines, all factors involved in the pathogenesis of inflammatory diseases. Due to its biological activities and lack of toxicity, a pharmacological activator of Nrf2, dimethyl fumarate (DMF), has been used in the clinical treatment of inflammatory diseases, such as multiple sclerosis and psoriasis, and several clinical studies have evaluated its therapeutic potential in other inflammatory pathologies such as cancer, diabetes, and rheumatoid arthritis. In periodontal disease, few studies have evaluated the role of Nrf2 on disease progression. Our research group was a pioneer in demonstrating that systemic administration of DMF in rats reduced cell infiltration and gene expression of TNF-± and iNOS, as well as increased levels of antioxidant markers in the gingival tissues of periodontally diseased rats. In order to explore the role of Nrf2 activation by DMF on the activity of cells important to the periodontal microenvironment, this study aims to investigate the effect of different concentrations of the compound on the activity of periodontal ligament fibroblasts (mPDL). Inflammatory mediators and markers of oxidative stress by cells stimulated with LPS and treated with different concentrations of DMF will be analyzed by RT-qPCR and biochemical tests, respectively. The effect of the compound on cell migration and proliferation will also be investigated. The same outcomes will be investigated. evaluated after inhibition of Nrf2 by siRNA The hypothesis of this study is that activation of Nrf2 by DMF can prevent the increase of pro-inflammatory mediators and inhibit oxidative stress, and favor cell proliferation and migration.(AU)