Abstract
Dental resin monomers such as 2-hydroxyethyl methacrylate (HEMA) disturb vital cell functions and induce mitochondrial intrinsic apoptosis via generation of oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the gene expression of antioxidative enzymes and plays a crucial role in the maintenance of cellular redox equilibrium and mitochondrial homeostasis. The present study investigated the functional significance of Nrf2 in cellular response toward HEMA. It was found that HEMA stimulation promoted nuclear translocation of Nrf2 and increased Nrf2 and heme oxygenase-1 (HO-1) expression, which was further enhanced by Nrf2 activator tert-butylhydroquinone (tBHQ), but suppressed by Nrf2 inhibitor ML385. Pretreatment of primary human dental pulp cells (hDPCs) with tBHQ protected the cells from HEMA-induced oxidative injury (increased reactive oxygen species production and apoptosis) and mitochondrial impairment (morphological alterations, decreased ATP production, suppressed oxidative phosphorylation activity, depolarization of mitochondrial membrane potential, and disrupted electron transport chain). In contrast, pretreatment with ML385 increased cell sensitivity to these injurious processes. This protective effect on mitochondria could be related to peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α)/nuclear respiratory factor 1 (NRF1) pathway. These results contribute to the understanding of the function of Nrf2 and the development of novel therapies to counteract the adverse effects of dental resin monomers.
Highlights
Significant concerns exist regarding the biological safety of resin-based dental materials despite their widespread use and long-term clinical success in contemporary dentistry
The potentials for tBHQ and ML385 at their respective, selected noncytotoxic concentrations to modulate Nuclear factor erythroid 2-related factor 2 (Nrf2) expression and related antioxidative enzymes in human dental pulp cells (hDPCs) exposed to 1 mM hydroxyethyl methacrylate (HEMA) were subsequently evaluated. Quantitative real-time PCR (qRT-PCR) analysis showed that the mRNA expression levels of NFE2L2 and HMOX1 genes, which encode Nrf2 and heme oxygenase-1 (HO-1) proteins, in the HEMA experimental group were significantly higher than those in the control group (Figure 1(b))
Consistent with the qRT-PCR results, western blot analysis showed that expression levels of Nrf2 and HO-1 proteins were weak in untreated cells but drastically increased in cells exposed to 1 mM HEMA (Figure 1(c))
Summary
Significant concerns exist regarding the biological safety of resin-based dental materials despite their widespread use and long-term clinical success in contemporary dentistry. Incomplete polymerization and biodegradation of resin components result in the release of resin monomers such as 2hydroxyethyl methacrylate (HEMA) into the oral environment, potentially causing local and/or systemic adverse effects [1, 2]. Because of their bioactivity, resin monomers are capable of diffusing rapidly through the dentinal tubules into dental pulp tissues [3, 4]. Along the dentin-pulp interface, bacterial and resin biodegradation by-products generate dynamic interactions and induce complex responses of the pulpal cells such as inhibition of lipopolysaccharide-stimulated NF-κB activation [7]. The beneficial effect of antioxidants such as N-acetylcysteine [14,15,16,17] suggests that the mechanism behind these specific cell responses is the generation of oxidative stress [18]
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