Oxidative Stress in Oral Diseases: Understanding Its Relation with Other Systemic Diseases

Abstract

Oxidative stress occurs in diabetes, various cancers, liver diseases, stroke, rheumatoid arthritis, chronic inflammation, and other degenerative diseases related to the nervous system. The free radicals have deleterious effect on various organs of the body. This is due to lipid peroxidation and irreversible protein modification that leads to cellular apoptosis or programmed cell death. During recent years, there is a rise in the oral diseases related to oxidative stress. Oxidative stress in oral disease is related to other systemic diseases in the body such as periodontitis, cardiovascular, pancreatic, gastric, and liver diseases. In the present review, we discuss the various pathways that mediate oxidative cellular damage. Numerous pathways mediate oxidative cellular damage and these include caspase pathway, PERK/NRF2 pathway, NADPH oxidase 4 pathways and JNK/mitogen-activated protein (MAP) kinase pathway. We also discuss the role of inflammatory markers, lipid peroxidation, and role of oxygen species linked to oxidative stress. Knowledge of different pathways, role of inflammatory markers, and importance of low-density lipoprotein, fibrinogen, creatinine, nitric oxide, nitrates, and highly sensitive C-reactive proteins may be helpful in understanding the pathogenesis and plan better treatment for oral diseases which involve oxidative stress.

Keywords: disease; free radicals; inflammation; oral; oxidative stress; pathways.

Figure 1

A schematic depiction of how caspase-associated pathways leads to oxidative damage via mitochondrial- and death receptor-mediated cellular apoptosis. In mitochondrial-mediated apoptosis, generation of ROS causes the release of cytochrome C from mitochondria, which via a cascade of cellular actions activates caspase-9 and then caspase-3 that eventually channels cell death. In death receptor-mediated apoptosis, oxidative stress-driven death ligands activates caspase-8, which then activates a pro-apoptotic protein known as Bid, which once activated travels to mitochondria to facilitate mitochondria-mediated apoptotic pathway. Death receptor-activated caspase-8 also activates caspase-3 to induce cell death.

Figure 2

A simplified representation on the role of NOX4 in cellular pathway toward ROS-induced oxidative stress. Activity of NOX4 is regulated through regulation of the enzyme's expression by various transcription factors, protein kinase, cellular receptor, and epigenetic regulator. Enhanced NOX4 expression or activity in mitochondria leads to increased ROS production that subsequently causes mitochondrial damage and cell death. Excess ROS also likely to travel toward cytoplasm and activate numerous pro-apoptotic proteins and also activate nuclear factor kappa beta to trigger a pro-inflammatory state of the cell.

Figure 3

A schematic diagram showing the mechanism of NRF2 in protection against oxidative stress. Under normal condition, a protein called Keap1 suppresses the activity of NRF2 by physically binding to NRF2 and at the same time anchored to cytoplasm. Following a period of inactivity, NRF2 is degraded by proteasomes. During oxidative stress, oxidants will be sensed by the Keap1/NRF2 complex via reactive cysteine residues in Keap1. Upon oxidant sensing, NRF2 undergoes phosphorylation at serine40 releasing Keap1 from the complex. This is followed by the translocation of NRF2 to nucleus where the protein forms a heterodimer with small transcription factor Maf and binds to antioxidant response enzyme (ARE) of numerous antioxidant gene promoter regions to initiate their transcription in response to oxidative stress.

Figure 4

Schematic diagram to show how oral disease may be linked to cardiovascular disease.