Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3β (GSK-3β) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP⁺-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPARγ) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3β enzyme inhibition against MPP⁺. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3β enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3β along with PPARγ activation may be responsible for neuroprotection.

Oral submucous fibrosis (OSMF) is a chronic oral potentially malignant disorder (OPMD). It is described as a scarring disease of the oral mucosa associated with excess oxidants and insufficient antioxidants. While it is becoming increasingly accepted that oxidative stress results in excessive accumulation of collagen and progressive fibrosis of the submucosal tissues, there is limited data regarding the moderation of oxidative stress to initiate or prevent OSMF. To assess the scope for mechanism-based approaches to prevent or reverse OSMF, we systematically evaluated the existing literature and investigated the role of oxidative stress in the pathogenesis and chemoprevention of OSMF. A search for relevant articles on PubMed and Scopus was undertaken using pre-defined inclusion and exclusion criteria. A total of 78 articles were selected in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. The articles eligible for assessment investigated both OSMF and/or oxidative stress biomarkers or specific antioxidants. Both in vitro and human studies consistently demonstrated variations in oxidative stress biomarker levels in OSMF and revealed an increase in oxidative stress, paralleling the development of the disease. Furthermore, the use of antioxidant supplements was overall associated with an improvement in clinical outcomes. Having identified the significance of oxidative stress in OSMF and the therapeutic potential of antioxidant supplements, this scoping review highlights the need for further well-designed studies in the development of mechanism-based interventions for managing OSMF.